API

Textbook of Medicine

Editor-in-Chief
Yash Pal Munjal

9 th
EDITION
The Association of Physicians of India

NOTICE
The editors have checked the information provided in the book and to the best of their knowledge, it is as per the standards
accepted at the time of publication. However, in view of the continuous changes in medical knowledge and the possibility of
human error, there could be variance. In view of the possibility of human error by the authors, editors, or publishers of the work
herein, or changes in medical knowledge, neither the authors, editors, publisher, nor any other party who has been involved in
the preparation of this work, warrants that the information contained herein is in every respect accurate or complete, and they are
not responsible for any errors or omissions or for the result obtained from the use of such information. Hence readers are
requested to confirm information, particularly laboratory values and drug dosages from the product information sheet included in
the package of each drug they plan to administer and from other sources as well, particularly in connection with new or infrequently
used drugs. The editor takes no responsibility for the views expressed or the material submitted by the various contributors to
this API Textbook of Medicine, Ninth Edition.

© All rights reserved. This book is protected by copyright. No part of it may be reproduced in any manner or by any means, without
written permission from the Editor-in-chief.

First Edition: 1969

Ninth Edition: 2012

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 API Textbook of Medicine
Ninth Edition
EDITOR-IN-CHIEF

Yash Pal Munjal

MD, FICP, MAMS, FIAMS, FACP, FIACMS, FRCP (Edin)
Medical Director and Hon. Senior Consultant Diabetes & Life Style Disease Centre
Banarsidas Chandiwala Institute of Medical Science, Kalkaji, New Delhi
Senior Consultant Diabetologist, Delhi Heart and Lung Institute
Past President of Association of Physicians of India
Past Dean of Indian College of Physicians
Hon. Professor of Indian College of Family Physician

EXECUTIVE EDITOR
Surendra K. Sharma
MD, PhD
Professor and Head, Chief, Division of Pulmonary, Critical Care and Sleep Medicine
Department of Medicine, All India Institute of Medical Sciences, New Delhi, India

EDITORS
A.K. Agarwal R.K. Singal
MD, FICP, FRCP (Edin) MD, FRCP, FICP, FACP
Head, Department of Medicine and Dean Senior Consultant and Head
Postgraduate Institute of Medical Education & Research Department of Medicine
Dr RML Hospital, New Delhi, India Dr BL Kapur Memorial Hospital
New Delhi, India
Pritam Gupta
MD (Medicine) Shyam Sundar
Senior Consultant and Head, Department of Medicine MD, FRCP, FAMS, FNA, FSc, FNASc
Sunder Lal Jain Hospital, New Delhi, India Professor of Medicine
Institute of Medical Sciences
Sandhya A. Kamath Banaras Hindu University, Varanasi
MD, FICP
Dean and Professor, Department of Medicine Uttar Pradesh, India
Lokmanya Tilak Municipal Medical College & Municipal Subhash Varma
General Hospital, Mumbai, Maharashtra, India MD, FICP
Professor and Head
Milind Y. Nadkar Department of Internal Medicine
MD, FICP
Professor of Medicine PGIMER, Chandigarh, India
Chief of Rheumatology and Emergency Medicine
Seth GSMC & KEM Hospital, Mumbai, Maharashtra, India

ASSISTANT EDITORS
Ghan Shyam Pangtey Anupam Prakash
MD MD (Medicine), PGCC (Hospital Management), FICP
Associate Professor, Department of Medicine Associate Professor, Department of Medicine
Lady Hardinge Medical College & Associated Hospitals Lady Hardinge Medical College & Associated Hospitals
New Delhi, India New Delhi, India
EMERITUS EDITOR
Siddharth N. Shah
MD, FICP, FACP (Hon.), FRCP (Edin.)
Postgraduate Teacher in Diabetes, University of Mumbai
Consulting Physician and Diabetologist
SL Raheja Hospital and All India Institute of Diabetes
Saifee Hospital, Bhatia Hospital, Sir Hurkisondas N. Hospital
Visiting Consultant Central Railway and Western Railway Hospitals, Mumbai, Maharashtra, India
 Editors-In-Chief

Late Dr. R.J. Vakil Late Dr. K.K. Datey Late Dr. Shantilal J. Shah
1st and 2nd Edition 3rd Edition 4th Edition

Dr. G.S. Sainani Dr. Siddharth N. Shah

5th and 6th Edition 7th and 8th Edition

Dr. Y.P. Munjal

9th Edition
PREFACE

Over four decades ago, a new compendium of medicine was published under the aegis of Association of Physicians
of India. This was due to the vision and hard work of the stalwarts at that time. The first edition of the book was
edited by an internationally famed physician Dr Rustam Jal Vakil. The book was well accepted all over the country.
Enthused by the response of Indian physicians, eight more editions of the book have been published. Each new
edition was an attempt to improve and incorporate the changing profile of medicine.
In the last decade, the progress has far outstripped the progress made in the previous decades. It is in this milieu of
continuous change that I have the pleasure of presenting to you the 9th edition of the popular, API Textbook of
Medicine. The book is completely revised, updated and better illustrated. There are around 2200 pages with nearly
1588 figures and 1384 tables. There has been a marked 20% increase in the number of figures and nearly 100 new
tables have been added than the last edition. This has been done so that the information is easily understood and
the reading is not a strain. The book has been divided into 28 sections and each section deals with a special set of
medical disorders.
An entirely new section has been added,‘Clinical Approach to Key Manifestations’. This section deals with the common
symptoms and signs with regard to how to scientifically and systematically analyse the problem to arrive at a definitive
diagnosis in a timely and cost-effective manner. New authors have been requested to contribute new chapters so
that the book is entirely re-written in most of the parts and some of the chapters have been exhaustively revised by
the previous authors. A few chapters and figures have been reproduced from the 8th edition. I, on my own behalf
and on behalf of the Editorial Board of the 9th edition, express our thanks to the erstwhile Editor-in-Chief, Dr Siddharth
N Shah of the 8th Edition for having given us this permission.
The explosion of knowledge in medicine is phenomenal and fast so it outpaces the printed textbook of medicine.
Therefore the 9th edition endeavours to reflect on some of these changes occurring in medicine during the preceding
few years. A number of new chapters have been added like Non Invasive Ventilation under Critical Care.
Pharmacotherapy of Cardiovascular Diseases has been added in the section of Cardiology. In the Section of
Gastrointestinal Disorders, a new chapter on the Gastrointestinal Symptoms due to Systemic Diseases has been
added. The Neurology section has been enriched by adding a chapter on Neuroimaging and separate chapters
have been written covering Amyotrophic Lateral Sclerosis and Hyperkinetic Movement Disorders. In the field of
Rheumatology, Emergencies have been discussed as a separate chapter altogether which reflects the new way of
thinking of treatment and diagnosis of various rheumatic emergencies. The section of Medical Genetics has been
thoroughly revised and updated. Genetics is better understood and human genome has been completely delineated.
This has tremendous potential for change in the way we practice medicine. Vascular Injury to Kidney and Chronic
Dialysis under the section of Nephrology have been discussed in separate chapters because of the better
understanding and growing importance of various facets of kidney disorders and diagnosis. An entirely new chapter
on Nano Technology and Nano Medicine has been added which is going to be a new paradigm in the field of
Clinical Pharmacology. The other sections have been duly revised and updated so that they provide contemporary
information and clinical thinking.
The expanse of medicine is vast and varied. The presentation of all disorders in a concise and systematic manner in
a book of this size has to be a joint collaborative effort. This has been possible due to the support, constructive
criticism and useful editorial guidance from all the members of my editorial team for which I am grateful to them.
I am especially indebted to Prof. SK Sharma who has been instrumental in guiding and planning this assignment at
the cost of his precious time despite his multifarious academic activities. Dr AK Agarwal and Dr RK Singal have been
closely associated and have provided useful inputs and suggestions in preparation of this book for which I am
grateful to them. Dr Milind Y Nadkar and Dr Sandhya A Kamath provided useful inputs as to how to circumvent
some of the key issues while editing a book of this nature because of their past experience of the 8th Edition of the
Textbook. Dr Shyam Sundar, Dr Subhash Varma and Dr Pritam Gupta were forthcoming in their help and suggestions
for which I owe my thanks to them. Dr Siddharth N Shah, the Emeritus Editor has guided and supported whenever
his help was sought for in the production of this book. I am obliged to him for all his help. The Sectional Editors were
generous with their time and suggestions while the authors of chapters contributed their chapters in time and as
per the common format which was agreed upon. For all this, I convey my sincere thanks to them.
In the era, of information technology, in consonance with the international practice, a new website for the book,‘API
Textbook of Medicine’, has been created (www.apitextbook.com). It is a novel feature starting from this edition with
online access which will be easily available to all those people who purchase the book. Periodically, the website will
be upgraded and new information will be added.
During the entire course of past three years of compiling of this book, my wife Dr Rama Munjal, son Dr Akshay
Munjal and daughter Er. Jaya Munjal were a source of great strength and motivation. They showed tolerance and
forbearance at all times during the preparation of this book. For all their support I wish to place on record my
heartfelt thanks. On the completion of this major task, I feel more humble and ever so grateful to the Governing
Body of API for having given me this opportunity to carry out this job for and on behalf of our organisation.

Dr Yash Pal Munjal

Editor-in-Chief
API Textbook of Medicine
9th Edition
ACKNOWLEDGEMENTS

The 9th Edition of the API Textbook of Medicine is now available to you.This has been possible due to the collaborative,
co-operative and untiring efforts of the Editorial team and many others. On the occasion of the successful completion
of this marathon job, it would be appropriate to acknowledge and express my gratitude to all those who have
helped in getting this job well done. I am especially grateful to Dr Anupam Prakash and Dr Ghan Shyam Pangtey.
They have been associated from the stage of conceptualisation and planning to the final production of this
manuscript and have provided unstinted help all through this exercise with dedication and commitment. Dr AP
Misra, Dr Anurag Saxena, Dr DG Jain and Dr Sumit Singla have provided useful help at various stages which is duly
acknowledged. The task of proof reading and organising the manuscripts was painstakingly and continuously carried
out by Mr RK Gupta, Mr DK Sahu, Mr MS Muddur and other members of their team. The efforts of Mr RK Gupta
especially stand out and I would like to express my thanks to all of them. I would like to express my thanks to Mr
Sanjeev Chaudhry of ‘Initials’ for having done the initial type setting of the book.
The final production of the book has been possible due to the hard work put in by the staff of Jaypee Brothers
Medical Publishers. The good work done deserves our appreciation and gratitude to Shri Jitendar P Vij, Chairman
and Managing Director of Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, which is now the second largest
Medical Publishers in the world.
Mr Tarun Duneja (Director Publishing) has been instrumental in getting the final shape of the book. The other
members of Jaypee Brothers, Ms Shikha Gupta (Editor), Mr Manoj Pahuja and Mr Ankit Kumar (Graphic Designers),
Mr Pramod Kumar Rout and Mr Kapil Dev Sharma (DTP Operators), and Mr KK Raman (Production Manager) have
done a marvellous job and put in hard work in the production of this book. They were receptive and wore the brunt
of this task willingly. They coordinated with the office of editorial board as a team and carried out the instructions
diligently. They deserve our appreciation and thanks.
I would like to express my sincere thanks to my Secretary, Ms Pushap Lata, for having taken up the additional
responsibility with a smile on her face at all times. Ms Neha Garg, who joined at a later stage in the book production,
was enthusiastic and co-ordinated the work very effectively and efficiently both in compiling as well as proof reading
in the final stages of the book.
I would be failing in my duty if I do not express my sincere thanks to Shri Autar Krishna, Chairman and Shri Bhuwan
Mohan, Secretary of Shri Banarsidas Chandiwala Sewa Smarak Trust Society for providing the office space and allowing
the use of infrastructure during the entire course of the publication of this assignment. Not only they provided the
infrastructural support but they also encouraged me in my task as the ‘Editor-in-Chief’ of this book.
The help of Sectional Editors for editing the section diligently and providing editorial inputs which were very useful
and timely is highly appreciated. I would like to extend our thanks on behalf of the Editorial Board and the authors
who have been provided useful assistance by their colleagues in preparation of their respective manuscripts.

Dr YP Munjal
and the Editorial Board
Chapter Section Assisted By Authors
Section 2
CLINICAL APPROACH TO KEY MANIFESTATIONS
06 Haemoptysis J.S. Guleria Randeep Guleria

Section 3
DIAGNOSTIC IMAGING
06 Positron Emission Tomography Shamim Ahmed Shamim Rakesh Kumar

Section 8
BONE DISORDERS
03 Rickets and Osteomalacia Gaurav Aggarwal Bindu Kulshreshtha

Section 12
CARDIOLOGY
09 Pharmacotherapy of Cardiovascular Disorders Bimalpreet Kaur J.C. Mohan
10 Heart Failure Ragavendra Baliga Donald Kikta
19 Acute Myocardial Infarction Naveen Kumar Gupta Gurpreet Singh Wander
28 Disorders of Myocardium Ajay Bahl K.K. Talwar
Uma Nahar Saikia

Section 14
HEPATOLOGY
11 Non-Alcoholic Fatty Liver Disease Harshal Rajekar Yogesh K. Chawla

Section 15
HAEMATOLOGY
03 Splenomegaly—A Clinical Approach Brijesh Arora Lalit Kumar

Section 16
HIV AND AIDS
03 Pathophysiology and Clinical Features Sonali Sanghavi U.L. Wagholikar

Section 19
NEPHROLOGY
06 Secondary Glomerular Diseases Sonal Sharma O.P. Kalra
Amit K. Dinda

Section 20
NEUROLOGY
10 Cerebrovenous Thrombotic Disorder Rita Christopher D. Nagaraja
16 Fungal and Parasitic Diseases of Nervous System Parul Dubey Ashok Panagariya
Vipin Satija
23 Demyelinating Diseases of Nervous System Prachi Mehndiratta Man Mohan Mehndiratta

Section 21
ONCOLOGY
04 Principles of Drug Treatment of Cancer Ankur Behl Lalit Kumar

Section 23
PULMONARY MEDICINE
03 Pulmonary Disorders—Diagnostic Procedures Archana Ahluwalia Gautam Ahluwalia

Section 28
MISCELLANEOUS
07 Adult Immunisation Surendra K. Sharma R.K. Singal
 SECTIONAL EDITORS
VOLUME 1
Section Editor Page
1. Introduction Yash Pal Munjal 1
2. Clinical Approach to Key Manifestations A.K. Agarwal 9
3. Diagnostic Imaging Raju Sharma 63
4. Clinical Pharmacology B.B. Thakur 119
5. Immunology Sita Naik 137
6. Medical Genetics Shyam Swarup Agarwal 169
7. Critical Care Medicine Surendra K. Sharma 223
8. Bone Disorders S.N.A. Rizvi 293
9. Diabetes Mellitus Anil Bhansali 319
10. Endocrinology Nikhil Tandon 397
11. Dermatology Vibhu Mendiratta 461
12. Cardiology Gurpreet Singh Wander 555
13. Gastroenterology Rakesh Tandon 769
14. Hepatology Rajesh Upadhyay and S.K. Sarin 841
15. Haematology Rajat Kumar 915
16. HIV and AIDS Alaka Deshpande and B.B. Rewari 1011

VOLUME 2
17. Infectious Diseases Shyam Sundar and Subhasish Kamal Guha 1039
18. Disorders of Metabolism B.K. Sahay 1227
19. Nephrology Vinay Sakhuja 1281
20. Neurology M.V. Padma Srivastava 1343
21. Oncology S.K. Bichile 1555
22. Psychiatric Medicine Yash Pal Munjal 1635
23. Pulmonary Medicine Surendra K. Sharma 1685
24. Rheumatology Rohini Handa 1803
25. Nutrition S.V. Madhu 1895
26. Poisoning and Toxicology N.P. Singh 1933
27. Environmental Medicine Randeep Guleria 1989
28. Miscellaneous R.K. Singal 2037
API Textbook of Medicine

CONTRIBUTORS

O.C. Abraham MD MPH Vikas Agarwal MD Alan F. Almeida MD MNAMS FISN

Department of Medicine Associate Professor Section Co-ordinator, Nephrology Section
Unit 1 and Infectious Diseases Department of Immunology Department of Medicine
Christian Medical College, Vellore Sanjay Gandhi Postgraduate Institute P.D. Hinduja National Hospital and Medical
Tamil Nadu, India of Medical Science, Lucknow Research Centre, Mumbai
Uttar Pradesh, India Maharashtra, India
Philip Abraham MD DNB FCPS FICP
Consultant Amita Aggarwal MD Y.K. Amdekar MD DCH
Gastroenterologist and Hepatologist Additional Professor (Clinical Immunology) Medical Director
PD Hinduja National Hospital and Department of Immunology B.J. Wadia Hospital for Children, Mumbai
Medical Research Centre, Mumbai Sanjay Gandhi Postgraduate Institute Consultant Paediatrician
Maharashtra, India of Medical Sciences, Lucknow Jaslok Hospital and Research Centre, Mumbai
Uttar Pradesh, India Maharashtra, India
S.K. Acharya DM
Professor and Head Ashutosh Nath Aggarwal MD (Medicine) A.C. Ammini MD DM (Endo)
Department of Gastroenterology DM (Pulmonary Medicine) Professor and Head
All India Institute of Medical Sciences Associate Professor of Pulmonary Department of Endocrinology and Metabolism
New Delhi, India Medicine All India Institute of Medical Sciences
Postgraduate Institute of Medical New Delhi, India
Prabha Adhikari MD
Professor and Head Education and Research
Chandigarh, India Deepak Amrapurkar MD (Medicine) DM (Gastro) DNB
Department of Medicine Consultant
Kasturba Medical College, Mangalore Praveen Aggarwal MD (Medicine) Gastroenterology and Hepatology
Karnataka, India Bombay Hospital and Medical
Professor
C. Adithan MD DNB PhD Department of Emergency Medicine Research Centre, Mumbai
Professor and Head All India Institute of Medical Sciences Maharashtra, India
Department of Pharmacology, JIPMER New Delhi, India
A.C. Anand MD (Medicine)
Puducherry, India DM (Gastroenterology) FICP FACP FACG
Aparna Agrawal MD (Medicine)
P. Advaitham MD DM Director Professor Senior Consultant (Medicine)
Professor and Head Department of Medicine Armed Forces Medical Services
Department of Gastroenterology Lady Hardinge Medical College Army Hospital (R and R), Delhi Cantt
Madurai Medical College, Madurai and Associated Hospitals New Delhi, India
Tamil Nadu, India New Delhi, India Inder S. Anand MD FRCP DPhil (Oxon)
S.H. Advani MD DNB FICP PhD FNAMS Gautam Ahluwalia MD (Medicine) Professor of Medicine
Director University of Minnesota Medical School
Medical Officer In-charge
Medical Oncology Director, Heart Failure Program
Emergency Services, Dayanand Medical
Jaslok Hospital and Research Centre VA Medical Center 111C Minneapolis MN 55417
College and Hospital, Ludhiana
Mumbai, Maharashtra, India Punjab, India Late M. Paul Anand FRCP (Lond) FRCP (Ed) FICA
(USA) FICP FIMSA FCCP (USA) FISCD
A.K. Agarwal MD FICP FRCP (Edin) Jamal Ahmad MD (General Medicine)
Head of Department of Medicine Physician Cardiologist
DM (Endocrinology)
Dean, PGIMER, Dr RML Hospital Everest Chambers, Mount Pleasant Road
Professor of Endocrinology
New Delhi, India Malabar Hill, Mumbai
Director Maharashtra, India
M.B. Agarwal MD MNAMS Centre for Diabetes and Endocrinology
Department of Haematology, Faculty of Medicine, Jawaharlal Nehru Dharamvir Singh Arya MD
Bombay Hospital Institute of Medical Medical College Hospital Assistant Professor
Sciences, Mumbai, Aligarh Muslim University, Aligarh Department of Pharmacology
Maharashtra, India Uttar Pradesh, India All India Institute of Medical Sciences
New Delhi, India
Shyam Swarup Agarwal MD FRCP FAMS FNA FNASc Mansoor Ahmed MD
Senior Medical Consultant and Honorary Medical Officer Vivek Arya MD
Director (Academics and Research) Department of Cardiology Associate Professor
Vivekananda Polyclinic and Institute PBM Group of Hospitals Department of Medicine
of Medical Sciences, Lucknow Associated to SP Medical College, Bikaner PGIMER and Dr Ram Manohar Lohia Hospital
Uttar Pradesh, India Rajasthan, India New Delhi, India

Sanjay K. Agarwal MD Parag Aland Naved Aslam MD

Professor and Head Department of Nuclear Medicine Associate Professor of Cardiology
Department of Nephrology Jaslok Hospital and Research Dayanand Medical College and Hospital
All India Institute of Medical Sciences Centre 15, Mumbai Unit Hero DMC Heart Institute, Ludhiana
New Delhi, India Maharashtra, India Punjab, India
x
K. Govind Babu MD DM (Onoclogy) Ashu Seith Bhalla MD

Contributors
Anuj Kumar Bansal DM (Oncology)
Associate Professor of Medical Onoclogy Department of Medical Oncology Additional Professor
Kidwai Memorial Institute of Institute Rotary Cancer Hospital (IRCH) Department of Radiodiagnosis
Oncology, Bengaluru All India Institute of Medical Sciences All India Institute of Medical Sciences
Karnataka, India New Delhi, India New Delhi, India
K.K. Raja Babu MD Atma Ram Bansal MD DM (Neurology) Rajvir Bhalwar MD MNAMS PhD
Ex Professor and Head Professor and Head and Senior Advisor in
Associate Consultant
Department of Dermatology Institute of Neurosciences Preventive Med and Epidemiology
Gandhi Hospital/Gandhi Medical Department of Community Medicine
Medanta – The Medicity, Gurgaon
College, Hyderabad Armed Forces Medical College, Pune
Haryana, India
Andhra Pradesh, India Maharashtra, India
V.K. Bahl MD DM (Cardiology) Beena Bansal MD DM Anil Bhansali DM (Endocrinology)
Professor and Head Department of Endocrinology Professor and Head
Department of Cardiology Medanta – The Medicity, Gurgaon Department of Endocrinology, Postgraduate
All India Institute of Medical Sciences Haryana, India Institute of Medical Education and Research
New Delhi, India Chandigarh, India
N.O. Bansal MD (Medicine) DM (Cardiology)
Ragavendra Baliga MD MBA FRCP DNB (Cardiology) Pallavi Bhargava MD
FACC FRS (Med) Professor and Head of Cardiology Diplomate
Assistant Division Director Grant Medical College and J.J. Group American Board of Internal Medicine
Division of Cardiovascular Medicine Hospitals, Mumbai and Infectious Diseases
Professor of Internal Medicine Maharashtra, India Consultant Infectious Diseases
The Ohio State University Columbus, OH, USA HIV and Travel Medicine
Reema Bansal Deenanath Mangeshkar Hospital, Pune
Amal Kumar Banerjee MD DM FACC FESC Advanced Eye Centre Maharashtra, India
Senior Consultant and Intervention Postgraduate Institute of Medical
Cardiologist, AMRI Hospital, Salt Lake, Kolkata Education and Research Nadir E. Bharucha MD (Bom) FAMS (India)
West Bengal, India FRCP (Lond) FRCP Neurology (Canada)
Chandigarh, India
Diplomate American Board of Neurology
Ashok Kumar Bajaj MD FICAI and Psychiatry (N)
Ex Professor
P.P. Bapsy MD DM
Senior Consultant Medical Oncologist Professor and Head
Dermatology and STD Department of Neurology
MLN Medical College, Allahabad Apollo Hospital, Bengaluru
Karnataka, India Bombay Hospital Institute of Medical
Uttar Pradesh, India Sciences, Mumbai
B.K. Bajaj MD (Medicine) DM (Neurology) Sandeep B. Bavdekar MD Head
Associate Professor (Neurology) Professor of Paediatrics Department of Neuroepidemiology
Department of Neurology Seth GS Medical College and KEM Medical Research Centre
Postgraduate Institute of Medical Education Hospital, Mumbai Bombay Hospital, Mumbai
and Research and Dr RML Hospital Maharashtra, India Maharashtra, India
New Delhi, India
Usha K. Baveja MD MNAMS Atul Bhasin DNB (Internal Medicine) MNAMS
V. Balakrishnan MD, DM Senior Consultant Senior Consultant
Professor of Gastroenterology Pathology and Lab Medicine, Department of Internal Medicine
Digestive Diseases Institute Medanta – The Medicity, Gurgaon Dr BL Kapur Memorial Hospital
Amrita Institute of Medical Sciences (AIMS),Kochi Haryana, India New Delhi, India
Kerala, India
Deepak Kumar Bhasin MD DM FAMS FASGE
H.S. Bawaskar MD
Pradeep Bambery MD FRCP (Glasg) FRACP Professor
Bawaskar Hospital and Research Department of Gastroenterology
Professor
Center, Mahad Postgraduate Institute of Medical
Department of Internal Medicine
Maharashtra, India Education and Research (PGIMER)
Postgraduate Institute of Medical Education
and Research, Chandigarh, India Rahul Ramnik Baxi DM Chandigarh, India
Associate Professor of Medicine Department of Endocrinology
Rural Medical School (Bundaberg Campus) Eesh Bhatia MD DNB (Endocrinology)
Diabetes and Metabolism Professor
The University of Queensland
Christian Medical College, Vellore Department of Endocrinology
Acting Director of Medicine
Tamil Nadu, India Sanjay Gandhi Postgraduate Institute
Bundaberg Hospital
Queensland, Australia of Medical Sciences, Lucknow
D.P. Bhadoria MD (Medicine)
DM (Pulmonary/Critical Care Medicine)
Uttar Pradesh, India
Debabrata Bandyopadhyay MD
Professor Jagriti Bhatia MD
Professor and Head
Department of Dermatology, Venereology Maulana Azad Medical College Assistant Professor
and Leprosy Lok Nayak, GB Pant, GNEC and Department of Pharmacology
RG Kar Medical College, Kolkata CNBC Hospitals All India Institute of Medical Sciences
West Bengal, India New Delhi, India New Delhi, India

Samar Banerjee MD Ashit M. Bhagwati MD (Med) FICP (India) Shobna J. Bhatia MD (General Medicine) DM (Gastro)
Professor, Department of FICA (USA) ADHA (Hosp Adm) Professor and Head
Medicine, Specialist, Diabetic Clinic Consulting Physician and Intensivist Department of Gastroenterology
Vivekananda Institute of Medical Bhatia Hospital, Sir Hurkisondas Hospital Seth GS Medical College and KEM
Sciences, Kolkata Smt Motiben B Dalvi Hospital, Mumbai Hospital, Mumbai
West Bengal, India Maharashtra, India Maharashtra, India
xi
API Textbook of Medicine

Vijayalakshmi Bhatia MD Ashok Chacko MD MNAMS (Gastro) DM (Gastro) Dhruva Chaudhry MD DNB DM (Pulmonary
Professor Professor and Head and Critical Care)
Department of Endocrinology Department of Gastrointestinal Sciences Senior Professor and Head Department of
Sanjay Gandhi Postgraduate Institute Christian Medical College, Vellore Pulmonary and Critical Care Medicine
of Medical Sciences, Lucknow Tamil Nadu, India Pt BDS PGIMS, Pt BDS University of
Uttar Pradesh, India Health Sciences, Rohtak
Partha Pratim Chakraborty MD
Haryana, India
Neerja Bhatla MD Assistant Professor
Department of Obstetrics and Gynaecology Department of Medicine Uday Chaudhuri MD DNB DPN
All India Institute of Medical Sciences Midnapore Medical College and Hospital Assistant Professor
New Delhi, India Paschim Medinipur Vivekanand Institute Medical Sciences
West Bengal, India Visiting Psychiatrist
Mohit Bhatt MD DM
Hemraj B. Chandalia MD FACP RK Mission Sewa Prathisthan
Consultant and Head
Endocrinologist and Diabetologist Hospital, Kolkata
Department of Neurology
Jaslok, Breach Candy and Saifee Hospitals West Bengal, India
Kokilaben Dhirubhai Ambani
Hospital and Medical Research Director, Diabetes Endocrine Nutrition Yogesh K. Chawala MD
Institute, Mumbai Management and Research Centre Director
Maharashtra, India (DENMARC), Mumbai, Postgraduate Institute of Medical
Maharashtra, India Education and Research
Jina Bhattacharyya DM
P. Sarat Chandra MCh Chandigarh, India
Associate Professor
Department of Haematology Additional Professor Anuj Chawla MD (Physiology) DNB (Physiology)
Guwahati Medical College, Guwahati Department of Neurosurgery MNAMS FCGP
Assam, India All India Institute of Medical Sciences Associate Professor
Visiting Professor, International Department of Physiology
Prabhash Chandra Bhattacharyya MD Neurosciences Institute Armed Forces Medical College, Pune
Senior Consultant Physician Hannover, Germany Maharashtra, India
Down Town Hospital, Guwahati
Assam, India Laxmisha Chandrashekar MD DNB
Rajesh Chawla MD FCCM FCCP EDIC
Assistant Professor
Consultant Intensivist
Prasanta Kumar Bhattacharya MD Department of Dermatology and STD
Apollo Hospitals
(General Medicine) PhD (Cardiology) Jawaharlal Institute of Postgraduate
Professor of Medicine, Medical Education and Research (JIPMER) New Delhi, India
Gauhati Medical College, Guwahati Puducherry, India Vaibhav C. Chewoolkar MD
Assam, India Assistant Professor
Mammen Chandy MD
S.K. Bhattacharya MD Professor Department of Medicine
Medical Officer Department of Haematology Seth GS Medical College
WHO, South East Asia Regional Office Christian Medical College, Vellore and KEM Hospital, Mumbai
Indraprastha Estate Tamil Nadu, India Maharashtra, India
New Delhi, India
S.M. Channabasavanna MD DPM FAMS S.K. Chhabra MD (Pulmonary Medicine)
Lata S. Bichile MD FICP Professor Head, Department of
Consultant Emeritus in Psychiatry Cardiorespiratory Physiology
Rheumatologist, Saifee Hospital, Mumbai Ex Director and Vice Chancellor National Viswanathan Chest Hospital
Seth GS Medical College and KEM Institute of Mental Health Vallabhbhai Patel Chest Institute
Hospital, Mumbai and Neuro Sciences, Bengaluru Delhi, India
Maharashtra, India Karnataka, India
Shibba Takkar Chhabra MD DM (Cardiology)
S.K. Bichile MD FICP Mitali Chatterjee MD PhD Assistant Professor
Consultant Haematologist Associate Professor Dayanand Medical College and Hospital
Saifee Hospital and Bhatia Department of Pharmacology Unit Hero DMC Heart Institute, Ludhiana
Hospital, Mumbai Institute of Postgraduate Medical Punjab, India
Maharashtra, India Education and Research, Kolkata
West Bengal, India Sanjat S. Chiwane MD (Medicine)
Aspi R. Billimoria MD DM (Cardiology)
Sarit Chatterjee MD DNB (General Medicine)
Hon. Cardiologist Associate Consultant
Consulting Physician and
Conwest and Manjula Badani Department of Cardiology
Assistant Professor
Jain Hospital, Mumbai Artemis Health Institute, Gurgaon
Department of Medicine
Maharashtra, India PGIMER, Dr RML Hospital Haryana, India
Anita M. Borges MD FRCPath New Delhi, India Dharma R. Choudhary MD DM
Consultant Histopathologist Anil Chaturvedi MD FICP FIACM FIAMS Haematologist and BMT Physician
SL Raheja Hospital, Mumbai Senior Consultant Preventive and BL Kapur Memorial Hospital
Director Centre of Excellence in Internal Medicine New Delhi, India
Histopathology Delhi Heart and Lung Institute
Piramal Diagnostic Sevices Ltd, Mumbai Gourdas Choudhuri MD DM FICP FAMS
New Delhi, India
FACG FRCPI
Maharashtra, India
Ved Chaturvedi MD DM Professor and Head
Nishigandha Burute MD Chief Consultant Department of Gastroenterology
Consultant Radiologist Armed Forces Medical Services Sanjay Gandhi Postgraduate Institute
Jankharia Imaging, Mumbai Army Hospital RR of Medical Sciences, Lucknow
Maharashtra, India New Delhi, India Uttar Pradesh, India
xii
Ranjit Roy Choudhury MD Biswa B. Dash MD DNB MICOG Radha K. Dhiman MD DM MNAMS FACG

Contributors
Chairman Department of Obstetrics and Gynaecology Additional Professor
Task Force for Research All India Institute of Medical Sciences Department of Hepatology
Apollo Hospitals Educational and Research New Delhi, India Postgraduate Institute of Medical
Foundation Education and Research
Indraprastha Apollo Hospital, Hostel Complex Avinash Deo MD Chandigarh, India
New Delhi, India Consultant
Medical Oncologist and Haematologist Tuphan Kanti Dolai MD DNB DM
S.N. Chugh MD MNAMS FICP FICN FIACM FISC Holy Family, Guru Nanak and Haematologist and BMT Physician
Senior Professor and Pro Vice Chancellor Dhanwantari Hospital, Mumbai Assistant Professor, Haematology Department
Pt BD Sharma University of Health Maharashtra, India NRS Medical College, Kolkata
Sciences, Rohtak West Bengal, India
Haryana, India Anita Desai
Department of Neurovirology Lakshman Dutt MD
S. Criton MD National Institute of Mental Health and Shri Krishna Prasad Psychiatric Nursing
Professor and Head Neurosciences (NIMHANS), Bengaluru Home and Research Center, Ahmedabad
Department of Dermatology Karnataka, India Gujarat, India
Amala Institute of Medical Sciences, Thrissur Koushik Dutta MD DM
Kerala, India Mukesh Desai MD DNB
Prof. of Paediatric Haematology Oncology Pulmonary/Critical Care Medicine
Sanjay D’ Cruz MD DNB DM (Nephrology) MAMS Hon. Haematologist Oncologist and Professor of Medicine
Associate Professor Immunologist Maulana Azad Medical College, Lok Nayak
Department of Medicine Chief Division of Immunology GB Pant, GNEC and CNBC Hospitals
Government Medical College and Hospital Department of PHO, BJ Wadia Hospital for New Delhi, India
Chandigarh, India Children, Mumbai Tarun Kumar Dutta MD
Consultant Haematologist Nanavati Hospital Professor and Head
M.K. Daga Sir HN Hospital, Saifee Hospital
Professor Department of Medicine
Department of Medicine Shrinivas B. Desai MD Jawaharlal Institute of Postgraduate
Maulana Azad Medical College Head Medical Education and Research
Department of Imaging and Puducherry, India
New Delhi, India
Interventional Radiology S. Dwivedi MD (Internal Medicine, BHU) PhD
Ashwin Dalal MD (Paediatrics) DM (Medical Genetics) Jaslok Hospital and Research (Cardiology BHU) FRCP (London)
Head Centre, Mumbai Dean, Principal, Professor and Head
Diagnostics Division Maharashtra, India Department of Medicine and Preventive
Centre for DNA Fingerprinting and
Cardiology at Hamdard Institute of Medical
Diagnostics, Hyderabad Vinay H. Deshmane MS DNB FRCS (Glasg) Sciences and Research (Hamdard University)
Andhra Pradesh, India MD (London) FICS New Delhi, India
Consultant, Surgical Oncology
P.M. Dalal MD FICP FAMS FAHA C.E. Eapen MD DM (Gastro)
PD Hinduja Hospital and Asian Institute
Senior Consultant, Neurologist and Research Professor
of Oncology, Mumbai
Director Department of Gastrointestinal Sciences
Maharashtra, India
LKMM Trust Research Centre Christian Medical College, Vellore
Lilavati Hospital, Mumbai Alaka Deshpande MD MAMS FIMSA FICP Tamil Nadu, India
Maharashtra, India Professor of Medicine and Chief
HIV Unit, Grant Medical College and Natasha Edwin MD
Debashish Danda MD (Medicine) Assistant Professor
DM (Clinical Immunology) Sir JJ Gr of Govt Hospitals, Mumbai
Maharashtra, India Department of General Medicine
Professor and Head Christian Medical College, Vellore
Clinical Immunology and Rheumatology Richa Dewan Tamil Nadu, India
Christian Medical College, Vellore Director
Tamil Nadu, India Veronica Franco MD MSPH FACC
Professor and Head
The Ohio State University
Ashok Kumar Das MD (General Medicine) Department of Medicine
Division of Cardiovascular Diseases, DHLRI
Senior Professor of Medicine and Medical Maulana Azad Medical College 200, Section of Advanced Heart Failure and
Superintendent New Delhi, India Transplantation, Section of Pulmonary
Jawaharlal Institute of Postgraduate Medical Hypertension Columbus, OH 43210 USA
Anil Dhall MD (Medicine) DM (Cardiology)
Education and Research (JIPMER)
Puducherry, India FACC FSCAI FCSI Ankur Gadodia MD DNB
Director and Head Department of Radiodiagnosis
E. Mohan Das MD Psychiatry (AIIMS) Department of Cardiology All India Institute of Medical Sciences
Chief Consultant Artemis Health Institute, Gurgaon New Delhi, India
Elite Mission Hospital, Trichur Haryana, India
M.J. Gandhi MD FAMS FICC FICP FICE
Kerala, India Prof. Emeritus, Cardiology, Nanavati Hospital
Sandipan Dhar MD
Shyamal Kumar Das DM Consultant Dermatologist and Heart Institute.
Professor and Head AMRI Hospital (Dhakuria), Kolkata V.P. Gangadharan MD
Department of Neurology West Bengal, India Department of Medical Oncology
Bangur Institute of Neuroscience, Kolkata Lakeshore Hospital and Research Centre, Kochin
West Bengal, India Pankaj Dhawan MD DNB DM
Kerala, India
Consultant Gastroenterologist and
Siddharth Kumar Das MD Co-ordinator of GI Endoscopy Dwijendra Nath Gangopadhyay MD MS
Professor and Head Jaslok Hospital and Research Centre, Mumbai Professor
Department of Rheumatology Chief Interventional Gastroenterologist Department of Dermatology
CSM Medical University, Lucknow Digestive Diseases and Endoscopy, Mumbai School of Tropical Medicine, Kolkata
Uttar Pradesh, India Maharashtra, India West Bengal, India xiii
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Dhiman Ganguly Sankar Prasad Gorthi MD DNB Naveen Kumar Gupta MD (Medicine)
Department of Medicine Senior Advisor Med and Neurology Jr Consultant Physician
Vivekananda Institute of Medical Sciences Command Hospital (Central Command) Dayanand Medical College and Hospital
Ramakrishna Mission Seva Pratisthan, Kolkata Lucknow Cantt, Lucknow Unit Hero DMC Heart Institute, Ludhiana
West Bengal, India Uttar Pradesh, India Punjab, India
Ajay Garg MD Ravinder Goswami MD DM FNASc FASC Rakesh K. Gupta
Consultant, Neuroradiology Additional Professor Endocrinology Professor
All India Institute of Medical Sciences and Metabolism Department of Radiodiagnosis
New Delhi, India All India Institute of Medical Sciences Sanjay Gandhi Postgraduate Institute
New Delhi, India of Medical Sciences, Lucknow
Gunjan Garg MD Uttar Pradesh, India
Department of Endocrinology R.K. Goyal MD
All India Institute of Medical Sciences Ex Professor and HOD Medicine M.C. Gupta MD DM
New Delhi, India JLN Medical College, Ajmer Dean and Head
Rajasthan, India Faculty of Para Clinical Sciences
Ravindra Kumar Garg MD DM Professor Department of Pharmacology
Department of Neurology Chander Grover Pt BD Sharma University of
Chhatrapati Shahuji Maharaj Medical Department of Dermatology, Venerology Health Sciences, Rohtak
University, Lucknow and Lephrology Haryana, India
Uttar Pradesh, India University College of Medical Sciences
Nitin Gupta MS MCh
and Guru Tegh Bahadur Hospital
Rohit Kumar Garg MD Consultant, Gastroenterology
New Delhi, India
Department of Neurology Jaipur Golden Hospital
GB Pant Hospital N.K. Grover MS FICS FIAMS FIMSA New Delhi, India
New Delhi, India Senior Consultant Surgeon Piyush Gupta MD MAMS FIAP
Medical Director, Vinayak Hospital, Bengaluru Professor of Paediatrics
Taru Garg Karnataka, India University College of Medical Sciences
Associate Professor
Subhasish Kamal Guha DTM & H MD New Delhi, India
Department of Dermatology and STD
Lady Hardinge Medical College and Associate Professor Pritam Gupta MD (Medicine)
Associated Hospitals, Connaught Place Department of Tropical Medicine Senior Consultant and Head
New Delhi, India School of Tropical Medicine, Kolkata Department of Medicine
West Bengal, India Sunder Lal Jain Hospital
A.R. Gayathri MD FCCP FRCP FIAB New Delhi, India
Consultant Deb Sankar Guin
Department of Respiratory Medicine Medical Officer cum Clinical Tutor Rajeev Gupta MD PhD
Apollo Hospital, Chennai Department of Neurology Department of Medicine
Tamil Nadu, India Bangur Institute of Neuroscience, Kolkata Fortis Escorts Hospital, Jaipur
West Bengal, India Rajasthan, India
Muhammad Abid Geelani MCh (CTVS)
P.D. Gulati MD FAMS FAIID FICAI FIMSA Subash Gupta MS FRCS
Professor
Senior Hon Consultant Senior Consultant
Department of CTVS
Tirath Ram Shah Hospital, Delhi Liver Transplant and Gastrointestinal Surgery
GB Pant Hospital, Maulana Azad Medical College
Formerly Head Indraprastha Apollo Hospital
New Delhi, India
Division of Nephrology Maulana Azad New Delhi, India
Alakendu Ghosh MD Medical College and Associated Hospitals
Sudeep Gupta MD DM
Professor New Delhi, India
Professor of Medical Oncology and Convener
Department of Medicine and Head Randeep Guleria MD DM (Pulmonary Breast Cancer Working Group
Department of Rheumatology and Critical Care) Tata Memorial Hospital,Mumbai
Institute of Postgraduate Medical Professor and Head Maharashtra, India
Education and Research, Kolkata Department of Pulmonary Diseases and
West Bengal, India Sleep Disorders Vaibhav Gupta MD
All India Institute of Medical Sciences Department of Gastroenterology
Kanjaksha Ghosh MD MRCP MRCPI FRCPath Rockland Hospital
FACP FICP
New Delhi, India
New Delhi, India
Director Amod Gupta MS
Institute of Immunohaematology Soneil Guptha MD FACC FESC FCCP FICA Dip Pharm Med
Advanced Eye Centre
KEM Hospital, Mumbai Hon Director
Postgraduate Institute of Medical
Maharashtra, India Jaipur Heart Watch Foundation, Jaipur
Education and Research
Rajasthan, India
Chandigarh, India
Uday Chand Ghoshal MD DNB DM FACG
Associate Professor Anil Gurtoo MD
Ankur Gupta DM (Nephrology) Director Professor
Department of Gastroenterology Department of Nephrology Department of Medicine
Sanjay Gandhi Postgraduate Institute All India Institute of Medical Sciences Lady Hardinge Medical College
of Medical Sciences, Lucknow New Delhi, India Associate Hospital
Uttar Pradesh, India
Dheeraj Gupta MD DM MAMS New Delhi, India
B.K. Girdhar MD Additional Professor Ashutosh Halder MD DNB DM MAMS
Senior Consultant Department of Pulmonary Medicine Associate Professor
Dermatology, STD and Leprosy Shanti Postgraduate Institute of Medical Department of Reproductive Biology
Manglick Hospital, Agra Education and Research All India Institute of Medical Sciences
xiv Uttar Pradesh, India Chandigarh, India New Delhi, India
 Jyotsna M. Joshi MD

Contributors
Rohini Handa MD DNB FAMS FICP FACR FRCP (Glasgow) Sanjay Jain MD DM MAMS
Senior Consultant Rheumatologist Professor of Internal Medicine Professor and Head
Apollo Indraprastha Hospital Postgraduate Institute of Medical Department of Pulmonary Medicine
New Delhi, India Education and Research TN Medical College and BYL Nair
Chandigarh, India Hospital, Mumbai
C.V. Harinarayan MD DM (Endo) FAMS Maharashtra, India
Professor and Head A.K. Jaiswal MD
Department of Endocrinology and Metabolism Professor and Head Prashant P. Joshi MD (Medicine) MSc
Sri Venkateswara Institute of Medical Department of Dermatology (Clinical Epidemiology, UNC, Australia)
Sciences, Tirupati Venereology and Leprosy Associate Professor in Medicine
Andhra Pradesh, India Vydehi Institute of Medical Sciences Senior Physician and Head
and Research Centre, Bengaluru Department of Medicine, Indira Gandhi
N.K. Hase MD DNB Karnataka, India Government Medical College, Nagpur
Professor and Head Maharashtra, India
Department of Nephrology Bhavin Jankharia MD DMRD
Shashank R. Joshi MD DM FICP FACP FACE (USA)
Seth GS Medical College and Consultant Radiologist FRCP (Glasg)
KEM Hospital, Mumbai Jankharia Imaging, Mumbai Faculty, Department of Endocrinology
Maharashtra, India Maharashtra, India Grant Medical College and Sir JJ Group
M.S. Jawahar MD MSc DLSHTM Hospital, Consultant Endocrinologist, Lilavati
A.K. Hooda MD DM
and Bhatia Hospital, Mumbai
Senior Advisor (Medicine and Nephrology) Deputy Director (Sr Gr) and Scientist ‘F’
Maharashtra, India
Command Hospital (Eastern Command),Kolkata Department of Clinical Research
West Bengal, India Tuberculosis Research Centre Shilpa S. Joshi
Indian Council of Medical Director
Arun C. Inamadar MD DVD Research, Chennai Mumbai Diet and Health Centre, Mumbai
Professor and Head Tamil Nadu, India Maharashtra, India
Department of Dermatology, Venereology
and Leprosy R.V. Jayakumar MD DM MNAMS FRCP V.R. Joshi MD
Sri BM Patil Medical College, Hospital and Professor of Endocrinology Director of Research and Cons Physician
Research Centre, BLDE University, Bijapur Amrita Institute of Medical and Rheumatologist
Karnataka, India Sciences, Kochi PB Hinduja National Hospital and
Kerala, India Research Centre, Mumbai
Vara Prasad IR MD DM Maharashtra, India
Consultant Rheumatologist Venu Gopal Jhanwar MD
NIMS, Hyderabad Consultant Psychiatrist Jyotsana
Andhra Pradesh, India Deva Mental Health Care/RKM Home Department of Gastroenterology
of Service, Varanasi RML and PGIMER, Chandigarh
Priya Jagia MD DNB (Radiology) Uttar Pradesh, India New Delhi, India
Assistant Professor
Department of Cardiac Radiology Madhulika Kabra MD
Farah F. Jijina
All India Institute of Medical Sciences Additional Professor
Professor and Head
Division of Genetics
New Delhi, India Department of Haematology Department of Paediatrics
Seth GS Medical College and KEM All India Institute of Medical Sciences
Ankit Jain MD DM
Hospital, Mumbai New Delhi, India
Assistant Professor
Maharashtra, India
Department of Medical Oncology J. Kalita DM
Regional Cancer Center, JIPMER S.K. Jindal MD Additional Professor of Neurology
Puducherry, India Professor and Head Department of Neurology
Department of Pulmonary Medicine Sanjay Gandhi Postgraduate Institute
D.G. Jain MD FRCP (Dublin) FRCP (Glasgow) FICP
FNCCP (Ind) FIMSA FIACM FCPS (DLT)
Postgraduate Institute of Medical of Medical Sciences, Lucknow
Education and Research Uttar Pradesh, India
Adjunct Visiting Professor of Medicine
Kasturba Medical College, Mangalore and Chandigarh, India
O.P. Kalra MD DM (Nephrology) FAMS FISN FICP FIACM
Manipal NAHE Deemed University Manipal Sadhna Joglekar MD Commonwealth Fellow in Nephrology
Hony. Physician, Fortis Jessa Ram Hospital Vice President Leicester (UK)
New Delhi, India Medical and Clinical Research Professor of Medicine
GSK Pharmaceuticals Ltd, Mumbai Head, Division of Nephrology
Narender Pal Jain University College of Medical
Associate Professor Maharashtra, India
Sciences and GTB Hospital
Department of Medicine Delhi, India
George T. John MD DM FRCP FRACP
Dayanand Medical College and
Senior Consultant
Hospital, Ludhiana Sandhya A. Kamath MD FICP
Department of Renal Medicine
Punjab, India Dean and Professor
Level 9, Ned Hanlon Building Department of Medicine
Naresh Jain MD Royal Brisbane and Women’s Hospital Lokmanya Tilak Municipal Medical College
Department of Dermatology and Venereology Herston Qld 4029 and Municipal General Hospital, Mumbai
All India Institute of Medical Sciences Maharashtra, India
New Delhi, India Anant Joshi MS (Ortho) D Ortho
Master of Sports Sciences (USA) Madhuchanda Kar MD (Medicine) PhD (Cancer Research)
Sachin K. Jain Cons Orthopaedic Surgeon and Senior Consultant Medical and
Director Arthroscopy Specialist Hemato-Oncologist
Professor, Department of Medicine, LHMC Bombay Hospital, Mumbai Apollo Gleneagles Cancer Hospital, Kolkata
New Delhi, India Maharashtra, India West Bengal, India xv
 Gurudas Khilnani MD (General Medicine)
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Premashis Kar MD DM PhD FRCP FACG FAMS FICPs Raj Kubba MRCP (UK) FRCP (Edin) FRCP (Canada)
Director Professor of Medicine and MD (Pharmacology) DHRM Adjunct Associate Professor of Dermatology
Gastroenterologist Professor and Head Boston University School of Medicine Boston,MA
Department of Medicine Department of Pharmacology Consultant Dermatologist
Maulana Azad Medical College RNT Medical College, Udaipur Delhi Dermatology Group, Kubba Clinic
New Delhi, India Rajasthan, India New Delhi, India
N. Karthik Uday Khopkar MD Amit Kulkarni DNB DPM
Department of Neurology Professor and Head of Dermatology Consultant Psychiatrist
National Institute of Mental Health and KEM Hospital and Seth GS Medical Asha Parekh BCJ Hospital
Neurosciences, Bengaluru College, Mumbai Santacruz west, Mumbai
Karnataka, India Maharashtra, India
J.S. Kulkarni MD Dip AV Med
Surender Kashyap MD DNB Donald Kikta MD Principal Medical Officer WAC
Principal-cum-Dean Division of Cardiology Formerly Principal
Professor and Head Case Western University Institute of Aerospace Medicine
Pulmonary Medicine Cleveland, OH, USA IAF, Bengaluru
Indira Gandhi Medical College, Shimla Karnataka, India
Ashok L.Kirpalani MD (Medicine) MNAMS (Nephrology)
Himachal Pradesh, India
Professor and Head of Nephrology Bindu Kulshreshtha MD DM
Upendra Kaul MD DM FCSI FICC FACC FAMS FSCAI Bombay Hospital Institute of Assistant Professor
Executive Director and Dean Medical Sciences, Mumbai Endocrinology, PGIMER and
Cardiac Sciences, Fortis Escorts Heart Maharashtra, India Dr Ram Manohar Lohia Hospital
Institute Okhla Road and Fortis New Delhi, India
Suman Kirti MD FRCP (London) FRCP (Edin) FICP
Hospital, Vasant Kunj
Senior Consultant Ajay Kumar MD DM MAMS FRCP (Glasgow)
New Delhi, India
Holy Family Hospital Senior Consultant Gastroenterology
Gurleen Kaur New Delhi, India and Hepatology
Internal Medicine Indraprastha Apollo Hospital
Girisha K.M. MD DM (Medical Genetics) New Delhi, India
Westlake Hospital, Illinois State, USA
Consultant Genticist and Associate Professor
Vineet Kaur DNBE (Derm and Ven) Dip GUM (UK) Department of Paediatrics Arohi Kumar
Consultant Kasturba Medical College, Manipal Consultant Physician, Muzaffarpur
Dermatologist and Member Karnataka, India Bihar, India
Advisory Board International Skincare Abhishek Kochar Bhushan Kumar MD FRCP (Edin)
Nursing Group Consultant Dermatologist, Silver Oaks
Assistant Professor
The Skin Institute, Varanasi Department of Medicine Multi-Speciality Hospital, Mohali
Uttar Pradesh, India SP Medical College, Bikaner Punjab, India
Rohini Kelkar MD DPB Rajasthan, India
Jaya Kumar MD
Professor and Head Dhanpat Kumar Kochar MD DN (VIENNA) Department of Medicine
Department of Microbiology Consultant Neurologist All India Institute of Medical Sciences
Tata Memorial Centre, Mumbai Kothari Medical and Research Institute, Bikaner New Delhi, India
Maharashtra, India Rajasthan, India
Lalit Kumar MD DM FAMS FASc
S.V. Khadilkar MD Rakesh Kochhar MD DM Professor of Medical Oncology
Professor Professor Institute Rotary Cancer Hospital (IRCH)
Department of Neurology Department of Gastroenterology All India Institute of Medical Sciences
Grant Medical College and Sir J.J. Group Postgraduate Institute of Medical New Delhi, India
of Hospitals, Mumbai Education and Research
Maharashtra, India Rajat Kumar MD (Med) DNB (Med) FICP FRCP (Edin)
Chandigarh, India FRCP (London) FRCPC
Deepak Khandelwal MD Professor
Abraham Koshy MD DM Department of Medical Oncology and
Department of Endocrinology and Department of Gastroenterology
Metabolism Haematology
Lakeshore Hospital and Research, Kochi Cancer Care Manitoba
All India Institute of Medical Sciences Kerala, India Professor, University of Manitoba, Canada
New Delhi, India
Jatin P. Kothari Rakesh Kumar MD
P.D. Khandelwal MD Department of Medicine Associate Professor
Director, Professor of Medicine PD Hinduja National Hospital and Department of Nuclear Medicine
SMS Medical College, Jaipur Medical Research Centre, Mumbai All India Institute of Medical Sciences
Rajasthan, India Maharashtra, India New Delhi, India
Sudeep Khanna MD DM Prakash Kothari MD PhD R. Krishna Kumar MD DM FACC FAHA
Senior Gastroenterologist Professor and Head Clinical Professor and Head of Department
Pushpawati Singhania Research Institute Department of Sexual Medicine Paediatric Cardiology
for Liver, Renal and Digestive Diseases Seth GS Medical College and Amrita Institute of Medical Sciences
New Delhi, India KEM Hospital, Mumbai Ponekkara PO, Kochi
Maharashtra, India Kerala, India
Vijay Kher MD DM FAMS FRCPE
Chairman Shyam S. Kothari MD FACC Rakshit Kumar
Medanta Kidney and Urology Professor (Cardiology) Department of Medicine
Institute, Gurgaon All India Institute of Medical Sciences Maulana Azad Medical College
xvi Haryana, India New Delhi, India New Delhi, India
Sunil Kumar Ashok A. Mahashur MD FRCP

Contributors
U.V. Mani
Professor Consultant Chest Physician Professor and Head
Department of Radiodiagnosis PD Hinduja National Hospital and Department of Foods and Nutrition
Sanjay Gandhi Postgraduate Institute Medical Research Centre, Mumbai MS University of Baroda, Vadodara
of Medical Sciences, Lucknow Maharashtra, India Gujarat, India
Uttar Pradesh, India
P.K. Maheshwari DM (Neurology) C.N. Manjunath MD DM
Uma Kumar Department of Medicine Department of Cardiology
Associate Professor of Medicine SN Medical College and Hospital, Agra Sri Jayadeva Institute of Cardiovascular
Head, Clinical Immunology and Rheumatology Uttar Pradesh, India Sciences and Research, Bengaluru
All India Institute of Medical Sciences Karnataka, India
New Delhi, India Sunita Maheshwari ABP ABPC (USA)
Senior Consultant Paediatric Cardiologist Aijaz H. Mansoor MD
Vinod Kumar MD RXDX and Narayana Attending Cardiologist
Emeritus Professor Hrudayalaya, Bengaluru Fortis Escorts Heart Institute
Department of Medicine Karnataka, India New Delhi, India
St Stephens Hospital
New Delhi, India M. Maiya FRCP (Lond) FRCP (Edin) FRCP (Glasg)
FICP (Ind) FICC (Ind)
B.G. Mantur
Vivek Kumar Consultant Physician Professor and Head
Department of Medicine Maiya Multispeciality Hospital, Bengaluru Department of Microbiology
Maulana Azad Medical College Karnataka, India Belgaum Institute of Medical
New Delhi, India Sciences, Belgaum
D. Maji MD DM Karnataka, India
S. Lahiri Professor and Head of Department Medicine
Consultant Cardiology Vivekanand Institute of Medical Neelam Marwaha MD FAMS
Delhi Heart and Lung Institute Sciences, Kolkata Professor and Head
New Delhi, India West Bengal, India Department of Transfusion Medicine
Postgraduate Institute of Medical
Bashir Ahmad Laway MD DM (Endocrinology) Govind K. Makharia MD DM DNB MNAMS Education and Research
Additional Professor Endocrinology Associate Professor Chandigarh, India
Sher-i-Kashmir Institute of Medical Department of Gastroenterology
Sciences, Srinagar and Human Nutrition Dilip Mathai MD PhD FRCP FCAMS FIDSA FICP
Jammu and Kashmir, India All India Institute of Medical Sciences Professor of Medicine
Ramchandra D. Lele MRCP (Edin) FRCP New Delhi, India Infectious Disease Training and
Hon. Director of Nuclear Medicine and PET-CT Research Centre
Ishwar Chandra Malav DM Christian Medical College, Vellore
Jaslok Hospital and Research Centre Consultant and Interventional Cardiologist
Hon Director, Dept of Nuclear Medicine and Tamil Nadu, India
Bharat Vikas Parishad Hospital
RIA, Lilavati Hospital and Research Centre and Research Centre, Kota Praveen Mathew
Emeritus Professor of Medicine
Rajasthan, India Department of Gastroenterology
Grant Medical College and Sir JJ
Hospitals, Mumbai KEM Hospital, Mumbai
A.N. Malaviya MD FRCP (Lond) ACR ‘Master’ FACP
Emeritus Professor of the National Academy FICP FAMS FNASc
Maharashtra, India
of Medical Sciences, India Consultant Rheumatologist, ‘A and R Clinic’ Vikram Mathews MD DM
and Visiting Senior Consultant Professor of Clinical Haematology
Vikram R. Lele MD (Med) DRM DNB (Nucl Med) Rheumatologist
Head, Department of Nuclear Medicine Department of Haematology
ISIC Superspeciality Hospital Christian Medical College and
Jaslok Hospital and Research Centre 15, Mumbai
New Delhi, India
Maharashtra, India Hospital, Vellore
Hemant Malhotra MD MNAMS FICP FUICC FIMSA Tamil Nadu, India
Yash Y. Lokhandwala DM (Cardiology)
Professor of Medicine and Head
Arrhythmia Associates, Mumbai Prashant Mathur MD
Division of Medical Oncology
Quintiles Cardiac Safety Services, Mumbai Consultant,
Birla Cancer Center
Maharashtra, India MHRC, Ajmer, Rajasthan, India
SMS Medical College Hospital, Jaipur
Kaushal Madan Rajasthan, India P.S. Mathuranath DNB DM (Neurology)
Senior Consultant Additional Professor of Neurology
Department of Digestive and Prabhat Singh Malik
Medical Oncology Sree Chitra Tirunal Institute for Medical
Hepatobiliary Science Sciences and Technology,Thiruvananthapuram
Medanta - The Medicity, Gurgaon Institute Rotary Cancer Hospital (IRCH)
All India Institute of Medical Sciences Kerala, India
Haryana, India
New Delhi, India
A.K. Meena MD DM
S.V. Madhu MD DM (Endocrinology)
Sourabh Malviya MD Professor
Division of Endocrinology and Metabolism
Department of Medicine Department of Medicine Department of Neurology
University College of Medical Sciences All India Institute of Medical Sciences Nizam’s Institute of Medical
and GTB Hosptal New Delhi, India Sciences, Hyderabad
Delhi, India Andra Pradesh, India
R. K. Mani MD
M. Mahapatra MD Director Man Mohan Mehndiratta DM
Associate Professor Department of Pulmonology, Critical Professor of Neurology
Department of Haematology Care and Sleep Medicine Department of Neurology
All India Institute of Medical Sciences Artemis Health Institute, Gurgaon GB Pant Hospital
New Delhi, India Haryana, India New Delhi, India
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Narinder K. Mehra M. Modi MD (Medicine) DM (Neurology) Yash Pal Munjal MD FRCP (Edin) FACP FICP MAMS
Professor and Head Assistant Professor Director
Department of Transplant Immunology Department of Neurology, Postgraduate Diabetes and Life Style Disease Centre
and Immunogenetics Institute of Medical Education and Research Banarsidas Chandiwala Institute of
All India Institute of Medical Sciences Chandigarh, India Medical Science
New Delhi, India New Delhi, India
Alladi Mohan MD
Vibhu Mendiratta MD (Dermatology and VD) Chief A. Muruganathan MD FRCP (Glasg)
Professor Division of Pulmonary Adjunct Professor
Department of Dermatology Critical Care and Sleep Medicine AG Hospital
Lady Hardinge Medical College and Assoc Professor and Head The Tamilnadu Dr Mgr Medical
Sucheta Kriplani and Kalawati Department of Medicine University, Chennai
Saran Children’s Hospital Sri Venkateswara Institute of Medical Tamil Nadu, India
New Delhi, India Sciences, Tirupati
Andhra Pradesh, India Milind Y. Nadkar MD FICP
Vandana Midha Professor of Medicine
Professor Bishav Mohan Chief of Rheumatology and
Department of Medicine Professor of Cardiology Emergency Medicine
Dayanand Medical College and Dayanand Medical College and Hospital Seth GS Medical College and KEM
Hospital, Ludhiana Unit Hero DMC Heart Institute, Ludhiana Hospital, Mumbai
Punjab, India Punjab, India Maharashtra, India
Aditya Prakash Misra J.C. Mohan MD DM D. Nagaraja DM (Neuro) DPM (Psych) MAMS
Fortis Jessa Ram Hospital Department of Cardiology Professor of Neurology
Gurudwara Road, Karol Bagh Ridge Heart Centre, Sunder Lal Jain Hospital Ex Director, Vice Chancellor
New Delhi, India Delhi, India National Institute of Mental Health
and Neurosciences, Bengaluru
Anoop Misra MD V. Mohan MD FRCP (UK) FRCP (Glasg) PhD DSc Karnataka, India
Director and Head Chairman and Chief Diabetologist
Department of Diabetes and Metabolic Dr Mohan’s Diabetes Specialities Centre T.S. Nagesh
Diseases President and Chief of Diabetes Research Assistant Professor
Fortis Flt Lt Rajan Dhall Hospital Madras Diabetes Research Department of Dermatology
New Delhi, India Foundation, Chennai Venereology and Leprosy
Ramnath Misra MD FRCP (London) Tamil Nadu, India Sapthagiri Institute of Medical
Professor and Head Sciences, Bengaluru
Vipul Mohan Karnataka, India
Department of Clinical Immunology
Department of Cardiology
Sanjay Gandhi Postgraduate Institute Sita Naik MD
Ridge Heart Centre, Sunder Lal Jain Hospital
of Medical Sciences, Lucknow Ex Professor of Immunology
Delhi, India
Uttar Pradesh, India and Dean
K.M. Mohandas MD DNB Sanjay Gandhi Postgraduate Institute
U.K. Misra DM FAMS
Senior Consultant of Medical Sciences, Lucknow
Professor and Head
Medanta Institute of Digestive Uttar Pradesh, India
Department of Neurology
Dean, Sanjay Gandhi Postgraduate and Hepatobiliary Sciences
Medanta – The Medicity, Gurgaon, Haryana Ranjith Nair MD DM
Institute of Medical Sciences, Lucknow
Dean, Academic Army Hospital (R and R), Delhi Cantt
Uttar Pradesh, India
Tata Memorial Centre Mumbai New Delhi, India
Ambrish Mithal MD DM Maharashtra, India
Velu Nair MD
Chairman
Prasanta Raghab Mohapatra MD MAMS Professor and Head
Division of Endocrinology and Diabetes
Medanta – The Medicity, Gurgaon
FNCCP FIAB FCCP (USA) Department of Clinical Haematology and
Department of Pulmonary Medicine Bone Marrow Transplantation
Haryana, India
Government Medical College and Hospital Army Hospital (Research and Referral)
Amit Mittal MD DM Chandigarh, India Delhi Cantt
Assistant Professor New Delhi, India
Department of Cardiology Niranjan P. Moulik
GB Pant Hospital, Maulana Department of Medicine Praveen Namboothiri MD DM (Nephrology)
Azad Medical College MS Ramaiah Medical College, Bengaluru Consultant in Nephrology
New Delhi, India Karnataka, India Sankar’s SIMS Hospital and Research
Institute, Kollam
B.R. Mittal MD DRM DNB MNAMS FICNM Sukumar Mukherjee MD FRCP FRCPE FICP FICN Kerala, India
Professor and Head FISE FIAMS FSMF
Department of Nuclear Medicine and PET Consultant Physician Research Shiva Narang
Postgraduate Institute of Medical Calcutta Medical Research Institute Assistant Professor
Education and Research Kothari Medical Centre Department of Medicine
Chandigarh, India Kolkata GD Diabetes Institute, Kolkata University College of Medical Sciences
West Bengal, India GTB Hospital
Veena Mittal MD (Microbiology) New Delhi, India
Consultant and Head Rita Mulherkar PhD
Zoonosis Division Scientific Officer ‘G’ Mulherkar Lab R. Narasimhan MD FCCP FRCP FIAB
National Centre for Disease Control Advanced Centre for Treatment Research Senior Consultant
Formerly National Institute of and Education in Cancer Department of Respiratory Medicine
Communicable Diseases Tata Memorial Centre, Navi Mumbai Apollo Hospital, Chennai
xviii Delhi, India Maharashtra, India Tamil Nadu, India
G. Narsimulu MD FICP FIACM Ashish Kumar Panigrahi K. Pavithran

Contributors
Senior Consultant Rheumatologist Assistant Professor Senior Consultant
Ex Prof and Head Rheumatology Department of Medicine Department of Dermatology
NIMS, Hyderabad Aarupadai Veedu Medical College and Hospital MIMS Hospital, Calicut
Andhra Pradesh, India Puducherry, India Kerala, India

A.S. Narula MD DM FACP Manotosh Panja MD DM FICP FACC K. Pavithran MD DM

Additional Director General Director, ICVS Professor of Medical Oncology
Armed Forces Medical Services AMRI Hospital, Kolkata Amrita Institute of Medical Sciences and
Professor of Medicine West Bengal, India Research Centre, Cochin, India
Army College of Medical Sciences Satish Kumar Parashar MD FACC FCSI
New Delhi, India Shubha R. Phadke MD (Paediatrics)
Senior Consultant Cardiologist and Director DM (Medical Genetics)
Swapan Kumar Niyogi Non-Invasive Cardiac Laboratory Professor
Deputy Director Metro Hospitals and Heart Institute Department of Medical Genetics
National Institute of Cholera and Enteric New Delhi, India Sanjay Gandhi Postgraduate Institute
Diseases, Kolkata Falguni S. Parikh MD DNB MNAMS FICP of Medical Sciences, Lucknow
West Bengal, India Consultant Internal Medicine Uttar Pradesh, India
Kokilaben Dhirubhai Ambani Pawan Poddar MD DM
Mohd. Talha Noor MD DM
Hospital, Mumbai Department of Cardiology
Department of Gastroenterology
Ex Associate Professor TN Medical
Postgraduate Institute of Medical Postgraduate Institute of Medical
College and BYL Nair Charitable
Education and Research Education and Research
Hospital, Mumbai
Chandigarh, India Chandigarh, India
Maharashtra, India
Nagaraja Rao Padaki MD DM R. Porkodi MD DM
Purvish M. Parikh MD DNB FICP PhD ECMO CPI MB
Chief of Hepatology and Nutrition Professor and Head
Medical Oncologist and Haematologist
Asian Institute of Gastroenterology, Hyderabad Department of Rheumatology
BSES GH Municipal Hospital, Mumbai
Andhra Pradesh, India Maharashtra, India Madras Medical College, Chennai
Tamil Nadu, India
Pramod Kumar Pal MD Rakesh Parikh MRCP FCPS PDCR
Additional Professor of Mental Health S. Prabhakar MD (Medicine) DM (Neurology)
Chief Consultant Diabetologist FAMS FIAN
and Neurosciences, NIMHANS, Bengaluru SK Soni Hospital and D Clinic, Jaipur
Karnataka, India Professor and Head
Rajasthan, India Department of Neurology
Tanvi Pal MD Kirti C. Patel MD (Mumbai) FRCP (UK) Postgraduate Institute of Medical
Consultant Paediatric Dermatologist Honorary Physician Education and Research
Delhi Dermatology Group, Kubba Clinic Bharatiya Arogya Nidhi Hospital Chandigarh, India
New Delhi, India Juhu and BSES Hospital, Mumbai
M.P. Ram Prabhu MD
Maharashtra, India
Aparna Palit MD Department of Medical Oncology
Associate Professor Kirti M. Patel MD Institute Rotary Cancer Hospital (IRCH)
Department of Dermatology, Venereology Professor of Medical Oncology All India Institute of Medical Sciences
and Leprosy BJ Medical College, Ahmedabad New Delhi, India
Sri BM Patil Medical College, Hospital and Dy Director(Medical) and Chief of
Research Centre, BLDE University, Bijapur Medical Oncology, Gujarat Cancer and Anupam Prakash MD (Medicine) PGCC (Hospital
Karnataka, India Research Institute, Ahmedabad Management) FICP
Gujarat, India Associate Professor of Medicine
Ashok Panagariya MD DM (Neurology) FRCP (UK) Lady Hardinge Medical College and
Professor and Head Lekha Adik Pathak Smt. Sucheta Kriplani Hospital
Department of Neurology Former Director, Professor and Head New Delhi, India
SMS Medical College, Jaipur Department of Cardiology
Rajasthan, India Grant Medical College & JJ Group of Hospitals Shruti Prem
Head of the Department of Cardiology Consultant Haematology
A. Pandey Nanavati Heart Institute, Mumbai Department of Medical Oncology
Postgraduate Department of Medicine Maharashtra, India Regional Cancer Centre, Thiruvanathapuram
SN Medical College and Hospital, Agra Kerala, India
Uttar Pradesh, India Nikhil Prakash Patil MS (Gen Surgery) MRCS (England)
Department of Cardiothoracic and Susanne A. Pulimood MD
Ramesh Balwant Pandit Vascular Surgery Department of Dermatology
Hon. Consultant GB Pant Hospital, Maulana Azad Venereology and Leprosy
New Bombay’s MGM Hospital Medical College Christian Medical College,Vellore
Fortis Hiranandani Hospital, Mumbai New Delhi, India Tamil Nadu, India
Maharashtra, India
Binoy J. Paul MD PhD DNB Ratna Dua Puri MD (Paeds) DM (Medical Genetics)
Ghan Shyam Pangtey MD Additional Professor Consultant Geneticist
Associate Professor Rheumatology Division Center of Medical Genetics
Department of Medicine Department of Medicine Sir Ganga Ram Hospital
LHMC and Associated Hospitals Medical College, Calicut New Delhi, India
New Delhi, India Kerala, India
Pendsey Sharad Purushottam MD (Medicine)
Gopi Krishna Panicker Apoorva Pauranik MD DM Dip Diabetology (Yugoslavia) MDDG (West Germany)
Manager-Research Associate Professor and Neurophysician Diabetes Clinic and Research Centre
Quintiles Cardiac Safety Services, Mumbai MGM Medical College, Indore ‘Shreeniwas’, opp Dhantoli Park, Nagpur
Maharashtra, India Madhya Pradesh, India Maharashtra, India xix
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D. Raghunadharao MD DM Prema Ramachandran K. Ravishankar MD

Head Director Consultant In-charge
Department of Medical Oncology Nutrition Foundation of India The Headache and Migraine Clinic
Nizam’s Institute of Medical Sciences,Hyderabad New Delhi, India Jaslok Hospital and Research Centre
Andhra Pradesh, India Lilavati Hospital and Research
Shaji V. Ramachandran MSc PhD Centre, Mumbai
M. Raghunath MSc PhD Professor of Haematology Maharashtra, India
Scientist F and Head Department of Haematology
Endocrinology, Instrumentation Christian Medical College and D. Raja Reddy FRCS (Edin) FRACS
and Isotope Divisions Hospital, Vellore Senior Consultant Neurosurgeon
National Institute of Nutrition, Hyderabad Tamil Nadu, India Apollo Hospital, Hyderabad
Andhra Pradesh, India Andhra Pradesh, India
B.S. Ramakrishna MD DM PhD FAMS
Abhay Narain Rai MD MRCP (UK) FRCP (Glasgow) Department of Gastrointestinal Sciences B.B. Rewari MD
Ex Professor and Head of Medicine and Principal Christian Medical College, Vellore Associate Professor
AN Magadh Medical College, Gaya Tamil Nadu, India Department of Medicine
Bihar, India PGIMER and Dr Ram Manohar
M. Ramam Lohia Hospital
Madhukar Rai Additional Professor New Delhi, India
Professor
Department of Dermatology and
Department of Medicine S.N.A. Rizvi MD FICP FISN FIAMS
Venereology
Institute of Medical Sciences Senior Consultant Physician and Nephrologist
All India Institute of Medical Sciences
Banaras Hindu University, Varanasi Apollo Hospital and Sanjeevan
New Delhi, India
Uttar Pradesh, India Medical Research Centre
B.S. Rama Murthy MD DMRD DNB New Delhi, India
Ramesh Roop Rai MD DM (Gastro)
Professor and Head Consultant Radiologist
Camilla Rodrigues MD
Department of Gastroenterology Srinivasa Ultrasound Scanning
Consultant Microbiologist
Fortis Hospital, Jaipur Centre, Bengaluru
PD Hinduja National Hospital and
Rajasthan, India Karnataka, India
Medical Research Centre, Mumbai
Bharath Rangarajan MD DM ECMO Maharashtra, India
Senthil Rajappa MD DNB DM
Head Medical Oncologist
Rakesh Roy MD (Pharmacology)
Department of Medical Oncology Mazumdar Shaw Cancer Center
Department of Palliative Care, Cancer
Indo-American Cancer Center Narayana Hrudayalaya, Bengaluru
Centre, Kolkata
Banjara Hills, Hyderabad Karnataka, India West Bengal, India
Andhra Pradesh, India
D. Rama Rao MD FICA FIMSA FICC FICP Priscilla Rupali MD DTM and H
C. Panchapakesa Rajendran MD DM Consultant Physician and Cardiologist Professor of Medicine
Professor and Head Karnataka, India Christian Medical College and Hospital
Department of Rheumatology Department of Medicine Unit 1 and
SRM Medical College, Potheri M. Hanumantha Rao
Professor and Head Infectious Diseases, Vellore
Tamil Nadu, India Tamil Nadu, India
Department of Anaesthesiology
G. Rajesh and Critical Care M. Sabir MD
Associate Professor Sri Venkateswara Institute of Medical Professor
Digestive Diseases Institute Sciences (SVIMS), Tirupati Department of Medicine MAMC
Amrita Institute of Medical Sciences (AIMS) Andhra Pradesh, India AGROHA, India
Ponekkara PO Kochi
Kerala, India Murlidhar S. Rao MD FACP FCCP FICP FICC FCSI B.K. Sahay MD FICP FAMS FACP
President and Senior Consultant Ex Professor and Head
S. Rajesh MD Dhanvantari Charitable Trust Department of Medicine
Department of Rheumatology Hospital, Gulbarga Osmania Medical College and
Madras Medical College, Chennai Karnataka, India General Hospital, Hyderabad
Tamil Nadu, India
Andhra Pradesh, India
U.R.K. Rao MD (Med)
S. Rajeswari MD DM Director Manisha Sahay MD DNB MAMS
Reader in Rheumatology
Sri Deepti Rheumatology Center, Hyderabad Professor and Head
Madras Medical College and
Andhra Pradesh, India Department of Nephrology
Govt. General Hospital, Chennai
Osmania Medical College and
Tamil Nadu, India G.K. Rath MD General Hospital, Hyderabad
Professor and Head Andhra Pradesh, India
Rajesh Rajput MD DM (Endocrinology) FICP FIACM FIAMSA
Department of Radiotherapy
Senior Professor and Head
and Chief Institute of Rotary Cancer Rakesh K. Sahay MD
Department of Medicine and
Hospital (IRCH) Professor of Endocrinology
Endocrinology (PGIMS), Rohtak
All India Institute of Medical Sciences Osmania Medical College, Hyderabad
Haryana, India
New Delhi, India Andhra Pradesh, India
A. Ramachandran MD PhD DSc MNAMS
FICP (London) FRCP (Edinburg) V. Ravi MD FAMS FASc Tapan Kumar Saikia MD
Chairman and Managing Director of India Professor and Head Head of Medical Oncology and
Diabetes Research Foundation and Department of Neurovirology Director of Research
Dr A Ramachandran’s Diabetes National Institute of Mental Health and Prince Aly Khan Hospital
Hospital, Chennai Neurosciences (NIMHANS), Bengaluru AGA Hall, NESBIT Road, Mumbai
Tamil Nadu, India Karnataka, India Maharashtra, India
xx
G.S. Sainani MD FRCP (Lond & Edin) V. Seshiah MD FRCP (G) DSc (Hony) Varun Shandal MD

Contributors
Hon FRCP PhD DSc Director Department of Nuclear Medicine
Director Dr V Seshiah Diabetes Research Institute,Chennai All India Institute of Medical Sciences
General Medicine Department Tamil Nadu, India New Delhi, India
Jaslok Hospital and Research
Centre, Mumbai K.K. Sethi MD DM FHRS FACC P.S. Shankar MD
Emeritus Professor of Medicine Director of Cardiology Emeritus Professor of Medicine
Grant Medical College & JJ Delhi Heart and Lung Institute Rajiv Gandhi University of Health Sciences
Hospital, Mumbai New Delhi, India Based at MR Medical College, Gulbarga
Maharashtra, India Karnataka, India
Nusrat Shafiq MD DM (Clinical Pharmacology)
R. Sajithkumar MD PhD Department of Pharmacology S.K. Shankar MD FAMS FNASc FIC Path
Chief, Infectious Diseases Postgraduate Institute of Medical Professor of Neuropathology
Govt. Medical College Hospital, Kottayam Education and Research National Institute of Mental Health
Kerala, India Chandigarh, India and Neurosciences, Bengaluru
Karnataka, India
Vinay Sakhuja MD DM Ashok Shah MD
Dean and Head of Nephrology Professor G. Shanmugasundar DM
Postgraduate Institute of Medical Department of Respiratory Medicine Department of Endocrinology
Education and Research Vallabhbhai Patel Chest Institute Postgraduate Institute of Medical
Chandigarh, India University of Delhi Education and Research
Delhi, India Chandigarh, India
A.M. Samuel MD (Ped) DCH FAMS
Ex Director Bio Medical Group Hardik Shah Atul Sharma MD DM
Bhabha Atomic Research Centre, Mumbai Hon. Assistant Professor Additional Professor
Maharashtra, India Department of Nephrology Department of Medical Oncology
Bombay Hospital Institute of Medical Institute of Rotary Cancer Hospital (IRCH)
Rakesh Sanghadiya Sciences, Mumbai All India Institute of Medical Sciences
Shri Krishna Prasad Psychiatric Nursing Maharashtra, India New Delhi, India
Home and Research Center, Ahmedabad
Gujarat, India Nalini S. Shah Bhawna Sharma MD DM (Neurology)
Professor and Head Associate Professor
Vivek Anand Saraswat MD DM Department of Endocrinology Department of Neurology
Department of Gastroenterology Seth GS Medical College and KEM SMS Medical College, Jaipur
Sanjay Gandhi Postgraduate Institute Hospital, Mumbai Rajasthan, India
of Medical Sciences, Lucknow Maharashtra, India
Uttar Pradesh, India M.P. Sharma MD DM FAMS FICP FIMSA FACG
Pankaj Manubhai Shah MD Department of Gastroenterology
Kavitha Saravu MD DNB Medical Oncologist Rockland Hospital
Associate Professor Director, Gujarat Cancer and Research New Delhi, India
Department of Medicine Institute
Kasturba Medical College Civil Hospital Campus, Ahmedabad Navneet Sharma MD MNAMS
Manipal University Gujarat, India Additional Professor, Internal Medicine
Karnataka, India Postgraduate Institute of Medical
Samir R. Shah MD DM
Rajiv Sarin Education and Research
Consultant Gastroenterologist
Professor In-Charge Chandigarh, India
Jaslok and Breach Candy Hospital, Mumbai
Cancer Genetics Unit, Advanced Centre for Maharashtra, India Raju Sharma MD MNAMS
Treatment Research and Education in Cancer Professor
Tata Memorial Centre, Navi Mumbai Sharad Shah MD MRCP RCPS MRCP (Ed)
Hon. Gastroenterologist Department of Radiodiagnosis
Maharashtra, India All India Institute of Medical Sciences
Jaslok Hospital Mumbai
Anurag Saxena MD (Medicine) FICP Maharashtra, India New Delhi, India
Senior Consultant Physician
Siddharth N. Shah MD FICP FACP (Hon) FRCP (Edin) Sangeeta Sharma
Fortis Jessa Ram Hospital
Postgraduate Teacher in Diabetes Professor and Head
New Delhi, India
University of Mumbai Department of Neuropsychopharmacology
Renu Saxena MD Consulting Physician and Diabetologist Institute of Human Behavior and
Professor and Head SL Raheja Hospital and All India Institute Allied Sciences
Department of Haematology of Diabetes, Saifee Hospital New Delhi, India
All India Institute of Medical Sciences Bhatia Hospital, Sir Hurkisondas
New Delhi, India Sanjiv Sharma MD (Radiology)
N Hospital, Mumbai
Professor and Head
Maharashtra, India
Sumit Sengupta Department of Cardiac Radiology
Consultant, Chest Physician Viral Shah All India Institute of Medical Sciences
AMRI Hospital, Kolkata Department of Endocrinology New Delhi, India
West Bengal, India Postgraduate Institute of Medical
Education and Research Surendra K. Sharma MD PhD
M.S. Seshadri Chandigarh, India Professor and Head
Professor and Head Department of Medicine
Department of Endocrinology Shalimar DM Chief, Division of Pulmonary, Critical Care
Diabetes and Metabolism Department of Gastroenterology and Sleep Medicine
CMC Hospital, Vellore All India Institute of Medical Sciences All India Institute of Medical Sciences
Tamil Nadu, India New Delhi, India New Delhi, India
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Vinod K. Sharma MD FAMS Navneet Singh MD DM MAMS B.S. Singhal MD FRCP (London) FRCP (Edin) FAMS
Professor and Head Assistant Professor Professor and Head
Department of Dermatology and Department of Pulmonary Medicine Department of Neurology
Venereology Postgraduate Institute of Medical Education Bombay Hospital, Mumbai
All India Institute of Medical Sciences and Research Maharashtra, India
New Delhi, India Chandigarh, India
M.K. Singhi MD
Ashit Sheth MD DPM N.P. Singh MD FICP MNAMS FINSA Professor and Head
Consulting Psychiatrist Director Professor of Medicine Department of Skin, STD and Leprosy
Bombay Hospital, Mumbai Maulana Azad Medical College and Dr SN Medical College, Jodhpur
Maharashtra, India Associated, Lok Nayak Hospital Rajasthan, India
New Delhi, India
A. Shobhana MD IDCC Rajiv Singla MD DNB MNAMS
Consultant Raminder Singh MD Department of Medicine
Critical Care and Stroke Medicine Professor of Medicine and Chief of Maulana Azad Medical College
Institute of Neurosciences, Kolkata Geriatric Services New Delhi, India
West Bengal, India Seth GS Medical College and
KEM Hospital, Mumbai Rupak Singla MD (TB and Chest Diseases)
Garima Shukla Maharashtra, India DNB (Respiratory Medicine)
Associate Professor Head, Department of Tuberculosis
Department of Neurology Sandeep Singh MD DM and Respiratory Diseases
Neurosciences Centre Additional Professor (Cardiology) LRS Institute of Tuberculosis
All India Institute of Medical Sciences All India Institute of Medical Sciences and Respiratory Diseases
New Delhi, India New Delhi, India New Delhi, India
Jamshaid A. Siddiqui S.K. Singh Sumeet Singla MD DNB MNAMS
Department of Transplant Immunology Department of Endocrinology and Metabolism Consultant Physician
and Immunogenetics Institute of Medical Sciences Air India
All India Institute of Medical Sciences Banaras Hindu University, Varanasi New Delhi, India
New Delhi, India Uttar Pradesh, India
Sanjeev Sinha MD
R.K. Singal MD FRCP FICP FACP Sumit Singh MD DM (Neurology) Associate Professor
Senior Consultant and Head Head of Neuromuscular Disorders Department of Medicine
Department of Medicine Institute of Neurosciences All India Institute of Medical Sciences
Dr BL Kapur Memorial Hospital Medanta – The Medicity, Gurgaon New Delhi, India
New Delhi, India Haryana, India
Sanjib Sinha MD DM
Ajeet Singh Surinder Singh MD Additional Professor of Neurology
Medical Officer Professor of Anaesthesia National Institute of Mental Health
Indira Gandhi Medical College, Shimla and Neurosciences, Bengaluru
Allergy and Pulmonary Division
Himachal Pradesh, India Karnataka, India
Department of Medicine
SMS Medical College, Jaipur Surjit Singh MD
Rajasthan, India Pradyot Sinhamahapatra
Professor of Paediatrics Assistant Professor
Paediatric Allergy Immunology Unit
A.K. Singh MS Mch (Neurosurgery) Department of Rheumatology
Advanced Paediatrics Centre
Executive Director Institute of Postgraduate Medical
Postgraduate Institute of Medical
Department of Neurosciences Education and Research, Kolkata
Education and Research
Fortis Hospital, Noida and Vasant Kunj West Bengal, India
Chandigarh, India
New Delhi, India
C. Snehalatha MSc DPhil DSc
Surjit Singh
Daljit Singh Head of the Department of Biochemistry
Professor
Professor of Neuro Surgery Research, Director of India Diabetes
Department of Internal Medicine
GB Pant Hospital Research Foundation and
Postgraduate Institute of Medical
New Delhi, India Education and Research Dr A Ramachandran’s
Chandigarh, India Diabetes Hospital, Chennai
Guneet Singh Tamil Nadu, India
Consultant Intensivist Virendra Singh
Indraprastha Apollo Hospitals Professor Rajeev Soman MD
New Delhi, India Allergy and Pulmonary Division Consultant Physician
Department of Medicine PD Hinduja Hospital, Mumbai
Gurmohan Singh DNBE (Derm and Ven), Maharashtra, India
Dip GUM (UK)
SMS Medical College, Jaipur
Rajasthan, India Ajit Sood MD (Medicine) DM (Gastro)
Consultant Dermatologist and Member
Advisory Board Vivek Pal Singh Professor and Head
International Skincare Nursing Group Department of Medicine Department of Gastroenterology
The Skin Institute, Varanasi Postgraduate Institute of Medical Dayanand Medical College and
Uttar Pradesh, India Education and Research Hospital, Ludhiana
Dr RML Hospital Punjab, India
Inderpaul Singh MD DNB
New Delhi, India Rita Sood MD
Department of Pulmonary
and Critical Care Medicine Yudh Dev Singh MD FIACM DIT Professor
Pt BDS, PGIMS, Pt BDS University of Health Professor (Internal Medicine) Department of Medicine
Sciences, Rohtak SKN Medical College and General Hospital,Pune All India Institute of Medical Sciences
xxii Haryana, India Maharashtra, India New Delhi, India
 K.K. Talwar MD DM R. Thara MD

Contributors
D. Sreeramulu MSc PhD
Endocrinology and Metabolism Division Director, Professor and Head Director
National Institute of Nutrition Department of Cardiology Schizophrenia Research Foundation, Chennai
Indian Council of Medical Postgraduate Institute of Medical Tamil Nadu, India
Research, Hyderabad Education and Research
Andhra Pradesh, India Chandigarh, India Urmilla Thatte MD
Professor and Head
G.R. Sridhar MD DM A.B. Taly MD DM Department of Clinical Pharmacology
Director Professor of Neurology TN Medical College and BYL Nair Hospital,Mumbai
Endocrine and Diabetes Centre,Visakhapatnam Department of Neurology Maharashtra, India
Adjunct Professor of Bioinformatics National Institute of Mental Health
and Neurosciences, Bengaluru Nihal Thomas MD MNAMS DNB (Endo)
Andhra University College of Engineering
FRACP (Endo) FRCP (Edin)
Andhra Pradesh, India Karnataka, India
Professor in Endocrinology
M.V. Padma Srivastava MD DM FAMS Nikhil Tandon MD Diabetes and Metabolism
Professor Professor of Endocrinology Christian Medical College, Vellore
Department of Neurology All India Institute of Medical Sciences Tamil Nadu, India
All India Institute of Medical Sciences New Delhi, India
Sanjeev V. Thomas MD DM
New Delhi, India Professor of Neurology
P.N.Tandon MD FRCS DSc (hc) FAMS FNASc FASC FTWAS
D.K.S. Subrahmanyam MD Consultant Neurosurgeon Sree Chitra Tirunal Institute for Medical
Additional Professor Metro Hospital Sciences and Technology,Thiruvananthapuram
Department of Neuro Surgery Kerala, India
Department of Medicine, JIPMER
Puducherry, India New Delhi, India Anil Kumar Tripathi
Rakesh Tandon MD PhD FRCP (Edin) FAMS FICP FAGA Professor
A.P. Sugunan
Head, Department of Gastroenterology Department of Medicine Nodal Officer
Scientist ‘E’
Pushpawati Singhania Research Institute (Art centre)
Regional Medical Research Chhatrapati Sahuji Maharaj Medical
Centre (ICMR), Port Blair for Liver, Renal and Digestive Diseases
New Delhi, India University, Lucknow
Andaman and Nicobar Islands, India Uttar Pradesh, India
T.K. Suma Shruti M. Tandan MD FNB (Critical Care)
J.K.Trivedi MD MRC Psych (UK) FAPA (USA) FAMS (India)
Additional Professor Intensivist
Professor
Department of Medicine Jaslok Hospital and Research
Department of Psychiatry
Govt TD Medical College, Vandanam Centre, Mumbai
Chhatrapati Shahuji Maharaj Medical University
Kerala, India Maharashtra, India
(Formerly KG Medical University), Lucknow
Sunil Taneja Uttar Pradesh, India
Jamshed D. Sunavala MD FCCP (USA) FICP FISE
Head of Department Department of Hepatology Pankaj Tyagi MD DM (Gastroenterology)
Critical Care Medicine Postgraduate Institute of Medical Consultant Gastroenterology
Jaslok Hospital and Research Centre Education and Research Sir Ganga Ram Hospital
Hon Physician and Intensivist Chandigarh, India New Delhi, India
Breach Candy Hospital, Mumbai
Uma Tekur MD MNAMS Sanjay Tyagi MD DM
Hon Physician, BD Petit Parsee
Director, Professor and Head Director, Professor and Head
General Hospital, Mumbai Department of Pharmacology
Maharashtra, India Department of Cardiology
Maulana Azad Medical College GB Pant Hospital
Shyam Sundar MD FRCP FAMS FNA FSc FNASc New Delhi, India Maulana Azad Medical College
Professor of Medicine New Delhi, India
Kamlesh Tewary MD FICP FIAMS
Institute of Medical Sciences Professor and Head Seema Tyagi
Banaras Hindu University, Varanasi Department of Medicine Associate Professor
Uttar Pradesh, India SK Medical College, Muzaffarpur Department of Haematology
Bihar, India All India Institute of Medical Sciences
Dipika Sur MD
Deputy Director New Delhi, India
Ashish K. Thakur
National Institute of Cholera and Consultant Interventional Cardiologist Vrajesh Udani MD
Enteric Diseases, Kolkata The Mid Yorkshire NHS Trust and Consultant – Child Neurology and Epilepsy
West Bengal, India Yorkshire Heart Centre Diplomate of the American Board of
England, UK Neurology with Special Competence in
Vikas Suri MD
Child Neurology
Assistant Professor B.B. Thakur MD FICP FIAMS FIACM FISPA PD Hinduja National Hospital and Medical
Internal Medicine Consultant Physician Research Centre, Mumbai
Postgraduate Institute of Medical Cardio-Diabetologist and 4 Maharashtra,India
Education and Research Juran Chapra, Muzaffarpur
Chandigarh, India Bihar, India Farokh E. Udwadia MD FCPS FRCP (Edinburgh)
FRCP (London) Master FCCP FACP FAMS DSc
Rupjyoti Talukdar MD Devinder Mohan Thappa MD DHA MNAMS Consultant Physician and Physician
Consultant Professor and Head In-Charge of ICU
Pancreatologist and Gastroenterologist Department of Dermatology and STD Breach Candy Hospital, Mumbai
(Fellowship, Mayo Clinic, Rochester, USA) Jawaharlal Institute of Postgraduate Medical Consultant Physician, Parsee
NEMCARE Hospital, Guwahati Education and Research (JIPMER) General Hospital, Mumbai
Assam, India Puducherry, India Maharashtra, India
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Rajesh Upadhyay MD MRCP (UK) FRCP (Glasgow) FICP Shailendra P. Verma Gurpreet Singh Wander MD (PGI) DM (Cardio)
Senior Consultant and Chairman Lecturer Professor and Head of Cardiology
Department of Gastroenterology Department of Medicine, CSMMU, Lucknow Dayanand Medical College and Hospital
Jaipur Golden Hospital Uttar Pradesh, India Unit Hero DMC Heart Institute, Ludhiana
New Delhi, India Punjab, India
Deepti Vibha
Vihang N. Vahia MD DPM MAPA Department of Neurology Vidhyadhar Watve MD DPM FIPS
Honorary Professor of Psychiatry Institute of Liver and Biliary Sciences Poona Hospital and Research
Cooper Hospital and GS Medical College New Delhi, India Centre, Pune
Visiting Psychiatrist: Breach Candy Hospital Maharashtra, India
Lilavati Hospital and Sir Hurkison Das J.C. Vij MD (Medicine) DM (Gastroenterology)
Hospital, Mumbai Senior Consultant Gastroenterology Naveet Wig
Maharashtra, India and Endoscopy Additional Professor
Pushpawati Singhania Research Institute Department of Medicine
P.P. Varma MD DNB DM (Nephrology) MNAMS FICP FISN for Liver, Renal and Digestive Diseases All India Institute of Medical Sciences
Army Hospital (R and R) New Delhi, India New Delhi, India
New Delhi, India
V.K. Vijayan MD (Med) PhD DSc FAMS Pushpa Yadav MD
Subhash Varma MD FICP Director Consultant in Medicine and
Professor and Head Vallabhbhai Patel Chest Institute Associate Professor
Internal Medicine New Delhi, India Dr. Ram Manohar Lohia Hospital
Postgraduate Institute of Medical New Delhi, India
Education and Research R. Kasi Visweswaran MD DM
Chandigarh, India Senior Consultant Nephrology M.E. Yeolekar MD (Medicine) MNAMS FICP
Ananthapuri Hospital and Director
Varsha MSc PhD RD CNIS Research Institute, Thiruvananthapuram NEIGRIHMS, Shillong
Founder Chair Kerala, India Meghalaya, India
Indian Institute of Nutritional Sciences
Amit Vora MD DM DNB Sanjay Zachariah MD (Medicine)
B. Vengamma DM (Neuro) Glenmark Cardiac Centre, Mumbai Assistant Professor
Director and Dean Maharashtra, India Department of Medicine
Professor and Head SUT Academy of Medical Sciences
Department of Neurology R.S. Wadia MD FIAN FICP Vencode, Vattapara, Thiruvananthapuram
Sri Venkateswara Institute of Medical Department of Neurology Kerala, India
Sciences, Tirupati Ruby Hall Clinic, Pune
Andhra Pradesh, India Maharashtra, India Abdul Hamid Zargar
Professor and Head
S.Venkataraman MD DM (Neurology) FICA FICP FIAN U.L. Wagholikar Department of Endocrinology
Consultant Physician and Neurologist Consultant Histopathologist, India Director, Sher-i-Kashmir Institute of
Mata Chanan Devi Hospital Medical Sciences, Srinagar
Rama Walia
New Delhi, India Jammu and Kashmir, India
Assistant Professor
S.K. Verma Department of Endocrinology
Professor Postgraduate Institute of Medical
Cancer Research Institute, HIHT University Education and Research
Uttarakhand, India Chandigarh, India

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CONTENTS

SECTION 1: INTRODUCTION
1. The Practice of Medicine 2
Yash Pal Munjal

SECTION 2: CLINICAL APPROACH TO KEY MANIFESTATIONS

2.1 Pain—Mechanisms and Management 10
D. Rama Rao, Niranjan P. Moulik
2.2 Headache 12
K. Ravishankar
2.3 Chest Pain 16
Sanjay Tyagi, Amit Mittal
2.4 Acute Abdomen—Non-Surgical Causes 20
Sumeet Singla, A.K. Agarwal
2.5 Cough 25
Suman Kirti
2.6 Haemoptysis 29
Randeep Guleria, Jaya Kumar
2.7 Jaundice 32
Aparna Agrawal
2.8 Upper Gastrointestinal Bleeding 39
J.C. Vij
2.9 Fever of Unknown Origin 42
Priscilla Rupali
2.10 Generalised Lymphadenopathy 47
S.K. Verma
2.11 Dizziness and Vertigo 49
M. Maiya
2.12 Syncope 53
Pushpa Yadav, Vivek Arya
2.13 Coma 57
B. Vengamma

SECTION 3: DIAGNOSTIC IMAGING

3.1 Conventional Radiology 64
Ashu Seith Bhalla, Ankur Gadodia
3.2 Ultrasound in Medicine 78
B.S. Rama Murthy
3.3 Computed Tomography 84
Bhavin Jankharia, Nishigandha Burute
3.4 MRI in Medicine 91
Raju Sharma, Ankur Gadodia
3.5 Nuclear Imaging 100
B.R. Mittal
3.6 Positron Emission Tomography 113
Rakesh Kumar, Varun Shandal
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SECTION 4: CLINICAL PHARMACOLOGY

4.1 Introduction and Scope of Clinical Pharmacology 120
Ranjit Roy Choudhury, Urmilla Thatte
4.2 Rational Use of Drugs 123
Sangeeta Sharma
4.3 Adverse Drug Reactions and Pharmacovigilance 125
M.C. Gupta
4.4 Prescribing in Special Situations 128
Uma Tekur
4.5 New Drug Development 133
Sadhna Joglekar
4.6 Pharmacoeconomics 135
Gurudas Khilnani

SECTION 5: IMMUNOLOGY
5.1 An Overview of the Immune System 138
Sita Naik
5.2 General Concepts of Immunoinflammatory Disorders 146
Ramnath Misra
5.3 Immunology of Infectious Diseases 149
Sita Naik
5.4 Primary Immunodeficiency Disorders—A Clinical Approach 151
Surjit Singh
5.5 Laboratory Investigations in Immune-Mediated Diseases 155
Amita Aggarwal
5.6 Pharmacological Manipulation of the Immune System 159
Mitali Chatterjee
5.7 Immunology of Organ and Haematopoietic Stem Cell Transplantation 164
Narinder K. Mehra, Jamshaid A. Siddiqui

SECTION 6: MEDICAL GENETICS

6.1 Introduction to Medical Genetics 170
Shyam Swarup Agarwal
6.2 Mendel and Beyond 173
Ratna Dua Puri
6.3 Clinical and Molecular Cytogenetics 180
Ashutosh Halder
6.4 Genetic Tests 189
Ashwin Dalal
6.5 Inborn Errors of Metabolism 193
Madhulika Kabra
6.6 Molecular Genetics, Human Genome Project and Genomic Medicine 201
Girisha K.M.
6.7 Gene Therapy 206
Rita Mulherkar
6.8 Genetic Counselling and Prenatal Diagnosis 209
Shubha R. Phadke
6.9 Pharmacogenomics and Personalised Medicine 215
C. Adithan
6.10 Cancer Genetics 217
Rajiv Sarin

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Contributors
SECTION 7: CRITICAL CARE MEDICINE
7.1 Basic Considerations in Critical Care 224
R.K. Mani
7.2 Monitoring of Critically Ill Patients 227
M. Hanumantha Rao
7.3 Fluid and Electrolyte Balance in Health and Disease 232
Sanjay Jain
7.4 Acid-Base Disorders 239
Alladi Mohan, Surendra K. Sharma
7.5 Enteral and Parenteral Nutrition in Critically Ill Patients 246
Shilpa S. Joshi
7.6 Acute Respiratory Failure 251
Ashit M. Bhagwati
7.7 Sepsis and Acute Respiratory Distress Syndrome 256
Alladi Mohan, Surendra K. Sharma
7.8 Mechanical Ventilation 263
Surender Kashyap, Surinder Singh
7.9 Non-Invasive Ventilation 271
Dhruva Chaudhry, Inderpaul Singh
7.10 Hypotension and Shock 277
Anil Dhall, Sanjat S. Chiwane
7.11 Cardiopulmonary Resuscitation 282
Ashit M. Bhagwati
7.12 Brain Death and Support of the Brain-Dead Organ Donor 289
Rajesh Chawla, Guneet Singh

SECTION 8: BONE DISORDERS

8.1 Bone and Mineral Metabolism in Health and Disease 294
Deepak Khandelwal, Ravinder Goswami
8.2 Investigations and Diagnosis of Bone Disorders 299
Sukumar Mukherjee
8.3 Rickets and Osteomalacia 305
Bindu Kulshreshtha, Sachin K. Jain
8.4 Osteoporosis 309
S.N.A. Rizvi
8.5 Developmental Disorders of Bone 313
Rakesh K. Sahay
8.6 Miscellaneous Bone Disorders 316
C.V. Harinarayan

SECTION 9: DIABETES MELLITUS

9.1 Epidemiology and Basic Considerations of Diabetes 321
A. Ramachandran, C. Snehalatha
9.2 Pathogenesis of Type 1 Diabetes Mellitus 324
V. Mohan, Rakesh Parikh
9.3 Pathogenesis of Type 2 Diabetes Mellitus 327
Hemraj B. Chandalia
9.4 Clinical Features and Diagnosis of Diabetes Mellitus 331
D. Maji
9.5 Lifestyle Modifications in Management of Diabetes 336
B.K. Sahay

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9.6 Oral Anti-Diabetic Drugs 339

Anil Bhansali, Viral Shah
9.7 Insulin Therapy 343
Rama Walia
9.8 Newer Modalities of Treatment in Type 2 Diabetes Mellitus 347
Anil Bhansali, G. Shanmugasundar
9.9 In-Hospital Management of Diabetes Mellitus 350
Nihal Thomas, Rahul Ramnik Baxi
9.10 Hypoglycaemia 354
Siddharth N. Shah
9.11 Diabetic Ketoacidosis, Hyperosmolar Hyperglycaemic State and Lactic Acidosis 359
Rajesh Rajput
9.12 Infections in Diabetes Mellitus 364
Samar Banerjee
9.13 Macrovascular Complications of Diabetes 368
Murlidhar S. Rao
9.14 Microvascular Diseases—Pathogenesis of Chronic Complications 372
Suman Kirti
9.15 Diabetes and Kidney Disease 375
Jamal Ahmad
9.16 Diabetic Retinopathy 377
Amod Gupta, Reema Bansal
9.17 Diabetic Neuropathy 382
Manish Modi
9.18 Sexual Dysfunction in Diabetes 385
Shashank R. Joshi
9.19 The Diabetic Foot 387
Pendsey Sharad Purushottam
9.20 Diabetes and Pregnancy 390
V. Seshiah
9.21 Prevention of Diabetes Mellitus 393
Yash Pal Munjal

SECTION 10: ENDOCRINOLOGY

10.1 Basic Considerations of Endocrinology 398
Ashok Kumar Das
10.2 Endocrine Disorders—A Clinical Approach 403
M.S. Seshadri
10.3 Disorders of Hypothalamus and Pineal Gland 407
Abdul Hamid Zargar, Bashir Ahmad Laway
10.4 Disorders of Anterior Pituitary 410
R.V. Jayakumar
10.5 Disorders of Posterior Pituitary 417
G.R. Sridhar
10.6 Disorders of Thyroid Glands 419
Nikhil Tandon, Gunjan Garg
10.7 Disorders of Parathyroid Glands 430
Ambrish Mithal, Beena Bansal
10.8 Disorders of Adrenal Glands 433
Eesh Bhatia, Vijayalakshmi Bhatia
10.9 Disorders of Puberty 442
A.C. Ammini
10.10 Disorders of Growth and Development 446
Nalini S. Shah
10.11. Disorders of Gonads 452
Shashank R. Joshi
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Contributors
SECTION 11: DERMATOLOGY
11.1 Introduction and Principles of Diagnosis in Dermatology 462
Vibhu Mendiratta
11.2 Cutaneous Infections 470
Vineet Kaur, Gurmohan Singh
11.3 Infestations and Insect Bites 475
Devinder Mohan Thappa, Laxmisha Chandrashekar
11.4 Eczemas 480
Ashok Kumar Bajaj
11.5 Drug Reactions 487
M. Ramam
11.6 Abnormal Vascular Responses 491
A.K. Jaiswal, T.S. Nagesh
11.7 Papulosquamous Disorders 494
K. Pavithran
11.8 Autoimmune Bullous Disorders 498
K.K. Raja Babu
11.9 Disorders of Pigmentation 501
Bhushan Kumar
11.10 Disorders of Skin Appendages 507
Raj Kubba, Tanvi Pal
11.11 Cutaneous Responses to Physical Factors 512
S. Criton
11.12 Genodermatoses 515
Vibhu Mendiratta
11.13 Skin in Connective Tissue Diseases 520
Sandipan Dhar
11.14 Skin in Systemic Diseases 526
Uday Khopkar
11.15 Leprosy 534
B.K. Girdhar
11.16 Sexually Transmitted Infections 541
Vinod K. Sharma, Naresh Jain
11.17 Premalignant Conditions and Malignant Tumours of the Skin 546
Arun C. Inamadar, Aparna Palit
11.18 Therapy of Dermatological Diseases 549
M.K. Singhi

SECTION 12: CARDIOLOGY

12.1 Basic Considerations in Cardiology 557
Upendra Kaul, Aijaz H. Mansoor
12.2 Cardiovascular Diseases—A Clinical Approach 561
G.S. Sainani
12.3 Electrocardiology 570
M.J. Gandhi
12.4 Exercise Testing 580
Yash Pal Munjal
12.5 Echocardiography 585
Satish Kumar Parashar
12.6 Cardiac Imaging 595
Priya Jagia, Sanjiv Sharma
12.7 Nuclear Cardiology 605
Vikram R. Lele, Parag Aland
12.8 Cardiac Catheterisation and Angiocardiography 610
Lekha Adik Pathak, N.O. Bansal xxix
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12.9 Pharmacotherapy of Cardiovascular Disorders 615

J.C. Mohan, Vipul Mohan
12.10 Heart Failure 621
Donald Kikta, Veronica Franco
12.11 Heart Failure Management 624
Veronica Franco, Ragavendra Baliga
12.12 Acute Rheumatic Fever 629
R. Krishna Kumar
12.13 Valvular Heart Disease (I) 637
C.N. Manjunath
12.14 Valvular Heart Disease (II) 643
V.K. Bahl, Ishwar Chandra Malav
12.15 Infective Endocarditis 652
Shyam S. Kothari
12.16 Atherosclerosis 661
K.K. Sethi, S. Lahiri
12.17 Ischaemic Heart Disease 666
Inder S. Anand, Shibba Takkar Chhabra
12.18 Acute Coronary Syndrome 673
Gurpreet Singh Wander, Naveen Kumar Gupta
12.19 Acute Myocardial Infarction 677
Gurpreet Singh Wander, Naved Aslam
12.20 Hypertension 685
M. Paul Anand
12.21 Management of Hypertension 691
Sandhya Kamath
12.22 Secondary Hypertension 698
B.B. Thakur, Arohi Kumar
12.23 Bradyarrythmias 702
Yash Y. Lokhandwala, Gopi Krishna Panicker
12.24 Tachyarrhythmias 707
Amit Vora
12.25 Sudden Cardiac Death 713
Ashish K. Thakur
12.26 Congenital Heart Disease 716
Sunita Maheshwari
12.27 Heart in Systemic Disease 724
Aspi R. Billimoria
12.28 Disorders of Myocardium 728
K.K. Talwar, Pawan Poddar
12.29 Diseases of the Pericardium 737
Sanjay Tyagi, Amit Mittal
12.30 Surgical Management of Heart Disease 746
Muhammad Abid Geelani, Nikhil Prakash Patil
12.31 Diseases of the Aorta 750
Manotosh Panja
12.32 Vascular Disorders of the Extremities 757
Gurpreet Singh Wander, Bishav Mohan
12.33 Pregnancy and Heart Disease 764
Amal Kumar Banerjee

SECTION 13: GASTROENTEROLOGY

13.1 Clinical Approach—Gastrointestinal Disorders 770
A.C. Anand
13.2 Investigations—Gastrointestinal Disorders 774
Ashok Chacko
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Contents
Contributors
Gourdas Choudhuri
13.4 Diarrhoea and Malabsorption 782
B.S. Ramakrishna
13.5 Constipation—Diagnosis and Management 787
Uday Chand Ghoshal
13.6 Gastrointestinal Bleeding 791
Rakesh Kochhar, Mohd. Talha Noor
13.7 Oesophageal Disorders 799
Shobna J. Bhatia, Praveen Mathew
13.8 Diseases of the Stomach and Duodenum 806
Pankaj Dhawan
13.9 Diseases of the Pancreas 813
V. Balakrishnan, G. Rajesh
13.10 Functional Gastrointestinal Disorders 819
Philip Abraham
13.11 Abdominal Tuberculosis 823
Govind K. Makharia
13.12 Inflammatory Bowel Disease 829
Ajit Sood, Vandana Midha
13.13 Ischaemic Bowel Disorders 834
Deepak Kumar Bhasin
13.14 Gastrointestinal Symptoms in Systemic Diseases 837
Rakesh Tandon, Sudeep Khanna

SECTION 14: HEPATOLOGY

14.1 Basic Considerations of Hepatobiliary Disorders 842
Vivek Anand Saraswat
14.2 Hepatobiliary Disorders—A Clinical Approach 846
Nagaraja Rao Padaki
14.3 Hepatobiliary Disorders—Investigations 851
Radha K. Dhiman
14.4 Hepatobiliary Disorders—Imaging 855
Shrinivas B. Desai
14.5 Acute Viral Hepatitis 862
Deepak Amarapurkar
14.6 Chronic Viral Hepatitis 867
Rajesh Upadhyay, Nitin Gupta
14.7 Chronic Non-Viral Hepatitis 870
C.E. Eapen
14.8 Alcoholic Liver Disease 873
Nitin Gupta, Rajesh Upadhyay
14.9 Cirrhosis of the Liver 878
Philip Abraham
14.10 Extra-Hepatic Portal Venous Obstruction 883
Sharad Shah
14.11 Non-Alcoholic Fatty Liver Disease 885
Yogesh K. Chawla, Sunil Taneja
14.12 Acute Liver Failure 888
S.K. Acharya, Shalimar
14.13 Inherited Metabolic Disorders of the Liver 892
P. Advaitham
14.14 Parasitic Diseases of the Liver 895
Samir R. Shah
14.15 Toxic and Drug Induced Liver Injury 898
Abraham Koshy
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14.16 Liver Transplantation 899

Subash Gupta, Ajay Kumar
14.17 Pregnancy and Liver Disease 901
Ramesh Roop Rai
14.18 Liver in Systemic Disease 905
Premashis Kar, Rajiv Singla
14.19 Tumours of the Liver 908
Kaushal Madan, Pankaj Tyagi
14.20 Diseases of Gall Bladder and Biliary Tract 911
Rakesh Tandon

SECTION 15: HAEMATOLOGY

15.1 Haematopoiesis 916
Shaji V. Ramachandran, Vikram Mathews
15.2 Anaemia—A Clinical Approach 922
Renu Saxena, M. Mahapatra
15.3 Splenomegaly—A Clinical Approach 926
Lalit Kumar, Anuj Kumar Bansal
15.4 Iron Deficiency Anaemia 928
Subhash Varma
15.5 Megaloblastic Anaemia 933
Tarun Kumar Dutta
15.6 Hereditary Haemolytic Anaemia 938
M.B. Agarwal
15.7 Acquired Haemolytic Anaemia 947
Farah F. Jijina
15.8 Aplastic Anaemia 952
Dharma R. Choudhary, Tuphan Kanti Dolai
15.9 Acute Leukaemia 956
S.H. Advani
15.10 Chronic Myeloid Leukaemia and Other Myeloproliferative Disorders 963
Tapan Kumar Saikia
15.11 Myelodysplastic Syndromes 966
Rajat Kumar, Seema Tyagi
15.12 Chronic Lymphocytic Leukaemia 970
M. Mahapatra, Renu Saxena
15.13 Lymphoid Neoplasms 974
Bharath Rangarajan, Purvish M. Parikh
15.14 Plasma Cell Dyscrasias 979
Pankaj Manubhai Shah
15.15 Bleeding Disorders 984
Kanjaksha Ghosh
15.16 Platelet Disorders 987
S.K. Bichile
15.17 Disorders of Coagulation 990
Jina Bhattacharyya
15.18 Hypercoagulable Disorders 996
Mammen Chandy
15.19 Transfusion Medicine 1000
Neelam Marwaha
15.20 Haematopoietic Stem Cell Transplantation 1004
Velu Nair

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Contributors
SECTION 16: HIV AND AIDS
16.1 Epidemiology 1012
O.C. Abraham, Susanne A. Pulimood
16.2 Virology, Immunology and Diagnosis 1014
V. Ravi, Anita Desai
16.3 Pathophysiology and Clinical Features 1017
U.L. Wagholikar
16.4 Antiretroviral Therapy 1023
B.B. Rewari, Sanjeev Sinha
16.5 Drug Resistance 1026
Alaka Deshpande
16.6 Non-Opportunistic Infections 1029
Anil Kumar Tripathi, Shailendra P. Verma
16.7 Opportunistic Infections 1032
Natasha Edwin, Dilip Mathai
16.8 Non-Pharmacologic Interventions and Prevention 1036
R. Sajithkumar

SECTION 17: INFECTIOUS DISEASES

A. General Considerations
17.1 Basic Considerations of Infections 1042
Subhasish Kamal Guha
17.2 Laboratory Diagnosis of Infections 1044
Camilla Rodrigues
17.3 Syndromic Approach to Infectious Diseases 1048
Rajeev Soman
17.4 Anti-Microbial Therapy—An Overview 1051
Jagriti Bhatia, Dharamvir Singh Arya
17.5 Infections in the Immunocompromised Host 1058
Ghan Shyam Pangtey, Anupam Prakash
17.6 Hospital Acquired Infections/Nosocomial Infections 1060
A. Shobhana
17.7 Prevention of Health Care Associated Infections 1063
B.B. Rewari, Usha K. Baveja
17.8 Hospital Infection Control 1067
Rohini Kelkar
B. Bacterial Infections
17.9 Staphylococcal Infections 1069
Rita Sood
17.10 Streptococcal Infections 1072
Abhay Narain Rai
17.11 Pneumococcal Infections 1074
D.P. Bhadoria, Koushik Dutta
17.12 Meningococcal Infections 1077
R.K. Singal, Vivek Pal Singh
17.13 Gonococcal Infections 1080
Chander Grover
17.14 Typhoid Fever (Enteric Fever) 1083
Swapan Kumar Niyogi
17.15 Bacillary Dysentery 1086
Pankaj Tyagi, Jyotsana
17.16 Cholera 1088
S.K. Bhattacharya, Dipika Sur
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17.17 Diseases Caused by Gram-Negative Enteric Bacilli 1090

Richa Dewan, Vivek Kumar
17.18 Haemophilus Influenzae Infections 1094
M. Sabir, Mansoor Ahmed
17.19 Legionnaires’ Disease 1097
P.S. Shankar
17.20 Plague and Other Yersinia Infections 1099
Veena Mittal
17.21 Clostridial Infections 1102
M.K. Daga, Rakshit Kumar
17.22 Diphtheria 1107
Sandeep B. Bavdekar
17.23 Pertusis—Whooping Cough 1109
Y.K. Amdekar
C. Miscellaneous Bacterial Infections
17.24 Syphilis 1111
Debabrata Bandyopadhyay
17.25 Non-Syphilitic Treponematoses 1115
Taru Garg
17.26 Leptospirosis 1117
A.P. Sugunan
17.27 Lyme Disease, Rat Bite Fever, and Other Spirochaetal Infections 1120
Kamlesh Tewary
17.28 Anaerobic Infections 1122
R. Sajithkumar
17.29 Atypical Mycobacteria 1124
P.D. Khandelwal
17.30 Brucellosis 1125
B.G. Mantur
17.31 Donovanosis 1127
Dwijendra Nath Gangopadhyay
17.32 Actinomycosis and Nocardiosis 1129
A. Muruganathan
17.33 Bartonella Infections 1132
Pallavi Bhargava
17.34 Melioidosis 1134
Kavitha Saravu
D. Rickettsial, Chlamydial and Mycoplasma Infections
17.35 Rickettsial Infections 1135
Raminder Singh
17.36 Chlamydial Infections 1138
T.K. Suma
17.37 Mycoplasma Infections 1141
Dilip Mathai
E. Viral Infections
17.38 Basic Considerations of Viral Diseases 1143
Usha K. Baveja
17.39 Herpes Virus Infections 1148
Aditya Prakash Misra
17.40 Human Papilloma Virus and Parvovirus Infections 1151
Neerja Bhatla, Biswa B. Dash
17.41 Bird Flu and Swine Flu 1155
Sandhya Kamath
17.42 Dengue 1158
M.E. Yeolekar
17.43 Ebola and Marburg Infections 1161
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Contents
Contributors
U.K. Misra, J. Kalita
17.45 Rabies 1166
Tarun Kumar Dutta, Ashish Kumar Panigrahi
17.46 Viral Gastroenteritis 1170
Prabhash Chandra Bhattacharyya, Rupjyoti Talukdar
17.47 Mumps 1171
Falguni S. Parikh
17.48 Measles (Rubeola) 1172
R.K. Goyal, Prashant Mathur
17.49 Smallpox 1174
Ramesh Balwant Pandit
17.50 Lymphocytic Choriomeningitis and Other Arena Virus Infections 1175
Deepti Vibha, Garima Shukla
17.51 Prion Diseases 1176
P.K. Maheshwari, A. Pandey
F. Protozoal Diseases
17.52 Malaria 1177
A.K. Agarwal, Sarit Chatterjee
17.53 Amoebiasis and Giardiasis 1185
M.P. Sharma, Vaibhav Gupta
17.54 Leishmaniasis 1188
Shyam Sundar
17.55 Toxoplasmosis 1192
Madhukar Rai
17.56 Trypanosomiasis 1195
Prashant P. Joshi
17.57 Cryptosporidiosis, Trichomoniasis, Balantidiasis and Isosporiasis 1198
Atul Bhasin
G. Helminthic Diseases
17.58 Ankylostomiasis, Ascariasis and Other Nematodal Infestations 1200
Narender Pal Jain
17.59 Tapeworm and Hydatid Diseases 1207
Anurag Saxena
17.60 Filariasis and Other Related Infestations 1211
Sanjay Zachariah
17.61 Schistosomiasis/Bilharziasis 1216
Kirti C. Patel
H. Fungal Infections
17.62 Systemic Fungal Infections 1218
Shruti Prem, Rajat Kumar
17.63 Pneumocystis Jirovecii Infections 1224
Prasanta Raghab Mohapatra

SECTION 18: DISORDERS OF METABOLISM

18.1 Basic Considerations of Metabolism 1228
B.K. Sahay
18.2 Inborn Errors of Carbohydrate Metabolism 1229
Siddharth N. Shah
18.3 Lipids and Lipoprotein Metabolism 1232
Soneil Guptha
18.4 Disorders of Purine and Pyrimidine Metabolism 1240
R.V. Jayakumar
18.5 Iron Metabolism and Iron Overload Syndrome 1243
Mukesh Desai xxxv
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18.6 The Porphyrias 1253

Dhanpat Kumar Kochar, Abhishek Kochar
18.7 Wilson’s Disease 1257
Sanjib Sinha, A.B. Taly
18.8 Lysosomal Storage Disorders 1263
Prasanta Kumar Bhattacharya
18.9 Inherited Disorders of Membrane Transport 1266
S.K. Singh
18.10 Amyloidosis 1271
Manisha Sahay
18.11 Disorders of Adipose Tissue and Obesity 1275
Shashank R. Joshi
18.12 Metabolic Syndrome 1279
Anoop Misra

SECTION 19: NEPHROLOGY

19.1 Kidney—Structure and Functions 1282
Sanjay K. Agarwal
19.2 Kidney Disease—A Clinical Approach 1286
Vijay Kher
19.3 Acute Kidney Injury 1291
Alan F. Almeida, Jatin P. Kothari
19.4 Chronic Kidney Disease 1295
Ashok L. Kirpalani, Hardik Shah
19.5 Primary Glomerular Diseases 1302
Vinay Sakhuja, Sanjay D’ Cruz
19.6 Secondary Glomerular Diseases 1310
O.P. Kalra
19.7 Urinary Tract Infections 1316
R. Kasi Visweswaran, Praveen Namboothiri
19.8 Nephrolithiasis and Urinary Tract Obstruction 1319
P.D. Gulati
19.9 Vascular Injury to Kidney 1323
A.S. Narula, A.K. Hooda
19.10 Polycystic Kidney Disease and Inherited Tubular Disorders 1327
P.P. Varma, Ranjith Nair
19.11 Dialysis for Chronic Renal Failure 1333
N.K. Hase
19.12 Renal Transplantation 1339
George T. John

SECTION 20: NEUROLOGY

20.1 Basic Considerations in Neurology 1345
R.S. Wadia
20.2 Neurological Disorders—A Clinical Approach 1351
M.V. Padma Srivastava
20.3 Clinical Neurophysiology 1357
J. Kalita, U.K. Misra
20.4 Neuroimaging 1364
Rakesh K. Gupta, Sunil Kumar
20.5 Epilepsy 1371
Sanjeev V. Thomas

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Contents
Contributors
Apoorva Pauranik
20.7 Disorders of Cranial Nerves 1390
Sankar Prasad Gorthi, Sundaram Venkatraman
20.8 Ischaemic Cerebrovascular Diseases 1401
P.M. Dalal
20.9 Haemorrhagic Cerebrovascular Diseases 1411
M.V. Padma Srivastava, Ajay Garg
20.10 Cerebrovenous Thrombotic Disorder 1418
D. Nagaraja, N. Karthik
20.11 Bacterial Meningitis and Brain Abscess 1422
Ravindra Kumar Garg
20.12 Neurotuberculosis 1428
Shyamal Kumar Das, Deb Sankar Guin
20.13 Neurosyphilis 1434
S. Prabhakar, M. Modi
20.14 Acute Viral Infections of Central Nervous System 1437
Nadir E. Bharucha
20.15 Slow Virus Infections and Prion Diseases 1443
S.K. Shankar
20.16 Fungal and Parasitic Diseases of Nervous System 1446
Ashok Panagariya, Bhawna Sharma
20.17 Raised Intra-Cranial Pressure and Hydrocephalus 1451
Daljit Singh
20.18 Dementia 1454
P.S. Mathuranath
20.19 Extrapyramidal Disorders 1459
B.S. Singhal
20.20 Hyperkinetic Movement Disorders 1464
Mohit Bhatt
20.21 Cerebellar Disorders 1468
Pramod Kumar Pal
20.22 Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases 1477
B.K. Bajaj
20.23 Demyelinating Diseases of Nervous System 1482
Man Mohan Mehndiratta, Rohit Kumar Garg
20.24 Nutritional and Toxic Disorders of the Nervous System 1490
U.K. Misra
20.25 Metabolic Disorders of Nervous System 1496
Vrajesh Udani
20.26 Intra-Cranial Space Occupying Lesions 1505
P. Sarat Chandra, P.N. Tandon
20.27 Head Injury 1511
A.K. Singh
20.28 Myelopathies 1518
S.Venkataraman
20.29 Peripheral Neuropathy 1529
A.K. Meena
20.30 Disorders of Autonomic Nervous System 1540
Garima Shukla
20.31 Myasthenia Gravis 1543
Sumit Singh, Atma Ram Bansal
20.32 Diseases of Muscles 1546
S.V. Khadilkar

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SECTION 21: ONCOLOGY

21.1 Basic Considerations of Oncology 1556
S.H. Advani
21.2 Principles of Cancer Biology and Pathology 1561
Anita M. Borges
21.3 Cancer Screening and Prevention 1565
Atul Sharma, M.P. Ram Prabhu
21.4 Principles of Drug Treatment of Cancer 1568
Lalit Kumar, Prabhat Singh Malik
21.5 Principles of Radiotherapy 1576
G.K. Rath
21.6 Head and Neck Cancers 1579
V.P. Gangadharan
21.7 Breast Cancer 1581
Vinay H. Deshmane
21.8 Tracheobronchial and Lung Cancers 1586
Kirti M. Patel
21.9 Tumours of the Gastrointestinal Tract (Stomach and Oesophagus) 1594
K.M. Mohandas
21.10 Colorectal Cancer 1598
K. Govind Babu
21.11 Genitourinary Cancers 1601
Sudeep Gupta
21.12 Gynaecological Malignancies 1606
P.P. Bapsy, Ankit Jain
21.13 Soft Tissue Sarcomas 1613
Avinash Deo
21.14 Cancer of Unknown Primary Site 1616
Hemant Malhotra
21.15 Paraneoplastic Syndromes 1622
Senthil Rajappa, D. Raghunadharao
21.16 Cancers in the Predisposed Host 1626
K. Pavithran
21.17 Oncological Emergencies 1629
Avinash Deo
21.18 Supportive Care in Cancer 1632
Madhuchanda Kar, Rakesh Roy

SECTION 22: PSYCHIATRIC MEDICINE

22.1 Basic Considerations in Psychiatry 1636
Ashit Sheth
22.2 Anxiety Disorders 1640
Uday Chaudhuri
22.3 Bipolar Mood Disorders 1645
Lakshman Dutt, Rakesh Sanghadiya
22.4 Somatoform Disorders 1649
Vihang N. Vahia, Amit Kulkarni
22.5 Psychotic Disorders and Schizophrenia 1652
R. Thara
22.6 Delirium, Dementia and Other Cognitive Disorders 1657
Venu Gopal Jhanwar
22.7 Substance Related Disorders 1661
S.M. Channabasavanna
22.8 Psychiatric Emergencies 1670
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22.9 Psychotherapy 1674

Contributors
Vidhyadhar Watve
22.10 Biological and Somatic Treatments of Psychiatric Disorders 1678
E. Mohan Das

SECTION 23: PULMONARY MEDICINE

23.1 Respiratory System—Structure and Functions 1686
S.K. Chhabra
23.2 Pulmonary Disorders—A Clinical Approach 1690
Jyotsna M. Joshi
23.3 Pulmonary Disorders—Diagnostic Procedures 1695
Gautam Ahluwalia, Surendra K. Sharma
23.4 Upper Respiratory Tract Infections 1701
D.G. Jain
23.5 Bronchial Asthma 1704
Virendra Singh, Ajeet Singh
23.6 Chronic Obstructive Pulmonary Disease 1711
Surendra K. Sharma
23.7 Pneumonia 1719
Dhiman Ganguly, Sumit Sengupta
23.8 Suppurative Pleuro-Pulmonary Diseases 1726
Dheeraj Gupta, Navneet Singh
23.9 Pulmonary Tuberculosis 1734
M.S. Jawahar
23.10 Fungal Infections of Lungs 1740
Ashok Shah
23.11 Diffuse Interstitial Lung Disease 1745
S.K. Jindal
23.12 Eosinophilic Lung Disease and Tropical Pulmonary Eosinophilia 1751
Farokh E. Udwadia
23.13 Occupational and Environmental Lung Diseases 1754
Ashutosh Nath Aggarwal
23.14 Sarcoidosis 1758
V.K. Vijayan
23.15 Sleep Related Breathing Disorders 1764
R. Narasimhan, A.R. Gayathri
23.16 Pulmonary Embolism and Deep Vein Thrombosis 1767
Jamshed D. Sunavala, Shruti M. Tandan
23.17 Diseases of Pleura, Mediastinum, Diaphragm and Chest Wall 1774
Alladi Mohan
23.18 Atelectasis and Pulmonary Fibrosis 1784
Rupak Singla
23.19 Benign and Malignant Tracheobronchial Tumours 1790
Lalit Kumar, M.P. Ram Prabhu
23.20 Cor Pulmonale 1798
Sandeep Singh

SECTION 24: RHEUMATOLOGY

24.1 Basic Considerations of Rheumatology 1804
Rohini Handa
24.2 Soft Tissue Rheumatism and Regional Rheumatic Pain Syndromes 1808
Ved Chaturvedi
24.3 Low Backache 1813
C. Panchapakesa Rajendran, S. Rajeswari
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24.4 Osteoarthritis 1818

Siddharth Kumar Das
24.5 Gout and Other Crystal Arthritides 1822
U.R.K. Rao
24.6 Rheumatoid Arthritis 1829
A.N. Malaviya
24.7 Spondarthritides 1844
Milind Y. Nadkar
24.8 Sjögren’s Syndrome 1851
Uma Kumar
24.9 Systemic Lupus Erythematosus 1853
V.R. Joshi
24.10 Antiphospholipid Syndrome 1860
Vikas Agarwal
24.11 Systemic Sclerosis 1863
R. Porkodi, S. Rajesh
24.12 The Vasculitides 1867
Pradeep Bambery
24.13 Mixed Connective Tissue Disease and Overlap Syndromes 1876
G. Narsimulu, Vara Prasad IR
24.14 Inflammatory Muscle Diseases 1879
Alakendu Ghosh, Pradyot Sinhamahapatra
24.15 Rheumatic Manifestations of Systemic Diseases 1883
Debashish Danda
24.16 Miscellaneous Rheumatic Disorders 1886
Binoy J. Paul
24.17 Emergencies in Rheumatology 1891
Lata S. Bichile, Vaibhav C. Chewoolkar

SECTION 25: NUTRITION

25.1 Nutrition—Basic Considerations 1896
S.V. Madhu
25.2 Assessment of Nutritional Status 1900
Prema Ramachandran
25.3 Protein Energy Malnutrition 1904
Piyush Gupta
25.4 Water Soluble Vitamins 1909
Milind Y. Nadkar
25.5 Fat Soluble Vitamins 1913
Ghan Shyam Pangtey
25.6 Minerals, Trace Elements and Antioxidants 1917
M. Raghunath, D. Sreeramulu
25.7 Food Allergy and Food Intolerance 1922
U.V. Mani
25.8 Eating Disorders 1924
Anupam Prakash
25.9 Enteral and Parenteral Nutrition 1927
Varsha

SECTION 26: POISONING AND TOXICOLOGY

26.1 Poisoning—Basic Considerations and Epidemiology 1934
N.P. Singh, Gurleen Kaur
26.2 Aluminium Phosphide Poisoning 1936
S.N. Chugh
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26.3 Organophosphorous Poisoning 1939

Contributors
Surjit Singh
26.4 Corrosive Poisoning 1941
Rakesh Kochhar
26.5 Alcohol Poisoning 1944
Pritam Gupta, Ankur Gupta
26.6 Plant Poisoning 1947
D.K.S. Subrahmanyam
26.7 Drug Overdose 1950
Nusrat Shafiq
26.8 Snake Bite Poisoning 1955
H.S. Bawaskar
26.9 Scorpion Sting 1960
H.S. Bawaskar
26.10 Fluorosis 1965
D. Raja Reddy
26.11 Lathyrism 1970
U.K. Misra, J. Kalita
26.12 Epidemic Dropsy 1972
Navneet Sharma
26.13 Heavy Metal Poisoning 1974
Praveen Aggarwal
26.14 Miscellaneous Poisoning 1983
Subhash Varma, Vikas Suri

SECTION 27: ENVIRONMENTAL MEDICINE

27.1 Basic Considerations of Environmental and Occupational Diseases 1990
Randeep Guleria
27.2 Climate Change—Health and Disease 1993
Anil Gurtoo
27.3 Environmental Pollution 1998
Ashok A. Mahashur
27.4 Air-Borne Pollutants and Smoke-Related Hazards 2001
Rajeev Gupta
27.5 Drowning, Near-Drowning and Submersion Injury 2006
Yudh Dev Singh
27.6 Electric Shock and Lightning Injury 2008
Naveet Wig, Sourabh Malviya
27.7 Effects of Extremes of Temperature 2011
Rajvir Bhalwar
27.8 High Altitude Medicine 2017
Anuj Chawla
27.9 Aviation Medicine 2024
J.S. Kulkarni
27.10 Radiation Hazards 2028
A.M. Samuel
27.11 Environmental Disasters 2034
M.E. Yeolekar, Milind Y. Nadkar

SECTION 28: MISCELLANEOUS

28.1 Geriatric Medicine 2038
Vinod Kumar
28.2 Sexual Medicine 2042
Prakash Kothari
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28.3 Sports Medicine 2046

Anant Joshi
28.4 Diet in Medical Diseases 2050
Siddharth N. Shah
28.5 Care of Terminally Ill 2058
Anil Chaturvedi
28.6 Exercise and Yoga in Health and Disease 2061
S. Dwivedi, Shiva Narang
28.7 Adult Immunisation 2063
R.K. Singal, A.K. Agarwal
28.8 Perioperative Management 2069
Prabha Adhikari
28.9 Law and Medicine 2073
N.K. Grover
28.10 Travel Medicine 2077
Yash Pal Munjal
28.11 Nanotechnology and Nanomedicine 2081
Ramchandra D. Lele

Index I–1

xlii
Section 1

Introduction
The Practice of Medicine
Yash Pal Munjal
 1.1 The Practice of Medicine

Yash Pal Munjal

INTRODUCTION AMALGAMATING THE ART AND SCIENCE OF MEDICINE

The history of practice of medicine is as old as the history of The scientific technology has enabled the physician to arrive
mankind. Over the years, medicine has gradually evolved at a diagnosis at the molecular level. It is now possible to
and the modern medicine in its present form came into understand the cause and complex mechanisms involved in
existence about 400 years ago. The last century has seen the pathogenesis of disease. This constitutes the science of
tremendous progress which is phenomenal and a lot more medicine. Once the diagnosis is established, the doctor has to
than in the preceding three centuries. Despite this explosion inform the patient about the diagnosis, plan of management,
of knowledge, medicine still remains ‘an art and science’ to and prognosis. He has to get the concurrence from the
be practiced with compassion, empathy, and effective patient for the line of management to be followed. It is this
communication with the patient. In today’s practice, the patient communication skill of the clinician which wins confidence, faith
is an informed partner in the plan of his management. and builds a healthy relationship between the doctor and the
This sea change in the medical practice is due to the emergence patient. This is an ‘art’ to be nurtured.
of new technologies which facilitate a physician to delve into The task of a physician becomes rather delicate especially
the disease at its molecular level with the help of various in situations which involve management of incurable and
biochemical, immunological, and genetic tests. There has been terminal stages of diseases. In a situation like this, the scientific
a marked improvement in the imaging technology. We have knowledge at the command of a doctor is to provide adequate
travelled a long distance from the time of conventional and effective relief from symptoms. The doctor and his team
radiology to an era of PET and SPECT scanning. These have should not be carried away by the life-saving procedures used
improved our capabilities to look into every nook and corner in the hospitals. In such situations, the doctor has to inform
of the body and its organs.This has helped in arriving at a correct the relatives and the patient about the gravity and prognosis
diagnosis and also to evaluate the functional status of the organ of the terminal diseases in a manner that the patient can
system. All these investigations with their sensitivity and understand and discuss with his doctor properly. It is an exercise
specificity have armed the clinician to arrive at a diagnosis, plan to prepare the relatives and the patient to face the grave
effective treatment and prevent disease, if possible. Not only situation with forbearance and equanimity. This exercise has to
science has made rapid strides in diagnosis but also there has be carried out by the doctor with all the compassion and
been a very significant improvement in the therapeutic modalities. empathy at his command so that he is able to communicate to
The growing knowledge of genetics and immunology has the patient effectively and subtly. The doctor who can handle
enabled the clinician to provide treatment based on the such delicate situations effectively earns the respect of the
molecular defect and individualising therapy accordingly. patient and the family. This is in true sense of the word an ‘art’
The advent of information technology and internet has which a doctor has to imbibe and master over the years.
changed the way we learn medicine and keep our knowledge
up-to-date about the latest innovations in medicine. It has PRINCIPLES OF MEDICAL PRACTICE
given us the capability of maintaining medical records in a Clinical Evaluation
comprehensive manner so that they are more useful to the The art of clinical evaluation has to be learnt and mastered by
patient as well as help the doctor to follow the patients very everyone studying medicine. This forms the basic foundation on
effectively. Difficult clinical problems can be solved easily. which the future course and technological advancement can be
Patient’s records can be transmitted to other institutions and used effectively and rationally in a cost effective manner. Therefore,
doctors for information.Telemedicine as a discipline has a great it is absolutely essential for every practising doctor not to lose
relevance, particularly in the context of developing countries, sight of this part of clinical medicine thinking that technological
especially India, where there is a shortage of trained and expert advances can take away the importance of clinical examination.
medical manpower. This helps to provide medicare to patients The clinical evaluation of a patient comprises of two major
in remote places where trained personnel are not available. aspects:
Even sitting at one place, a senior surgeon can guide surgical
1. History of sickness of the patient
procedures at more than one centre.
2. Comprehensive physical examination
In this phenomenal progress of scientific knowledge, the basic
goal remains to diagnose and treat the patient effectively and History
as early as possible. In this exercise, due consideration has to be The history of illness should include all the facts of medical
given to the quality of life achieved and cost benefit ratio. It is significance in a chronological order and in a comprehensive
the latter part which is the practice of the ‘art’ of medicine. This way. Eliciting the history of the patient is an art which a doctor
is learnt and mastered by practice, experience, and gradual develops over a period of time. He should be able to guide
2 understanding of the diverse human nature over the years. the patient and to encourage him to narrate the history of his
 The Practice of Medicine
illness with all its details in a manner which is useful and easily Investigations
comprehensible. He guides the patient to give the details rather The investigations have significantly improved in their
than getting into trivia which may be irrelevant to the medical sensitivity and specificity so as to provide accurate diagnosis.
problem. He may pose questions which guide the patient to The diagnostic tests help clinicians to:
narrate the relevant details. To complete the history, personal,
 Establish the diagnosis
past, and family history have to be recorded. The family history
is important as it can provide useful clues to certain genetic  Assess the degree of malfunction and extent of disease
disorders as well as certain communicable diseases which may  Make a rational plan for management which may be
be transmitted from one member of the family to the other. medical, surgical, or palliative
Similarly, the details of history provided by the family members  Assess the benefit of therapeutics and interventions.
may be helpful especially in dealing with psychological
disorders. A good clinician is able to plan the investigations which are
essential and appropriate in a given clinical situation. After the
The history taking and talking to the patient is the first step results of constellation of tests are available he should be able
towards developing an effective and unique doctor-patient to interpret them in the clinical context. The judicious use of
relationship. The patient is encouraged at all times to narrate investigations limits the cost and helps to arrive at a diagnosis
his condition in detail. This will give him the satisfaction of in an effective and useful manner.
having communicated to the doctor all about his sickness. The
feeling that the doctor was receptive to his condition and Decision-Making in Clinical Practice
sickness helps in building a rapport between the patient and A physician has to take decisions at various stages during the
the doctor. clinical course of sickness. These have to be in consonance with
the informed consent of the patient. The first level of decision-
Physical examination
making is to arrive at a provisional diagnosis based on the
The physical examination should be carried out at a place which history and physical examination. At this level, he has to plan
is comfortable, ensures privacy and maintains dignity of the the investigations as well as start provisional treatment so that
patient. It has to be comprehensive and complete from head
there is no further deterioration in the condition of the patient.
to toe. The physical examination has to identify the clinical signs
As soon as the results of investigative procedures are available,
of disease and confirm the structural and functional changes.
his clinical skill is once again called into play to arrive at a
The clues may have been provided by the patient in his history.
definitive diagnosis by following the principle of deductive
There are no shortcuts in physical examination as they may
science and plan a definitive course of treatment. This is the
lead to major errors in diagnosis. Competence in physical
second level of decision-making. After the treatment has been
examination comes by knowledge, experience, and following
initiated and continued, the response can be an improvement
the methods of clinical examination in all its detail. Progress
in the condition of the patient or there may be no change in
of clinical disease alters the physical signs from time to time
the condition of the patient or it may get worse. This is the next
and therefore a good clinician must carry out the physical
level of decision-making where the doctor has to review his
examination repeatedly and periodically. Not only the ethical
attributes of the clinician but also an alert mind is absolutely previous diagnosis, order fresh investigations so that missing
mandatory for getting the best information from the physical link is detected. In case the patient shows benefit of treatment
examination. The success of a good history and physical then he has to decide how long to continue the treatment so
examination yields information which prepares the clinician that the patient is restored to his health. Not only the subjective
to prescribe diagnostic tests which will clinch his diagnosis improvement but also an objective assessment has to be made
rather than unnecessary and multitude of tests which cause based on the clinical and laboratory parameters which have to
unnecessary escalation of cost and add to confusion (Figure 1). be decided by him.
The clinical examination provides useful input to the clinician Evidence Based Medicine
about the line of investigation and whether to give credence
This concept means that the clinical decisions to be taken are
to some symptom and physical sign or not depends not only
fully supported by data that is derived from prospectively
on his knowledge but also is an art of medical practice.
designed randomised controlled clinical trials over a fairly long
period of time. This is in marked distinction to the previous
concept of following the treatment based on one’s experience
and bias towards one form of treatment than the other. It is
imperative for today’s doctor to take decisions based on hard
outcome data from large clinical trials. To get this implemented
many National and International Organisations have formulated
Practice Guidelines which help the physician and other
members of his team in making a diagnosis and taking
appropriate therapeutic decisions. These guidelines provide the
framework for managing patients with a diagnosis or clinical
symptoms and also help to create a standard of medical care
so that all patients get the benefit of cost effective and proven
therapies. They help to protect the doctors from frivolous
Figure 1: Hippocrates (460–380 BC).
charges of medical malpractice and cost overruns due to 3
 unplanned treatment. However, these guidelines have to respectful, and compassionate). The basic tenets of these
be used with caution and must be based on the clinical guidelines were to ‘provide patients good doctors’. The good
constellation of a particular clinical condition. In case more than doctors are supposed to make patient care their first concern
one options are available for treatment which is scientifically and, therefore, they need to be competent (good medical
proven, the physician cannot be faulted for choosing one option education). They should keep their knowledge and skills up-to-
for the other option. In planning a treatment, the other factors date (continuing medical education). They should maintain
which have to be taken into consideration are the age and sex good relationship with the patients and professional colleagues,
of the patient and associated medical conditions, and drug-drug be honest particularly to themselves and act with integrity
interaction. (Ethics of Medicine). The various national and international
agencies have provided guidelines for the practice of doctors
Assessment of the Success of Treatment
in their respective countries. In India, the Code of Conduct has
Previously the assessment of result was based on clinical been framed by the Medical Council of India. This is modified
examination and subjective feelings. Nowadays the evaluation from time to time based on the socio-cultural needs and
is based on hard outcomes data to judge the success of treatment. advancement of medical knowledge. The responsibilities and
This is in the form of prevention of morbidity and mortality. duties of a doctor formulated by various organisations are based
In case of chronic illnesses where cure is not possible, on the following principles enumerated in Table 1.
assessment of treatment is based on not only the symptomatic
relief but also by finding out that if the progress of the disease Table 1: Responsibilities and Duties of a Doctor
has been stalled and complications have been prevented.
Patient care should be your first priority
Another parameter which helps in assessing the benefit of
Keep the dignity and privacy of every patient and he should be dealt
treatment is the quality of life which the patient enjoys after
with politeness and consideration
the treatment. Therefore, summing up in today’s context, it is
Do not be judgmental. Listen to the patients and respect their
predominantly an objective outcome assessment as compared
information
to the olden times. There are certain modifying situations which
Communicate in a manner the patients understand and make
can change the parameters of assessment like the age and sex
patients equal partners in decision-making
of the individual.The delivery of medical care has to be assessed
Keep your professional knowledge and skills up-to-date
in the context of available resources and infrastructure.
You must practise and manage patients to the level of competence
It is essential and obligatory for the doctor to provide
and knowledge acquired by you
compassionate care with empathy, understanding and constant
Refer patients at appropriate time to a higher centre or a super
dialogue with the patient (this is always possible) even with
specialist at the earliest possible occasion, if required
limited resources and infrastructure.
Keep the information given to you confidential and to be divulged
MEDICAL ETHICS only under extremes of circumstances
Do not abuse your position as a doctor
As soon as the foundation of the modern system of medicine
Your dealings with the colleagues and pharmaceutical industry
was laid the practice of medicine was ‘put into guiding
should not raise conflict of interest and your conduct should be in
principles’ by the famous Hippocratic Oath. If we delve into the the best interest of the patient
ancient Indian literature, similar guidelines were propounded
Provide adequate information and take ‘informed consent’ before
much earlier by Sushruta/Charak Samhita, Aryabhatta Smriti, any drug trial or ‘off label use’ of any drug
etc. (Figures 2A and B).They have elaborated on various aspects
of code of conduct, qualities of physician as well as human
Implementing Medical Ethics
aspects of relationship. Among the qualities and characteristics
of physician, special emphasis was laid on character (purity, Medical ethics are also concerned with the standards of care
honesty, and integrity), qualification (knowledge, skill, and and the ethical issues raised by the practice of medicine. Recent
experience), professional attitude (alert, responsive, scientific knowledge and their usage have thrown many difficult
communicative, and responsible), and behaviour (friendly, ethical problems which are still in the process of debate. In these
situations the doctor has to decide based on his belief and the
sociocultural milieu. Some of the issues under debate are
cloning, genetic medicine, abortion, care of the brain dead for
organ transplant, and need of live tissues. Another issue which
is a matter of concern and debate is the issue of assisted suicide
or euthanasia. In clinical practice the ethics come into play in
three vital areas. The clinical ethics are concerned with the
relationship between the doctor and the patient. Another area
is the conduct of research on patients which is guided by the
research ethics while public health ethics deal with the health
of the community, state, or country as a whole.

CLINICAL ETHICS
A B In clinical ethics, four principles are important and they can be
abbreviated to autonomy, beneficence, non-maleficence, and
Figures 2A and B: (A) Sushruta (800 BC); (B) Charak (300 BC).
4 justice.
 The Practice of Medicine
Autonomy must be shared with the patient so that he is able to make an
The respect and dignity of the patient has to be maintained at informed decision.
all times. Truthful communication with the patient is always a Justice
must though it is not essential to inform him of the facts in the
This means availability and access to the health care by every
first instance especially in critical illnesses or certain disorders
individual irrespective of caste, creed, social and economic
(HIV) which have a lot of social stigma attached.
status. It mandates an equitable distribution of health care
Informed consent resources. One associated concept is that of utility, i.e. greatest
It is the fundamental right of an individual that his body is good for the greatest number must be evaluated for an
inviolable. Therefore, a doctor needs to have permission from individual patient. Justice means being fair to him and it
the individual for his examination, investigations and involves evaluation of the needs of the patient, respecting his
therapeutic procedures including interventions and surgeries. rights as well as the merit.
The patient has to be informed about the method adopted for
diagnosis and the line of his management. In case, there are PUBLIC HEALTH ETHICS
more than one options for treatment then the details of all the Public health involves the health of the community, state or
options with their pros and cons have to be explained. This country as a whole; no direct doctor patient relationship exists.
communication must be done in a manner that the patient This involves preventive measures like education, mass
understands and in his language. After this, he should give his vaccination, mass screening for diseases and precautions to be
consent in writing to carry out that treatment or procedure. taken at the community level. In prevention of certain lifestyle
Legally and morally, the patient has the absolute right to take a diseases like diabetes, coronary artery disease and obesity,
decision about what is right or wrong for him. Sometimes, the there may be a conflict of interest with the corporates who are
choice of the patient may seem irrational and not in accordance dealing with the marketing and advertisement of such
with the professional advice. But it should not be construed substances like alcohol, tobacco, junk food, etc. To resolve these
that he lacks the capacity and mind to take appropriate decision situations of conflict of interest social organisations and
for himself. In situations where he is incapacitated to take a medical professionals may have to lobby with the politicians
decision on his own, e.g. in children, unconscious patients or to educate the society to demand action against the sale,
insane individuals, the treatment may be planned in marketing and use of these substances if necessary, by laws.
consultation with the explicit permission of the relatives. In case In India, a major step has been implemented that all
the relatives are not available then a group of physicians may advertisements pertaining to tobacco and its derivatives (e.g.
take a decision on behalf of the patient depending on the local cigarettes, bidis, hookah and chewing tobacco) have been
laws and culture. banned and even at the individual level their use at public places
is prohibited (by law).
Confidentiality
The details of the history, treatment, and prognosis have to be Restrictive measures may at times become a necessity. In an
kept confidential. All communications and other records explosion of epidemic to prevent its further spread certain
relating to the patient’s care are to be treated as confidential legislations may have to be passed. This was recently amplified
documents. This information can be shared between health care and implemented in cases of severe acute respiratory syndrome
professionals if the patient is referred to another institution or (SARS) and avian flu. Such interventions are for the good of the
a consultant. In other situations, the authorisation in writing by general community at large. Another important aspect of public
the patient is a must. The confidentiality clause can be rescinded health ethics is the uniform and equitable distribution of funds
for due process of law and in cases of insurance or a medical for various disorders with a view that maximum people may
claim. This right of confidentiality has been over-ruled in cases draw benefit.
where the condition is infectious (e.g. HIV or AIDS) by right to RESEARCH ETHICS
healthy life of the other person who is likely to be in his contact
or where the community interest suffers. The conduction of research is a vital component of medical
practice. It may provide a sound basis of care for a better and
Beneficence more effective treatment for subsequent patients.The principles
This means acting in the best interest of the other person. of information, beneficence, non-maleficence and justice should
In clinical ethics, it means the benefit of individual patient be strictly adhered to in all research protocols. The guidelines
based on the patients’ point of view as well. In situations where for conduct of good research have been formulated and must
there is a conflict of interest between the benefit of the be strictly followed. The patients consenting for trial should be
individual patient over that of the community, the declaration offered due care and they must be compensated both for their
of Geneva by World Medical Association entitles a doctor to time, travel and reimbursement of the other expenditure
follow the dictum “Health of my patient will be my first incurred by them. Such reimbursement should not appear to
consideration”. be an inducement to the patient, health care institutions and
the doctors.
Non-Maleficence
This means do no harm. In traditional medicine, the concept END OF LIFE SITUATIONS
followed is ‘primum non nocere’. In the practice of medicine A doctor is faced with the dilemma of communicating the
beneficence and non-maleficence have to be balanced (benefit diagnosis of certain incurable diseases or a disease in its terminal
versus risk). Relevant information on the above two grounds stage to the patient and/or his relatives. In such situations, the 5
 doctor must be sure about the diagnosis that the disease is technological advancement by science is useful to the mankind
incurable, or it has advanced to such an extent that it is in its most of the time but due to an accident it may lead to a disaster.
terminal stage. The doctor is not necessarily bound to divulge To mention a few examples of technology related disasters
the complete information at the time of first contact with the are—the Gas leak in Bhopal (MP) in 1984 the so called Union
patient, but it is imperative for him that he must confide, educate Carbide Gas Leak, the Chernobyl Russian Nuclear Power Plant
the patient and the relatives about the gravity of situation and Explosion in 1986, and the radiation spread by the damage of
its consequences. This can be done slowly and progressively. the Nuclear reactors in the area of Tsunami in Japan in 2011
The physician should provide this information in a manner that have led to disastrous consequences. Man himself can unleash
it is easily understood by the patient and other persons disasters like the bombing of Hiroshima and Nagasaki in Japan,
attending him so that they can appreciate the gravity of the chemical and biological warfare. It is the management of such
situation. The doctor should be willing to discuss the details emergencies in which there are mass casualties that it needs
and answer necessary questions of the patient or his family courage, presence of mind and a well-planned action so that
members. This exercise has to be done with compassion, misery can be minimised. In this situation, the health care
empathy, and it is an art which a physician has to master and professionals have to work in close collaboration with the
practice by knowledge and understanding. The doctor society. The various phases in which the emergency
sometimes gets overwhelmed with the prospect and management has to be carried out are described below.
availability of advanced life saving methods (e.g. ventilators, Mitigation
pacemakers, etc.) in an aggressive manner. But it is always
Mitigations are concerted efforts to prevent hazards from
important for him to remember the basic fact about the
developing into disasters altogether or to reduce the effects of
gravity of the sickness and its consequences. Symptomatic and
disasters when they occur. The mitigation phase differs from
pain relief have to be addressed aggressively to provide comfort
the other phases because it focuses on long-term measures for
to the patient round the clock. During the terminal stages of
reducing or eliminating risk. Mitigation is the most cost efficient
any disease it is not only the medical treatment which has to
method for reducing the impact of hazards while it may not
be provided but religious, cultural and other supportive
always be feasible.
measures also have to be used judiciously, and they should be
facilitated so that the patient and his relatives are at peace and Preparedness
comfort. It is to train people to fight the disease and, therefore, it involves
planning, organising, training, equipping, exercising, evaluation
ENVIRONMENTAL MEDICINE
and improvement over a period of time. It helps to ensure co-
A number of chronic and infectious diseases are emerging and ordination and increased capability to deal with disasters,
posing a threat to the health of countries. It is believed that due terrorist attacks and man induced disasters.
to rapid industrialisation and urbanisation which has led to the
degradation of the environment polluting the air, water, and Response
significant lowering of the hygiene. According to WHO This phase includes the mobilisation of the necessary
estimates, nearly one-fourth (24%) of the global disease burden emergency services and first responders in the disaster area.
and 23% of all deaths can be ascribed to environmental factors. Recovery
This deterioration in the environment can lead to a spurt in
the infectious diseases, chronic non-communicable diseases, The recovery phase aims at restoring the affected area and
and trigger certain genetic disorders due to mutation of genes. population to its normal state.The focus of this phase is different
Due to global warming and increasing carbon dioxide in the from response phase, recovery efforts are started after
immediate needs are addressed. In recent years there has been
atmosphere, it is estimated that the prevalence of vector
a shift in emphasis from response and recovery to strategic risk
borne diseases, like malaria and some of the infectious
management and reduction. There is more emphasis on
diseases, are likely to increase manifold. The environmental
community participation rather than a Government centred
factors that lead to genetic variation concerning the cholesterol
approach. Efforts involve the provision of emergency
synthesis may precipitate increase of coronary artery disease
management training for first responders, the creation of a
significantly. A physician has to be well-versed with the various
single emergency telephone number and the establishment
environmental pollutants, environment at work place, and have
of standards for emergency medical staff, equipment and
a working knowledge of some of the environmental and
training. The physician therefore has to learn how to handle
occupational diseases.
acute emergencies especially in situations where there are mass
DISASTER MANAGEMENT casualties.
The environment and nature are friendly to the human beings In India, the Disaster Management Authority of India has been
most of the times but at times the ravages of nature can bring set up by the Government of India to deal with such situations
death, destruction and disease in a sudden and unexpected and prepare the infrastructure in the country.
manner. Some natural disasters that have struck in the recent
times where thousands of lives were lost—Tsunami in South MEDICAL GENETICS
India and Sri Lanka and a few years later we had a very severe The study of genes and their function in health is called
Tsunami and earthquake in Japan. These natural disasters led Genetics in Medicine while the understanding of the
to the outbreak of many infectious diseases and there was an aberrations in the function and structure of genes is Medical
6 associated increase in vector borne illnesses. The marvel of Genetics. The advent of medical genetics has profound
 The Practice of Medicine
influence on our understanding of the pathophysiology of of learning skills for a clinician who can take the benefit of the
disease and has opened new vistas of therapy especially the same at a place and time of his convenience. Video conferencing
concept of planning and executing individual requirement provides useful tool for interactive learning and teaching a large
based therapy. The greatest breakthrough was achieved in the number of students at different locations by an expert in the
spring of 2003 when complete sequencing of human genome field from a common site. Live case demonstrations and
was officially announced and released. This has ushered in an procedures can be learnt by direct telecast.The other advantage
era of immense possibilities of not only cloning of species but is that one can assess his grasp of the subject by taking web
repairing of many organ systems. The science of genetics has based examinations in the privacy of his chamber. The internet
provided us the speed to understand the pathogenesis of has also served the purpose of educating the patients about
disease epidemics. The discovery of new variant of coronavirus their sickness and disease.
as a causative agent for SARS and the virus of avian flu; this
has helped to quickly plan the management of these COMPLEMENTARY AND ALTERNATIVE SYSTEMS
conditions. OF MEDICINE
Complementary and alternative medicine (CAM) is a diverse
The understanding of genetic disorders and how we can
group of health care medical systems which does not conform
manipulate them has provided a new dimension to the art of
to the commonly practised modern system of medicine. CAM
genetic counselling in which the patient can be briefed about
is used and practised globally and in one survey it was found
the likelihood of the genetic disorders which the offspring is
that 36% of people opted for CAM in the year 2002 in USA, while
likely to suffer. In case it is possible to correct the genetic defect
in a recent survey in UK, homoeopathy was used as a method
the same may be done by genetic engineering. If it is as yet
of treatment in approximately 48% of patients. If we include
not correctible then counselling can be done about the
faith, spiritual healing and prayers, then the number goes to
consequences of the genetic disorder and its prognosis so that
approximately 62%. In India, this percentage is much higher and
the parents can take appropriate decision at the beginning of
the various commonly used alternative systems of medicine are
the conception.
Ayurveda, Unani, Siddha, Homoeopathy (Figure 3), religious,
Another important area of genetics is pharmacogenomics. It yogic practices, and household remedies. Systems from other
deals with pharmacological manipulation of the genes for countries, such as accupuncture, reflexology, and osteopathy,
correction of have also been used quite frequently in recent times.
(a) Genetic defects or management of certain disease states
especially cancer
(b) Choosing the appropriate medicine for a particular disease
based on the genetic profile of the individual
(c) Another aspect of this is the use of stem cells. Stem cells
are totipotent cells which can grow up into various tissues.
These are now being used in many areas of clinical medicine
like coronary artery disease, diabetes mellitus, healing of
the wounds and rejuvenating organs.
Stem cells are being extracted from the cord blood on the birth
of the child. These can be preserved for a number of years and
are capable of providing treatment or repair of certain damaged
organs at a later stage in life. These stem cells provide the
individual with homologous graft.
The interaction between the genes and environmental factors
i.e. phenotype can predispose to the common chronic diseases
of the 21st century like obesity, diabetes, hypertension, and
Figure 3: Christian Friedrich Samuel Hahnemann, Founder of Homoeopathy
coronary artery disease which can be partially prevented or (1755-1843).
ameliorated by modifying the lifestyle factors.

CONTINUING MEDICAL EDUCATION The large acceptance of CAM therapy is due to the perception
The science of medicine is galloping at a fast pace and, therefore, that it does not have side effects (which may not always be true);
it is essential for the practising physician to learn new skills and it is easily accessible and comparatively cheaper form of therapy.
knowledge so that he can serve the best interest of his patients. All these therapies are based on perception and individual
A doctor has to keep learning all through the time he is beliefs. The other major disadvantage and shortcoming of
practising. The avenues available for medical education these this therapy is that it is not backed by clinical evidence and poor
days consist of learning from the peers in the field, the books or no standardisation of the medicines is done.
and journals which are being brought at a fast pace. Since this form of therapy is used very widely and frequently,
The technological advancement has significantly improved the therefore gradually and universally people and politicians are
way one can learn medicine. The availability of internet and taking it up and certain regulatory bodies are established. In
video conferencing has added new tools with great potential India, also there is a registering body which registers the doctors
7
 who are trained in Homoeopathy, Ayurvedic, or Unani systems has improved the sensitivity and specificity of tests.The complete
of medicine. sequencing of genes, the ease and the cost with which it can be
The government is making efforts to put these forms of medical mapped and modified have raised immense possibilities of even
management on scientific basis and trying to amalgamate it managing certain incurable and difficult clinical conditions. It has
with the modern system of medicine. This concept of integrated opened vistas of individualised and highly specific treatment.The
health care is being developed. Therefore, today’s physician has use of stem cell therapy has enabled to cure and repair organs.
to know the good and bad of CAM so that he can keep abreast This relentless progress is likely to continue during this century.
with the changing times and practice of medicine. Therefore a physician has to be well informed and trained in these
advances and their rationale use. In this backdrop, the importance
Integrated Health Care
of clinical skills to provide a good humane treatment with
This concept of amalgamated complementary and alternative kindness, justice, and autonomy, to the patient will remain of
medicine with modern system of medicine in a manner that it is prime importance for centuries to follow.
useful to the patient is gradually evolving itself. How effective
and useful will it be to medical profession and patients? The coming RECOMMENDED READINGS
few years may answer this question a little more definitively. 1. Blank L, Kimball H, McDonald W, et al. Medical professionalism in the new
millennium: A physician charter 15 months later. Ann Intern Med 2003; 138:839.
The 21st Century Physician
2. Bligh J. Learning about science is still important. Medical Education 2003;
The science based technology has expanded at a very fast pace 37:944-5.
in the later part of 20th century. The cytomolecular basis of 3. BMA Ethics Department. Medical Ethics Today: The BMA’s Handbook of Ethics
disease is better understood. The progress in imaging modalities and Law; 2nd Ed. London: BMJ Publishing; 2004.

8
Section 2
Clinical Approach to
Key Manifestations
Section Editor: A.K. Agarwal
2.1 Pain—Mechanisms and Management 10
D. Rama Rao, Niranjan P. Moulik
2.2 Headache 12
K. Ravishankar
2.3 Chest Pain 16
Sanjay Tyagi, Amit Mittal
2.4 Acute Abdomen—Non-Surgical Causes 20
Sumeet Singla, A.K. Agarwal
2.5 Cough 25
Suman Kirti
2.6 Haemoptysis 29
Randeep Guleria, Jaya Kumar
2.7 Jaundice 32
Aparna Agrawal
2.8 Upper Gastrointestinal Bleeding 39
J.C. Vij
2.9 Fever of Unknown Origin 42
Priscilla Rupali
2.10 Generalised Lymphadenopathy 47
S.K. Verma
2.11 Dizziness and Vertigo 49
M. Maiya
2.12 Syncope 53
Pushpa Yadav, Vivek Arya
2.13 Coma 57
B. Vengamma
 2.1 Pain—Mechanisms and Management

D Rama Rao, Niranjan P Moulik

Pain serves to protect the body from harm and promotes Although, pain being a subjective phenomenon, is not easy to
healing of damaged tissues. The International Association for assess, a variety of validated pain scales are available to assist in
the Study of Pain defines pain as ‘an unpleasant sensory and the measurement of pain. Pain assessment tools include simple
emotional experience associated with tissue damage and/or unidimensional scales or multidimensional questionnaires.
described in terms of such damage’. It is important to recognise
Unidimensional scales include the numeric rating scale, the visual
that pain is a perception and not a sensation. The perception of
analogue scale and the faces pain scale. The former two include
pain is believed to be the summation of sensory-discriminative
pictorial line scales which the patient uses and marks the intensity
component (e.g. location, intensity, quality), a motivational-
on a scale of 1 to 10 or no pain at all to worst possible pain.The faces
affective component (e.g. depression, anxiety), and a cognitive-
scale has pictures of 6 to 8 different facial expressions depicting a
evaluative component (e.g. thoughts concerning the cause and
range of emotions again along a 0 to 10 linear scale. It is particularly
significance of pain). The patient’s account of pain should be
useful for use in young children, patients with language barriers,
evaluated and treated as per the patient’s perception of pain.
or having mild-to-moderate cognitive impairment.
This can be irrespective of the existence and severity of tissue
damage. A noxious stimuli is sensed by the body’s ‘nociceptive’ The multidimensional pain scales/questionnaires detail a more
system and generates a physiological and behavioural response. comprehensive pain assessment and apart from the intensity
This stimulus can be generated by traumatic, inflammatory, of pain also focus on the location and quality and effect of pain
neoplastic or other mechanisms, and sustained by neuroplastic on mood and function. They are a bit time-consuming and
changes even after healing. It is believed that it is this cognitively-impaired and uneducated may find them difficult.
neuroplasticity which maintains chronic pain, although the The McGill Pain questionnaire and the Brief Pain Inventory are two
exact pathophysiology of chronic pain is yet to be elucidated. such well-validated multidimensional pain measurement tools.
Nociceptive stimuli are carried by primary afferent neurons the TREATMENT
cell body of which lie in the dorsal root ganglia (Figure 1).These
Pain treatment can be divided into pharmacological, non-
are small diameter nerve fibres, type A delta and C fibres and
pharmacological and alternative medicine approaches.Acute pain
are usually free nerve endings found in the skin, muscle, joints
effectively responds to nonsteroidal anti-inflammatory drugs
and some visceral tissues/organs.The processes of transduction,
(NSAIDs) or to mild-to-moderate efficacy opioids. Acetaminophen
transmission, modulation and perception are all involved in the
and NSAIDs are effective in mild-to-moderate intensity pain while
activation of the sensory system. The first order neurons relay
opioids can be used for moderate-to-high intensity pain. A
to the axons of second order neurons, the cell bodies of which
combination of NSAID and opioid can be used for severe intensity
lie in the thalamus and they in turn transmit the sensations to
pain and has been found to be beneficial in achieving adequate
the somatosensory cortex in the post-central gyrus of the
pain relief. Common NSAIDs usually block both cyclooxygenase-1
cerebrum. However, there are considerable areas of modulation
and -2 enzymes and hence, COX-2 inhibitors were developed.
in the central as well as the peripheral components of the pain
However, use of COX-2 inhibitors has fallen into disrepute and the
pathways; and these form the basis for differing action of various
traditional NSAID like ibuprofen, diclofenac, nimesulide, naproxen,
pain-alleviating therapies.
ketorolac, indomethacin continues to be used.
Nociceptive pain primarily involves injury to somatic or visceral
Chronic or persistent pain benefits transiently with these agents.
tissues. However, neuropathic pain results from direct injury or
Physiotherapy measures and physical treatments can be offered
dysfunction of the nervous system (central or peripheral). Pain
for chronic pain, while behavioural and psychological therapies
is classified usually as acute (short-duration and usually
do play a significant role as adjuncts in chronically depressed
remittent) or chronic (longer duration and persistent).
patients. Stimulation therapies like acupuncture and
ASSESSMENT OF PAIN transcutaneous electrical nerve stimulation (TENS) have also
been found to be beneficial. Apart from the NSAID and opioids
A comprehensive assessment is required for optimal pain
which are also used for chronic pain, other pharmacological agents
management. The aim is to have a clear understanding of
used include antidepressants (tricyclics, serotonergic uptake
the patient’s pain problem, in terms of its aetiology,
inhibitors and selective norepinephrine reuptake inhibitors),
pathophysiology and syndrome. This requires a detailed history,
membrane stabilising agents like carbamazepine, gabapentin
and systemic examination is carried out to unravel the pain
and pregabalin, local lidocaine plasters/patches. The commonly
characteristics, impact of pain on multiple domains, relevant
used drugs along with their dosages are listed in Table 1.
pre-morbid conditions, existing co-morbidities, history of
substance use, previous investigations carried out and Despite the availability of numerous analgesic drugs, the
treatment taken. clinical relief to patients for chronic pain has remained far from

10
 Pain—Mechanisms and Management
Figures 1A and B: Pain signals are transmitted to the brain by two main pathways. The lateral system (A) is made up of long thick fibres that transmit information
about the onset of injury and its precise location and intensity. They are designed to carry a rapid flow of pain signals to the thalamus to stimulate an immediate
anti-nociceptive response. The medial system (B) is composed of phylogenetically older fibres that carry slower signals and probably transmit information related
to the persistence of injury and level of response induced.
Contd...
Table 1: Commonly Used Drug Dosages for Pain Indomethacin 50 mg 8 hourly
Anti-depressants Piroxicam 20 mg 24 hourly
Tricyclic anti-depressants—amitriptyline 10 to 25 mg bedtime, Ketoprofen 50 mg 8 hourly
increase step-wise to 150 mg twice/day Ibuprofen 400 mg 6 hourly
Duloxetine 30 mg twice/day, increase to 120 mg/day. Diclofenac 50 mg 8 hourly
Venlafaxine: 25 mg tid
satisfactory. Researchers are presently investigating role of
Anti-convulsants
Carbamazepine 200 mg tid; nerve growth factor monoclonal antibodies, targeting sodium
Clonazepam 0.5 mg tid; and calcium membrane ion channels and mechanisms based
Gabapentin 100 to 300 mg at bedtime to 3,600 mg/day in 3 on activated microglia (non-neuronal cells implicated in the
divided doses; pathophysiology of chronic pain) to achieve breakthrough in
Pregabalin: 75 mg twice daily to 600 mg/day alleviating chronic pain.
Opioid agonist
Tramadol 50 mg once or twice to maximum of 400 mg/day RECOMMENDED READINGS
Morphine Analogues: 1. Burgess G, Williams D. The discovery and development of analgesics: new
Morphine 30 mg every 4 hours or as needed; mechanisms, new modalities. J Clin Invest 2010; 120: 3751-7.
Codeine 200 mg every 3 to 4 hourly.
2. Recommendation for pharmacological management of neuropathic pain:
Nonsteroidal anti-inflammatory drugs: An overview and literature update. Robert Dworkin, AK Bannox Joseph
Aspirin 650 mg 4 to 8 hourly Audette et al. Mayo Clin Proceedings 2010; 85 (3): S3-S14. 11
Contd...
 2.2 Headache

K Ravishankar

INTRODUCTION chronic recurrent headache or a chronic non-progressive daily

Headache is one of the most common of human complaints. It headache represents a primary headache, such as migraine,
could be due to a number of causes ranging from a mild head cluster headache or tension-type headache. Sudden onset of a
injury to a serious brain tumour or more often it could be a severe headache suggests possible vascular involvement such
disorder unto itself such as migraine. as a subarachnoid bleed or an acute infective cause like
meningitis. There are some forms of primary headaches which
Headaches can be primary or secondary. Primary headaches
may have a sudden onset such as coital headache or crash
are benign headaches where clinical examination and
migraine and although the suddenness and severity may
investigation including imaging are normal, e.g. migraine,
suggest an organic illness, it may be possible to diagnose them
tension-type headache and cluster headache. Secondary
in retrospect only after their recurrent nature manifests.
headaches have an underlying structural, vascular, metabolic
Progressively worsening headache suggests increasing
or infective cause, e.g. headaches due to brain tumours,
intracranial pressure or uncontrolled systemic disease. Although
meningitis or subarachnoid haemorrhage. Approximately 90%
presence of focal or lateralising features makes the diagnosis
of headaches seen in practise are primary headaches.
easier, it is the subacute headache which is more difficult to
The skull, much of the pia-arachnoid, the dura over the convexity interpret. These headaches develop over weeks or months and
of the brain, and the parenchyma of the brain are insensitive to the aetiology could be benign or serious. Therefore, specific
pain. The pain-sensitive structures in the head are given below: information regarding progressive worsening needs to be
1. The skin, subcutaneous tissue, muscles, extracranial arteries, sought.
and the periosteum of the skull.
Some headaches like cluster headache may occur at the
2. The intracranial venous sinuses, especially in the same time everyday. In some the headaches may increase
pericavernous region. towards the evening as with tension-type headache, and in
3. Parts of the dura at the base of the brain and the arteries some like migraine, the headaches may occur first thing in
within the dura and pia-arachnoid. the morning and awaken the patient from sleep. Rare
4. The middle meningeal and superficial temporal arteries. primary headaches like cluster headaches and their variants
are grouped together as trigemino-autonomic cephalgias
5. The structures of the eye, the ear, the nasal cavities, and the ( TACs). These are short-lasting and occur several times in a
sinuses.
day and are diagnosed by their characteristic pattern and
6. Optic, oculomotor, trigeminal, glossopharyngeal, vagus and associated autonomic features like conjunctival injection,
the first three cervical nerves. lacrimation or rhinorrhoea.
Sensory stimuli are conveyed to the central nervous system The age of onset is also important. Migraine begins at a younger
through the trigeminal nerve, particularly the first and to some age and is more common in females aged 25 to 40 years
extent the second division; they carry impulses from the whereas tension-type headache is common in middle age.
forehead, orbit, anterior and middle cranial fossa. A specific Headaches beginning after 50 years of age should be
classification system — ‘the classification and diagnostic criteria investigated for potential secondary causes. Any change in
for headache disorders, cranial neuralgias and facial pain’ was headache pattern should always raise suspicion of an organic
proposed by the International Headache Society in 1988 and pathology. The longer the history the more the likelihood of a
the same was revised in the year 2004. All headache disorders benign underlying cause.
have been organised into 14 major groups and divided into 257
different subtypes. Groups 1 to 4 cover primary headaches and When the head pain is chronic and occurs on a daily or near
groups 5 to 14 cover secondary headaches. daily basis for more than 15 days per month, one uses the label
of chronic daily headache (CDH). It is essential to establish if we
APPROACH TO THE PATIENT WITH HEADACHE are dealing with primary CDH or secondary CDH. The following
History entities are included under the heading of long-lasting primary
Pattern recognition is most important for headache diagnosis. CDH:
The same patient can have more than one type of headache. It 1. Chronic migraine
is better to generate a routine set of questions under pre-set
2. Chronic tension-type headache
headings. The following aspects of the history are important in
arriving at a diagnosis. 3. Hemicrania continua
Temporal Profile 4. New daily persistent headache
The mode of onset and progression are critical in deciding All these conditions may present with or without medication
12 whether one is dealing with a benign or a serious headache. A overuse. When faced with a patient who has CDH, it is essential
 Headache
to determine the duration of the headache. With an arbitrary use of certain drugs, e.g. beta blockers would be contraindicated
time limit of 4 hours, daily headaches can be grouped as short- in a diabetic or an asthmatic.
lasting (< 4 hours) or long-lasting (> 4 hours). Examples of short-
lasting CDH are cluster headache and other TACs. Recurrent Table 1: Migraine Triggers
attacks of short duration head pain would favour the diagnosis Food items Cheese, dairy products, paneer (cottage
of cluster headache or one of its variants like chronic paroxysmal cheese), citrus fruits, chocolates, onions,
hemicrania. sea food
Food additives Monosodium glutamate (MSG), aspartame,
Location and Type of Headache nitrates, caffeine
The type of pain, its location and severity are important for Alcohol Red wine, beer
diagnosis. Unilateral pulsating or throbbing headaches indicate Hormonal changes Menstruation, ovulation
an underlying vascular involvement as in migraine but migraine Physical exertion Excessive exercise, fatigue
Visual stimuli Bright lights, glare
headaches are also known to be bilateral. Other vascular
Auditory stimuli Loud noise or music
headaches can also be throbbing in nature. Cluster headaches
Olfactory stimuli Perfumes and certain odours
are almost always unilateral in the same location during a cluster Sleep Too much or too little
period, and rarely shifts sides.Tension-type headaches are diffuse, Weather changes
dull and generally bilateral. With secondary headaches, the Head or neck trauma
location of the headache, the nature and severity would vary Hunger
depending on the anatomical location of the lesion and the Stress and anxiety
mechanism involved in pain production. In addition to getting
the patient to describe the site and quality of the pain, rating EXAMINATION OF THE PATIENT WITH HEADACHE
the severity on a 10-point scale is useful in assessing progress Routine examination helps exclude hypertension, meningitis,
of the headache and in gauging the response to treatment. or systemic febrile illnesses. Additional examination may be
The Accompaniments necessary in order to increase the yield in headache patients.
Palpation over the head and neck is necessary to detect tender
In all patients with headache, one must establish the presence
trigger-points; auscultation over the skull, the carotid and
or absence of nausea, vomiting, hypersensitivity to light and
vertebral vessels can identify bruits; temporomandibular joint
noise and associated neurological involvement. Absence of an
and cervical spine palpation for tenderness and movement
established history of recurrent headaches or precipitation by
limitations; look for temporal artery tenderness; check the
triggers should prompt consideration of an underlying organic
mental status, the cranial nerves and look for asymmetry in
cause. Associated features like fever, arthralgias and malaise
power and look for reflexes.
suggest systemic disease. Associated neurological deficits or
auras, such as transient visual symptoms or hemisensory INVESTIGATION OF THE PATIENT WITH HEADACHE
deficits, support a diagnosis of migraine with aura. Other
Certain features in the history or examination (Table 2) should
neurologic accompaniments need appropriate investigations to
raise the suspicion of ominous disease and warrant further
differentiate between complicated migraine and transient
work-up. These are termed as danger signals’ or ‘red flags’.
ischaemic attacks (TIAs), vascular anomalies or a seizure disorder.
The typical behaviour of a migraine patient who tries to sleep Table 2: Headache Danger Signals
undisturbed in a dark room is in contrast to that of the patient Sudden onset of a new severe headache
with a cluster headache who cannot stay still and keeps pacing Progressively worsening headache or change in the pattern of
around. A positive family history can provide a clue to the the headache
diagnosis of migraine. Headache that is unresponsive to treatment
Headache that occurs regularly just before or during the Onset of headache with exertion, such as sexual activity,
coughing or sneezing
menstrual periods is likely to be menstrual migraine.
Hypertensive headache is more common in the morning, Onset of headache after 50 years of age
sinusitis headache is worse on bending, eyestrain headache Headache associated with change in neurological status
occurs more towards the evening and the headache of cervical Headache with abnormal examination findings
arthritis is more intense after a period of inactivity.
Laboratory Testing
Provoking and Relieving Factors The CBC, erythrocyte sedimentation rate (ESR) and relevant
Primary headaches such as migraine can frequently be blood chemistry should be obtained in all patients. It helps to
provoked by missing meals or going out in the hot sun. Trigger rule-out unsuspected systemic diseases. In an elderly patient
factors in the Indian setting are listed in Table 1. suspected with giant cell arteritis, ESR and C-reactive protein
are helpful.
Medical History
Careful questioning for systemic illnesses is essential, e.g. Cerebrospinal Fluid Examination
malignancy anywhere in the body should raise the possibility Cerebrospinal fluid (CSF) examination must be considered in
of cerebral metastases. Likewise vascular headaches in a patient patients when there is fever or associated cranial nerve deficit.
with a history of spontaneous abortions or thromboembolic Opening and closing pressures must be documented,
events should raise the possibility of antiphospholipid antibody particularly in cases of pseudotumour cerebri or idiopathic
syndrome. Systemic diseases can be a contraindication to the intracranial hypertension which can sometimes present with 13
 intractable migraine-like headache and may not always be to severe unrelenting migraine attacks that last more than
associated with papilloedema. 72 hours.
Neuroimaging Management
Imaging must be done whenever there are danger signals. Once trigger factors are identified, preferably with the help of a
Avoid imaging scans if there is a history of similar headaches in ‘headache diary or headache calendar’, drug treatment needs
the past or if examination is normal, or if the headache improves to be selected depending on the severity and the level of
with treatment. disability. Ideal management of migraine should concentrate
on three major areas:
Magnetic resonance imaging (MRI) is now rapidly becoming
the standard diagnostic test for head and face pain, particularly 1. Control of trigger factors
with the advantage of non-invasive evaluation of the 2. Treatment of the acute attack
vasculature by MR angiography and MR venography. An MRI 3. Long-term prophylactic medication
has many advantages over a CT in a headache patient. In the
appropriate setting one must investigate further with digital Pharmacotherapy
subtraction angiography (DSA). For mild-to-moderate attacks, simple analgesics like aspirin or
acetaminophen suffice. Combining with an anti-emetic like
PRINICIPAL HEADACHE VARIETIES metoclopramide or domperidone, which increases gastric
Primary Headaches motility and enhances the absorption of other drugs, is more
Migraine beneficial. Nonsteroidal anti-inflammatory drugs (NSAIDs) are
Migraine manifests with recurrent headaches associated with also effective in mild to moderate cases.
nausea, vomiting, photophobia or phonophobia with or without For moderate-to-severe attacks, triptans and ergotamine are
an aura. It is more common in women (2 to 3:1) and a family useful as abortive drugs. When the patient is vomiting,
history is often present (60% of cases). Attacks begin in late injectable diclofenac or ketorolac is recommended. Narcotic
childhood, adolescence and early twenties. Majority of the injections should not be used in migraine. Sumatriptan is a 5-
patients with migraine, 80% have migraine without aura. HT 1D agonist that blocks neurogenic inflammation in the
Clinical features trigemino-vascular system. It is available as 25 mg, 50 mg, and
100 mg tablets and as a nasal spray. Unlike ergotamine, it is
Migraine should always be thought of as a complex neurological
effective when given at any time during the attack and has a
disorder with headache being one of the common presenting
better safety profile; it works rapidly and also relieves nausea,
features. There may be other accompanying neurological,
vomiting, photophobia and phonophobia. Recurrence of
gastrointestinal or autonomic features as shown in Table 3.
headache because of the short half-life is a major disadvantage
Table 3: Accompaniments of Migraine with sumatriptan, but is less with the newer second generation
triptans, like rizatriptan, eletriptan, zolmitriptan and nara-
Gastrointestinal: Anorexia, nausea, vomiting, diarrhoea triptan. Chest symptoms including tightness and pressure in
Visual disturbances: Blurring, photophobia the throat, neck and chest are more common with sumatriptan
Motor abnormalities than with other triptans. Contraindications to triptans include
Brainstem features: Vertigo, ataxia, diplopia, dysarthria ischaemic heart disease, uncontrolled hypertension or
Autonomic disturbances: Hypertension, hypotension, tachycardia, concomitant use of ergotamine derivatives or other 5-HT1
bradycardia, nasal congestion, and peripheral vasoconstriction agonists. Rizatriptan is available as 5 mg and 10 mg tablets.
Fluid retention Steroids may occasionally be used as alternatives when all
Psychological upsets, confusional states other drugs fail.
The typical attack of migraine consists of a sequence of events Recurrent episodes of migraine need simultaneous
divided into four different phases, that blend imperceptibly with prophylactic treatment. Beta-blockers, calcium-channel
each another: the prodrome, the aura, the headache and the blockers, methysergide, cyproheptadine, tricyclic anti-
postdrome. depressants and anticonvulsants like divalproex and topiramate
are used prophylactically. In most instances, prophylaxis need
Pathophysiology
not be continuous, but is used for specific trial periods with
The possibility that a migraine attack may be initiated by cortical drug-free intervals until the frequency is controlled.
spreading depression is the most favoured hypothesis. This
condition is a transient disruption of neuronal activity in the Tension-Type Headache
brain accompanied by a flux of sodium, calcium ions into the Tension-type headache occurs more commonly in patients
cells. This results in a brief burst of electrical activity followed subjected to stress, anxiety and depression. It begins as episodes
by electrical silence, which progresses as an expanding and progresses to a chronic form where headaches occur
concentric wave through the brain at the same rate as a almost daily and do not appear to be associated with any overt
developing migraine aura. psychological factors.
Migraine variants Clinical features
Depending on the accompanying neurologic deficit, there are The headache is usually generalised and of long duration. The
different variants of migraine, such as hemiplegic migraine patient experiences a constant pain and obtain temporary relief
14 and basilar migraine. Status migrainosus is the term applied with analgesics and sleep. There are no associated symptoms,
 Headache
like vomiting, photophobia or phonophobia. The diagnosis can Secondary Headaches
be established by a good history. Raised intracranial pressure
Treatment Any lesion that increases intracranial pressure is likely to cause
The physician should attempt to identify the stress or emotional a progressively increasing headache. Headache as a presenting
problem underlying the headache. Anxiety may be controlled feature will depend on the nature and location of the mass.
by use of a mild antidepressant. Depressed patients may benefit Posterior fossa lesions raise intracranial pressure rapidly. The
from a tricyclic antidepressant such as imipramine or headache is usually generalised, may not fit into any particular
amitriptyline. When sleep is disturbed, it is important to establish pattern, slowly increases in intensity and leads to drowsiness
a normal sleep pattern using short-acting hypnotic agents. and confusion following which focal neurological signs develop.
When tension-type headache is associated with an emotional Neuroimaging helps in the early detection of some of these
problem, the patient should be referred for psychiatric lesions.
evaluation and treatment. Intracranial haemorrhage
Cluster Headache Head trauma can lead to epidural or subdural haematomas.
Cluster headache is a devastating painful headache, mostly Intracerebral haemorrhage is usually sudden in onset and can
affecting men.The term ‘cluster headache’ reflects the clustering produce incapacitating headache with focal neurological
of headache attacks in time. It is considerably less common than symptoms and depressed consciousness. A subarachnoid
migraine and begins in the second or third decade of life. There haemorrhage due to rupture of an aneurysm or arteriovenous
is a periodicity to the attacks with seasonal clustering. Typically malformation produces an explosive incapacitating headache
pain peaks lasts from 30 to 180 minutes and may occur 1 to 3 with vomiting, decreased level of consciousness and signs of
times per day. The pain is usually spontaneous, but can be meningeal irritation.This possibility should be kept in mind in every
provoked by alcohol. Patients describe the pain as excruciating patient who presents with sudden onset headache and the
or penetrating and on the same side during each cluster. The diagnosis must be confirmed by doing a CT or lumbar puncture.
pain is accompanied by lacrimation, rhinorrhoea or ptosis. Meningitis
Differential diagnoses include diseases of the orbit, tumours of The headache is usually accompanied by fever, stiff neck,
the brainstem or occipitocervical junction, infiltration/infection vomiting, and the diagnosis is confirmed by CSF examination.
of the brainstem and cavernous sinus disorders. MRI should
be done in all patients with cluster headache. Idiopathic intracranial hypertension
Idiopathic intracranial hypertension or pseudotumour cerebri
Treatment
presents with headache and visual obscurations along with
Symptomatic treatment includes oxygen inhalation at about 7 other signs of increased intracranial pressure. It usually occurs
litres per minute, parenteral dihydroergotamine (DHE), or in young, obese women; CT/MRI reveals small ventricles and
parenteral sumatriptan 6 mg. Zolmitriptan nasal spray has been on examination the patient may have decreased vision and
found to be useful for the acute treatment of cluster headache. usually but not necessarily there is papilloedema. Lumbar
Drugs for the prophylactic therapy of cluster headache include: puncture shows evidence of increased opening pressure. MR
1. Verapamil given in doses as required, starting with 120 to Venography is a must in these patients.
240 mg daily.
Medication overuse headache
2. Lithium carbonate in a dose of 150 mg twice daily with
Medication overuse headache has been variously referred to as
periodic check-up of drug levels and watch for side-effects.
analgesic/ergotamine/drug-rebound headache. The headache
3. Steroids are very effective in preventing attacks, but are not sufferer who consumes medications for acute attacks on a regular,
indicated for long-term use. repeated and predictable basis is at risk of developing chronic
4. Methysergide is an effective medication in treating chronic daily headaches that are caused by overuse of medication. The
cluster headaches; 2 mg is the starting dose and the dosage most significant feature is that the headache typically persists
is gradually increased, but retroperitoneal fibrosis is a throughout the whole day, is present on waking and is described
side-effect. as a dull, diffuse headache. Complete withdrawal of the analgesic
5. Divalproex and other anticonvulsants like topiramate is the only effective treatment. Withdrawal headaches can be
have also been found to be useful in prevention of cluster treated with NSAIDs and, if detoxification fails, in-patient
attacks. treatment with chlorpromazine or intravenous dihydroergotamine
or subcutaneous sumatriptan can be tried.
Other Trigemino-Autonomic Cephalgias (TACs) and Short-
Lasting Headaches RECOMMENDED READINGS
There are some head pains which are considered variants of 1. Bigal ME, Lipton RB, Tepper SJ, Rapoport AM, Sheftell FD. Primary chronic
cluster headache, but they differ in being very responsive to daily headache and its subtypes in adolescents and adults. Neurology 2004;
63: 843-7.
indomethacin and in their short duration and high frequency
2. Headache Classification Subcommittee of the International Headache
of attacks. The best example of this is chronic paroxysmal Society.The International Classification of Headache Disorders. Cephalalgia
hemicrania which is characterised by frequent daily attacks 2004; 24 (suppl. 1): 1-160.
of severe, short-lasting, unilateral, orbital, or temporal pain of 3. Ravishankar K. Headache pattern in India a headache clinic analysis of 1000
20 to 45 minutes duration with associated autonomic features. patients. Cephalalgia 1997; 17: 316-7.
It is seen mostly in females and is usually responsive to 4. Ravishankar K. Optimising primary headache management. J Assoc
indomethacin. Physicians India 2006; 54: 928-34. 15
 2.3 Chest Pain

Sanjay Tyagi, Amit Mittal

INTRODUCTION PATHOPHYSIOLOGY
Chest pain is a very common complaint most often caused by The thoracic viscera provide afferent visceral input through
benign conditions, but occasionally it may be due to life- the same thoracic autonomic ganglia as the chest wall. A
threatening medical emergencies. Chest pain may be caused painful stimulus in these organs is typically perceived as
by almost any condition affecting the thorax, abdomen or originating in the chest but because afferent nerve fibers
internal organs. The approach to chest pain, therefore, is to overlap in the dorsal ganglia, thoracic pain may be felt (as
exclude benign conditions and to rapidly identify and treat referred pain) anywhere between the umbilicus and the ear,
potentially fatal and serious conditions. So, it is critically including the upper extremities. When the sensation is visceral
important to distinguish the two major presentations of chest in origin, many patients deny having pain and insist that it is
pain: emergent and nonemergent. Many patients are aware that merely ‘discomfort’.
it is a warning of potentially life-threatening disorders and seek
evaluation for minimal symptoms. Other patients, including APPROACH TO THE PATIENT
many with serious disease, minimise or ignore its warnings. Pain While the priority in any patient who presents with chest pain
perception (both character and severity) varies greatly between is to exclude catastrophic or life-threatening (cardiac) causes,
individuals as well as between men and women. So chest non-life-threatening aetiologies, which may be functionally
pain as a symptom should never be dismissed without an disabling, are much more common. The diagnosis of chest
explanation for its cause. pain is difficult but the history often gives an indication of the
underlying cause. If there is any suspicion of an acute coronary
CAUSES syndrome (ACS) or other serious cause or any concern regarding
Chest pain may originate from the cardiovascular, pulmonary, the patient’s general well being, then urgent hospital admission
gastrointestinal, neurologic, or musculoskeletal systems should be arranged.
(Table 1).
The history and physical examination, complemented by
Table 1: Common Causes of Chest Pain selected tests such as an electrocardiogram or chest radiograph
help to reach an accurate diagnosis for most causes of chest
Cardiovascular Pulmonary pain, especially CAD, and to judge which patients are likely to
Acute coronary syndrome Pulmonary embolism have a benign aetiology (Tables 2 and 3).
Aortic dissection Pneumothorax
Pericarditis and cardiac Pneumonia DESCRIPTION OF THE CHEST PAIN
tamponade Pleurisy A thorough description of the pain is an essential first step in
Stable angina pectoris Gastrointestinal the diagnosis of chest pain.
Chest wall Oesophageal reflux disease
Quality of the Pain
Costochondritis or Hiatus hernia
Tietze’s syndrome Cholecystitis The patient with myocardial ischaemia often vigorously denies
Fibromyalgia Gastritis feeling chest ‘pain’. More typical descriptions include squeezing,
Radiculopathy Pancreatitis tightness, pressure, constriction, strangling, burning, heartburn,
Herpes zoster Others fullness in the chest, a band-like sensation, knot in the centre
Psychological Da Costa’s syndrome of the chest, lump in the throat, ache, a heavy weight on the
Somatisation disorder Bornholm disease chest and toothache (when there is radiation to the lower jaw).
Anxiety and panic disorders In some cases, the patient cannot qualify the nature of the
Hypochondriasis discomfort, but places his or her fist on the centre of the chest
(the Levine sign).
Overall, the most common causes are: A ‘sharp’ or ‘stabbing’ pain with a pleuritic or positional
 Chest wall disorders (i.e. those involving muscle, rib, or component that is fully reproducible by palpation, in patients
cartilage) who have no history of angina or myocardial infarction,
 Pleural disorders probably indicates a low-risk for the episode being ischaemic.

 GI disorders (e.g. oesophageal reflux or spasm, ulcer disease, Region or Location of the Pain
cholelithiasis) Ischaemic pain is a diffuse discomfort that may be difficult to
localise. Pain that localises to a small area on the chest is more
 Idiopathic likely of chest wall or pleural origin rather than visceral. Referred
 Acute coronary syndromes pain is an exception.
16
 Chest Pain
Table 2: Causes of Chest Pain
Cause Suggestive findings Diagnostic approach
Cardiovascular
Myocardial ischaemia Acute, crushing pain radiating to the jaw or arm Serial ECGs and cardiac markers
(acute MI/unstable Exertional pain relieved by rest (angina pectoris) Stress imaging test considered in patients
angina/angina) S4 gallop with negative ECG findings and no elevation
Sometimes a systolic murmur of cardiac marker
Thoracic aortic Sudden, tearing pain radiating to the back Chest X-ray, transthoracic or transoesophageal
dissection Some patients have syncope, stroke, or leg ischaemia echocardiography
Pulse or BP may be unequal in the extremities CT scan of aorta for confirmation
Pericarditis Constant or intermittent sharp pain often ECG and echocardiography usually diagnostic
aggravated by breathing, swallowing food, or supine
position and relieved by sitting leaning forward
Pericardial friction rub
Myocarditis Fever, dyspnoea, fatigue, chest pain, ECG, serum cardiac markers
recent viral or other infection ESR, C-reactive protein
Sometimes findings of heart failure, pericarditis, or both Usually echocardiography
Gastrointestinal
Oesophageal reflux Recurrent burning pain radiating from epigastrium Clinical evaluation, endoscopy
(GERD) to throat that is exacerbated by bending down or Sometimes motility studies
lying down and relieved by antacids
Peptic ulcer Recurrent, vague epigastric or right upper quadrant Clinical evaluation, endoscopy
discomfort in a patient who smokes or uses alcohol Sometimes testing for H. pylori
excessively that relieved by food, antacids, or both
Pancreatitis Pain in the epigastrium or lower chest that is often Serum amylase and lipase
worse when lying flat and is relieved by leaning forward
Vomiting, upper abdominal tenderness Sometimes abdominal CT
Often history of alcohol abuse or biliary tract disease
Pulmonary
Pulmonary embolism Often pleuritic pain, dyspnoea, tachycardia D-dimer, echocardiography, CT scan of chest,
Sometimes, mild fever, haemoptysis, shock chest X-ray, lower limb Doppler study
Pneumonia Fever, chills, cough, and purulent sputum Chest X-ray
Often dyspnoea, tachycardia, signs of consolidation
on examination
Pneumothorax Sometimes, unilateral diminished breath sounds, Chest X-ray
subcutaneous air
Pleuritis May have preceding pneumonia, pulmonary Usually clinical evaluation
embolism, or viral respiratory infection
Pain with breathing, cough, pleural rub
Other
Musculoskeletal chest Often suggested by history Clinical evaluation
wall pain (including Pain typically persistent (typically days or longer),
trauma, overuse, worsened with passive and active movement
costochondritis) Diffuse or focal tenderness
Herpes zoster infection Sharp, band-like pain mid-thorax unilaterally Clinical evaluation
Classic linear, vesicular rash
Pain may precede rash by several days

Table 3: Clinical Features Associated with Specific Diagnostic Categories of Chest Pain
Clinical Features Cardiac Diagnostic Category Musculoskeletal
Gastrointestinal
Predisposing Male sex Smoking Physically active
factors Smoking Alcohol use New activity
Hypertension Overuse
Hyperlipidaemia Repeated activity
Family history
Onset At consistent level of exertion After meals or on an empty stomach With or after activity
Duration Minutes Minutes to hours Hours to days
Character Pressure or tightness Pressure or gnawing pain Sharp, localised and movement
related
Relieved by Rest, sublingual nitrate Food, antacids Rest, analgesics, NSAID
17
 The pain of myocardial ischaemia may radiate to the neck, distinguish gastrointestinal from ischaemic chest pain. On
throat, lower jaw, teeth, upper extremity, or shoulder. A wide the other hand, pain that abates with cessation of activity
extension of chest pain radiation increases the probability that strongly suggests an ischaemic origin.
it is due to myocardial infarction. Radiation to both arms is an  The pain of pericarditis typically improves with sitting up
even stronger predictor of acute myocardial infarction. Acute and leaning forward.
cholecystitis can present with right shoulder pain, although
concomitant right upper quadrant or epigastric pain is more Severity
typical than chest discomfort. Chest pain that radiates between The severity of pain is not a useful predictor of CAD. As many as
the scapulae may be due to aortic dissection. one-third of myocardial infarctions may go unnoticed by the
patient.
Temporal Elements
The time course of the onset of chest pain may be a very useful ASSOCIATED SYMPTOMS
distinguishing feature: Associated symptoms may not reliably distinguish between a
 The pain associated with a pneumothorax or a vascular cardiac and gastrointestinal origin of chest pain.
event such as aortic dissection or acute pulmonary  Belching, a bad taste in the mouth, and difficult or painful
embolism typically has an abrupt onset with the greatest swallowing are suggestive of oesophageal disease,
intensity of pain at the beginning. although belching and indigestion also may be seen with
 The onset of ischaemic pain is most often gradual with an myocardial ischaemia.
increasing intensity over time. A crescendo pattern of pain  Vomiting may occur in the setting of myocardial ischaemia
can also be caused by oesophageal disease. (particularly transmural myocardial infarction), in addition
 ‘Functional’ or nontraumatic musculoskeletal chest pain to gastrointestinal problems such as peptic ulcer disease,
might have a much more vague onset. cholecystitis, and pancreatitis.
 The duration of pain is also helpful. Chest discomfort that  Diabetic ketoacidosis, which can be precipitated by acute
lasts only for seconds or pain that is constant over weeks is myocardial infarction, is another cause of vomiting.
not due to ischaemia. A span of years without progression  Diaphoresis is more frequently associated with myocardial
makes it more likely that the origin of pain is functional. infarction than with oesophageal disease.
 The pain from myocardial ischaemia generally lasts for a
 Dyspnoea: Exertional dyspnoea is common when chest pain
few minutes; it may be more prolonged in the setting of a
is due to myocardial ischaemia and may precede the
myocardial infarction.
sensation of angina. Dyspnoea that occurs concurrently
 Myocardial ischaemia may demonstrate a circadian pattern.
with chest pain may be due to myocardial ischaemia or a
It is more likely to occur in the morning than in the number of pulmonary disorders including diseases of the
afternoon, correlating with an increase in sympathetic tone. airways, lung parenchyma, or pulmonary vasculature.
Provoking Factors  Cough: The differential diagnosis of chest pain and cough
The patient should be asked about factors that provoke or make includes infection, as well as congestive heart failure,
the pain worse: pulmonary embolus, and neoplasm. Cough, hoarseness, or
 Discomfort that reliably occurs with eating is suggestive of
wheezing may also be the result of gastro-oesophageal
upper gastrointestinal disease. reflux disease.
 Post-prandial chest pain may be due to gastrointestinal  Syncope: The patient with myocardial ischaemia may
or cardiac disease; in the latter case it can be a marker of present with presyncope. However, syncope associated
severe myocardial ischaemia (e.g. left main or three-vessel with chest pain should raise a concern for aortic dissection,
CAD). a haemodynamically significant pulmonary embolus, a
ruptured abdominal aortic aneurysm, or critical aortic
 Chest discomfort provoked by exertion is a classic symptom
of angina, although oesophageal pain can present similarly. stenosis (particularly if the patient has a history of exertional
dyspnoea).
 Other factors that may provoke ischaemic pain include cold,
emotional stress, meals, or sexual intercourse.  Palpitations: Patients with ischaemia can feel palpitations
resulting from ventricular ectopy, or may have an abnormal
 Truly pleuritic chest pain is worsened by inspiration and
awareness of their sinus rhythm. While atrial fibrillation is
may be exacerbated when lying down.
associated with chronic CAD, new onset, isolated atrial
 Causes of pleuritic chest pain include pulmonary embolism,
fibrillation is uncommon in patients with acute myocardial
pneumothorax, viral or idiopathic pleurisy, pneumonia, and
infarction.
a pleuropericarditis.
 Psychiatric symptoms: Symptoms of panic disorder,
Relieving Factors generalised anxiety, depression, or somatisation may occur
Factors that make the pain better should be established: in patients with chest pain. Panic disorder is present in 30%
 Pain that is reliably and repeatedly palliated by antacids or or more of patients with chest pain who have no or minimal
food is likely to be of gastro-oesophageal origin. CAD; it may also coexist with CAD.
 Pain that responds to sublingual nitroglycerin may be of RISK FACTORS
either oesophageal or cardiac aetiology. The clinical impression raised by the patient’s description of pain
 Relief of pain following the administration of a ‘GI cocktail’ must be interpreted together with other aspects of the history,
18 (e.g. viscous lidocaine and antacid) does not reliably including risk factors for various aetiologies of chest pain.
 Chest Pain
Knowledge about such risk factors provides important CVS Examination
information regarding disease likelihood, which may ultimately A complete cardiac examination including auscultation and
guide the type and extent of evaluation performed. The palpation should be performed in a sitting and supine position
presence of hyperlipidemia, smoking, cocaine use, or a family to establish the presence of a pericardial rub or signs of acute
history of premature CAD increases the risk for myocardial aortic insufficiency or aortic stenosis. Ischaemia may result in a
ischaemia. Hypertension is a risk factor for both CAD and aortic mitral insufficiency murmur or an S4 or S3 gallop.
dissection. Cigarette smoking is a nonspecific risk factor for
serious diseases; it is associated with CAD, thromboembolism, Respiratory System Examination
aortic dissection, pneumothorax, and pneumonia. A recent Determine if the breath sounds are symmetric and if wheezes,
infection, especially viral or tuberculosis may precede an crackles or evidence of consolidation is present.
episode of pericarditis. Other risk factors for pericarditis Abdominal Examination
include a history of chest trauma, autoimmune disease, recent
A careful examination of the abdomen is important, with
myocardial infarction or cardiac surgery, and the use of certain
attention to the right upper quadrant, epigastrium and the
drugs such as procainamide, hydralazine, or isoniazid. Age is an
abdominal aorta.
important risk factor for CAD; among patients older than 40
years, chest pain resulting from stable CAD or an acute coronary Findings which Raise Suspicion of a Serious Aetiology of
syndrome (unstable angina or myocardial infarction) becomes Chest Pain
increasingly common. Men older than 60 years are most likely  Abnormal vital signs (tachycardia, bradycardia, tachypnoea,
to suffer aortic dissection, while young men are at the highest hypotension) and pulsus paradoxus > 10 mmHg
risk for primary spontaneous pneumothorax.
 Signs of hypoperfusion (confusion, ashen colour, diaphoresis).
PAST HISTORY  Shortness of breath.
A past history of CAD, symptomatic gastro-oesophageal reflux,  Asymmetric breath sounds and pulses.
peptic ulcer disease, gallstones, panic disorder, bronchospasm,  New heart murmur.
or cancer is very helpful in making a diagnosis. It is important
to establish if the present symptoms are similar to those which DIAGNOSTIC TESTING
occurred when the diagnosis was previously established. A ECG is important in critical evaluation of chest pain particularly
history of diabetes mellitus should heighten the concern for a when a cardiac aetiology is a possibility. Presence of ECG
nonclassic presentation of CAD. It is important to exclude recent changes of ischaemia or infarction warrants admission to a
blunt trauma to the chest that can result in pneumothorax, CCU. Chest radiography (when cardiac or pulmonary disease
disruption of the aorta, tracheobronchial tree, and oesophagus, is a consideration) may support the initial diagnosis and
myocardial or pulmonary contusion, or chest wall injury with help avoid missing serious aetiologies of chest pain such as
associated musculoskeletal discomfort. aortic dissection, pneumonia, pulmonary embolism or
pneumothorax. Serial measurement of cardiac biomarkers, i.e.
PHYSICAL EXAMINATION creatine kinase (CK), CK-MB and cardiac troponins (I and T)
The focused physical examination is used to support or disprove are useful in the emergency department for evaluation of
hypotheses generated by the history. Thus, the extent of the acute chest pain. However, markers may take several hours
examination is primarily determined by the diagnoses that are after the onset of infarction to rise, hence treatment should
being considered. not be delayed awaiting the results of enzyme levels.
General Physical Examination Other Useful Investigations
 The general appearance of the patient suggests the severity Other useful investigations are:
and possibly the seriousness of the symptoms (e.g. pallor,  Complete blood counts (to exclude anaemia)
diaphoresis, cyanosis, anxiety).  Renal function tests blood sugar
 A full set of vital signs can provide valuable clues to the
 Liver function test (Cholecystitis) and amylase (pancreatitis)
clinical significance of the pain, and may in some cases aid
 Exercise electrocardiography and stress echocardiography
in establishing its origin.
for evaluation of coronary artery disease in non-acute chest
 A marked difference in blood pressure between the two
discomfort
arms suggests the presence of aortic dissection. So pulses
are palpated in both arms and both legs, BP is measured in  Endoscopy for gastrointestinal causes of chest pain.
both arms. Carotid artery is auscultated for a bruit. KEY POINTS/CONCLUSION
 The neck is inspected for venous distension and venous
 With careful history taking and physical examination,
wave forms are noted. supplemented by targeted diagnostic tests, chest pain
Chest Wall Examination caused by serious conditions can often be quickly identified
for early and immediate treatment.
Palpation of the chest wall may evoke pain; if so the patient
 Immediate life threats must be ruled out first. Quick review
should be asked if this sensation is identical to the chief
complaint. Chest wall tenderness may be present concomitantly of ECG is useful.
with myocardial ischaemia. Hyperesthesia, particularly when  Some serious disorders, particularly coronary artery disease and
associated with a rash, is often due to herpes zoster. pulmonary embolism, may not have a classical presentation.
19
 2.4 Acute Abdomen—Non-Surgical Causes

Sumeet Singla, AK Agarwal

Acute abdomen is defined as a recent or sudden onset – Lateralised and radiating from back to front of
abdominal pain (usually within 24 to 72 hours) with frequently abdomen—spinal pain associated with radiculopathy
associated gastrointestinal symptoms and signs. Acute
 Aggravating factors
abdomen is taught classically as a ‘surgical’ topic. A significant
number of patients presenting with acute abdominal pain suffer – Increased on deep inspiration/coughing—pleurisy,
from non-surgical conditions. Hence, an effective approach to pleural effusion, pneumonia, spinal pain
the patient with acute abdomen must take into account the – Increased during menstruation—endometriosis
realisation that 3 out of every 4 such patients will be suffering – Increased in supine position—pancreatitis
from disorders requiring non-surgical intervention.This chapter  Associated features
is focussed on the approach to non-surgical causes of acute
– Vomiting—if vomiting precedes pain, a medical cause
abdominal pain.
is more likely
APPROACH TO DIAGNOSIS – Appetite—retention of appetite is more likely in a
medical cause
The most important attribute of the physician evaluating a
– Diarrhoea, dysentery—indicates infection or
patient with acute abdominal pain is the ability to think ‘out of
inflammation of the bowel
the (abdomen) box’. One must be familiar with the various
– Rectal bleeding—seen in bowel ischaemia/infarction,
causes of this presentation and then proceed to refute or
inflammatory bowel disease
confirm the individual entities. A structured approach (Figures
1A to C) is easy to remember, fast, useful in resource-poor
settings and minimises errors. Once a surgical cause has been
excluded (no signs of peritonitis, perforation or obstruction),
one can search for medical causes (Table 1). A non-rigid
abdomen suggests a medical cause. However, certain surgical
processes, initially confined to the visceral peritoneum, manifest
as a non-rigid abdomen and only later progress to frank
peritonitis when the parietal peritoneum is involved. Such a
progression invariably portends the need for surgery.

CLINICAL CLUES TO MEDICAL AETIOLOGIES

History
 Age >65 years consider coronary artery disease,
abdominal atheroemboli causing mesenteric ischaemia/
infarction.
 Sex in females specific causes like ectopic pregnancy,
threatened abortion, endometriosis, ovarian cyst and pelvic
inflammatory disease (PID) must be looked for; in males
epididymo-orchitis, prostatitis, and varicocoele are common
causes of lower abdominal pain.
 Nature of the abdominal pain
– Insidious onset, diffuse or midline pain—visceral pain
– Colicky pain—acute enteritis
– Dysaesthetic type of pain—radiculopathy, neuropathy
 Radiation of the pain
– To the back—pancreatitis, pericarditis
– To the right shoulder—Budd-Chiari syndrome,
congestive hepatomegaly
– To the left shoulder—splenic infarct, massive
splenomegaly
Figure 1A: Approach to the diagnosis of a non-rigid acute abdomen.
20 – Testicular/penile radiation—epididymo-orchitis
 Acute Abdomen—Non-Surgical Causes
Figure 1B: Algorithm for diagnosing medical causes of upper abdominal pain.

Figure 1C: Algorithm for diagnosing medical causes of lower abdominal pain.
(Figure 1A, 1B, 1C based on Martin RF, Rossi RL. The acute abdomen. An overview and algorithm. Surg Clin North Am 1997; 77: 1227-43).

– High grade fever with/without chills—suggests abdominal wall haematoma), neuroleptics (neuroleptic
pyelonephritis, enteritis, pneumonia malignant syndrome), drugs which can precipitate acute
 Urethral/vaginal discharge—suggestive of pelvic inflam- intermittent porphyria (barbiturates, phenytoin, rifampicin,
matory disease, STD. oral contraceptives, etc).
 Frequency and urgency of urine associated with dysuria/  Drug withdrawal—steroids (withdrawal may precipitate
haematuria/graveluria/lithuria—urinary tract infection. acute Addisonian crisis), narcotics, alcohol, and nicotine.
 Bloody/unusually dark urine—haematuria, haemoglobin-  Occupational exposure to heavy metals like lead (battery
uria due to intravascular haemolysis, acute intermittent makers, brass makers, cable makers, foundry workers, paint
porphyria. factory workers and painters), mercury (tube light, CFL and
 Drug history—nonsteroidal anti-inflammatory drugs mercury vapour lamp industry), arsenic (production of glass
(NSAIDs) (acute erosive gastritis), vincristine (recent or wood preservation), copper (mining, electrical wires,
chemotherapy), anti-coagulants (intra-abdominal or electroplating industry), asbestos (miners, stone crushers,
21
 insulations, asbestos sheet industry); risk of scorpion (black Physical Examination
widow spider) or snake bites (common krait or Bungarus The overall appearance of the patient can be very helpful.
caeruleus)—farmers, rural areas, sleeping on the floor, living Patients whose pain is relieved by leaning forward may have
in mud huts. pancreatitis. Most patients would be having tachycardia;
 Recent travel to areas endemic for malaria, typhoid, enteric unusual bradycardia should suggest typhoid, inferior wall
infections. myocardial infarction, drugs/toxins, and hyperkalaemia. Marked
 Menstrual history—relation of pain with menses; hypertension could signify porphyria, connective tissue
amenorrhoea. disorders, uraemia, and hyperthyroidism. A patient may be
 Psycho-social history—unemployed, living alone, divorced, dyspnoeic because of underlying pneumonia, pulmonary
diminutive personality, treated for anxio-depressive embolism, massive pleural or pericardial effusion, myocarditis,
disorders, underlying psychoses. In these groups, a higher myocardial infarction, or metabolic acidosis (Kussmaul
possibility of psychosomatic causes exists. breathing). Tachycardia, mildly raised blood pressure and

Table 1: Differential Diagnosis of Medical Causes of Abdominal Pain

Metabolic/Haematologic Referred: Extraperitoneal Causes
A. Familial metabolic A. Pulmonary
Acute intermittent porphyria Pneumonia
Haemochromatosis Pulmonary embolism
Hereditary angioneurotic oedema Pleurisy
B. Endocrine Spontaneous pneumothorax
Diabetic ketoacidosis B. Cardiac
Addisonian crisis Angina: acute myocardial infarction
Hyperthyroidism/hypothyroidism Pericarditis
Hypercalcaemia (hyperparathyroidism) Myocarditis
C. Haematologic Congestive hepatomegaly
Sickle cell crisis C. Urologic
Acute haemolytic states Pyelonephritis
Leukaemia Renal infarct
Coagulopathies Cystitis
Inflammatory Conditions Prostatitis
A. Infections D. Obstetric, gynaecologic
Enteric infections Non-pregnant
Salmonella, typhoid fever Ovarian cyst
Shigella Salpingitis
Staphylococcal Dysmenorrhoea
Yersinia Endometriosis
Campylobacter First-trimester pregnancy
Tuberculosis Ectopic pregnancy
Viral enterocolitis Normal pregnancy
Parasitic Threatened/incomplete abortion
Spontaneous bacterial peritonitis E. Neurologic; spinal
Hepatitis (viral, Q fever, malarial) Multiple sclerosis
Mesenteric lymphadenitis Tabes dorsalis; gastric crisis
Infectious mononucleosis Diabetic thoracic radiculopathy
Mumps Herpes zoster
AIDS-related disorders Abdominal migraine
B. Non-infectious Abdominal epilepsy
Acute rheumatic fever F. Abdominal wall—rectus sheath haematoma, myositis
Systemic lupus erythematous G. Skeletal
Polyarteritis nodosa Thoracolumbar spine
Henöch-Schoenlein purpura Osteomyelitis
Inflammatory bowel disease Hip—arthritis
Crohn’s disease H. Adynamic ileus and pseudo-obstruction
Ulcerative colitis Uraemia
Pancreatitis Hypokalaemia
Drug-and toxin-related Conditions Constipation
Heavy metal poisoning—Pb, Hg, As, Cu I. Splenic infarct
NSAIDs Functional
Mushroom ingestion Somatisation disorders
Staphylococcus toxin Hypochondriasis
Black widow spider bite Malingering
Anti-coagulants
Narcotic, steroid withdrawal
Neuroleptic malignant syndrome
22 Krait envenomation
 Acute Abdomen—Non-Surgical Causes
tachypnoea may be seen in an apprehensive patient. The examinations (and laboratory investigations) do not yield
elderly, diabetic, uraemic, and immunosuppressed may be anything, a non-organic cause must be considered.
normothermic despite being seriously ill. Next, the head and
neck should be examined for intraoral lesions, icterus, cyanosis, Table 2: Imaging Studies in Acute Abdominal Pain
lymphadenopathy, jugular venous pressure, smell of ketones Retroperitoneal disease—CT scan
in the breath, carotid bruits, and lead line on gums. Fundus Right upper quadrant and epigastric symptoms—Ultrasound
should be examined for emboli and lipaemia retinalis. Nailbeds Left upper quadrant symptoms—CT scan with IV contrast
should be inspected for infarcts or splinter haemorrhages. Pallor Left lower quadrant symptoms—CT scan with IV and oral
may signify external or internal blood loss, plumbism, addisonian contrast
crisis, and haematologic causes such as sickle cell disease, Right lower quadrant symptoms—Ultrasound
leukaemia or acute haemolysis; patients suffering form chronic
diseases such as cirrhosis, uraemia, AIDS and connective tissue Table 3: Clues to the Diagnosis of Medical Causes of Abdominal
disorders, who have become acutely ill, may also be anaemic. Pain
Pedal oedema signifies congestive cardiac failure or chronic liver Abdominal pain associated with:
disease. A general visual survey may help characterise the nature Neurological symptoms and signs—porphyria, snake (krait bite),
of rashes; photosensitive rash of acute intermittent porphyria; plumbism, barium carbonate poisoning, collagen vascular disorders,
purpuric rash of Henöch-Schoenlein purpura or leukaemia; illicit drug use
vasculitic rash of systemic lupus erythematosus, polyarterits Dark/cola coloured urine—porphyria, acute haemolysis, renal
nodosa or scleroderma; nodular painful rash of fat necrosis in infarction
acute pancreatitis; ulcers in sickle cell disease; vesicular rash of Jaundice—cirrhosis with spontaneous bacterial peritonitis,
herpes zoster and eruptive xanthomas in hyperlipidemia. congestive hepatomegaly, acute Budd-Chiari syndrome, acute
Examination of joints for active arthritis and of the spine for local hepatitis
tenderness, deformity and paraspinal muscle spasm (suggestive High fever with/without chills—acute pyelonephritis, atypical
of spinal disease) is not to be missed. pneumonia, basal pneumonia, bacterial enterocolitis, malaria,
typhoid fever
The examination of the cardiovascular and respiratory systems Multisystem involvement—SLE, PAN
may provide very important information viz. rubs, rhonchi, Anaemia—sickle cell disease, leukaemia, haemolysis, plumbism,
crackles, and murmurs. Examination of the abdomen starts coeliac disease, inflammatory bowel disease
with a careful visual inspection of the skin looking for rashes, Alcoholism—hepatitis, pancreatitis, abdominal tuberculosis,
discolouration (Grey-Turner’s sign, Cullen’s sign), distension spontaneous bacterial peritonitis
(ascites). Palpate the abdomen for assessing the site of Dyspnoea—metabolic acidosis (DKA, sepsis, mesenteric ischaemia,
maximal tenderness, presence or absence of rigidity, any poisonings), pneumonia, myocardial infarction
intramural swelling/tenderness (haematoma of the rectus Rectal bleeding—inflammatory bowel disease, enterocolitis, bowel
sheath), hepatosplenomegaly (leukaemia, malaria, or infarction
tuberculosis), shifting dullness (ascites), and costovertebral Diabetes—diabetic ketoacidosis, thoracic truncal radiculopathy,
angle tenderness (pyelonephritis, pyonephrosis, or acute pancreatitis, acute inferior wall myocardial infarction,
perinephric abscess). While a diffusely rigid abdomen strongly mesenteric ischaemia
points to an underlying surgical cause, a soft, non-rigid Arthritis—Henöch-Schoenlein purpura, connective tissue disorders,
abdomen increases the likelihood of a medical cause. As a inflammatory bowel disease, reactive arthritis associated with
enteric infections
corollary, when abdominal signs are minimal, but the patient’s
Pleural effusion—acute pancreatitis, congestive cardiac failure,
distress is severe, the physician should consider a medical
disseminated tuberculosis, pulmonary embolism, pneumonia,
condition as the cause of pain. Abdominal bruits signify that
empyema, SLE
vascular occlusion may be the cause of pain, as do splenic rubs.
Ascites—acute pancreatitis, congestive cardiac failure, spontaneous
A digital rectal examination is not to be omitted. It provides bacterial peritonitis
an opportunity to look for perianal skin tags, fistulae and Skin rash—herpes zoster, Henöch-Schoenlein purpura, vasculitides
sinuses (Crohn’s disease), to detect blood in the anal canal
Azotaemia or uraemia—prerenal causes (diarrhoea, dehydration,
[inflammatory bowel disease (IBD), colonic infarction], to acute blood loss), acute glomerulonephritis, collagen vascular
examine the male external genitalia (epididymo-orchitis, disorders
varicocoele) and is especially useful in patients with lower Weight loss—tuberculosis, diabetes mellitus, AIDS, chronic liver
abdominal pain (pelvic abscess, mass, prostatitis) and when a disease, inflammatory bowel disease
rigid abdomen prevents adequate examination. Likewise, Recurrent episodes of acute abdominal pain—acute pancreatitis,
per vaginum examination by a gynaecologist may provide porphyria, vaso-occlusive crisis of sickle cell disease, chronic lead
valuable information. It is a good practice to involve a poisoning, peptic ulcer, inflammatory bowel disease, mesenteric
gynaecologist in the evaluation and management of young ischaemia
female patients with acute lower abdominal pain due to the
far higher frequency of gynaecological (and hence, surgical) DIAGNOSIS
causes in this group. Finally, a neurological examination should Laboratory/radiologic investigations must be viewed as
be done in patients with gross neurological deficits (weakness confirmatory rather than screening tools. Other than a
of limbs or cranial muscles, sensory deficits, paraesthesiae, haemogram and a routine urine examination, all other
seizures and altered sensorium). Lack of objective clinical investigations need to be justified keeping in mind the
findings is most often due to observer error; but, if repeated diagnoses being sought. A low haemoglobin suggests blood 23
 loss or haemolysis. Leucocytosis is rather non-specific; amenorrhoea, it is mandatory to obtain a urine β-hCG test to
however, a neutrophilic leucocytosis suggests an infectious rule-out pregnancy. Free fluid in the peritoneal cavity/pleural
pathology. A lymphocytic or monocytic leucocytosis would cavity should be tapped if the situation demands or if the
be more in line with a viral aetiology, such as infectious diagnosis is unclear. In critically ill patients, peritoneal lavage
mononucleosis. Leucopenia portends a grave prognosis and is a good bedside test to detect peritoneal inflammation. A
may be due to severe sepsis, leukaemia, SLE or typhoid. red cell count of ≥100,000/mm3 and/or a white cell count of
Surgical illness is rare when both TLC and DLC are normal. ≥500 /mm3 in the lavage fluid represent a positive finding, as
A routine urine examination is useful in diagnosing urinary does the return of grossly purulent material, enteric contents,
tract infections, urolithiasis, glomerulonephritis and diabetic or other fluids that should not be present in the peritoneal
ketoacidosis. An electrocardiogram should be obtained cavity. A surgical cause, and the need for surgery, is then much
when evaluating a patient with risk factors/past history of more likely. Imaging of the abdomen should be a planned
atherosclerotic disease and may reveal inferior wall myocardial activity and not ordered blindly. When considering the use of
infarction, myocarditis or pericarditis. A radiograph of the chest imaging, the presence of localised symptoms can be useful in
is required if physical findings are suggestive of pneumonia, directing the choice of study as shown in Table 2.
effusion, embolism or congestive cardiac failure. Serum
A simplified, syndromic approach for the diagnosis of medical
amylase and lipase are required when acute pancreatitis is a
causes of acute abdomen is shown in Table 3.
strong possibility; beware of false positives due to non-
pancreatic hyperamylasemia. Imaging helps to differentiate RECOMMENDED READINGS
the two. In a patient with right hypochondrial pain with/
1. Agarwal N, Andley M. Acute abdomen in non-surgical disorders. In:
without jaundice and hepatomegaly, it is prudent to order Agarwal AK, Singal RK, et al. editors. Emergency Medicine; 1st Ed. New Delhi:
serum bilirubin, AST, ALT, and ALP levels. Serum sodium API (DSC ); Jaypee Brothers; 2005: pp 495-501.
and potassium estimation may help in diagnosing certain 2. Hammond ZT, Brunt LM. Evaluation of acute abdominal pain. In: Doherty
conditions. Hyponatremia may be seen in porphyria, acute GM, Meko JB, Olson JA, et al. editors. The Washington Manual of Surgery;
Addisonian crisis, and diabetic ketoacidosis. Only 45% of 2nd Ed. Washington; Lippincott Williams and Wilkins; 1999: pp 179-89.
patients in Addisonian crisis will have hyponatremia and 3. Hiatt JR. Management of the acute abdomen. Postgrad Med 1990; 87:
38-51.
potassium levels will be typically normal (as opposed to 65%
who have hyponatremia and 95% who have hyperkalemia in 4. Martin RF, Rossi RL. The acute abdomen. An overview and algorithms. Surg
Clin North Am 1997; 77: 1227-43.
chronic Addison’s insufficiency). Microscopic examination of
5. Powell DW. Approach to the patient with gastrointestinal disease. In:
the stool is useful in patients with fever and diarrhoea/ Goldman L, Ausiello D, editors. Cecil Textbook of Medicine; 22nd edn, Vol 1.
dysentery. Arterial blood gas estimation is useful for patients Philadelphia: Saunders; 2004: pp 782-3.
in cardio-respiratory distress, suspected illicit drug use, 6. Purcell TB. Non-surgical and extraperitoneal causes of abdominal pain.
poisonings, and unexplained causes (unexplained metabolic Emerg Med Clin North Am 1989; 7: 721-40.
acidosis is the hallmark of mesenteric ischaemia). In young 7. Steinheber FU. Medical conditions mimicking the acute surgical abdomen.
female patients with lower abdominal pain with/without Med Clin North Am 1973; 57: 1559-67.

24
 2.5 Cough

Suman Kirti

Cough is a sudden, explosive, often-repetitive expiration, which initiates airway inflammation, which sensitises the airway
helps to clear the tracheobronchial tree of secretions, irritants, to other irritants, and both cause persistent cough. Gastro-
foreign particles and microbes. Often called the watchdog of oesophageal reflux disease (GERD) causes cough by aspiration
the respiratory tract, it is the commonest and most important of gastric contents into the upper airways as well as vagal reflex
respiratory symptom. secondary to acid in the distal oesophagus.
MECHANISM Cough occurs whenever there is inflammation, constriction,
Cough can be initiated voluntarily or reflexively. The cough infiltration or compression of the airways. Inflammation
reflex has an afferent limb with receptors in the sensory occurs due to infections like viral or bacterial bronchitis or
distribution of trigeminal, glossopharyngeal, superior laryngeal, bronchiectasis. Viral bronchitis is usually acute, but persistent
and vagus nerves, that carries impulses to the cough centre inflammation can cause a prolonged cough. Pertussis can
located in the tractus solitarius in the medulla of the brainstem, also cause prolonged cough in adults. Constriction and
which is connected to the central respiratory generator. The inflammation occur in asthma and the diagnosis is made
efferent limb consists of the recurrent laryngeal nerve and the clinically. Rarely, there is a cough-variant asthma where there is
spinal nerves. Cough starts with a deep inspiration followed by cough without wheezing or dyspnoea. Tropical pulmonary
glottic closure, relaxation of the diaphragm and muscle eosinophilia (TPE) also causes cough. Infiltration of airways
contraction against a closed glottis causing airway pressure to with granulomas as in tuberculosis (TB), which is common in
rise (50 to 300 mmHg). This causes marked rise in positive India or endobronchial sarcoidosis, or by neoplasms like
intrathoracic pressure that results in tracheal narrowing. As the bronchogenic carcinoma and carcinoid, also triggers cough.
glottis opens the large pressure differential between airways Extrinsic compression of airways from lymph node masses,
and the atmosphere coupled with tracheal narrowing produces mediastinal tumours or rarely aortic aneurysm also causes
rapid flow rates (600 to 800 km/hr) through the trachea. These cough.
shearing forces aid in the elimination of mucus and foreign Parenchymal lung diseases causing cough are pneumonia,
materials. interstitial lung disease and lung abscess. Congestive
AETIOLOGY heart failure (CHF) can cause cough by interstitial as well as
peribronchial oedema.
Exogenous irritants like smoke, fumes, dust, foreign bodies or
endogenous irritants like upper airway secretions or gastric A dry cough may occur with angiotensin-converting enzyme
contents may trigger cough, by stimulating the receptors in the (ACE) inhibitors in 5% to 20% of users usually within a week
upper airway (pharynx or larynx) or inhalation or aspiration in or up to 6 months of starting the drug, possibly due to
the lower airways (tracheobronchial tree). Endogenous irritants accumulation of bradykinin or substance P which are degraded
from postnasal drip or gastric contents may go unrecognised by ACE. The angiotensin II receptor antagonists do not increase
and cough may continue. Prolonged exposure to irritants bradykinin levels and do not cause cough.

Figure 1: Acute cough algorithm for the management of patients ≥15 years of age with cough lasting <3 weeks.
Based on: Irwin RS et al. Chest 2006; 129: 1S-23S. (With permission).
25
 Beta-blockers can cause increased airway resistance due to eosinophils can give a yellow colour. Foul smelling sputum can
unopposed para-sympathetic activity especially in patients who occur in bronchiectasis and lung abscess.
already have obstructive airway disease.
Cough may occur more at night (asthma, left heart failure,
CLASSIFICATION pulmonary eosinophilia) or early morning (CB). It may be
Cough can be classified by its onset and duration, character, seasonal as in asthma.
quality, and timing. The onset may be acute (<3 weeks) which is Cough may be aggravated by or related to occupational irritant
most often due to upper respiratory infections like common exposure (e.g. byssinosis). It may increase after eating as in GERD
cold, bacterial sinusitis and pertussis; or lower respiratory tract or in tracheo-oesophageal fistulas and swallowing disorders.
infections like pneumonia, acute exacerbation of chronic Sometimes GERD may complicate asthma or COPD.
obstructive pulmonary disease (COPD); acute episodes of
asthma. CHF and pulmonary embolism can also present with Cough may be postural as in patients with bronchiectasis, lung
acute cough. Inhalation of a foreign body is another cause. An abscess or bronchopleural fistula. These patients have large
algorithm for evaluating acute cough is shown in Figure 1. amounts of sputum. Sputum increases on waking in the morning
in CB.Worsening of cough in CB may herald a bronchial carcinoma.
Sub-acute cough (3 to 8 weeks) is commonly post-infectious
due to persistent airway inflammation and/or postnasal drip The character of cough may be like barking in children with
following viral infection, pertussis or Mycoplasma or Chlamydia croup. Staccato cough is seen in Chlamydia pneumoniae. Patients
infection. In India, TB and TPE are important causes. An with chronic postnasal drip try to clear the throat and cough.
algorithm for the approach to a case of sub-acute cough is Patients with bronchial and lung parenchymal diseases have a
shown in Figure 2. deep, ‘loose’ cough; those with tracheal compression have a
brassy cough and those with laryngeal paralysis have a ‘bovine’
Causes of chronic cough (> 8 weeks) include TB, TPE, sarcoidosis, sounding cough.
cystic fibrosis, COPD and bronchogenic carcinoma. In non-
smokers with a normal chest radiograph, the common causes DIAGNOSTIC APPROACH
are postnasal drip [PNDs now called upper airway cough History
syndrome (UACS)], asthma, GERD, non-asthmatic eosinophilic
Is it acute, sub-acute or chronic? Are there any symptoms of
bronchitis (NAEB) and ACE inhibitors. Left ventricular failure can
infection? Is it seasonal? Aggravating factors? Nasal discharge,
cause sub-acute or chronic cough. Evaluation of chronic cough
frequent throat clearing, tickle in the throat (postnasal drip)? Is
can be done using the algorithm shown in Figure 3. The
there heartburn or a sensation of regurgitation (GERD)?
differential diagnosis of sub-acute and chronic cough is shown
Postural? Description of sputum produced. ACE-inhibitor or
in Table 1.
beta-blocker use? Risk factors like smoking, environmental
Cough can be dry or productive of sputum, the product of exposures, HIV risk factors, immunosuppressive agents, chronic
mucus glands and goblet cells of the bronchial walls. In a normal renal disease (opportunistic infections).
individual, 100 mL of secretions are produced daily. In
Examination
respiratory disease, secretions may be mucoid, mucopurulent
or purulent. Mucoid sputum is white or colourless, and General physical
gelatinous [as in chronic bronchitis (CB)]. Purulent sputum is Signs of heart failure, primary non-pulmonary neoplasm,
yellow or green due to pus from infection. Large number of cervical lymph nodes suggestive of tuberculous infection,

Figure 2: Sub-acute cough algorithm for the management of patients ≥15 years of age with cough lasting 3 to 8 weeks.
Based on: Irwin RS et al. Chest 2006;129: 1S-23S. (With permission).
26
 Cough
Figure 3: Chronic cough algorithm for the management of patients ≥15 years of age with cough lasting >8 weeks.
Modified from: Irwin RS et al. Chest 2006; 129: 1S-23S. (With permission).

fever, rash, cyanosis, clubbing. Oro-pharynx may show Sputum Examination

oro-pharyngeal mucus or erythema, ‘cobblestone’ mucosa Purulent sputum is seen in CB, bronchiectasis, pneumonia and
(postnasal drip). lung abscess. Haemoptysis occurs in the same conditions as well
Examination of the Chest as in TB and tumours. Sputum eosinophils >3% in patients
Inspiratory stridor in upper airway disease, rhonchi or expiratory without asthma suggests NAEB. Gram-stain, acid-fast bacilli
wheezing in lower respiratory disease, inspiratory crackles in stain and sputum culture will identify bacteria, TB and fungal
lung parenchymal disease like pneumonia, interstitial lung infections. Cytology will help in identifying malignancy.
disease (ILD) or pulmonary oedema. Pulmonary Function Tests
Examination of Blood and Stool Assess functional abnormalities of the lung. Reversible airflow
Complete blood counts may reveal leucocytosis, high obstruction is seen in asthma. If airflow rates are normal but
erythrocyte sedimentation rate, and marked eosinophilia in TPE there is strong suspicion of asthma broncho-provocation tests
and hemoparasites on peripheral smear. Stool examination may be done with methacholine or cold-air inhalation or
may reveal helminths that cause TPE. capsaicin to show bronchial hyper-reactivity. Restrictive pattern
and abnormality in diffusion studies are seen in diffuse ILD.
Chest Radiography Oxygen saturation and arterial blood gas analysis are also useful
May reveal fibro-infiltrative or cavitatory lesions suggestive of in assessing lung function.
TB, reticulo-nodular shadows with prominent hila suggestive
of TPE, diffuse interstitial or alveolar disease, honey-combing Fibreoptic Bronchoscopy
or cysts as in bronchiectasis, or bilateral hilar adenopathy as in Helps diagnose endobronchial granulomas (TB, sarcoidosis,
sarcoidosis, or a mass lesion. fungi), tumours, foreign bodies, and collection of secretions 27
 Table 1: Differential Diagnosis of Sub-acute and Chronic Cough
Common Causes Clinical Features
Transient airway hyper-responsiveness Cough persistent for many weeks, resolves (e.g. post-viral upper-respiratory infection)
Rhinosinus infection/inflammation Cough follows infection or exposure to allergen; post-nasal drip is common
Asthma Worse at night, on exercise, or following exposure to allergen, cold air or dust
Cough-variant asthma Absence of wheezing or dyspnoea, dry nocturnal cough, bronchial hyper-responsiveness
Non-asthmatic eosinophilic bronchitis No variable airflow obstruction; no hyper-responsiveness; sputum eosinophils >3%;
Increased CO2 in exhaled air
Chronic obstructive pulmonary disease Usually seen in smokers. When smoking, and environmental irritants stop, cough
eventually ceases
Gastro-oesophageal reflux Heartburn, acid reflux, throat clearing, hoarseness or asymptomatic reflux
Pulmonary tuberculosis Constitutional symptoms (fever, night sweats, weight loss, haemoptysis)
Bronchiectasis Productive sputum, often purulent; cough (and sputum production) often positional
Tropical pulmonary eosinophilia Cough, dyspnoea, wheeze, scanty sputum, blood and sputum eosinophilia, helminthic
infestation
Bronchial carcinoma Cough worse than usual in a smoker; sometimes, new persistent cough
Less Common Causes
Repeated bronchial aspiration Oesophageal disorders, neurological swallowing disorders
Pulmonary fibrosis Patient is breathless; cough ‘dry’
Aspirated foreign body May have no history of aspiration
Lung compression (e.g. pleural effusion, mass) Sometimes positional
Drug-induced cough ACE-inhibitors: dry cough; beta-blockers: cough and usually wheezing
Pneumocystis jiroveci Immune deficient patients with persistent cough
Psychogenic Patient otherwise well; no cough at night or when distracted; no response to cough
suppressants
Based on: Symptoms and Signs. Medicine International (Indian Ed) 1995; 9: 222; Philp EB. Chronic cough. Am Fam Physician 1997; 56: 1395-1408.

and endobronchial biopsies and transbronchial lung biopsies antihistamines, decongestants, nasal glucocorticoids, nasal
helps in further diagnosis. ipratropium may help improve UACS. In the absence of an
appropriate response, empirical treatment for asthma, NAEB
High Resolution Computed Tomography (HRCT)
and GERD can be tried. Symptomatic therapy for cough is given
Helps in diagnosing ILD and can confirm the presence of when the cause is unidentified or no specific treatment is
bronchiectasis. CT of para-nasal sinuses can help in diagnosing available or there is sleep disturbance and distressing cough.
UACS. Dextromethorphan or codeine are cough suppressants and
COMPLICATIONS provide relief in dry irritating cough. Productive cough should
not be suppressed, as the sputum will be retained in the
The complications of coughing can be classified as either acute
respiratory tract and result in reduced ventilation. Cough
or chronic. Acute complications include cough syncope due to
suppressants should be strictly avoided in obstructive airway
markedly positive intrathoracic and alveolar pressures,
disease.
decreased venous return, and decreased cardiac output when
cough is prolonged and forceful, insomnia, cough-induced
RECOMMENDED READINGS
vomiting, sweating, rupture of bullae causing pneumothorax,
sub-conjunctival haemorrhage, cardiac arrhythmias, seizures, 1. Chen HH, Jafek BW. Chronic cough. eMedicine Specialities-
Otolaryngeology and facial plastic surgery-laryngology. http://
splenic and venous ruptures, disruption of surgical wounds, emedicine.medscape.com/article/1048560-overview. Accessed on June 4,
coughing defaecation, cough syncope and in women with a 2010.
prolapsed uterus, urinary incontinence. Chronic complications 2. Chung KF, Pavord ID. Prevalence, pathogenesis, and causes of chronic
are common and include abdominal or pelvic hernias, fatigue, cough. Lancet 2008; 371: 1364-74.
fractures of lower ribs and costochondritis. 3. Dicpinigaitis PV, Colice GL, Goolsby MJ, Rogg GI, Spector SL, Winther B.
Acute cough: a diagnostic and therapeutic challenge. Cough 2009; 5: 11.
TREATMENT
4. Irwin RS, Baumann MH, Bolser DC, Boulet LP, Braman SS, Brightlin CE, et al.
Specific treatment can be given once the cause is evident such Diagnosis and management of cough. Executive Summary: ACCP evidence-
as stopping smoking or an ACE-I, or beta-blocker, treating post- based clinical practice guidelines. Chest 2006; 129: 1S-23S.
nasal drip or GERD, infections, bronchodilators for airway 5. Nadri FR, D’Souza GA. Investigation of chronic cough in tropics: a cost
obstruction, inhaled glucocorticoids for NAEB, treating TB, effective analysis. Lung India 2007; 24: 11-6.
TPE, sarcoidosis and ILD, tumours, bronchiectasis. In patients 6. Pavord ID, Chung KF. Management of chronic cough. Lancet 2008; 371:
with chronic unexplained cough empirical therapy with 1375-84.

28
 2.6 Haemoptysis

Randeep Guleria, Jaya Kumar

INTRODUCTION submucosa of the bronchial wall. Bleeding from the

Haemoptysis is defined as coughing up of blood from the pulmonary vasculature is less common and minimal as it is a
respiratory tract. It can range from streaks of blood in the low pressure system. Also hypoxic pulmonary vasoconstriction
expectoration to coughing up of large quantities of blood. diverts blood away from the diseased portion of the lung.
Haemoptysis is alarming for the patient and can be caused by Massive haemoptysis originating from the pulmonary
a spectrum of disorders ranging from a respiratory tract circulation is therefore uncommon. The bronchial circulation
infection, bronchogenic carcinoma and rarely with systemic is a more important cause of significant haemoptysis as it runs
diseases which causes alveolar haemorrhage. Sometime, a along the bronchial tree and supplies blood to the airways.
minimal haemoptysis initially may be followed by a bout of Inflammation in the airways leads to hypertrophy of the
massive haemoptysis which can be life-threatening. Massive bronchial vessels and an increased propensity to bleed. Also
haemoptysis is a medical emergency, most often due to being a high pressure system it leads to more profuse bleeding
asphyxiation which occurs due to flooding of the airways and and accounts for most cases of massive haemoptysis.
alveoli with blood and also due to significant haemodynamic Causes
compromise. Despite a lot of focus on the management of
Haemoptysis has a varied aetiology with the common
massive haemoptysis the definition is highly variable. It is most
causes being tuberculosis (TB), bronchiectasis, bronchitis,
commonly defined as expectoration of 100 to 600 mL of blood
bronchogenic carcinoma and pneumonia in different
in 24 hours. The problem with this definition is that it is very
proportions depending on the population studied. The causes
difficult for a patient to quantify haemoptysis. Also the
can be categorised according to the site of origin within the
morbidity and mortality depends on the rate of bleeding, the
lung and the underlying disorder (Table 1).
condition of the underlying lungs and the ability of the patient
to clear the airways of the blood rather than on the absolute The frequency of the different causes of haemoptysis varies in
quantity of blood loss. Any amount of haemoptysis which the developed and developing world. Recent literature from
causes haemodynamic instability or respiratory embarrass- the developed world shows TB to be an infrequent cause of
ment should be considered massive. Life-threatening haemoptysis. The leading causes of haemoptysis in these
haemoptysis is recommended as a better term which countries are bronchitis, pneumonia, bronchiectasis and
encompasses the quantity of haemoptysis, haemodynamic bronchogenic carcinoma with TB accounting for only 1.4% to
instability and impairment of gas exchange. The unpredictable 8% in different studies. In our country and most of the
course of haemoptysis with a possibility of potentially life- developing world TB still remains the most common cause for
threatening massive haemoptysis and the various serious haemoptysis. In a study from Lucknow, India, the TB accounted
aetiologies mandates a prompt and focused assessment and for 79.2% cases of haemoptysis followed by bronchogenic
management. carcinoma.

AETIOPATHOGENESIS Various mechanisms are responsible for haemoptysis in active

TB and post-tubercular sequelae:
Vascular Anatomy
It is important to understand the blood supply of the lung to A. Active tuberculosis
get an idea of the mechanism of significant haemoptysis. The 1. Bronchiolar ulceration and necrosis of adjacent vessels
lungs have a dual blood supply from the pulmonary and and alveoli.
bronchial circulation. The pulmonary circulation is a low 2. Erosion of a vessel wall of a cavity.
pressure system which is responsible for gas exchange. The 3. Tubercular involvement of the vessel wall causes
pulmonary arteries run along the bronchial tree and carry the formation of aneurysms called Rasmussen’s aneurysm.
entire cardiac output for oxygenation in the pulmonary Rupture of these aneurysms can cause massive
capillaries, but the only interaction with the airways is at the haemoptysis.
level of the terminal bronchioles where the pulmonary
capillary bed arises around the alveoli for gas exchange. The B. Sequelae of tuberculosis
bronchial tree on the other hand carries a small portion of 1. Bronchiectasis due to destruction of the normal lung
the cardiac output but has a pressure at par with the systemic architecture by TB.
pressure. The bronchial arteries arise from the aorta or the 2. Aspergilloma formation in an old tubercular cavity.
intercostals arteries and supplies blood to the airways, hilar
lymph nodes visceral pleura and parts of the mediastinum. 3. Erosion of bronchial arteries due to healed, calcified
They branch along the bronchial tree and form an extensive nodes rupturing through the bronchial tree.
plexiform network in the peri-bronchial space and in the 4. Scar carcinoma.
29
 Table 1: Causes of Haemoptysis Table 2: Differences Between Haemoptysis and Haematemesis
A. Pulmonary Haemoptysis Haematemesis
1. Airway disease Clinical evidence of lung Clinical evidence of gastric or
Bronchiectasis disease hepatic disease
Bronchitis (acute and chronic) Bright red or pink blood Brown to black, coffee ground
Neoplasms Liquid clotted appearance appearance
Bronchogenic carcinoma Cough, breathlessness Nausea vomiting, abdominal pain
Endobronchial metastatic carcinoma chest pain present
Bronchial carcinoid Malaena rare Malaena may be present
Kaposi’s sarcoma
Examination shows Mixed with ingested food
Foreign body
macrophages or neutrophils particles
Airway trauma
Alkaline pH Acidic pH
2. Parenchymal disease
Infectious
The priority in massive haemoptysis is to protect the airway,
Tuberculosis
maintain ventilation and circulation and avoid the other lung
Pneumonia/lung abscess
Aspergilloma
from flooding. An evaluation for cause would follow once
Lung parasite (ascariasis, schistosomiasis) the patient is stabilised. Non-massive haemoptysis entails an
Inflammatory or immune disorders evaluation for the cause of haemoptysis so as to start treatment
Wegener’s granulomatosis, SLE for the same. Initial evaluation, depending on the presentation,
Good pasture’s syndrome should include—haemogram with haematocrit , white blood
Idiopathic pulmonary haemosiderosis cell count and platelet count, erythrocyte sedimentation rate
Other pulmonary vasculitis (ESR), arterial blood gas analysis, sputum for acid fast bacilli (AFB),
3. Vascular causes Gram-stain, culture, and cytology, blood urea and serum
Pulmonary embolism creatinine, serum chemistry, HIV serology, autoimmune work-
Pulmonary arteriovenous malformation up and urine analysis if systemic vasculitis is suspected;
B. Cardiovascular prothrombin time, partial thromboplastin for coagulation
Pulmonary hypertension per se, Mitral stenosis disorders; D-dimer for suspected pulmonary embolism.
Tricuspid endocarditis The evaluation for the aetiology begins with a chest radiograph
Aortic aneurysm and has changed drastically with the advent of computed
C. Trauma tomography (CT) scans and bronchoscopy. When the chest
Chest injury radiograph is normal with a history suggestive of airway disease
Iatrogenic and there is no apparent risk factors for carcinoma lung the
Percutaneous lung biopsy patient can be observed. No further evaluation is necessary if
Bronchoscopy with bronchial biopsy or transbronchial bleeding does not recur. Further evaluation with a contrast
lung biopsy enhanced and high resolution computed tomography (HRCT)
Swan ganz catheterisation causing pulmonary artery is indicated even if the chest radiograph is normal if bleeding
perforation recurs or if risk factors for carcinoma lung are present or the
D. Miscellaneous history is not compatible with bronchitis. When the chest
Drug induced (anti-coagulants, penicillamine, bevacizumab, radiograph shows parenchymal involvement sputum for AFB
cocaine) must be done. If the sputum is negative for AFB, the CT of the
Pulmonary endometriosis chest is required followed by treatment of the underlying
Cryptogenic disease, if a specific diagnosis is established. Further evaluation
with bronchoscopy is advised when the CT chest does not
DIAGNOSTIC APPROACH suggest a specific diagnosis. When a chest radiograph reveals a
A good history is very essential as it guides towards a likely mass, further evaluation with CT chest, bronchoscopy and a
aetiology. The first step is to distinguish haemoptysis (bleeding biopsy from the mass is indicated.
from the upper respiratory tract) from haematemesis (bleeding
CT scan of the chest specially contrast enhanced HRCT has
from upper G.I. tract) (Table 2). Once haemoptysis is confirmed
changed the diagnostic algorithm for haemoptysis. CT scan can
the history should include assessment of the quantity of
help diagnose several conditions where the chest radiograph
haemoptysis as an aggressive approach is required for massive
is normal or help in further characterising lesions seen on the
haemoptysis. Also history of associated symptoms, including
radiograph. These include bronchiectasis, lung carcinoma,
fever, cough, expectoration, dyspnoea, constitutional symptoms
sequelae of TB, aspergilloma, pulmonary aneurysm and
related to the underlying aetiologies helps the physician to
lung nodule. In addition it may also help to direct fine needle
narrow the differential diagnosis and develop a focused
aspiration cytology (FNAC) and biopsy. Also it may help in
approach. History related to any suspected, underlying systemic
deciding the better mode of tissue sampling in a particular case,
illness, smoking, use of any drug, past illnesses like TB, severe or
bronchoscopic biopsy or CT guided per-cutaneous biopsy.
recurrent pneumonia should also be included. A complete
physical examination including the vitals, general physical Flexible fiberoptic bronchoscopy (FOB) along with HRCT
30 examination, respiratory and cardiovascular system is essential. chest is the mainstay of diagnosis in patients with haemoptysis.
 Haemoptysis
Bronchoscopy helps in the diagnosis when the radiology is identify the side and specific site of bleeding. If the side is
normal or non-localising and if done acutely may help identify identified but the specific site cannot be seen selective
the source of bleeding. It is specifically useful in diagnosing single intubation of the lung can be done to prevent
endobronchial lesions, bronchitis and subtle mucosal flooding of the other lung. Double lumen endotracheal
abnormalities. A bronchoscopy should always be done in a tube can be used in experienced centres when the side
patient with haemoptysis if there are risk factors for lung cannot be localised and bleeding persists. Rigid
carcinoma even if the CT scan is normal. bronchoscopy may be required when there is massive
bleeding because it is difficult to visualise the airway with
The rigid bronchoscopy is being more and more infrequently
an FOB in such a situation.
used as the flexible scope gives greater access to the distal
airways, but it has the advantage of providing better airway 3. Bronchoscopic measures to stop bleeding: Once the
control and suctioning and can be used to remove large clots specific site of bleeding is located, specific measures can
or foreign bodies. Bronchial and pulmonary angiography is be used to control the bleeding.
rarely done as a diagnostic test with the advent of CT and  Bronchial lavage with iced saline has been successfully
bronchoscopy. It is done when bronchial artery embolisation is used in several studies.
planned to stop bleeding. Specific tests like CT pulmonary
 Vasoconstrictive agents like epinephrine can be used
angiography, ventilation perfusion scan and echocardiography
to control bleeding.
may be required depending on the underlying aetiology.
 Bronchoscopic balloon tamponade: A 4 French, 100 cm
MANAGEMENT fogarty catheter is inflated in the segmental/sub
The goal of the management is to stop the bleeding, prevent segmental bronchus leading to the bleeding site for
asphyxiation and to treat the underlying disorder. The most 24 to 48 hours. It is deflated for several hours after 1 to
important step is to quantify the haemoptysis and ensure that 2 days and removed if bleeding does not recur.
airway, breathing and circulation are maintained. It is important  Laser photocoagulation and electrocautery have been
to remember that a minor bleed may herald a massive, life- tried in endobronchial tumours to control bleeding.
threatening haemoptysis. 4. Angiography and embolisation: Patients who continue to
Management of Non-Massive Haemoptysis bleed despite above measures can be taken up for
angiography to localise the bleed and the bleeder can then
Non-massive haemoptysis can be managed on an out-patients
be embolised. This procedure is used as a bridge to surgery
basis. However, the patient should be advised to report
or in patients who are not candidates for surgery. It is
immediately to the emergency, if the haemoptysis increases or
considered to be semi-definitive as rebleeding can occur
does not settle. The management is based on preventing further
in 10% to 20% patients in the next one year. Currently
bleed from occurring and to find and treat the underlying cause.
bronchial artery embolisation is a commonly used method
Basic investigations including a chest radiograph, haemogram
to stop massive haemoptysis in most centres. It is also
and sputum for AFB must be done. Once the cause of
used in patients who have recurrent moderate to massive
haemoptysis is found appropriate treatment should be initiated.
haemoptysis and are not candidates for definitive surgery.
To prevent further bleeding cough suppressants, haemostatic
agents and anxiolytic should be used. A broad spectrum 5. Surgery: It is the only definitive option in massive
antibiotic is given at times to prevent secondary bacterial haemoptysis not responding to above mentioned
infection in the lung. measures. Unfortunately most patients are not fit for
surgery which is contraindicated in patients with diffuse/
Management of Massive Haemoptysis
bilateral disease, active TB and in patients with poor
It is a medical emergency, as it can cause sudden death by respiratory reserve. Also the mortality and morbidity is
asphyxiation. The first step is to protect ABC—airway, breathing much higher in emergent surgery in comparison to elective
and circulation. Protection of the airway is of utmost importance, surgery in the non-bleeding patient.
as asphyxiation is the most common cause of death in these
patients. PROGNOSIS
The steps in management include: The outcome of haemoptysis varies in various series depending
on the underlying aetiology, the number of patients with
1. Airway protection and haemodynamic stability: The patient massive haemoptysis and the expertise of the treating centre.
should be admitted in the intensive care unit. If the site of The mortality is 8% to 10% in various studies. The prognosis is
bleeding is known the patient should be placed in a lateral improving with the newer modalities of treatment. All patients
position with the bleeding lung in the dependent position. with haemoptysis, minimal or massive should be aggressively
This helps to protect the non-bleeding lung from spillage. managed at well equipped centres to further improve the
Endotracheal intubation with a wide bore tube is indicated outcome.
in patients with massive ongoing haemoptysis, haemo-
dynamic instability and inadequate gas exchange. This also RECOMMENDED READINGS
helps in better airway protection, suction and resuscitation 1. Bidwell JL, Pachner RW. Haemoptysis: Diagnosis and management. Am Fam
in case of cardio-respiratory arrest. Physician 2005; 72: 1253-60.
2. Prasad R, Garg R, Singhal S, Srivastava P. Lessons from patients with
2. Localisation of the bleed and protection of the non- haemoptysis attending a chest clinic in India. Ann Thorac Med 2009; 4:
bleeding lung: Bronchoscopy is the procedure of choice to 10-12. 31
 2.7 Jaundice

Aparna Agrawal

Jaundice is a common presentation of liver and biliary tract  In unconjugated hyperbilirubinaemia due to haemolysis,
disease, characterised by yellowish discoloration of skin, sclerae usually serum bilirubin is < 5 mg/dL. If it is more than this,
and mucous membranes. It is clinically detectable when serum check for combination of haemolytic anaemia with an
bilirubin is >3.0 mg/dL. It manifests more in tissues with – high inherited disorder of bilirubin metabolism—Gilbert’s
elastic content (skin, sclera, blood vessels), high blood flow, low syndrome or Crigler Najjar syndrome, coexistent renal and
interstitial fluid and in fluids with high protein content (urine, hepatocellular dysfunction or acute haemolytic crisis.
sweat, semen, milk, exudates, etc.).
CLASSIFICATION AND CAUSES OF JAUNDICE
It manifests less in paralysed parts and oedematous areas.
These are given in Table 1.
Yellowing of the skin can also occur in carotenoderma (spares
the sclera), with use of quinacrine and with excessive exposure APPROACH TO JAUNDICE
to phenols. A careful history, physical examination and standard laboratory
tests help us in arriving at an accurate diagnosis in >80% of
CLINICAL EVALUATION patients. In adult patients with a new-onset jaundice, the
 Inspection should be done in bright day light to detect following disorders account for >95% of the diagnosis:
jaundice.  Viral hepatitis.
 Inspect the sclera, tongue, hard palate, skin and fingers.  Alcohol-induced liver disease.
 Ask the patient to look down and inspect the unexposed  Drug induced liver disease.
portion of the sclera because bulbar conjunctiva can be
discoloured due to dust.  Infections involving the liver including liver abscess and sepsis.
 Note whether the hue is lemon yellow (unconjugated  Chronic hepatitis (all causes).
hyperbilirubinaemia stains the tissues lightly because of its  Gall stones and their complications.
water insolubility); orange yellow (in patients with  Pancreatitis.
hepatocellular and cholestatic jaundice there is increase
 Carcinoma of the pancreas.
in conjugated bilirubin which penetrates body fluids
more because of its water solubility), or greenish yellow  Haemolytic anaemia.
(in prolonged cholestasis because of formation of
I. History
biliverdin).
 Staining of clothes by secretions is a good clue (specially The onset, evolution and duration of jaundice should be noted.
urine, sweat, milk and semen). The associated features should also be enquired into.

 Look for high coloured urine and pale coloured stools (avoid History suggestive of acute viral hepatitis
early morning specimen).  Low grade fever for 1 to 2 days, usually associated with
headache, myalgias, anorexia, nausea and vomiting
AETIOPATHOGENESIS
followed by jaundice.
Jaundice results from a disorder of bilirubin metabolism in the
 Change in taste and smell of food.
form of increased formation or a decrease in hepatic clearance
of bilirubin. Unconjugated bilirubin is lipid soluble and it is  Contact with individuals with jaundice.
converted to water soluble bilirubin mono-and-diglucuronide  Needle stick exposure or any injection, body piercing,
by conjugation, which allows its excretion into the bile. tattoos, shared razors or tooth brushes.
Some Practice Points  Blood or blood product transfusions.
 In late stages of cholestatic or hepatocellular jaundice,  Intravenous drug abuse.
despite high serum bilirubin levels, none can be detected  Health care professionals.
in the urine.This is due to a third type of bilirubin—a bilirubin  Sex with commercial sex workers, multiple partners or with
mono conjugate (not mono-and-diglucuronide), covalently individuals with hepatitis B or C.
bound to albumin, which is not filtered by the glomerulus,
 History of sexually transmitted disease.
hence absent in the urine.
 Travel to endemic areas or eating raw shell fish (especially
 The high elastic content of tissues is responsible for the
for hepatitis A).
disparity between the depth of jaundice in the skin and
sclera and serum bilirubin levels during recovery from  Occasionally, pain with or without swelling of joints and
32 hepatitis or cholestasis. transient skin rash may indicate hepatitis B or C.
 Jaundice
Table 1: Classification and Causes of Jaundice
Type Cause Basic Laboratory Abnormalities
Pre-hepatic ↑ Bilirubin production
Haemolysis
(a) Intravascular haemolysis
– G6PD deficiency, PNH, malaria Unconjugated ↑ SBR
– Blood transfusion Normal STA + ALP
– Ineffective erythropoiesis
(b) Extravascular haemolysis
– Pneumonia, PTE, resorption of haematomas, haemoglobinopathies
Hepatic (a) ↓ Hepatocellular uptake
– Drugs (Rifampicin, probenecid, ribavirin)
– Gilbert’s syndrome
(b) ↓ Conjugation
– Gilbert’s syndrome, Crigler-Najjar Syndrome I and II
– Physiologic jaundice of newborn
– Drugs (e.g. Indinavir)
(c) ↓ Transport Conjugated ↑ SBR
i. Congenital hyperbilirubinaemia Normal STA+ALP
– Dubin-Johnson syndrome
– Rotor’s syndrome
ii. Acute/ subacute hepatocellular disease Mixed ↑ SBR
– Viral hepatitis A-E, EBV, CMV, HSV (↑ SBR +
– Hepatotoxins (ethanol, Amanita Phalloides) ↑ STA ±
– Drugs – Dose dependent (Acetaminophen) Idiosyncratic (INH, phenytoin, etc.) ↑ ALP)
– Ischaemia (hypotension, Budd-Chiari syndrome, hepatic veno-occlusive disease)
– Metabolic disorders (Wilson’s disease, Reye’s syndrome)
– Pregnancy related (AFLP, pre-eclampsia)
iii. Chronic hepatocellular disease
– Viral hepatitis (B, C, D)
– Alcohol
– Hepatotoxins (Vinyl chloride, Vit. A. hypervitaminosis)
– Autoimmune hepatitis
– Metabolic (haemochromatosis, Wilson’s disease, NASH, α1-antitrypsin deficiency)
– Coeliac sprue
Cholestatic
(a) Hepatic disorders with prominent cholestasis ↑ SBR +
i. Diffuse infiltrative disease of liver ↑ STA +
– Granulomatous disease (Mycobacterial infection, Brucella, fungal disease, ↑ ALP
sarcoidosis, lymphoma, drugs, Wegener’s granulomatosis)
– Amyloidosis
– Malignancy
ii. Inflammation of intrahepatic bile ductules and/or portal tracts
– Primary biliary cirrhosis
– Drugs (erythromycin, trimethoprim-sulphamethoxazole)
– Graft versus host disease
iii. Miscellaneous
– Benign recurrent intrahepatic cholestasis
– Intrahepatic cholestasis of pregnancy
– Drugs (estrogen, anabolic steroids)
– Total parenteral nutrition
– Infections
– Post-operative cholestasis
– Vanishing bile duct syndrome
(b) Obstruction of bile ducts
i. Choledocholithiasis
– Cholesterol gall stones
– Pigment gall stones
ii. Diseases of the bile ducts Conjugated ↑ SBR +
– Cholangiocarcinoma Normal STA +
– Inflammation/Infection ↑↑ ALP
– Primary sclerosing cholangitis
– AIDS cholangiopathy
– Post surgical strictures
iii. Extrinsic compression of the biliary tree
– Neoplasms (pancreatic carcinoma, hepatocellular carcinoma, nodes at porta hepatis)
– Pancreatitis
– Vascular enlargement (e.g., aneurysm, cavernous transformation of portal vein)
SBR = Serum bilirubin, STA = Serum transaminases, ALP = Alkaline phosphatase, AFLP = Acute fatty liver of pregnancy.
33
 History suggestive of chronic hepatitis/cirrhosis with portal  History of recurrent jaundice or non-healing ulcer.
hypertension  Family history of anaemia.
 Recurrent jaundice.  Known haemoglobinopathy or having artificial heart valves.
 Swelling of feet.
Miscellaneous
 Distension of abdomen.
 Age and sex: Type A hepatitis decreases as age advances
 Massive haematemesis or melena may indicate portal but no age is exempt from hepatitis B and C.
hypertension and variceal bleed. – A multiparous, middle-aged, obese female with
 Amenorrhoea. dyspepsia may have gall stones.
History suggestive of alcohol-induced liver disease – Chances of malignancy increase with increasing age.
 Occupation should be noted (particularly involving alcohol,
 Details of quantity and type of alcohol being consumed
now or in the past should be obtained from the patient, other hepato-toxic industrial chemicals or contact with rats
for Weil’s disease).
friends and family members. (The threshold for alcohol-
induced hepatic injury appears to be 30 gms/day for  Painless jaundice—check for malignancy.
women and 60 gms/day for men if ingested over 5 to 10  Significant weight loss—check for malignancy.
years. Less, if additional factors for liver disease are present).  History of joint pain or swelling (check for hepatitis B or
 History of binge drinking and day time drinking should be C, autoimmune hepatitis, drug induced hepatitis,
noted. inflammatory bowel disease with primary sclerosing
 History of withdrawal symptoms or seizures should be cholangitis or granulomatous disorders such as
taken. CAGE criteria (cut down, annoyed, guilty, eye opener) sarcoidosis).
should be looked for as indicators of excessive alcohol  Diabetes, arthritis and pigmentation—check for haemo-
usage. chromatosis.
 History suggestive of other alcohol related illness, e.g.  Chronic obstructive pulmonary disease with jaundice—
pancreatitis, gastritis, peripheral neuropathy should be suspect α1 antitrypsin deficiency.
taken.  Chronic diarrhoea with blood and mucous—rule-out primary

History suggestive of drug induced liver disease sclerosing cholangitis.

 Family history of liver disease (check for Wilson’s disease,
 Review all prescription medications.
haemochromatosis, α1 antitrypsin deficiency).
 Enquire specifically about alternative forms of medicine
 Family history of biliary disease.
being taken.
 History of pruritic rash, joint pain or swelling related to Jaundice after biliary tract surgery
some drug intake. Check for:
History suggestive of infections/liver abscess  Residual calculus
 Fever moderate to high grade with chills/rigors, with dull  Traumatic stricture of bile duct
aching pain right upper abdomen especially when  Sepsis
associated with dysfunction of other organs.  Drug induced hepatitis
 Rule-out leptospirosis in patients with combined renal and  Hepatic metastasis in case of malignancy
hepatic dysfunction.
Jaundice in a liver transplant recipient
History suggestive of cholestatic jaundice Causes:
 High coloured urine with pale coloured stools.  Hepatocellular injury resulting from impaired organ
 Pruritus. preservation
 Colicky pain right upper abdomen associated with fever,  Vascular occlusion in immediate postoperative period
rigors/chills (suggestive of choledocholithiaisis with  Graft rejection
ascending cholangitis).
 Obstruction of the bile ducts
History suggestive of pancreatitis  Acute viral hepatitis especially cytomegalovirus infection
 Recurrent upper abdominal pain with radiation to the back.  Immunosuppressive drug toxicity
 History suggestive of steatorrhoea.  Recurrent disease (e.g. Hepatitis B or C, primary sclerosing
 Fever with severe pain and distension of the abdomen may cholangitis)
be suggestive of acute pancreatitis. Jaundice in pregnancy
History suggestive of haemolytic anaemia The following causes are specific to pregnancy:
 History of pale coloured urine with mild yellow dis-  Hyperemesis gravidarum (first trimester; self limiting)
colouration of eyes.  Intrahepatic cholestasis of pregnancy (third trimester;
 History of anaemia not responding to haematinics and pruritus; resolves within 2 weeks of delivery; tends to recur
requiring regular blood transfusions. with subsequent pregnancies)
34
 Jaundice
 Acute fatty liver of pregnancy (third trimester; may be fatal  HELLP syndrome (severe form of pre-eclampsia; urgent
unless delivery is performed promptly) delivery is indicated)
 Pre-eclampsia (third trimester; associated with  Hepatitis E induced fulminant hepatic failure is more
hypertension and proteinuria) common in pregnancy.

Figure 1: Clinical signs in jaundice.

35
 II. Examination [Localised dilatation of the transverse colon (toxic
There are many signs that we need to check in a patient present megacolon), fulminant colitis and ileus associated with
with jaundice (Figure 1). peritonitis or a perforated viscus may decrease the liver
dullness without a decrease in liver size].
General examination
(ii) Massive hepatomegaly (>10 cm below the costal
 Anaemia may indicate haemolysis, chronic liver disease or margin) may indicate:
malignancy. (a) Malignancy (primary/secondary)
 Pedal oedema may indicate chronic liver disease, inferior (b) Congestive liver (chronic congestive cardiac failure
vena cava obstruction due to malignancy or procoagulant (CCF)/Budd-Chiari syndrome)
state; severe anaemia with volume overload or (c) Alcoholic liver disease
hypoproteinaemia due to nutritional deficiency or
(d) Primary biliary cirrhosis
malabsorption.
(e) Prolonged extrahepatic cholestasis
 Lymphadenopathy may indicate an infectious aetiology,
(f) Infiltrative disease of the liver
lymphoma, tuberculosis or sarcoidosis. An enlarged left-
supraclavicular node (Virchow’s node) or periumbilical – Myelofibrosis
nodule (Sister Mary Joseph’s nodule) suggests an – Amyloidosis (especially when associated
abdominal malignancy. with macroglossia, peripheral neuropathy,
malabsorption, CCF or proteinuria)
 Altered mental state may indicate hepatic encephalopathy,
sepsis or brain metastasis in patients with late stages of (g) Chronic myeloid leukaemia
malignancy.  Whether it is tender (infections, congestion, bile stasis) or not.
 Kayser-Fleischer (KF) ring is usually seen in Wilson’s disease.  Whether the surface is nodular (malignancy, cirrhosis) or
 Xanthomas in primary biliary cirrhosis. smooth.
 Pigmentation of the shins and non-healing ulcer may  Whether the edge is rounded or sharp.
indicate haemoglobinopathy. Hyperpigmentation may  Whether the left lobe is palpable.A palpable left lobe suggests:
also be present in haemochromatosis or in primary biliary – Chronic liver disease
cirrhosis. – Malignancy
 Erythema nodosum may be seen in tuberculosis, sarcoidosis – Abscess/cyst
or syphilis. – Obstruction of left hepatic vein
 Migratory thrombophlebitis is suggestive of carcinoma of  Bruit over the liver indicates increased vascularity:
the body of pancreas. – Acute alcoholic hepatitis
Abdominal examination – Hepatocellular cancer
 Dilated abdominal veins can be seen in: – Hepatic artery aneurysm
– Portal hypertension – Hepatic arterio-venous fistula
– Inferior vena cava obstruction (functional or organic—  Friction rub over the liver suggests
dilated and tortuous veins indicate organic obstruction). – Liver metastasis
The direction of flow in the infraumbilical veins helps in – Primary hepatocellular carcinoma
distinguishing between portal hypertension (from above- – Infarction of the liver (as in sickle cell anaemia and
below) and IVC obstruction (from below-up). polyarteritis nodosa)
 Severe right upper quadrant tenderness with respiratory – Liver abscess
catch on inspiration (Murphy’s sign) suggests cholecystitis – Haematoma around the puncture site.
or occasionally, ascending cholangitis.  Check for pulsatile liver (indicative of significant tricuspid
 Ascites may be due to: regurgitation)
– Cirrhosis Peripheral stigmata of chronic liver disease
– Malignancy  Parotid enlargement
– Infections, e.g. tuberculosis, spontaneous bacterial  Gynaecomastia
peritonitis  Spider angioma (usually found in the distribution of superior
– Acute pancreatitis (Grey Turner’s sign, i.e. discolouration vena cava; >12 in number indicate portal hypertension)
of the abdomen is highly suggestive).  Paucity of axillary and pubic hair
 Liver: In liver examination the following should be noted:  Testicular atrophy
(i) The size and consistency of the liver  Palmar erythema
– hard liver indicates malignancy.  Dupuytren’s contracture
– Shrunken liver indicates: Signs suggestive of decompensated liver disease
(a) Cirrhosis Jaundice
(b) Fulminant hepatic failure Ascites
36
 Jaundice
Hepatic encephalopathy  Anti-mitochondrial antibody positivity indicates
Oliguria, hepatic failure primary biliary cirrhosis.
Altered behaviour  ANA, anti-SMA (smooth muscle antibodies) and anti-
Fetor hepaticus LKM Ab positivity suggests autoimmune hepatitis.
Asterixis  Serum Fe, transferrin and ferritin are elevated in haemo-
 Check for any masses in the abdomen. chromatosis.
 Genitalia must be examined and per rectal examination  Serum ceruloplasmin is reduced in Wilson’s disease.
is a must for piles, growth or nodules in the pouch of  Serum ALP: SBR of <2 or AST: ALT of >4, in a young
Douglas. patient with Coomb’s –ve haemolytic anaemia and KF
 Jaundice with extrapyramidal neurological features ring on slit lamp examination is suggestive of Wilson’s
suggests Wilson’s disease especially in patients born of disease.
consanguinous marriage and having KF ring.  α1-antitrypsin phenotype for α1-antitrypsin deficiency.
 Transglutaminase Abs for coeliac sprue.
III. Laboratory Diagnosis
Integration of the patient’s history, clinical examination  Serum α-fetoproteins for hepatocellular carcinoma.
findings and laboratory results is essential for accurate  UGI endoscopy for any malignancy, evidence of portal
interpretation because non-specific aberrations in these tests hypertension (esophageal or gastric varices and portal
may occur. We can divide all jaundiced patients into three gastropathy features).
broad categories of patients (Table 1).  Doppler ultrasonogram to detect patency of hepatic
A. Isolated elevation of serum bilirubin (SBR) with normal veins, portal vein and inferior vena cava.
serum transaminases (STA) and alkaline phosphatase (ALP)  Liver biopsy is especially indicated in patients with
Hepatocellular disease or biliary obstruction is unlikely undiagnosed persistent jaundice. It permits diagnosis
in these patients. If SBR is predominantly unconjugated of viral hepatitis, alcoholic and non-alcoholic
(>80%) we need to check for haemolysis (Hb, peripheral steatohepatitis, haemochromatosis, Wilson’s disease,
smear, reticulocyte count, Coomb’s test, plasma and urine α 1-antitrypsin deficiency, fatty liver of pregnancy,
haemoglobin and other special tests for diagnosing the primary biliary cirrhosis, granulomatous hepatitis and
type of haemolytic anaemia). A detailed description is neoplasms with the use of special stains. Though liver
beyond the purview of this chapter. histology may be entirely normal in acute biliary
obstruction, it may occasionally provide a clue to
If there is no evidence of haemolysis on the peripheral unsuspected biliary tract obstruction. Iron and copper
smear, the diagnosis is congenital hyperbilirubinaemia in content of the liver can also be measured. In patients
the absence of history of drug intake. These can be with prolonged prothrombin time (PT)—a transjugular
definitely diagnosed with the help of special enzyme biopsy is advisable.
assays, genetic studies and liver biopsy (black pigment-
ation on liver biopsy in Dubin-Johnson Syndrome). C. Increased serum bilirubin with markedly elevated
alkaline phosphatase with normal to mildly elevated
B. Increased serum bilirubin with increased serum serum transaminases
transaminases and normal to mildly increased alkaline It is suggestive of cholestatic jaundice.Prolonged prothrombin
phosphatase time which normalises on Vitamin K administration is
The most likely cause is hepatocellular jaundice (Table 1). suggestive of extra-hepatic biliary obstruction.
The patient needs to be evaluated for acute versus chronic
liver disease and for aetiology. Imaging studies are very important in this group of patients
with ultrasonogram (USG) of the abdomen being the
Two biochemical tests that suggest chronic liver disease basic investigation. Dilated ducts on imaging confirm the
are a low serum albumin (<2.8 gm/dL) and a prolonged diagnosis of biliary obstruction (i.e. distinguishes between
prothrombin time (>16 sec. prolonged). A bedside intra-hepatic and extrahepatic biliary obstruction) and
diagnosis of cirrhosis can be made when it is associated further imaging tests can be planned based on the
with two physical findings of ascites and asterixis. Serum availability of the procedure, presence or absence of dilated
globulin levels are elevated in cirrhosis, resulting in reversal bile ducts on initial imaging, technical expertise, cost of the
of A:G ratio. Electrophoretic analysis shows increased γ- procedure and risk versus benefit of the procedure.
globulin fraction in hepatocellular jaundice (versus raised α2-
and β-globulins in cholestatic jaundice). The other tests that The various imaging techniques available are:
need to be done in suspected hepatocellular jaundice are:  Contrast enhanced computed tomography (CECT)

 Viral markers (serological tests for hepatitis A-E  Magnetic resonance cholangiopancreatography
viruses, viral load for hepatitis B and C especially, (MRCP)
serological tests for cytomegalovirus and Epstein-Barr  Endoscopic retrograde cholangiopancreatography
virus infection) should be done for suspected acute (ERCP)
or chronic viral hepatitis.  Percutaneous transhepatic cholangiography (PTC)
 If serum AST: ALT is > 2 : 1, suspect alcoholic hepatitis  Endoscopic ultrasound (EUS)
in the setting of alcoholism.  Nuclear imaging studies 37
 Both ERCP and PTC permit direct visualisation of the biliary haemoglobin level and some patients may require iron
tree as well as the pancreatic ducts. Biopsy can be done chelation if blood transfusion requirement is high. Bone
from any suspicious lesion and therapeutic intervention can marrow transplantation is an option for thalassaemia , being
be done in the same sitting. ERCP is used for lesions distal done in a few centres.
to the bifurcation of the right and left hepatic bile ducts
 Hepatocellular jaundice has to be treated as per the
whereas PTC is preferable when the level of biliary
cause. Drug induced hepatitis has to be recognised and
obstruction is proximal to the common hepatic duct or
the offending drug needs to be stopped. Cessation of
altered anatomy precludes ERCP. The sensitivity and
alcohol, administration of antiviral agents, phlebotomy
specificity of MRCP, ERCP and PTC are comparable.

Table 2: Differences between the Three Basic Types of Jaundice

Features Haemolytic Jaundice Hepatocellular Jaundice Extrahepatic Cholestatic Jaundice
Colour of urine Pale High coloured High coloured
Colour of stools Normal Normal to dark Pale coloured
Pruritus – –/+ ++
Jaundice Lemon yellow Deep yellow Orange yellow/greenish yellow
Antecedent history H/o anaemia requiring Injection/BT/tattoos Biliary surgery or gall stones
blood transfusions (BT) contact with a jaundiced patient
Family history Anaemia Jaundice Gall stones
Urine urobilinogen ++ + –
Haemogram Evidence of haemolysis Normal Normal
Serum bilirubin ↑ <5 mg/dL (usually) (unconjugated) ↑ – ↑↑↑ (mixed) ↑ – ↑↑↑ (predominantly conjugated)
Serum transaminases Normal ↑ – ↑↑↑ Normal/↑
Alkaline phosphatase Normal Normal/↑ ↑↑
Ultrasonogram/CT Hepatosplenomegaly liver ↑/normal Liver ↑/N spleen N/↑ Liver ↑↑ with dilated ducts
spleen ↑ – ↑↑↑

These tests help in delineating the exact site of obstruction, for haemochromatosis, copper chelation for Wilson’s
the cause of obstruction (by direct visualisation and biopsy) disease and steroids for autoimmune hepatitis are a few of
and the back pressure changes. them.
Intrahepatic biliary duct may not be dilated in some  Supplementation of fat soluble vitamins may be required
conditions with extrahepatic biliary obstruction—early or in some patients with cholestatic liver disease.
partial biliary obstruction,
 In patients with obstruction of the bile ducts, the
– Primary sclerosing cholangitis obstruction has to be relieved by interventional
– Co-existent cirrhosis (fibrosis prevents dilatation of endoscopic or radiologic approach (sphincterotomy,
biliary ducts) balloon dilatation and placement of drains or stents) or
 In patients with suspected cholelithiasis, USG is the surgery depending on the location and the likely
primary diagnostic imaging procedure but in patients aetiology of the obstructing lesion.
with suspected choledocholithiasis, ERCP is the preferred  The various drugs that can be used for treatment of pruritus
diagnostic procedure. Papillotomy may be indicated. are cholestyramine, rifampin, ursodeoxycholic acid and
 In patients with obstructive jaundice due to suspected naltrexone.
pancreatic carcinoma, EUS is superior to CT scanning
With the approach outlined above we are able to arrive
with regard of detecting a pancreatic mass but
at an accurate diagnosis in most patients with jaundice.
comparable with regard to tumour staging and
The differences between the three types of jaundice are
predicting resectability or nonresectability.
summarised in Table 2.
 In patients with unexplained hepatomegaly, either USG
RECOMMENDED READINGS
or CT scanning are appropriate initial imaging procedures.
1. Greenberger NJ. History taking and physical examination for the patient
 Liver imaging procedures are usually not necessary in with liver disease. In: Schiff ER, Sorrell MF, Maddrey WC, editors. Schiff’s
patients with a diagnosis of acute viral hepatitis or non- Diseases of the Liver; 10th Ed. Lippincott Williams and Wilkins; 2007.
alcoholic steatohepatitis (NASH). 2. Lidofsdy SD. Jaundice. In: Feldman editor. Sleisenger and Fordtran’s
Gastrointestinal and Liver Disease; 8th Ed. Philadelphia: WB Saunders; 2006.
 Increased serum amylase is suggestive of acute 3. Pratt DS, Kaplan MM. Jaundice. In: Fauci AS, Braunwald E, Kasper DL, et al
pancreatitis. (editors). Harrison’s Principles of Internal Medicine; 17th Ed. New York: McGraw
Hill; 2008: pp 261-6.
IV. Therapeutic Options 4. Rider ST. Clinical assessment of liver disease. Medicine 2007; 35: 1-4.
 Haemolytic anaemia has to be treated with repeated blood 5. Sherlock S (ed). Diseases of the Liver and Biliary System. Oxford: Blackwell
38 transfusions as and when required to maintain adequate Publishing House; 2002.
 2.8 Upper Gastrointestinal Bleeding

JC Vij

Gastrointestinal bleeding is a challenging emergency which is to gastric mucosa, increase the risk of bleeding from ulcers as
associated with a high mortality. The clinical presentation of GI do anticoagulants. The role of intragastric acid in causing peptic
bleeding depends on the location, rate of bleeding and ulcer is well established, but its role in causing haemorrhage is
aetiology of the disease. Haematemesis defined as vomiting not well understood. Several studies have shown the beneficial
of blood indicates upper gastrointestinal (UGI) bleeding and effects of acid-reducing agents like proton pump inhibitors in
the site of bleeding is above the ligament of Treitz. The blood controlling bleeding from ulcers, emphasising the important
may be fresh and red coloured or may be old having the role of acid. Portal hypertension, a serious complication of
appearance of coffee grounds. Malaena is defined as passage cirrhosis, is associated with bleeding. The most common cause
of black tarry stools which are often foul smelling. This results from of portal hypertension is cirrhosis followed by portal vein
degradation of blood to haematin and other haemochromes. thrombosis, splenic vein thrombosis, non-cirrhotic portal fibrosis
Melena is usually the result of UGI bleeding, but slow bleeding (NCPF), schistosomiasis. Bleeding may occur from various lesions
from distal small bowel, caecum and ascending colon can also associated with portal hypertension including oesophageal
lead to melena; about 50 to 100 ml of bleeding in the GI tract is varices, gastric varices, portal hypertensive gastropathy and
required to cause melena. Haematochezia refers to the passage rarely ectopic varices. In patients with cirrhosis, bleeding
of fresh red blood from the rectum, which suggests a lower GI from varices carries a high mortality and also a high morbidity.
source of bleeding but can also occur with massive bleeding Varices form at the rate of 5% to 15% per year and only 1/3rd of
from the UGI tract (usually more than 1000 mL). About 30% of them bleed. The risk of haemorrhage from varices is related to
patients with UGI bleeding present with haemetemesis, 30% their size and location. Endoscopic appearance, portal pressure
with melena and 50% with both. and the severity of the underlying liver disease. Large sized
varices and those having red wheal sign (a manifestation of
AETIOLOGY thinning of overlying mucosa) carry a high-risk of haemorrhage.
The common causes of UGI bleeding include peptic ulcer Bleeding usually occurs from varices present near the gastro-
disease, oesophageal/gastric varices, Mallory-Weiss tear, erosive oesophageal junction. Haemorrhage from varices stops
gastritis/duodenitis, malignancy, angiodysplasia and Dieulafoy’s spontaneously in about 50% of cases and the risk of rebleeding
lesions. Peptic ulcer disease is the most common cause, is high within six months. Interestingly 50% of re-bleeding
accounting for 50%. Bleeding from varices—oesophageal or episodes occur within 3 to 4 days of the first bleed. Bleeding
gastric—accounts for 10% to 30%. Studies from central and north from gastric varices is usually associated with a very high
India have described variceal haemorrhage to be more common mortality rate.
(45% to 50%). About 10% of patients with portal hypertension
may have a non variceal source of bleeding such as peptic ulcer DIAGNOSIS
or Mallory-Weiss tear. Mallory-Weiss tear usually occurs in the Endoscopy is the best method of diagnosing the cause of UGI
gastric mucosa at the gastro-oesophageal junction and is bleeding. Barium radiography although can diagnose some
considered to be caused by forceful retching. Dieulafoy’s lesion of the lesions in the oesophagus, stomach and duodenum, it
denotes erosion of mucosa by an underlying large sized has no value in patients who are bleeding actively. Besides,
arteriole. Though Dieulafoy’s lesions can be located anywhere endoscopy has tremendous therapeutic value.
in the GI tract, they are typically found in the upper part of the
stomach. MANAGEMENT
Basic management of all patients with GI bleeding whether
MECHANISM variceal or non-variceal remains almost the same and includes:
Bleeding from an ulcer occurs when it erodes into the wall of a monitoring of vital signs particularly hypotension, tachycardia
blood vessel. Though the exact cause of haemorrhage from a and anoxia and clearing of the airways. Two large bore
pre existing ulcer is not clear, a number of factors can predispose peripheral intravenous catheters should be placed for
an ulcer to bleed. Use of aspirin and other non-steroidal anti aggressive volume replacement in a haemodynamically
inflammatory drugs (NSAIDs) are perhaps the most important unstable patient and such patients should be managed in a
factors. The mechanism of action is complex and involves medical ICU. It is preferable to replace blood loss by packed red
reduced production of prostaglandins, (a cytoprotective agent) cells which may take some time to arrange. In the meantime
and platelet dysfunction. Though controversial, ethanol, H.pylori crystalloids and saline infusion should be started. The
infection and glucocorticoids may potentiate the deleterious hematocrit should be maintained around 30% and
effect of NSAIDs and increase the risk of bleeding. Cyclo haemoglobin level kept approximately at 9 to 10 g/dL. Over
oxygenase-2 (Cox-2) inhibitors also increase the risk of ulcer infusion of blood or fluids should be avoided in patients
bleeding, though the risk is less than with NSAID use. with variceal bleed to avoid increase in portal pressure
Antiplatelet agents such as clopidogrel, though less injurious which may precipitate early rebleeding. Coagulopathy and
39
 thrombocytopaenia should be adequately corrected. Patients modalities consist of organ plasma coagulation (OPC) and laser
with aggressive bleeding and/or altered mental status should therapy. Contact thermal methods are preferred as besides
be intubated. Other supportive measures include administration causing coagulation of tissue due to thermal heat, they also
of prophylactic antibiotics, preferably third generation cause tamponade of vessels by direct probe pressure.
cephalosporines in patient with cirrhosis and maintenance of Noncontact thermal methods are cumbersome and expensive
urine output above 50 mL/hour. Acid base and electrolyte and are not shown to be more efficacious.
disturbances should be monitored and treated. The blood
Mechanical Devices
glucose level should also be maintained.
These include metal haemoclips, rubber band ligation,
Placement of a nasogastric tube, though controversial, is helpful endoloops and sewing devices. Haemoclips have been widely
in clearing the gastric contents. Gastric lavage along with used to treat active bleeding ulcers or visible vessels. They act
intravenous administration of metoclopramide or erythromycin by direct compression of opposing tissues or vessels causing
(not available in India) is helpful in improving the examination of thrombosis and haemostasis.
the gastric mucosa on endoscopy and decreases the need for
repeat endoscopy. Besides, it provides information about the type Several studies have shown that a combination of endoscopic
of blood present in the stomach, which may be helpful in therapy such as injection plus thermal therapy or injection plus
planning the time of endoscopy. Fresh red blood indicates active haemoclips application are superior to monotherapy alone.
bleeding and the patient will need early endoscopic evaluation.
Pharmacological Therapy
However, an aspirate negative for blood does not rule-out upper
GI bleeding. Use of nasogastric aspiration as a primary tool for Proton pump inhibitors (PPI) due to their inhibitory action on
assessing GI bleed should not be relied upon. Assessment of vital hydrogen potassium adenosine triphophatase raise intragastric
signs is the most effective means of determining bleeding activity. pH. They have been found effective when given in high
The use of a nasogastric tube has not been shown to influence doses intravenously for 72 hours after successful endoscopic
the outcome in patients with GI bleeding. treatment of an ulcer with high-risk bleeding signs. They reduce
the recurrence of bleeding and need for blood transfusion but
MANAGEMENT OF PEPTIC ULCER BLEEDING not the mortality rate. The recommended dose is 80 mg
Peptic ulcers are the most common and important cause of upper omeprazole given as an intravenous bolus followed by 8 mg
GI bleeding. Management aims to: (a) stop active bleeding, (b) per hour intravenous infusion. In patients with low-risk
prevent rebleeding, and (c) treat the peptic ulcer. Endoscopic ulcer bleeding oral proton pump inhibitors in high doses
examination is useful in identifying lesions which have a high- are recommended. In one study it was shown that PPI if
risk of re-bleeding. Ulcers with a clean base, flat pigmented spot administered for 24 to 48 hours before endoscopy significantly
are at a low risk of re-bleeding (5%), while those with active lowered the prevalence of high-risk stigmata and decreased the
bleeding or with non-bleeding visible vessel and adherent blood need for endoscopic therapy but did not decrease the incidence
clot (Forrest classification) are at a high-risk of rebleeding (40% of recurrent bleeding, surgery or mortality.
to 55%). The presence of co-morbidities, old age (>60 years),
HEALING OF PEPTIC ULCER
clinical evidence of severe bleeding and ulcers greater than 2
cm in size are associated with a poor outcome. Bleeding stops Proton pump inhibitor therapy has similar healing rates for
spontaneously in 70% to 80% of patients with peptic ulcers. In bleeding and non-bleeding ulcers. The long-term treatment of
the remaining patients endoscopic therapy controls bleeding in ulcers depends on their aetiology. Patients with bleeding ulcers
80% to 90%. Surgery is needed in about 5% to 10% of patients. who have been taking NSAIDs should discontinue them.
Patients with H. pylori infection should receive therapy for H.
Endoscopic therapy is the most effective method of controlling pylori eradication.
bleeding and to some extent preventing re-bleeding thereby
reducing mortality. Endoscopic methods of controlling ulcer MANAGEMENT OF BLEEDING VARICES
bleeding fall into three broad categories: (a) injection therapy, Oesophageal variceal bleeding should be controlled swiftly and
(b) thermal methods, and (c) mechanical devices. promptly as continued bleeding is associated with high
mortality. The first episode of variceal bleeding is associated
Injection Therapy
with about 30% mortality. Haemostasis can be achieved by
Submucosal injection of diluted epinephrine (1: 10,000) is a simple, pharmacological treatment and endoscopic therapy.
effective and widely practiced method of controlling bleeding.
Local injection acts by a tamponade effect on nearby vessels thus Pharmacological Treatment
causing haemostasis. Besides it causes vasoconstriction and In the past, vasopressin, a powerful vasoconstrictor, was widely
platelet aggregation. It is recommended that a large volume (30 used to control bleeding from varices. The drug causes
to 45 mL) of epinephrine solution be injected in the four quadrants splanchnic arteriolar vasoconstriction leading to decrease in
near an actively bleeding or visible vessel. portal inflow and thus portal pressure. However, this drug is
Endoscopic Thermal Therapy associated with myocardial ischaemia, mesenteric ischaemia
and cerebrovascular accidents. Some of adverse effects of
This can be divided into two categories: (i) contact thermal; and
vasopressin can be reduced by concomitant use of nitrates, used
(ii) noncontact thermal modalities.
as intravenous infusions, sublingual or transdermal route. It is
Contact thermal modalities include heater probe coagulation rarely used now because of its adverse effect profile. This led to
and bipolar/multipolar electrocoagulation. Noncontact thermal the development of a safer synthetic analogue—terlipressin
40
 Upper Gastrointestinal Bleeding
which has a longer biological half life and is administered in a formation. EVL is performed by using multiband ligating
dose of 1 to 2 mg every four hours. Terlipressin is as effective as system. The banding device consists of a cylinder preloaded
other vasoactive drugs as well as endoscopic treatment. This with 6 to 8 elastic bands. The cylinder is attached to the tip of
drug has been found to be associated with improved survival the endoscope and bands are released by pulling a trigger
in several randomised trials. wire of a device placed over the biopsy channel after the varix
is sucked into the cylinder. EVL is associated with fewer
Somatostatin and its analogues
complications than EST. The procedure is effective in controlling
Somatastatin is a naturally occurring peptide. Its exact bleeding in 75% to 85% of patients.
mechanism of action is not clear. It causes an increase in
splanchnic vascular resistance by causing vasoconstriction and With the available pharmacological and endoscopic treatments,
decrease in portal blood flow. Somatostatin is given as an the rate of failure to control acute bleeding is approximately
intravenous bolus of 250 ug followed by continuous infusion 10% to 20%. Balloon tamponade using Sangstaken-Blakemore
of 250 ug per hour and therapy is continued for two to five days. balloon, though associated with complications, can accomplish
Boluses of 500 ug can be administered intermittently if fresh haemostasis in a difficult situation, such as massive variceal
episodes of bleeding occur during the course of treatment. bleeding. Transjugular intrahepatic shunt (TIPS) represents an
Octreotide, a synthetic analogue of somatostatin, has a longer artificial communication by placing a metallic stent between
duration of action, and has been found to be effective in the hepatic and the portal vein. It is an effective method of
controlling variceal haemorrhage. Octreotide is given in the controlling active bleeding from oesophageal and gastric
doses of 25 to 50 ug/hour by a continuous intravenous infusion. varices. It also prevents recurrent variceal bleeding. Although
Somatostain and octreotide should be started immediately the TIPS procedure needs expertise (not available at many
while waiting for more definitive endoscopic therapies to be centres in India), when placed successfully it can achieve
employed or when endoscopy is not possible due to non- haemostasis in 90% to 100% cases. TIPS is associated with long-
availability of trained personnel or contraindicated because of term complications of thrombosis and occlusion of stent and
haemodynamic instability. They can also be used as an adjunct hepatic encephalopathy. It is contraindicated in patient with
to endoscopic therapies. Both somatostatin and octreotide have poor cardiac function, pulmonary hypertension and polycystic
an excellent safety profile, with low complication rates. Their liver disease.
use may cause hyperglycaemia and abdominal cramping.
Prevention of Variceal Bleeding
Endoscopic Therapy Non-selective beta-blockers such as propranolol and nadolol
Endoscopic therapy is the cornerstone of controlling in doses that decrease the heart rate by 25% have been shown
haemorrhage from varices. These are two principal forms of to be effective in preventing primary and secondary variceal
endoscopic treatment: haemorrhage.
(a) Endoscopic sclerotherapy (EST) The majority of episodes of upper GI bleeding can be controlled
(b) Endoscopic variceal band ligation (EVL) with endoscopic and pharmacological therapy. Angiographic
therapy or surgery may be needed in those patients where
Endoscopic sclerotherapy (EST)
bleeding cannot be controlled or localised or in those with
It involves injection of sclerosing agents into the veins causing recurrent bleeding.
thrombosis and scarring. Various sclerosing agents used are
ethanolamine oleate, aethoxyskerol, sodium tetradecyl Upper GI bleeding is a serious emergency which carries a high
sulphate, sodium morrhuate and absolute alcohol. Tissue mortality. Overall survival is improving due to the availability of
adhesive such as N-butyl-cyanoacrylate have been used for new therapeutic methods and improved medical care.
sclerosing of gastric varices. Variceal injections are started at
gastro-oesophageal junction and are restricted to distal 5 cm RECOMMENDED READINGS
of oesophagus. Usually 1 to 2 ml of sclerosing agent is injected 1. Adler DG, Leighton JA, Davila RE, et al. ASGE guidelines: The role of
endoscopy in acute non-variceal upper-GI haemorrhage. Gastrointest
into each varix and a total of 10 to 15 mL is effective in Endosc 2004; 60: 497.
controlling bleeding. Sclerotherapy is repeated usually at 2. Barkun A, Bardou M, Marshall JK. Consensus recommendations for
intervals of 2 to 3 weeks. Endoscopic sclerotherapy is associated managing patients with nonvariceal upper gastrointestinal bleeding. Ann
with some local and systemic complications, which include Intern Med 2003;139: 843.
retrosternal pain, transient dysphagia, fever and mild pleural 3. Gevers AM, De Goede E, Simoens M, et al. A randomised trial comparing
effusions. Oesophageal stricture leading to dysphagia is seen injection therapy with hemoclip and with injection combined with
hemoclip for bleeding ulcers. Gastrointest Endosc 2002; 55: 466.
in approximately 15% of patients. Bleeding from post-EST ulcers
4. Lau JY, Sung JJ, Chan AC, et al. Stigmata of haemorrhage in bleeding peptic
and oesophageal perforation are potentially life-threatening
ulcers: An interobserver agreement study among international experts.
complications of endoscopic sclerotherapy. Gastrointest Endosc 1997; 46: 33.
Endoscopic variceal band ligation (EVL) 5. Lin HJ, Lo WC, Lee Fy, et al. A prospective randomised comparative trial
showing that omeprazole prevents rebleeding in patients with bleeding
It involves applying rubber bands around varices which lead to peptic ulcer after successful endoscopic therapy. Arch Intern Med 1998;
occluding the veins mechanically. The elastic rubber band 158: 54.
strangulates the varix producing thrombosis, inflammation, 6. Sharara AI, Rockey DC. Gastro-oesophageal variceal haemorrhage. N Engl
necrosis and finally sloughing of mucosa that heals by scar J Med 2001;345:669.

41
 2.9 Fever of Unknown Origin

Priscilla Rupali

Pyrexia or fever of unknown origin (FUO) remains an intellectual tuberculosis, abscesses and bacterial endocarditis predominated;
and diagnostic challenge. A developing country like India, with neoplasms were mostly non-Hodgkins’ lymphoma, Hodgkins’
its burden of endemic diseases like tuberculosis, fungal lymphoma and leukaemia and collagen vascular diseases
infections and limited access to diagnostic facilities, requires causing fever were systemic lupus erythematosus (SLE),
a radically different approach from that of the developed Takayasu’s arteritis and mixed connective tissue disease (MCTD).
countries for arriving at a diagnosis in a patient of FUO. About 14% remained undiagnosed in this series. This is in
contrast to that seen in the Western world where infections
DEFINITION contribute to less than a third of cases and about 30% to 50%
In 1961, FUO was defined by Petersdorf and Beeson as fever remain undiagnosed.
greater than 38.3°C (101°F) documented on several occasions,
Nosocomial FUO
for more than 3 weeks with no diagnosis despite 1 week
of inpatient investigation. With the advent of acquired There is no systematic series of nosocomial FUO in literature.
immunodeficiency syndrome (AIDS), complex surgical and ICU However, when evaluating a hospitalised patient with fever, the
protocols and increased diagnostic investigations, Durack and underlying susceptibility of the patient, surgical or investigative
Street proposed classifying FUO into four different categories: procedures done, invasive devices in situ, and the patient’s own
(1) classic FUO, (2) nosocomial FUO, (3) neutropaenic FUO and flora need to be taken into consideration. About 50% of nosocomial
(4) human immunodeficiency virus (HIV) associated FUO. fever is due to infections.Non-infectious causes include drug fever,
deep venous thrombosis, acalculous cholecystitis, pancreatitis and
TYPES OF FUO pulmonary embolism. Repeated physical examinations with
Classic FUO: The newer definition is similar to the one proposed multiple blood and fluid cultures often yield a clue towards
in 1961. Keeping in mind increasing diagnostic capabilities, this diagnosis. For critically ill patients, intravenous (IV) lines/invasive
has been modified to fever greater than 38.3°C (101°F) for more catheters must be changed swiftly. Empirical therapy with
than 3 weeks with no diagnosis after 3 outpatient visits or 3 antibiotics after taking at least three blood cultures must be started
days as inpatient in the hospital or 1 week of ‘intelligent and only if there is evidence of hypotension, acute respiratory distress
invasive’ ambulatory investigations. syndrome (ARDS) or multiple organ damage.
Nosocomial FUO: Fever greater than 38.3°C (101°F) on several Neutropaenic FUO
occasions in a hospitalised patient receiving acute care, not Data from Western literature documents that at least 50% of
manifesting or incubating an infection on admission with no neutropaenic patients who become febrile have an established
diagnosis after 3 days of investigations, including 2 days’ or occult infection and 20% of febrile patients with absolute
incubation of cultures. neutrophil count (ANC) less than 100 cells/mm3 are bacteraemic.
Neutropaenic FUO: Fever greater than 38.3°C (101°F) on several True neutropaenic FUO with no diagnosis at 96 hours varies in
occasions in a neutropenic (absolute neutrophil count <500 each series from 25% to 40%. Most often these are fungal
cells/mm3 or expected to fall to this level in 1 to 2 days) patient (Candida, Aspergillus) and viral infections [cytomegalovirus (CMV)
with no diagnosis after 3 days of investigations, including 2 days’ and herpes simplex virus (HSV)]. A detailed physical examination
incubation of cultures. including the fundus, skin, peri-rectal area and paranasal sinuses
is mandatory to localise a possible source of infection. Risk factors
HIV-associated FUO: Fever greater than 38.3°C (101°F) on several for occult infection include the degree of neutropenia, disruption
occasions in a HIV-infected patient, with no diagnosis after of skin and mucosal barriers, a rapid decline in ANC, prolonged
investigations for more than 4 weeks as an outpatient, or 3 days duration of neutropaenia, cancer not in remission, co-morbid
as an inpatient. illnesses, venous catheters and use of monoclonal antibodies
AETIOLOGY against cellular receptors. Empiric antibiotic regimens
recommended for use in India, after at least 3 blood cultures,
Classic FUO
based on the studies available should include coverage against
The major causes of a classic FUO have remained the same over extended spectrum β lactamase (ESBL) producing Gram-negative
the last 10 decades. The three major categories include organisms like E. coli, K.pneumoniae, and P.aeruginosa and
infections, neoplasms and non-infectious inflammatory Gram-positive organisms like S.aureus, coagulase negative
diseases (collagen vascular diseases and sarcoidosis). Other Staphylococcus spp.
minor categories include drug fever, factitious fever and
habitual hyperthermia. In a large series of classic FUO from HIV-Associated FUO
Eastern India, infections were the most dominant cause seen in Prolonged fever in HIV-infected persons is due to an infection
53% (half of these were tuberculosis), neoplasms in 17% and in 90% of cases. Risk of an opportunistic infection (OI) depends
42 collagen vascular diseases in 11%. Among the infections on the degree of immunosuppression and the burden of
 Fever of Unknown Origin
endemic pathogens in the environment. In India, tuberculosis – Bites (arthropod or others)
accounts for about 70% of cases of prolonged fever, followed – Pre-existing cardiac abnormalities
by disseminated cryptococcosis (10%), Pneumocystis jiroveci – Prostheses in situ
pneumonia (7%), community acquired pneumonia (2%) and – Exposure to other ill people
liver abscess (2%). A CD4 count, if available, can help and predict – High risk behaviour and exposure to sexually transmitted
which disease could be contributing to the cause of prolonged infections
fever. The spectrum of HIV associated FUO in India is – Co-morbid conditions like alcoholism, IV drug use, HIV and
slightly different from that reported in Western literature. malignancies
Mycobacterium avium intracellulare complex (MAIC) is not – Previous visit to hospital for trauma, burns or laceration
a common cause of FUO in India. One theory proposed to
– Foreign bodies like tampons, nasal packs and barrier
explain this is that we have so much endemic burden with
contraceptives
Mycobacterium tuberculosis that it confers some sort of
– Involvement or exposure to any domestic or international
immunity against atypical mycobacteria. With the advent of
bioterrorist activity
highly active antiretroviral therapy (HAART) it also becomes
imperative for us to consider possible causes for fever after start On examination, if a person appears ill, investigations should
of HAART. In the initial 6 months after the start of HAART, be expedited. A detailed skin and soft tissue examination to look
immune reconstitution inflammatory syndrome (IRIS), drug for rashes, eschar, petechiae, dusky skin and discoid lesions
fever, and antiretroviral therapy associated OIs (when the should be performed inclusive of the hidden areas like axillae,
baseline CD4 counts are really low and the person is still groin, inframammary folds and behind the ear. Palpation of
susceptible to OIs) are common whereas after 6 months, causes muscles or spine often reveals myositis and inter/intramuscular
of prolonged fever include various forms of tuberculosis, abscesses or spinal tenderness. The importance of looking for
neoplasms and non-infectious inflammatory diseases similar nuchal rigidity, per-rectal exam to look for prostatic abscess and
to a classic FUO. The common causes in each of these categories inspection of the genitalia and oral cavity cannot be over
are shown in Table 1. emphasised.

Table 1: Causes of FUO

Classic FUO Nosocomial FUO Neutropaenic FUO HIV-associated FUO
Tuberculosis Post-operative Bacterial infections Tuberculosis
– E. coli
Abscesses – abscesses – Klebsiella spp. Cryptococcosis
– haematomas – Pseudomonas spp.
Bacterial endocarditis – foreign bodies – S. aureus Pneumocystis jiroveci pneumonia
Infected prostheses – Coag neg staph
Visceral leishmaniasis Infected catheters Central venous catheter (CVC) Bacterial pneumonia
infections
Non-Hodgkins lymphoma Clostridium difficile colitis Invasive fungal infections: Amoebic liver abscess
Hodgkins lymphoma Acalculous cholecystitis Pneumonia and sinusitis Disseminated histoplasmosis
Acute leukaemia Deep venous thrombosis Dental abscesses Non-Hodgkins lymphoma
Systemic lupus erythematosus Pulmonary embolism Perianal infections, cytomegalovirus, Immune reconstitution
Takayasu’s arteritis Drug fever Herpes simplex virus infections inflammatory syndrome

DIAGNOSTIC APPROACH An initial laboratory evaluation inclusive of a total and

It is often said that a good clinician is the one who makes least differential count, three blood smears for malarial parasites,
mistakes in diagnosis of common conditions, not the one who urine microscopy, chest radiograph, typhidot and blood cultures
makes occasional brilliant guesses. A detailed history and could rule out a possible cause of an acute undifferentiated
physical examination often reveals potential diagnostic ‘clues’ febrile illness. If the patient is not in multi-organ system failure,
which could be critical towards making a diagnosis. The first previous antibiotics/drugs should be stopped, the patient
step would be a consistent documentation of fever (38.3°C or observed for at least 72 hours, at which point multiple blood
101°F) on several occasions by a health care professional. (and fluid, if indicated) cultures should be taken. Increased
Significant weight loss, night sweats and anaemia usually also number of blood cultures and a large volume in each culture
confirm an organic pathology. A detailed history should include bottle increases the yield significantly. A second tier of
the following: investigations, depending on the constellation of symptoms
– Immune status-immunocompromised state (HIV infection, and signs, could include liver function test (LFT), cerebrospinal
immunosuppressive drugs, neutropenia, lymphopenia, fluid (CSF) analysis, an ultrasound of the abdomen and bone
malignancies like lymphomas and congenital immune marrow aspiration with a biopsy and routine, mycobacterial and
deficiencies) fungal cultures. Rarely, an inappropriately treated enteric fever
– Occupation may be picked-up on a bone marrow culture even when the
– Medications blood cultures are negative, however, it is extremely rare for
– Travel typhoid fever to present after 3 weeks as it is most often an
– Immunisations acute febrile illness and should not usually present as a FUO.
– Exposure to pets Endemic diseases peculiar to specific geographic locations in
43
 India also need to be kept in mind while evaluating FUO consumption of unpasteurised dairy products with skeletal
(Figure 1). The diagnostic algorithms to evaluate prolonged or joint involvement and hepatosplenomegaly suggests
fever in India also depend on cost-effectiveness and not just brucellosis.
diagnostic yield and hence invasive tests like bone marrow  Resident of Nagaland or Manipur, possibly HIV-infected with
aspiration and biopsy with suitable cultures or even liver biopsy anaemia and umbilicated skin papules with evidence of
may often be done before expensive tests like computerised systemic involvement suggests ‘disseminated penicilliosis’.
tomography (CT) scan of the abdomen and thorax or positron
 Oral ulcers, arthralgia and discoid lesions with frothy urine
emission tomography (PET) scans. It would be difficult to
in a young person suggests SLE.
encompass all the FUO causing conditions into one single
algorithm, especially as most patients would have clues on  Young individual with arthragia, maculopapular rash,
history and physical examination. However, there could be leucocytosis, lymphadenopathy and hepato or spleno-
certain pointers in a person with prolonged fever and weight megaly suggests adult onset still’s disease.
loss towards a diagnosis and these are as follows: Despite the fact that there are numerous algorithms available
 Resident of North-East India with oral ulcers, skin lesions in different textbooks, it would be important to follow ‘Sutton’s
and adrenal enlargement on imaging suggests disseminated law’ or ‘look where the money is’. Do not carry out a battery of
histoplasmosis. ‘routine’ tests in a conventional sequence. Suggested
 Diabetic or immunosuppressed individual with non- algorithms, with the disclaimer that not all diseases would fit
resolving pneumonia with cutaneous, visceral or pleural into these, are shown in Figures 2 to 4.
abscesses suggests melioidosis. ADDITIONAL LABORATORY TESTS USEFUL IN THE
 Resident of Bihar or Jharkhand with pancytopaenia and DIAGNOSIS OF FUO
large spleen suggests visceral leishmaniasis. Additional tests that may provide clues include thick and thin
 Resident of Karnataka, North India or Kashmir with history blood smears to rule out malaria, babesia and trypanosomes if
of some exposure to animals, either by occupation or relevant travel history is present. Febrile serology for rickettsial

Figure 1: Evaluation of classic FUO in India.

Echo = Echocardiogram; FDG-PET = Fluorodeoxy glucose positron emission tomography; CRP = C-reative protein; ESR = Erythrocyte sedimentation rate; LFT = Liver function
test; U/S = Ultrasound; ANA = Antinuclear antibody; ACE = Angiotensin converting enzyme; OG = Obstetrics and gynaecology; ENT = Ear, nose, throat; ELISA = Enzyme
linked immunosorbent assay; dsDNA = Double stranded DNA, HIV = Human immunodeficiency virus.
44
 Fever of Unknown Origin
Figure 2: Evaluation of nosocomial fever.
CVC = Central venous catheter; VAP = Ventilator associated pneumonia; CPIS =
Clinical pulmonary infection score; IV = Intravenous catheter; ET = Endotracheal
tube. Am J (Respir Crit Care Med 1995;152:1982-91).

infections, salmonella and dengue may not be useful if history

of fever is around 3 weeks as most of these diseases would have
run through their natural course by this time. However, febrile
serology may be useful for brucellosis, visceral leishmaniasis
and prolonged mononucleosis syndromes. If bacteremia or
endocarditis is suspected, it may be prudent to maintain blood Figure 3: Evaluation of fever in neutropaenic patients.
cultures for 2 weeks to rule out HACEK organisms or use
HRCT = High resolution computerised tomography; CT = Computerised
alternative blood culture techniques like ‘lysis centrifugation’ if tomography; HSV = Herpes simplex virus, VZV = Varicella zoster virus; CMV =
bacterial load is suspected to be low. Autoimmune work-up Cytomegalovirus; ANC = Absolute neutrophil count.
should be considered early along with a check-list of signs
and symptoms of an autoimmune disorder to allow early
non-infectious inflammatory diseases. FDG-PET, as a second line
categorisation to a specific collagen vascular disease. In an
or third line procedure in FUO, has a sensitivity of 81% and
elderly individual with symptoms of anorexia and anaemia,
specificity of 86% in detecting the cause of fever. In most
examination for occult blood in stools should be considered
diagnostic protocols of FUO in Western literature, FDG-PET is a
with early gastroscopy or colonoscopy as indicated. Diagnostic
second line procedure. This is unrealistic in India due to the
clues like pancytopaenia may prompt an early bone marrow
enormous cost-constraints and hence we would need to
evaluation. Similarly, an elevated alkaline phosphatase (ALP)
develop our own protocols which would be cost-effective and
concurrent with an elevated gamma glutamyl transferase (GGT)
generalisable in a resource-limited setting.
indicative of an infiltrative liver disease or elevated enzymes
indicative of a granulomatous hepatitis may prompt a blind or TREATMENT
ultrasound guided liver biopsy for histopathology and relevant
In a classic FUO, the emphasis should be on obtaining a
cultures. Exploratory laparotomy would be advocated only if
diagnosis and empirical antibiotics, anti-tuberculous therapy
there is moderate splenomegaly with all other investigations
(ATT), nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids
being non-contributory and a high chance of a malignancy
may mask fever while permitting the spread of infection. Hence,
localised to the spleen, e.g. splenic lymphoma or T-cell
these are to be avoided while attempting to make a diagnosis.
lymphoma.
However, if the patient has deranged vital signs, is asplenic or
Non-invasive whole body radionuclide scans like 111Indium- neutropenic, after taking suitable cultures cautious use of
labelled leucocytes, 67Ga-citrate scan and Technetium Tc 99m antibiotics appropriate to the local flora or clinical picture may
delineate and localise inflammatory foci. Recently, 2-[18 F] fluoro- be advised. ‘Shotgun therapy’ with antibiotics, ATT, NSAIDs and
2-deoxy-D-glucose (FDG)-positron emission tomography (PET) steroids is to be assiduously avoided as it minimises the chance
has replaced other radionuclide techniques as it accumulates of a future diagnosis. Repeated physical examinations often
in pyogenic infectious foci, malignancies, granulomatous and reveal localising clues as the disease evolves. In the case of non- 45
 Figure 4: Evaluation of fever in PLWHA (people living with HIV/AIDS).
IRIS = Immune reconstitution inflammatory syndrome; CXR = Chest X-ray; CT scan = Computerised tomography scan; AFB = Acid fast bacilli; M. Tb = Mycobacterium
tuberculosis; CMV = Cytomegalovirus; LP = Lumbar puncture; HAART = Highly active antiretroviral therapy; BM = bone marrow.

infectious inflammatory diseases, a repeated evaluation after a  Emphasis in any FUO should be on obtaining a diagnosis.
follow-up of 2 to 3 months often helps characterisation into a Steroids, antibiotics or empirical ATT often mask the
particular autoimmune or granulomatous disease. Over the diagnosis and should be avoided unless there is evidence
years, in the many series of classic FUO, the number of patients of serious organ dysfunction.
with no diagnosis ranges from 30% to 50%. However, even if no
diagnosis is obtained, the prognosis has usually been good in RECOMMENDED READINGS
these patients. 1. Bleeker-Rovers CP, Vos FJ, de Kleijn EM, et al. A prospective multicentre
study on fever of unknown origin: the yield of a structured diagnostic
CONCLUSION protocol. Medicine 2007; 86: 26-38.
2. Cunha BA. Fever of unknown origin: focused diagnostic approach-based
 The four types of FUO include classic, nosocomial, neutropenic
on clinical clues from the history, physical examination, and laboratory
and HIV related. tests. Infect Dis Clin North Am 2007; 21: 1137-87.
 The important causes of classic FUO include the big three, 3. George B, Mathews V, Srivastava A, et al. Infections among allogeneic bone
i.e. Infections, neoplasms and connective tissue diseases. marrow transplant recipients in India. Bone Marrow Transplantation 2004;
33: 311-5.
 Nosocomial FUO is most often due to an infection, however
4. Gelfand JA, Callahan MV. Fever of unknown origin. In Fanci AS, Bramnwoald
non-infectious causes need to be kept in mind. E, Kasper DL, et al editors. Harrison’s Principles of Internal Medicine; 17th ed.
 Neutropaenic FUO most commonly is due to fungal New York: McGraw-Hill Companies, Inc; 2008: pp 130-4.
infections like candidiasis and aspergillosis and viral 5. Kejariwal D, Sarkar N, Chakraborthi SK, et al. Pyrexia of unknown origin: a
prospective study of 100 cases. J Postgrad Med 2001; 47: 104-7.
infections like CMV and HSV.
6. Rupali P, Abraham OC, Zachariah A, et al. Aetiology of prolonged fever in
 Tuberculosis contributes to 70% of the cases of HIV- antiretroviral-naïve human immunodeficiency virus infected adults. Natl
associated FUO. Med J India 2003;16(4):193-9.

46
 2.10 Generalised Lymphadenopathy

SK Verma

DEFINITION Malignancy: Acute leukaemias, lymphomas, chronic lymphocytic

Lymphadenopathy is an increase in the size of lymph nodes. leukaemia.
Enlargement of lymph nodes in three or more non-contiguous Autoimmune disorders: Juvenile rheumatoid arthritis, serum
areas is considered as generalised lymphadenopathy. sickness, rheumatoid arthritis, systemic lupus erthymatosis (SLE),
mixed connective tissue disorder, sarcoidosis and graft versus
BACKGROUND host disease.
Generalised lymphadenopathy (GL) is a common clinical
problem faced by primary care physicians. The majority of cases Metabolic and storage disease: Gaucher disease, Niemenn-Pick
have infective and non-specific aetiology or a reactive lymph- disease, cystinosis.
adenopathy whereas less than 1% have malignancy as the Drug hypersensitivity: Phenytoin, mephenytoin, carba-mezapine,
aetiology. GL usually occurs in response to systemic causes such pyrimethamine, phenylbutazone, allopurinol, and isoniazid.
as infections, autoimmune diseases, drug reaction but less
Other non-neoplasic aetiologies: Langerhans cell histiocytosis,
commonly due to malignant disorders, histiocytoses and
Epstein-Barr virus (EBV )-associated lympho-proliferative
storage disorders. As age advances, the incidence of serious
disease, Castleman disease and Kawasaki disease.
illnesses causing GL increases. Hence, it is important to have a
systematic approach to GL so as to avoid unnecessary APPROACH
investigations while at the same time not missing a serious
Approach to a case of GL requires detailed history, physical
disorder.
examination and appropriate lab testing to find out a possible
PATHOPHYSIOLOGY aetiology before attempting advanced testing and biopsy.
Lymphadenopathy may be caused by the following: History
1. Multiplication of cells within the node, e.g. lymphocytes, Age and duration
monocytes, plasma cells, or histiocytes. Most cases of GL in younger patients are due to infectious or
2. Infiltration by cells from outside, such as malignant cells or benign aetiology whereas in older adults autoimmune or
neutrophils. malignant causes are more commonly seen. GL in younger
3. Lymph nodes draining a source of infection. patients usually resolves within 2 to 3 weeks. Non-resolving GL
and progressive increase in size should raise a suspicion and
4. Depositions or storage disorders.
requires further work-up. In adults and in the elderly, GL should
5. Benign hyperplasia. be taken seriously at the onset without any delay in work-up.
CAUSES Exposures
Causes of GL include infections, autoimmune diseases, A history of chronic use of drugs, such as anti-epileptic drugs,
malignancies, histiocytoses, storage diseases, benign exposure to pets, animals and insect bites is important and a
hyperplasia, and drug reactions. history of travel to endemic areas must be noted. Occupational
and environmental exposures such as smoke, fumes, pesticides,
Infections tobacco and radiations must be evaluated.
1. Viral infections: Human immunodeficiency virus (HIV), Personal and family history
infectious mononucleosis, cytomegalovirus, varicella, and
adenovirus. Sexual history is important and HIV positivity is associated with
increased chances of rare and opportunistic infections and
2. Bacterial infections: Tuberculosis, brucellosis, plague, malignancies as a cause of GL. Family history of certain cancers
Streptococci, Staphylococci, cat-scratch disease, chancroid, raises suspicion of cancer as a cause of GL.
melioidosis, atypical mycobacterial infection, primary and
secondary syphilis, leprosy. Specific symptoms
GL associated with fever, upper respiratory symptoms, irritability
3. Fungal infections: Histoplasmosis, coccidioidomycosis, and anorexia points towards infective aetiology whereas weight
paracoccidioidomycosis. loss and cachexia suggest malignancy. The presence of joint
4. Chlamydial infections: Lymphogranuloma venereum. pain, mild fever, morning stiffness, skin and constitutional
symptoms suggests autoimmune disorder as the cause of GL.
5. Parasitic infections: Toxoplasmosis, filariasis, leishmaniasis,
Although fever is a very important feature of infection, it may
trypanosomiasis.
be absent in patients who are diabetic, immunocompromised
6. Rickettsial infections: Scrub typhus, Q fever, rickettsial pox. or those on steroids or immunosuppressive drugs.
47
 Physical Examination to its aetiology. Autoimmune disorders and HIV infection may
Physical examination includes examination of lymph nodes and have numerous clues in the history and physical examination.
their characteristics, presence of splenomegaly, bone Splenomegaly with GL is seen in lymphoproliferative disorders
tenderness, purpura, skin and complete systemic examination like lymphoma, acute and chronic lymphatic leukaemia or
for clues to the underlying cause for GL. systemic illnesses like infectious mononucleosis, tuberculosis,
brucellosis, salmonellosis, toxoplasmosis, leishmaniasis, filariasis,
Lymph node examination cat-scratch disease, SLE, rheumatoid arthritis and sarcoidosis.
Size: Lymph nodes measuring (<1 cm) are often palpable in Hepatomegaly and splenomegaly with GL is a common
normal adults and inguinal nodes up to 2 cm in size may be presentation of rare infiltrative, metabolic and storage
considered normal. Lymph nodes measuring <1.0 cm2 in area disorders.
(1.0 cm × 1.0 cm or less) are usually benign or reactive where as
INVESTIGATIONS
lymph node size of 2.25 cm2 (1.5 cm × 1.5 cm) should be
investigated further for the underlying cause. Lymph nodes Since most patients with GL have benign or reactive lymph-
measuring 1 cm to 2.25 cm2 in size may be kept under close adenopathy, extensive work-up is to be done only in cases
observation or investigated depending upon other features. suspected to have significant lymphadenopathy on physical
However, the presence of even shotty (< 0.5 cm) supraclavicular, examination. Supraclavicular, scalene, iliac, popliteal and
scalene, iliac, popliteal or epitrochlear nodes is considered epitrochlear nodes should be investigated to rule-out a
significant. Persistence and increasing size of a lymph node are malignancy. Complete blood counts with blood picture may
definite indications for further evaluation. rule-out leukaemias and immune cytopaenias. Viral serological
testing including HIV and immunological markers like anti-
Texture: A lymph node may be soft, rubbery, firm or hard in nuclear antibody (ANA) should be done when suspected on
consistency, discrete or matted, movable or fixed and may be history and physical examination. Chest radiographs and
tender or non-tender with or without features of inflammation. abdominal ultrasonography may show nodes and provide clues
Small, soft, discrete, non-tender nodes are seen mostly with to the aetiology. A computed tomography or magnetic
benign conditions. Pain and tenderness is mostly a feature of resonance imaging may be used to visualise deep seated nodes
inflammatory aetiology and rarely due to rapid enlargement like mediastinal and retroperitoneal nodes, when appropriate.
of nodes due to acute leukaemia. Large, symmetrical, discrete, Biochemical testing adds little to aetiological diagnosis
rubbery to firm, mobile and non-tender nodes are seen in although lactate dehydrogenase (LDH) is frequently raised in
lymphoma. Hard, non-tender and fixed nodes are highly cases of lymphoma.
suggestive of malignant deposits. Matted, firm and non-tender
nodes are mostly due to tuberculous lymphadenitis or a LYMPH NODE BIOPSY
malignancy. Development of draining sinuses is characteristic The decision to obtain a biopsy should be based on lymph node
of tuberculous lymphadenitis. characteristics, systemic examination and laboratory testing.
Excision biopsy should be taken from the most representative
Location: Certain locations may provide a clue to the possible
node. Inguinal nodes are best avoided. Fine needle aspiration
aetiology of GL. Supraclavicular, scalene, iliac, popliteal and
cytology is not a good method for initial diagnostic work-up.
epitrochlear nodes are to be investigated to rule out malignancy.
Indications for biopsy include lymph node area of >2.25 cm2
Presence of mediastinal nodes with GL points towards
(1.5 cm × 1.5 cm), hard, fixed, supra-clavicular, scalene, iliac,
lymphoblastic leukaemia, lymphoma, sarcoidosis, tuberculosis,
popliteal and epitrochlear nodes of any size or increasing size
histoplasmosis and coccidioidomycosis. Presence of supra-
of nodes.
clavicular nodes suggests lymphoma, tuberculosis, toxoplasmosis,
histoplasmosis, and coccidioidomycosis. Abdominal and RECOMMENDED READINGS
mesenteric nodes with GL may suggest lymphoma, tuberculosis, 1. Allhiser JN, McKnight TA, Shank JC. Lymphadenopathy in a family practice.
ulcerative colitis, brucellosis and salmonellosis. J Fam Pract 1985; 20: 449-58.
2. Ferrer R. Lymphadenopathy: differential diagnosis and evaluation. Am Fam
Systemic Examination
Physician 1998; 58: 1313-22.
GL is commonly caused by systemic disorders and systemic 3. Habermann TM, Steensma DP. Lymphadenopathy. Mayo Clin Proc 2000; 75:
infections, so detailed systemic examination may provide a clue 723-32.

48
 2.11 Dizziness and Vertigo

M Maiya

‘Dizziness’ is a common symptom. It refers to various types degeneration or a tumour in or near the cerebellum. The
of abnormal sensations relating to perception of the body’s multiple sensory deficit syndromes involve abnormalities
relationship to space. These sensations may be a feeling of in various proprioceptive systems like visual, auditory
rotation or spinning—known as vertigo; or others like non- disorders and peripheral neuropathy. The patient may
rotatory swaying, light-headedness, faintness and unsteadiness. complain of dizziness at night.
This ‘Dizziness syndrome’ is mostly benign but it may be
3. There may be a group of patients who complain of ill-
a manifestation of serious underlying cardiac or neuro-
defined light-headedness which the patient finds difficult
logical disease. Hence, it is essential to analyse the complaint of
to define. Such patients usually suffer from anxiety or
‘Dizziness’.
depression.
The first step in the analysis of dizziness is to differentiate vertigo
from other abnormal sensations of imbalance. If the patient VESTIBULAR DISORDER: VERTIGO
complains of a sensation of spinning or motion sickness, one Vertigo is a cardinal symptom of vestibular disease. Hence, it is
should suspect vertigo. It indicates a vestibular system disorder essential to understand the neuro-anatomy and physiology of
involving the inner ear or its connection to the brain; whereas the vestibular system before analysing the symptoms of vertigo.
the other sensations of imbalance suggest a non-vestibular
disorder. The clinical approach to a patient with dizziness is Anatomy and Physiology of the Vestibular System
shown in Figure 1. The end organ of the vestibular system consists of 3 semi-
circular canals and otolith apparatus (utricle and saccule) on
NON-VESTIBULAR DISORDERS either side, situated in the bony labyrinth of the inner ear. It is
1. Syncope or pre-syncope: Pre-syncope is a feeling of light concerned with the detection of head position, head movement
headedness and a sensation of an impending faint and control of the vestibulo-ocular reflex (VOR). This reflex
(syncope). It is episodic, lasting for a few seconds to minutes. automatically compensates for any movement of the head with
Pathophysiologically, it is due to decrease in cerebral blood an equal and opposite movement of the eyes.
flow, due to an underlying cardiovascular disorder.
The paired vestibular nuclei, situated in the medulla and lower
2. Disequilibrium: It refers to a sense of imbalance involving pons receive neural input from three sensory systems—
the legs and the trunk, without a sensation in the head. It is vestibular, visual (retina to occipital cortex) and the somato-
seen in cerebellar ataxia and multiple sensory deficit sensory system (information from the skin, joints, and muscle
syndromes. The cerebellar diseases are cerebellar receptors). The vestibular nuclei transmit the information to the

Figure 1: Approach to patient with ‘dizziness’.

49
 upper brainstem (nuclei of III, IV and VI cranial nerves), imbalance and vestibular ataxia. Vertigo itself is due to
cerebellum, cerebral cortex and spinal cord through neural disturbance of cortical projections. The associated nausea and
projections (Figure 2). vomiting are due to activation of the reticular formation and
the vomiting centre in the medulla.
Vertigo may be due to physiological or pathological causes.
Physiological vertigo is seen in normal individuals with
unfamiliar head movements, unusual head and neck position
or following spinning.
Pathological vertigo results from lesions of the visual, somato-
sensory or vestibular system. Visual vertigo is caused by
incorrect eye-glasses, and extra-ocular muscle paresis. Somato-
sensory vertigo is due to myelopathy or peripheral neuropathy
and is rarely seen in isolation.
The most common cause of pathological vertigo is vestibular
dysfunction. If may involve the end organ (labyrinth), the nerve
or central connections.Vertigo is associated with jerk nystagmus
frequently accompanied by nausea, postural unsteadiness and
gait ataxia.
Clinical Manifestations
Depending on the frequency and duration of attacks, vertigo
can be classified into 3 clinical types: prolonged spontaneous
attacks, recurrent spontaneous attacks and recurrent positional
vertigo. The lesion may be central or peripheral and can be
differentiated as shown in Table 1.
Prolonged Spontaneous Attacks of Vertigo
This occurs when due to unilateral loss of vestibular function.
The vertigo is acute in onset, may last for days and is aggravated
by head movement. The patient prefers to sit upright with
Figure 2: Connections of the vestibular system. the head still or to lie with the intact side down. On movement
the patient may fall towards the affected side. The vertigo is
The projection of the vestibular nuclei to the nuclei of the III, IV associated with nausea, vomiting and malaise. This type of
and VI cranial nerves is essential for VOR. This reflex maintains vertigo may be peripheral or central. Common causes of
visual stability during head movement. Lesions of these this type of vertigo include acute labyrinthine/vestibular
pathways result in nystagmus. The vestibulo-cerebellar dysfunction due to infection, trauma or ischaemia, brainstem
connection helps in modulation of VOR.The abnormal activation or cerebellar infarction/haemorrhage, multiple sclerosis and
and dysfunction of vestibulo-spinal pathway results in postural brainstem tumours/vascular malformations.

Table 1: Features of Peripheral vs Central Vertigo

Sign/Symptoms Peripheral Central

Direction of associated nystagmus Unidirectional; fast phase opposite lesion Bidirectional or unidirectional
Purely horizontal nystagmus without Uncommon Common
torsional component
Vertical or purely torsional nystagmus Never present May be present
Visual fixation Inhibits nystagmus and vertigo No inhibition
Severity of vertigo Marked Often mild
Direction of spin Towards fast phase (away from lesion) Variable
Direction of fall Towards slow phase Variable
Duration of symptoms Finite (minutes, days, weeks) but recurrent May be chronic
Tinnitus and/or deafness Often present Usually absent
Associated CNS abnormalities None Extremely common (e.g., diplopia,
dysarthria, hiccups, cranial neuropathies,
ataxia, hemi-sensory loss or even paralysis)
Common causes None, BPPV, infection (labyrinthitis), Meniere’s Vascular, demyelinating disease, neoplasm
disease, neuronitis, ischaemia, trauma, toxins
CNS = Central nervous system, BPPV: Benign paroxysmal positional vertigo.
50
 Dizziness and Vertigo
The vestibulopathy can be identified by the head thrust test. BPPV can be caused by head injury, stapes surgery, otitis media,
Head thrust test is a bed-side test of horizontal VOR. With the labyrinthine ischaemia and viral infection of the ear. Occasionally,
patient’s head held by the examiner’s hand he/she is asked the cause is not obvious. The diagnosis is confirmed by standard
to focus on the examiner’s nose. The head is then quickly positional testing test (Dix-Hallpike test).
moved about 10° to one-side. In patients with normal vestibular
function the VOR results in the movement of the eye in the Dix-Hallpike Test
direction opposite the head movement, so that the patient’s With the patient seated, the examiner turns the head of the
eye remain fixed on the examiner’s nose after the sudden patient 45° to one-side. Next, the examiner moves the patient
movement. The test is repeated in the opposite direction. to the supine position with tilted head and open eyes. He
Loss of VOR will prevent eye movement opposite to the slightly extends the neck so that the chin moves upwards. The
direction of head movements on the affected side. latency, duration and direction of nystagmus is noted along with
that of vertigo.
Recurrent Spontaneous Attacks of Vertigo
The vertigo is sudden, temporary and reversible due to Central Positional Vertigo
impairment of labyrinthine function. The vertigo of vascular Rarely, positional vertigo may be due to lesions near the fourth
origin like transient ischaemic attacks (TIA) lasts for minutes, ventricle affecting the vestibular nuclei or the cerebellar vermis.
whereas, that due to disease of the inner ear may last for hours. The common causative lesions are multiple sclerosis, cerebellar
The common causes of recurrent spontaneous vertigo include tumours and atrophy.
Meniere’s disease, autoimmune inner ear disease, syphilitic
labyrinthitis, migraine equivalent and vertebro-basilar TIA. Psychogenic Vertigo
The vertigo develops gradually, increasing with associated
Meniere’s Syndrome
anxiety and terminates abruptly. Organic vertigo occurs
This disease is due to recurrent unilateral labyrinthine abruptly and disappears gradually. Psychogenic vertigo is
dysfunction associated with signs and symptoms of cochlear sometimes called phobic postural vertigo, associated with panic
disease. It is characterised by severe vertigo, vomiting, tinnitus, attacks or agoraphobia (fear of large open spaces or crowds).
fluctuating and progressive hearing loss with spontaneous The vertigo is not associated with nystagmus or vomiting.
recovery over hours to days. The age of onset is 40 to 60 Most patients adapt to being ‘house-bound’, whereas in
years and the underlying pathology is endolymphatic organic vertigo patients attempt to function in spite of the
hydrops due to inflammatory, autoimmune, traumatic or incapacity.
idiopathic aetiology.
Positional Vertigo APPROACH TO THE PATIENT
Positional vertigo is precipitated by the movement of the head The first step in the diagnosis of dizziness and vertigo is to take a
either to the right or to the left from the recumbent position, detailed history focussing on the meaning of ‘dizziness’. Does it
triggering the vestibular pathway. The peripheral type of suggest ‘faintness’, sense of imbalance, light headedness or a
positional vertigo is more common than that of central origin sensation of spinning? This is followed by general medical
and the differentiating features are shown in Table 2. examination, which should focus on the presence of orthostatic
hypotension, cardiac arrhythmias, visual acuity and examination
Table 2: Peripheral vs Central Positional Vertigo of the musculo-skeletal system for evidence of arthritis and
Peripheral Central impairment of gait. The neurological examination is done with
a
particular reference to the VIII nerve (vestibular and cochlear
Latency 3-40 seconds Immediate vertigo and
component).
nystagmus
Duration < 1 min May persist longer Provocative tests to induce cerebral ischaemia or vestibular
Fatiguabilityb Yes No dysfunction may be necessary where the patient is vague in
Habituation c Yes No the description of ‘dizziness’. These tests include the Valsalva
Intensity Severe vertigo, Mild vertigo, less intense manoeuvre inducing orthostatic hypotension, and forced
marked nystagmus nystagmus hyperventilation which decreases cerebral blood flow.
Reproducibilityd Variable Good
Vestibular dysfunction is demonstrated by a simple ‘head
Mechanism Debris moving in Damage to central VOP
semi-circular canal
shaking nystagmus test’. The patient is asked to close his eyes
and bend his head down 30°. The head is oscillated horizontally
a = Time between attaining head position and onset of symptoms 20 times. Elicitation of nystagmus after the manoeuvre suggests
b = Disappearance of symptoms with maintenance of offending position
c = Lessening of symptoms with repeated trials vestibular imbalance. Further evaluation of vestibular
d = Livelihood of symptom production during any examination session dysfunction is essential to determine the side of the lesion, the
type of lesion and to distinguish central from peripheral lesions.
Benign Paroxysmal Positional Vertigo (BPPV) The standard tests include head thrust test, Dix-Hallpike test
BPPV is characterised by sudden onset of a peripheral vestibular and electro-nystamography. If a central aetiology is suspected,
syndrome with no auditory component. The vertigo occurs MRT is mandatory.
when the patient rolls to the side on lying down, or while gazing
upwards, or bending forwards. The episode lasts for 10 to 20 MANAGEMENT OF VERTIGO
seconds. BPPV occurs in bouts lasting for a few days or weeks Treatment of acute vertigo consists of bed rest for 1 to 2
and may recur after several weeks or months. 51
days and use of anti-vertiginous drugs. These drugs give
 symptomatic relief in acute vestibulopathy (Meniere’s vestibular nuclei and prevent motion sickness. These are
syndrome, vestibular neuritis), acute brain-stem lesions near the also used in frequent attacks of vertigo, vomiting and severex
BPPV. The drugs used with their recommended dosages are
Table 3: Drugs Used in the Treatment of Vertigo mentioned in Table 3. Surgical procedures like labyrinthectomy,
Drug Category Drugs and Dosage and section of 8th nerve are used in selected patients.
Anti-histamine Dimenhydrinate 25 to 50 mg 1 to 2 times In chronic and recurrent vertigo, exercises which provoke
per day vertigo may be tried in order to habituate the patient. Patients
Meclizine 25 mg three times per day who are refractory to conventional therapy may benefit from a
Cyclizine 50 mg daily
formal rehabilitation programme, habituation customised
Anti-cholinergics Scopolamine – patch 0.5 mg per day programme and use of instruments, like tilt tables.
Phenothiazine Promethazine 50 mg per day
Prochlorperazine 10 mg IM or 25 mg RECOMMENDED READINGS
rectally 1. Chawla N, Olshaker JS. Diagnosis and management of dizziness and vertigo.
Cinnarizine 25 mg per day Med Clin North Am 2006; 90: 291-304.
Benzodiazepines Diazepam 2.5 to 5 mg oral or IV 2. Kanagalingam J, Hajioff D, Bennett S. Vertigo. BMJ 2005; 330: 523.
Clonazepam 0.25 mg 1 to 3 times per day 3. Kerber KA. Vertigo and dizziness in the emergency department. Emerg Med
Clin North Am 2009; 27: 39-50.
Histamine analogue Betahistine 16 mg three time a day
4. Samuels M. The dizzy patient-a clear headed approach. Clin Experience 1984;
IM = Intramuscular; IV = Intravenous. 1: 23.
5. Tusa RJ. Dizziness. Med Clin North Am 2009; 93: 263-71.

52
 2.12 Syncope

Pushpa Yadav, Vivek Arya

Syncope is a clinical syndrome characterised by sudden, the standing position and is mediated by reflex mechanisms
transient loss of consciousness and postural tone followed by causing changes in vascular tone, heart rate or both. It is
spontaneous and prompt complete recovery. It is most often frequently recurrent and commonly precipitated by a hot or
due to transient, self-terminating global cerebral hypoperfusion. crowded environment. Episodes are often preceded by pre-
Syncope accounts for 1% to 3% of emergency department visits syncopal prodrome lasting seconds to minutes, and rarely
and 1% to 6% of all hospital admissions in the USA . The life- occur in the supine position. The two common variants include:
time risk of a syncopal episode is 50%. Advancing age is an vasovagal (e.g. in response to micturition, cough or defaecation)
independent risk factor for syncope. and carotid sinus syncope. Syncope associated with pain,
neuralgia, or panic and episodes associated with exercise
PATHOPHYSIOLOGY (without heart disease) are also included in this category.
Reduction of blood flow to both cerebral hemispheres or to Reflex-mediated syncope does not carry an increased risk of
the brainstem reticular activating system leads to loss of consci- cardiovascular morbidity or mortality.
ousness and postural tone. A positional change from supine to
erect causes a shift of 300 to 800 mL of blood from the thoracic Table 1: Causes of Syncope
cavity to the lower extremities. This is well tolerated in normal Neurally-Mediated Syncope
individuals without any compromise in cerebral blood Vasovagal (common faint)
flow which is maintained within a narrow range due to cere- Situational: cough, sneeze, laughter, micturition, defaecation,
brovascular autoregulation. Loss of autoregulatory mechanisms excessive heat, venipuncture (needle or blood phobia), post-
or depletion of blood volume will cause a fall in cerebral blood parandial
Valsalva induced (weight lifting, brass instrument playing)
flow. Older patients and patients with hypertension or aortic
Carotid sinus syncope
valve disease tend to have syncope with a relatively small Glossopharyngeal neuralgia
decrease in systemic blood pressure. Post-exercise
Orthostatic Hypotension
DIFFERENTIAL DIAGNOSIS
Autonomic failure
The first step in the assessment of syncope is to make a correct Primary autonomic failure syndromes (e.g. pure failure, multiple
diagnosis, ruling out other disorders with a similar presentation, system atrophy, Parkinson’s disease with autonomic failure) and
especially transient loss of consciousness. Shy-Drager syndrome
Secondary autonomic failure syndromes (e.g. diabetic
A seizure is a common differential diagnosis. The presence neuropathy, amyloid neuropathy)
of an aura, cry and tonic-clonic movements are suggestive of Use of medications (anti-hypertensives, vasodilators, negative
a seizure. Unconsciousness lasting more than 5 minutes, chronotropes).
disorientation after the event and slowness in returning to Volume depletion (e.g. haemorrhage, diarrhoea, Addisonism,
consciousness are characteristic of seizures. Clenching of teeth, diuretics)
frothing from the mouth and sphincter incontinence are more Alcohol abuse
commonly seen with seizures. In dizziness, pre-syncope, and Postural intolerance syndromes
Neurologic
vertigo there is no loss of consciousness. Drop attacks present
Migraine
as a sudden fall without loss of consciousness or warning and Vascular steal syndromes
with immediate recovery. Concussions, metabolic disturbances, Transient ischaemic attacks
intoxications and psychogenic pseudoepilepsy and cataplexy Arrhythmias
also have to be excluded. Sinus node dysfunction (including bradycardia/tachycardia
Syncope is often precipitated by exercise, pain, cough, syndrome)
Atrioventricular conduction system disease
micturition, defaecation or a stressful event. A pre-syncopal
Paroxysmal supraventricular and ventricular tachycardias
prodrome consisting of weakness, light-headedness, sweating
Inherited syndromes (e.g. long QT syndrome, Brugada syndrome,
and palpitations may precede the loss of consciousness. short QT syndrome, arrhythmogenic right ventricular dysplasia)
Episodes rarely occur in the supine position and are often Implanted device (pacemakers, defibrillator) malfunction
brought on by sitting or standing. Some limb jerking may be Structural Cardiac or Cardiopulmonary Disease
seen in 15% of patients during a syncopal event. Acute myocardial infarction/ischaemia
Obstructive valvular disease
CAUSES OF SYNCOPE Obstructive cardiomyopathy
Common causes of syncope are listed in Table 1. Based on the Acute aortic dissection
underlying mechanism, syncope can be divided into different Pericardial disease/tamponade
categories. Neurally mediated syncopes are the commonest Pulmonary embolus/pulmonary hypertension
cause of syncope. This type of syncopal event usually occurs in Psychiatric Disorders 53
 Orthostatic hypotension is a drop in systolic blood pressure of Table 2: Clinical Features Suggestive of Specific Causes of Syncope
20 mmHg or in diastolic pressure of 10 mmHg within 3 minutes
Type of Syncope Clinical Features/Precipitants
of standing. It is considered clinically important if the reduction
in blood pressure is sustained at or beyond 3 minutes and the Neurally mediated Posture change, coughing, defaecation,
original symptoms are reproduced during active or passive syncope micturition, strong emotions, fear,
standing. This occurs when the autonomic nervous system prolonged standing, crowded hot places
is incapacitated either as a result of age-related physiologic Carotid sinus syncope With head rotation, pressure on carotid
sinus (as in shaving, tight collars, tumours)
changes, use of certain medications (anti-hypertensives,
Syncope caused by After standing up, autonomic neuropathy
vasodilators and negative chronotropes), volume depletion,
orthostatic hypotension
primary autonomic failure or secondary autonomic failure due
Cardiac syncope Structural heart disease, during exertion
to diabetes mellitus, amyloidosis or alcohol abuse. Orthostatic
or while in supine position, palpitations,
hypotension is more common in the elderly because of blunted acute or old myocardial infarction, family
barorecepter responses resulting in the failure of compensatory history of sudden death
cardio-acceleration. Cerebrovasular syncope
Subclavian steal Arm exercise
APPROACH TO SYNCOPE syndromes
An algorithm for the evaluation of a patient with syncope is Aortic dissection Differences in blood pressure or pulse in
shown in Figure 1. In the absence of a diagnostic gold standard, both arms
history, physical examination and electrocardiography (ECG) are Psychiatric illness Frequent syncope with somatic
the cornerstones for the assessment of syncope and their symptoms but no heart disease
combined diagnostic yield is about 80%. A complete physical examination should be performed in all
The first step is to differentiate syncope from the other causes patients. Special attention should be paid to the following
of transient loss of consciousness, and the next step is to aspects (Table 3):
separate benign causes of syncope from potentially sinister 1. Vital signs: Fever may point to an infection. Blood pressure
ones. The clinical features suggestive of specific causes of must be measured in both arms and in supine and standing
syncope are shown in Table 2. Serious causes of syncope, such positions. Tachycardia may be due to pulmonary embolism,
as critical aortic stenosis, aortic dissection, pulmonary hypovolaemia, tachyarrhythmia, or an acute coronary
embolism, visceral bleeding, dysrrhythmias, myocardial syndrome. Bradycardia may point towards a cardiac
ischaemia and subarachnoid haemorrhage should first be conduction defect, an acute coronary syndrome or a
ruled out. In elderly persons a sudden faint without an obvious vasodepressor cause of syncope.
cause should arouse the suspicion of a complete heart block 2. Cardiac rhythm and auscultatory signs of aortic stenosis,
or tachyarrhythmia. pulmonary hypertension, idiopathic hypertrophic subaortic

Figure 1: Approach to syncope.

BP = Blood pressure; ECG = Echocardiography; SHD = Structural heart disease; ILR = Insertable loop recorder; EPS = Electrophysiological studies;
CSM = Carotid sinus massage
54
 Syncope
stenosis, myxomas, congestive heart failure (CHF) or aortic Signal-averaged electrocardiography
dissection. The signal-averaged ECG filters multiple QRS complexes to
3. Carotid bruits,cranial nerve deficits,motor and sensory deficits. uncover late potentials arising from abnormal myocardium,
4. Signs of trauma which may be secondary to syncope or may where re-entry and ventricular tachycardia may arise. It is useful
have caused syncope. for selecting patients for electrophysiologic studies when
ventricular tachycardia is suspected in the presence of
Table 3: Clinical Features Suggestive of the Cause of Syncope ischaemic heart disease.
Clinical Feature Likely Cause of Syncope Head-up tilt table (HUTT) testing
Orthostatic hypotension Drugs like beta blockers and It is recommended in patients with recurrent syncope in whom a
clonidine, diabetes mellitus cardiac cause of syncope,including arrhythmias has been excluded
Murmur changes with Atrial myxoma or thrombus and in patients with unexplained recurrent syncope. It may also
position be indicated for differentiation of convulsive syncope from
Headache, diplopia, Subarachnoid haemorrhage, epilepsy and for assessment of recurrent and unexplained falls.
dysarthria, pain in transient ischaemic attack,
occipital region subclavian steal, basilar migraine HUTT testing uses changes in position to reproduce the
Tachypnoea, syncope in Pulmonary embolism
symptoms of the syncopal event by inducing bradycardia
a bedridden patient or in or hypotension suggestive of reflex mediated syncope.
the post-operative period Pharmacologic augmentation with isoproterenol intra-
Asymmetric pulses, Dissecting aneurysm of aorta, venously or low dose nitroglycerine is required in patients who
back pain subclavian steal have a high pre-test probability of neurally mediated syncope
Elevated jugular venous Right heart failure, myocardial but a negative result on a passive tilt table test.
pressure ischaemia, tamponade or The test should not be performed in pregnant patients. In men
pulmonary embolus
older than 45 years of age and women older than 55 years of
Abdominal tenderness Visceral bleed (abdominal aortic
age should have stress testing before HUTT. A positive HUTT
or mass in an elderly patient aneurysm)
can be used to reassure the patients about the usually benign
Amenorrhoea in young Ruptured ectopic pregnancy
women, uterine spotting,
nature of the diagnosis. It can also be used to minimise, if not
adnexal tenderness eliminate, the unnecessary use of anti-epileptic drugs.
Carotid sinus massage
INVESTIGATIONS Carotid sinus massage should be carried out when carotid sinus
Cardiac Evaluation syncope is suspected (Table 2).The contraindications for carotid
Electrocardiography sinus massage are recent myocardial infarction, transient
ischaemic attacks, or stroke, ventricular fibrillation, ventricular
ECG should be performed in all patients. Abnormal ECG
tachycardia or a carotid bruit.
findings occur in about 90% of patients with cardiac-induced
syncope, but in only 6% of patients with neurally mediated Psychiatric Evaluation
syncope. Syncope due to psychiatric disorders is usually seen in younger
Exercise testing patients with no heart disease and does not cause injury.
Such events may be precipitated by anxiety, panic, or major
Indicated if clinical evaluation suggests ischaemic heart disease
depression as a neurally-mediated response.
or exercise-induced tachyarrhythmia. In patients with exertional
syncope, echocardiography should be done first to exclude Laboratory Studies
hypertrophic cardiomyopathy. The yield of most routine laboratory studies is low. A
24-hour Holter monitoring haemogram, blood glucose levels, serum electrolytes, renal
function tests, cardiac enzymes, brain natriuretic peptide (BNP)
Indicated when symptoms suggest arrhythmic syncope
levels and urinalysis may provide diagnostic clues in selected
(palpitations with syncope, episodic unconciousness with no
patients.
prodrome) or in those with an abnormal ECG, heart disease or
unexplained syncope. Imaging Studies
Continuous-loop event monitoring Computed tomography (CT) and magnetic resonance imaging
(MRI) of the head may be useful in the presence of head trauma
Recommended if no arrhythmias are found and no syncope
or neurological deficits.
occurs during 24-hour Holter monitoring; in patients with
recurrent syncope and a normal heart; syncope of unexplained SYNCOPE IN SPECIFIC SITUATIONS
cause; heart disease and abnormal ECG.
Exercise-Related Syncope in Young Athletes
Electrophysiologic studies (EPS) Exercise-related syncope, while generally a benign event, can
Patients with underlying organic heart disease and non- signal sudden death in young adults. It occurs either during or
diagnostic prolonged ECG monitoring, and those whose hearts immediately after a period of exercise. Causes of exercise-related
are normal, but ECG show conduction disturbances should syncope include hypertrophic cardiomyopathy , aortic stenosis,
undergo electrophysiologic studies. critical coronary artery disease, right ventricular dysplasia,
55
 congenital coronary artery anomaly, prolonged QT syndrome, Table 4: Indications for Hospital Admission in Patients with
high grade atrioventricular block, idiopathic ventricular Syncope
tachycardia, hyponatraemia, hypoglycaemia and hyperthermia
Definitely hospitalise patients with ‘high risk’ who meet any of
(heat stroke).
the following criteria:
The commonest cause is neuro-cardiogenic syncope. In all cases History of coronary artery disease, congestive heart failure or
of unexplained exertional and pre-exertional syncope, an ventricular arrhythmia
echocardiogram followed by a stress test should be done. In History of chest pain
such individuals, temporary restriction from vigorous activity Physical signs of congestive heart failure, valvular disease or focal
neurological deficit or new stroke, acute pulmonary embolism,
should be considered. Reassuring clinical features are non-
aortic dissection
recurrent syncope, occurring after exercise, no family history Electrocardiographic findings showing ischaemia, arrhythmia,
and a normal cardiac examination with ECG, echocardiogram, increased QT interval or bundle-branch block
and stress test being normal. Such athletes may return to Cardiac devices (pacemaker or defibrillator) with dysfunction
vigorous activity with an appropriate follow-up plan. Strongly consider hospitalising patients with ‘intermediate risk’
Syncope in Elderly Patients who meet any of the following criteria:
A history of exertional syncope even in the absence of any evidence
Syncope in elderly patients portends a poor prognosis. The suggestive of aortic stenosis or left ventricular outflow obstruction
high mortality rate is due to co-morbidites. Common risk Sudden recurrent loss of consciousness with injury
factors for syncope in the elderly are susceptibility to Age >70 years
situational syncope, polypharmacy and adverse drug effects Haematocrit <30 mL/dL
on heart rate, intravascular volume and vascular tone (with Frequent syncope, suspected cardiac disease or arrhythmia (e.g. use
use of beta-blockers, calcium-channel blockers anti- of medications associated with torsades de pointes)
arrhythmics, diuretics and anti-depressants) resulting in Moderate-to-severe orthostatic hypotension
Congenital heart disease
orthostatic hypotension. Several entities including carotid
Family history of sudden death
sinus hypersensitivity, aortic stenosis, myocardial infarction,
arrhythmias and transient ischaemic attacks are more Patients with ‘low risk’ may be evaluated as outpatients
No structural heart disease and a normal ECG
common in the elderly.
Suspicion of psychogenic pseudosyncope
HOSPITALISATION AND PROGNOSIS Neurally mediated syncope

Indications and risk factors for hospital admission in patients

with syncope are listed in Table 4. prudent advice for carotid sinus syncope, but cardiac pacing
may be recommended in some.
TREATMENT
The treatment of a patient with syncope depends on the 2. Syncope related to arrhythmias requires specific therapy.
underlying mechanism and identification of precipitants and Supraventricular tachycardia may respond to drugs or
contributory factors. radiofrequency ablation. Bradyarrhythmias require pacing.
Implantable defibrillators are helpful in the treatment of
1. For neurally mediated syncope, orthostatic hypotension
both ventricular tachyarrhythmias and bradyarrhythmias.
and carotid sinus syncope, patient education is the
foundation of treatment. Patients must be reassured about RECOMMENDED READINGS
the benign nature of the problem. Measures that help abort 1. Alboni P, Brignole M, Menozzi C, Raviele A, Del Rosso A, Dinelli M, et al.
an incipient attack include sitting with the knees drawn, Diagnostic value of history in patients with syncope with or without heart
squatting, lying with raised legs and performing physical disease. J Am Coll Cardiol 2001; 37: 1921-8.
counter-pressure manoeuvres, sustained hand grip and 2. Benditt DG, Nguyen JT. Syncope: therapeutic approaches. J Am Coll Cardiol
isometric exercises to raise blood pressure.The importance 2009; 53: 1741-51.
of assuming an upright posture slowly should be 3. Can I, Benditt DG. Syncope: to admit or not to admit. J R Coll Physicians
(Edinb) 2009; 39: 236-42.
emphasised in patients with orthostatic hypotension.
4. Chen LY, Benditt DG, Shen WK. Management of syncope in adults: An
For long-term prevention of attacks, adequate fluid and salt update. Mayo Clin Proc 2008; 83: 1280-93.
intake should be advised. In some cases, fludrocortisone for 5. Christopher J, Narsimhan C. Clinical evaluation of syncope. J Assoc
volume expansion and other drugs such as midodrine (an Physicians India 2007; 55 (Suppl): 54-7.
alpha-1 agonist with vasopressor activity) may be needed. 6. Linzer M, Yang EH, Estes NA 3rd, Wang P, Vorperian VR, Kapoor WN.
Compression stockings may also be beneficial. Medications Diagnosing syncope. Part 1: Value of history, physical examination, and
electrocardiography. Clinical Efficacy Assessment Project of the American
must be reviewed carefully to eliminate drug associated College of Physicians. Ann Intern Med 1997; 126: 989-96.
with hypotension. Beta-blockers are no longer recom- 7. Luzza F, Pugliatti P, di Rosa S, Calabrò D, Carerj S, Oreto G. Tilt-induced
mended for vasovagal syncope. For situational syncope, it pseudosyncope. Int J Clin Pract 2003; 57: 373-5.
might be possible to ameliorate or avoid triggers. Avoidance 8. Parry SW, Tan MP. An approach to the evaluation and management of
of tight collars, neck ties, and abrupt neck movements is syncope in adults. Br Med J 2010; 340: 468-73.

56
 2.13 Coma

B Vengamma

INTRODUCTION the extreme states of consciousness and coma stand a variety

The prompt diagnosis and effective management of a of altered states of consciousness (Table 1, Figures 1 and 2).
patient with altered consciousness, especially coma, is one
DIAGNOSTIC APPROACH
of the difficult tasks faced by a physician. The physiologic
components that govern conscious behaviour include content Early, appropriate diagnosis of the cause of unconsciousness
(sum of cognitive and affective mental function) and arousal is important because, several causes of coma (e.g. subdural,
(appearance of wakefulness). The physiology of arousal epidural haematomas, hypoglycaemia) can be fatal if not
emerges from the action of the reticular activating system recognised early and treated. The approach to a comatose
(RAS), a poorly localised network of cells in the rostral patient begins with a good, detailed history and clinical
brainstem and the diencephalon. The RAS receives stimuli examination.
from the environment via the somatosensory pathways, the Functional abnormality of the brain causes unconsciousness,
autonomic pathways and limbic system inputs. In turn, the either due to bilateral dysfunction of the cerebral hemispheres
RAS stimulates the brain, activating the cortex. Because it is a or damage or depression of the RAS or due to metabolic damage.
diffuse network of cells, there is no single transmitter system
The key to making a correct diagnosis in coma consists of
involved with the RAS. Physicians try to induce arousal in
accurate interpretation of a limited number of physical signs
comatose patients by stimulating the RAS. Although the term
that reflect the integrity or impairment of various levels of
‘coma’ is derived from the Greek word koma, meaning a
the brain. The abnormal findings of the examination indicate
deep (presumably unarousable) sleep, a range of anatomical
whether the cause of altered consciousness is supratentorial
sites, causes, and mechanisms may be involved in producing
(starts rostrally and evolves caudally), subtentorial (starts focally
coma.
in the brainstem), metabolic (produces from the onset signs of
While consciousness is the state of awareness of the self diffuse or multifocal dysfunction), or psychiatric (lacks signs of
and the environment, coma is its exact opposite. Between physiologic brain dysfunction (Table 2).

Table 1: Various States of Consciousness

Alert
A state where the patient is fully responsive and able to interact with the physician
Confusion
A state of disorientation in time, place and person or situation resulting in bewilderment, perplexity and lack of orderly thought
Delirium
An acute confusional state that may sometimes be marked by periods of irritability and hallucinations
Obtundation
A lesser state of decreased arousal with some responsiveness to touch or voice
Lethargy (somnolence)
Arousal, though diminished, is maintained spontaneously or with repeated light stimulation
Stupor
A state of severely impaired arousal with some responsiveness to vigorous stimuli
Coma
Total or near total unresponsiveness, i.e., the total absence of awareness of self and environment even when the subject is externally stimulated
Vegetative state
Wakefulness accompanied by lack of cognitive function. The patient opens eyes spontaneously in response to verbal stimuli
Akinetic mutism
Silent, alert appearing immobility with retainment of sleep wake cycles and absent mental and spontaneous motor activity
Apallic syndrome
Absent neocortical function with relatively intact brainstem function
Locked-in syndrome
A state in which weakness of all four limbs is associated with lower cranial nerve paralysis; but, the patient manifests signs of being appropriately
aware of himself and his environment and communicates with vertical eye movements
Inattention
A state where a person looks alert or even hyperalert. The eyes are open and the person is looking around, but cannot complete a simple task.
Abulia
A state where the patient is essentially quiet and has complete lack of spontaneity. It is usually associated with bilateral frontal lesions. There
is perseveration or repetitive movement
57
 Figures 1A to D: Locked-in state. (A) A patient with weakness all four limbs with lower cranial nerve paralysis. The patient manifests signs of being appropriately
aware of himself and his environment and communicates with vertical eye movements. (B) MRI brain (T2 weighted axial image) showing hyperintensity in the
pons (arrow). (C) Hyperintensity in right middle cerebellar peduncle (arrow head) and in left cerebellar hemisphere (asterisk). (D) Diffusion weighted images
(upper panel right) apparent diffusion coefficient map (lower panel, right) showing acute infarction in pons (arrow) and cerebellum (asterisk).

Figures 2A to C: Clinical photograph showing a delirious patient (A) NCCT head of the same patient showing acute haematoma in the left thalamus (thin arrow)
and corona radiate (asterisk) extending into lateral and third ventricles (thick arrow) (B and C).
58
 Coma
HISTORY AND GENERAL EXAMINATION
The history has to be obtained from an eyewitness account or
from a paramedic who had resuscitated the patient. Recent
events or preceding illnesses that lead to the comatose state
should be enquired into. A history of trauma, drug or alcohol
use is important. Possible ingestion of medications should be
evaluated. History regarding any psychiatric illness which might
be responsible for coma should also be elicited.
Bedside clinical evaluation should begin with measurement of
blood pressure. If blood pressure is elevated, careful evaluation
for signs of an acute ischaemic or haemorrhagic stroke, or
increased intracranial pressure is indicated. Certain breathing
patterns are very classical and facilitate anatomical localisation
in a comatose patient (Figure 3). Patients with Cheyne-Stokes
breathing manifest rapid shallow breathing to the point where
there is a cessation of breathing and apnoea. Thereafter, there
is an abrupt spontaneous return of respirations with deep
sighs, and the cycle repeats. This type of pattern is seen in head Figure 3: Various breathing patterns and their graphical depiction.
injury and metabolic conditions. Biot’s breathing, seen in
lesions of medulla oblongata (e.g. head trauma, stroke) refers irregular breathing pattern which is intermixed with irregular
to an abnormal breathing pattern consisting of rapid, shallow periods of apnoea (Figure 3). It is important to look for other
breaths followed by periods of apnoea. This pattern is often tell-tale signs of a traumatic injury, an infectious disease
confused with ataxic breathing. While in Biot’s breathing process, or an ingestion of drugs leading to the comatose state.
clusters of similar sized breaths occur, in ataxic breathing Signs of liver cell failure should also be looked for. Odour of
pattern, the respirations are completely irregular in both rate the breath (e.g. alcohol ingestion; acetone like in diabetic
and rhythm mimicking dysmetria of the extremities. Kussmaul ketoacidosis DKA, hepatic encephalopathy) can sometimes be
breathing is characterised by a deep, rapid breathing rate and helpful.
is seen in metabolic acidosis. Apneustic breathing usually seen
in trauma or stroke involving the medulla oblongata is an NEUROLOGIC EXAMINATION IN COMATOSE PATIENTS
The neurologic examination in comatose patients, should
Table 2: Differential Characteristics of State and Causing
include all parts of the traditional neurologic examination
Sustained Unresponsiveness
except, perhaps, the gait. But there is an emphasis on the
Supratentorial mass lesions compressing or displacing the level of arousal, the cranial nerve examination, and the motor
diencephalon or brainstem initiating signs usually of focal cerebral movements. Examination of the pattern of reflexes is also
dysfunction important. Most importantly, the general principle underlying
Signs of dysfunction progress rostral to caudal
the neurological examination in a comatose patient is pattern
Neurologic signs at any given time point to one anatomic area
(e.g. diencephalon, midbrain-pons, medulla)
recognition. The first step involves assessing the level of
Motor signs often asymmetrical consciousness (Table 1), traditionally using the Glasgow coma
Subtentorial masses scale (GCS), which is composed of eye movements, motor
History of preceding brainstem dysfunction movements, and spontaneous language.
Localising brainstem signs precede or accompany onset of coma
The fundoscopic examination gives information about raised
and always include oculovestibular abnormality
Cranial nerve palsies usually present
intracranial pressure and pathology. Blink test or menace reflex
‘Bizarre’ respiratory patterns common and usually appear at should be done which gives an idea about visual fields. Other
onset aspects of cranial nerve examination include pupils, eye
Metabolic Causes movements, sensory component of Vth cranial nerves and
Confusion and stupor commonly precede motor signs motor component of VIIth cranial nerves and the gag response
Motor signs are usually symmetrical as part of cranial nerves IXth and Xth.
Pupillary reactions are usually preserved
Asterixis, myoclonus, tremor, and seizures are common The pupils tend to be small and reactive and absent corneal
Acid-base imbalance with hyper- or hypo-ventilation is frequent oxycephalic reflex indicates metabolic injury. Symmetry of the
Psychiatric Unresponsiveness pupils is very important in differentiating nonstructural versus
Lids close actively structural injuries. Midbrain pupils, reflective of midbrain injury,
Pupils reactive of dilated (cycloplegics) tend to be midposition, fixed, slightly irregular with intact
Oculocephalics are unpredictable: oculovestibulars physiologic reaction to light. In contrast, small, thin, pin-point pupils that
(nystagmus is present) do not react to light are suggestive of pontine injury and can
Motor tone is inconsistent or normal also be seen in opiate intoxication. Asymmetry in the form of
Eupnoea or hyperventilation is usual
unilateral dilatation of the pupil in a comatose patient suggests
No pathologic reflexes are present
EEG is normal
unilateral third nerve palsy which could be an indication of an
uncal herniation, which is essentially a sign that the brain is
EEG = electroencephalogram. swelling to the point where the cortex is impinging on the 59
 brainstem and the third cranial nerve as it exits from the
brainstem itself; such patients may need urgent neurosurgical
intervention (Figures 4A to C).
In the examination of eye movements, it is most important to
open the eyelids and to see where the eyes are at rest. Any gaze
deviation away from the side that is weak is essentially a sign of
a hemispheric lesion. If it is towards the side of the hemiparesis,
it suggests that the lesion is at the brainstem, specifically in the
pons or the cerebellum. If the primary gaze is downwards it
suggests that the lesion might be within the midbrain, or
perhaps even something pushing down onto the midbrain
that is causing the eyes to stay down. Spontaneous eye rolling
movements suggest bilateral hemispheric dysfunction as seen
in metabolic encephalopathies. Ocular bobbing (the eyes, when
at rest, dip down and come back to the resting position) and
ocular dipping (the eyes bounce up and have a slow downward
phase) are pathognomonic of pontine injury.
The occurrence of eye movements that are spontaneous and
saccadic in motion, and rolling eye movements on opening the
eyelids excludes the possibility of the patient being in true coma
because saccadic movements involve a level of awareness
beyond just a level of arousal.
Due to the oculocephalic reflex, normally the eyes move
contralateral to the side of head movement. Absent
oculocephalic reflex is an indication of bilateral hemispheric
injury. This test should be avoided in patients with suspected
neck injury. Oculovestibular reflex, also known as a cold caloric
test, is another way to gauge brainstem integrity specifically
for pontine and cerebellar function. The test is done by
keeping the patient’s head end of the bed elevated at 30°,
instilling about 60 cc of ice water in each ear with a butterfly
catheter and a syringe. The normal response involves a tonic
movement of the eyes towards and fast saccades away from the
side of stimulation. Bilateral absent fast movements are a sign of
bihemispheric injury. An asymmetrical response suggests
brainstem dysfunction. A negative response to the caloric test
(no eye movements) indicates loss of brainstem integrity. In an
awake person or a person who is not comatose, this test induces
saccadic movements, nausea, and probably also vomiting.
In the motor examination, asymmetry of the response and
assessment of tone helps in localisation. The best way to look for
this is to look for spontaneous movements, i.e. sit at the bedside
and just watch the patient for some time to see whether or not
there is any movement whatsoever. If there are no spontaneous
motor movements, the patient may be asked to move a limb on
verbal commands, Still, if there is no perceptible movement, then
sequentially more noxious stimuli are applied to try and induce
a response. If the response elicited is a classical decorticate or
decerebrate posturing, it has prognostic significance. Decorticate
posturing, indicative of a hemispheric injury and damage to
corticospinal tracts, is characterised by adduction and flexion of
the arms with wrists and fingers flexed on the chest. The legs are
extended and internally rotated with plantar flexion of the feet.
Lesions located around the red nucleus cause decerebrate rigidity
which is characterised by internal rotation (adduction) and Figures 4A to C: Clinical photograph showing asymmetry of pupils. (A) NCCT
extension of arms, pronation of the wrists and finger flexion. The head (axial images) of the same patient showing sub-acute infarct in the left
legs are extended with forced plantar flexion of feet. In severe cerebral hemisphere (asterisk) with relative sparing of frontal lobe causing
subfalcine herniation arrows (B and C).
cases, ophisthotonus may be present.
60
 Coma
DIFFERENTIAL DIAGNOSIS Table 4: Toxic and Metabolic Causes of Coma and Confusion
Causes of coma can be classified as structural, non-structural,
Sedatives, hypnotics
toxic or metabolic (Tables 3 and 4). Among all patients in Opiates
coma, one-third have an evident structural lesion. The Benzodiazepines, barbiturates, and other sedatives
differential diagnosis tends to be trauma or vascular in origin; Tricyclic anti-depressant agents
meningitis, encephalitis, tumours, or hydrocephalus. Toxic or Phenothiazines, butyrophenones
metabolic injuries include post-cardiac arrest with global Stimulating exogenous toxins
hypoxic ischaemic injury exposure to a toxin such as carbon Amphetamines, cocaine
monoxide, drugs and electrolyte disorders. Psychiatric Phencyclidine
disorders, can present as coma. They can be difficult to Methylphenidate
differentiate from metabolic causes. Agents causing metabolic acidosis
Aspirin
Table 3: Some Causes of Coma Ethyl alcohol, methanol, ethylene glycol, and other hydrocarbons
Metabolic disorders
Focal disease Diabetes mellitus: Hyperglycaemia (diabetic ketoacidosis,
Trauma (contusion, ICH)
hyperosmolar coma), hypoglycaemia
Non-traumatic ICH
Thyroid disease (myxoedema, thyroid storm)
Ischaemic stroke
Renal failure (uraemia, dysequilibrium syndrome)
Infection (abscess, subdural empyema, focal encephalitis)
Electrolyte abnormalities (dehydration and volume contraction,
Tumour
hyponatraemia, hypercalcaemia
Demyelination (multiple sclerosis, acute demyelinating
Acid-base disorders
encephalomyelitis)
Hepatic failure: Hyperammonaemia
Non-focal disease
Hypoadrenalism
Trauma (elevated ICP, diffuse axonal injury)
Hypoxia, hypercarbia
Vascular syndrome
Hereditary metabolic disorders (i.e. porphyria, carbamoyl-
Subarachnoid haemorrhage
transferase deficiency carrier state)
Aneurysm in posterior fossa with mass effect
Hypoxic-ischaemic encephalopathy Withdrawal syndromes
Stroke (focal strokes with non-focal presentations, posterior Alcohol withdrawal
fossa infarct with mass effect, hydrocephalus) Benzodiazepine and other sedative withdrawal
Hypertensive encephalopathy (including ecclampsia)
Infection (meningitis, diffuse encephalitis) Table 5: Approach to the Initial Assessment and Management
Tumour-related of Coma
Tumour (brainstem invasion,posterior fossa mass effect, elevated Stabilisation
ICP, hydrocephalus) Airway control
Paraneoplastic syndromes (brainstem and limbic encephalitis,
Oxygenation and ventilation
vasulitis)
Adequate circulation (includes avoidance of hypotension in
Toxic and metabolic (Table 4)
stroke)
Withdrawal syndromes
Nutritional deficiencies ( Wernicke’s encephalopathy, Cervical stabilisation
pellagra) Immediate therapies given to all patients
Disordered temperature regulation Thiamine 100 mg IV
Seizure (postictal state, non-convulsive status epilepticus) Dextrose 50%, 50 cc IV (may be held if immediate finger-stick
Others glucose check establishes adequate serum glucose)
Basilar migraine Naloxone 0.4 to 2.0 mg IV (may be repeated)
TGA Life-threatening conditions to be considered early
TTP Elevated intracranial pressure: Head CT
Sleep deprivation Meningitis, encephalitis, or both: Consider LP, blood cultures
Situational (i.e. ICU psychosis) Myocardial infarction: ECG
Psychiatric (conversion, depression, mania, catatonia) Hypertensive encephalopathy: Early therapy
ICH = Intracranial haemorrhage; ICP = Intracranial pressure; ICU = Intensive care Status epilepticus: EEG
unit; TGA = Transient global amnesia; TTP = Thrombotic thrombocytopaenic Acute stroke: Consider thrombolytic therapy
purpura.
IV = Intravenous; CT = Computed tomography; EEG = Electroencephalogram

MANAGEMENT While carrying out the initial stabilisation and laboratory testing,
The approach to the initial assessment and management of it is important to treat treatable conditions immediately.
patients in coma is depicted in Table 5. The specific Correction of hypoglycaemia and the administration of
management depends on the underlying cause. At the time of thiamine can be life saving. Hypoglycaemia suppresses the RAS
initial evaluation, it is necessary to assess the ABCs namely, and leads to a metabolic coma. But this is quickly reversed once
assessing the adequacy of airway; ensuring that the patient’s the glycaemic levels are restored to normal. It is also important
breathing is spontaneous and adequate; and that the circulation to administer intravenous thiamine to prevent Wernicke’s
to the brain and other organs is adequate. encephalopathy. In the appropriate situation, naloxone for

61
 opiate overdosage or flumazenil for benzodiazepine poisoning, in differentiating structural lesions but, its overall predictive
should also be considered. value is less when compared to electrophysiologic tests or even
PROGNOSIS the clinical examination itself.
Coma due to toxic or metabolic causes has a better prognosis In coma due to hypoxic ischaemic injury, patients who have a
than that due to a structural lesion, with the exception that preserved light reflex, motor response is either flexor or extensor
traumatic injury fares better than anoxic injury. In other words, and have spontaneous eye movements have better survival. In
patients who have had cardiac arrest tend to have poorer head injuries, patients with concussion (defined as a loss of
outcome than patients who had a structural injury secondary consciousness for less than six hours) and those with a normal
to trauma. Clinical signs that are important for prognosis include CT tend to have a good outcome. When a patient has a loss of
the motor component of the GCS, the duration of coma (which consciousness for greater than six hours, axonal shearing or
is really a duration of lack of eye-opening) and other signs of diffuse external injury is likely. Magnetic resonance imaging
brainstem damage. (MRI) shows changes axonal retraction balls and micro-
Certain electroencephalogram (EEG) patterns are helpful in haemorrhages. Long-term recovery for these patients is very
assessing prognosis in patients with coma. Alpha coma, which variable. Cognitive deficits, motor and behavioural dysfunction
looks like a normal alpha rhythm but in an unarousable patient persist, and these patients tend to do poorly as far as functional
carries a higher mortality rate especially with hypoxic injury or recovery goes.
traumatic brain injury. The EEG may be sensitive to external
stimuli and may not reflect brainstem function and is influenced RECOMMENDED READINGS
by sedative drugs that are routinely used in such patients. 1. Shiel A, Gelling L, Wilson B, Coleman M, Pickard JD. Difficulties in diagnosing
Somatosensory evoked potentials can be used for testing the the vegetative state. Br J Neurosurg 2004; 18: 5-7.
brainstem and are helpful in patients with a traumatic injury or 2. Stevens RD, Bhardwaj A. Approach to the comatose patient. Crit Care Med
anoxic injury. When measured within 5 to 7 days, bilaterally 2006; 34: 31-41.
absent cortical somatosensory evoked potentials are strongly 3. Wijdicks EF, Cranford RE. Clinical diagnosis of prolonged states of impaired
associated with the instance of vegetative state or death. consciousness in adults. Mayo Clin Proc 2005; 80: 1037-46.
Neuroimaging, especially computed tomography (CT), is useful 4. Young GB. Coma. Ann N Y Acad Sci 2009; 1157: 32-47.

62
Section 3
Diagnostic Imaging
Section Editor: Raju Sharma
3.1 Conventional Radiology 64
Ashu Seith Bhalla, Ankur Gadodia
3.2 Ultrasound in Medicine 78
B.S. Rama Murthy
3.3 Computed Tomography 84
Bhavin Jankharia, Nishigandha Burute
3.4 MRI in Medicine 91
Raju Sharma, Ankur Gadodia
3.5 Nuclear Imaging 100
B.R. Mittal
3.6 Positron Emission Tomography 113
Rakesh Kumar, Varun Shandal
 3.1 Conventional Radiology

Ashu Seith Bhalla, Ankur Gadodia

INTRODUCTION Table 1: Additional Chest Radiographic Views and Their Role

Since the discovery of X-rays by Roentgen in 1895, conventional
Projection Role
radiology has played a vital role in the diagnosis and
management of patients affected by various diseases. Newer Lordotic projection Middle lobe collapse/consolidation,
imaging techniques, such as ultrasound, computed tomography apical opacity obscured by clavicle
and magnetic resonance imaging, have reduced the role of Lateral decubitus Small pleural effusion
conventional radiographs in several clinical scenarios. However, Lateral Localise mediastinal masses, posterior
conventional radiology still remains of great value, particularly basal consolidation
in diseases of chest, musculoskeletal system, contrast studies Expiratory films Air trapping, small pneumothorax
of gastrointestinal tract and fistulograms. This is owing to Anteroposterior Sick recumbent patient intensive care
simplicity of the procedure, low cost, easy reproducibility and unit (ICU patients)
low radiation dose. Advent of digital radiography has further
enhanced the quality and reproducibility of the conventional radiograph lungs, bones, soft-tissues like heart and diaphragm,
radiographs. The spectrum of the imaging findings of various fat and muscles. Because of the difference in the coefficient of
pathologies is vast and a full discussion of the same is beyond absorption of the X-rays which depends on the atomic number
the scope of this chapter. Hence, a brief summary of the present of the elements and density of the tissues, lungs appear black,
role of conventional radiology and approach to common bones appear white and soft-tissues have an intermediate
diseases classified on an organ system basis is discussed below. density. A schematic approach to analysis of the chest
radiograph is given in Table 2.
CHEST RADIOLOGY
Table 2: Suggested Scheme for Viewing the PA Radiograph
Chest radiograph is one of the most frequently performed
radiological examination constituting about 50% to 60% of the Patient information sheet
workload of any hospital or imaging centre. The standard chest Technical assessment: Centring, inspiration, exposure
radiograph is an erect posteroanterior (PA) projection (Figure 1). Mediastinum: Trachea, aorta, pulmonary arteries, superior vena cava
Additional radiographic views and their role is summarised Lungs: Lucency, localised/generalised abnormalities, hidden areas
in Table 1. Normally there are five different densities, in any Heart: Position, size, configuration
Hila: Density, shape, position
Bones and soft tissues
Diaphragm: Position, outline
Pleural space

Important Signs in Chest Radiology

1. Silhouette sign
Described by Felson and states that “An intra-thoracic radio-
opacity, if in anatomic contact with a border of heart or
aorta, will obscure that border. An intra-thoracic lesion not
anatomically contiguous with a border or a normal structure
will not obliterate that border”. This sign is useful in detection
and localisation of mediastinal and pulmonary diseases. For
example, right middle lobe pathology will obliterate the right
heart border (Figure 2).
2. Hilum overlay sign
Described by Felson and helps in distinguishing enlarged heart
from anterior mediastinal mass. Hilum is seen through the
mediastinal mass, whereas with enlarged heart, the hilum is
displaced laterally. If the bifurcation of the main pulmonary
artery is >1.25 cm medial to the lateral border of the cardiac
Silhouette, it is suggestive of a mediastinal mass. If the
pulmonary artery arises from the lateral heart border, this
Figure 1: Normal chest radiograph (posteroanterior PA view).
favours an enlarged heart.
64
 Conventional Radiology
3. Air-bronchogram Atelectasis/Lung Collapse
Branching, tubular air lucency representing a bronchus or Collapse is defined as partial or complete loss of the lung
bronchiole passing through airless lung parenchyma produces volume. Radiographic appearance depends on degree and
air bronchogram and is seen in lung disease unlike pleural/ mechanism of collapse. Signs of collapse may be considered as
mediastinal disease (Figure 3). direct or indirect (Table 4).

Table 3: Features and Aetiology of Basic Lung Patterns as Seen

on Chest Radiograph
Patterns Features Causes
Airspace/ Poorly defined nodular Pulmonary oedema
Alveolar lesions (4-10 mm) Exudate (pneumonia)
pattern Coalescence Pulmonary haemorrhage
(Figure 4A) Air-bronchogram Malignancy (bronchioalveolar
carcinoma, lymphoma)
Aspiration
Interstitial Reticular Interstitial lung disease, e.g.
(Figure 4B) Nodular (well-defined, Sarcoidosis
homogeneous and Miliary tuberculosis
variable sized) Pneumoconiosis
Reticulo-nodular

Figure 2: Silhouette sign. Chest radiograph (PA view) showing lingular lobe
consolidation silhouetting the left cardiac border. Diaphragm is not silhouetted
by the consolidation.

Figure 4A: Air space (alveolar) pattern. Chest radiograph (PA view) shows
homogeneous opacity in left lower zone with ill-defined margins of diaphragm
see 4B.

Pulmonary Disease
Figure 3: Air-bronchogram in a patient with pulmonary oedema. Chest Infections
radiograph (PA view) demonstrates air within the bronchial tree visible due to
Pneumonia: Pneumonia is one of the most frequent causes
surrounding airless lung parenchyma.
of morbidity and mortality, and chest radiograph plays
an important role in the detection and management of
Pattern Recognition in Chest Radiology patients with pneumonia. The term lobar pneumonia refers
Felson popularised a pattern recognition approach to lung to infection that predominantly involves the alveolar space
lesions on the basis of classifying them as either alveolar or and thus, produces uniform homogeneous opacification of
interstitial. Important features and causes of the alveolar or partial or complete segments of lung and occasionally an entire
interstitial lesions are described in Table 3. lobe.
65
 Bronchopneumonia is usually multifocal and infection is
centered in distal bronchioles. Radiologically, broncho-
pneumonia is characterised by bilateral heterogeneous,
scattered alveolar opacities. An air bronchogram is usually
absent. Streptococcus pneumoniae (common cause of
community-acquired pneumonia) causes lobar pneumonia
whereas Staphylococcus aureus and Gram-negative organisms
(causes nosocomial infection) produce bronchopneumonic
pattern. Klebsiella pneumoniae and Streptococcus pneumoniae
cause lobar pneumonia with bulging fissures. Round
pneumonia is cause by S. pneumoniae and S. aureus. Viral
pneumonia is common in infants and children but unusual in
adults and produces interstitial pattern on chest radiographs.

Table 4: Signs of Lung Collapse (Figure 5)

Direct Signs Indirect Signs
Displacement of interlobar fissure Elevation of hemidiaphragm
Loss of aeration Mediastinal displacement
Crowding of vessels and bronchi Hilar displacement
Compensatory overinflation

Figure 5: Left lower lobe collapse in a 20-year-old male. Chest radiograph (PA
view) demonstrates wedge-shaped left retrocardiac opacity (arrow) with
hyperinflation of the left lung.

of TB (ill-defined patchy opacities, linear striations, subsequently

nodular and reticular appearance due to fibrosis). Single or
multiple thick-walled cavities are the hallmark of active TB.
Bronchiectasis and bronchostenosis are commonly seen in
post-primary tuberculosis occur due to cicatrisation and fibrosis.
Broncho-stenosis can produce persistent lobar or segmental
collapse or obstructive emphysema or consolidation. Pleural
effusion is usually small and loculated. Radiological findings in
primary TB are detailed in Table 5.

Table 5: Radiological Features of Primary and Post-primary

Tuberculosis
Primary Tuberculosis Post-primary Tuberculosis
Parenchymal consolidation Local exudative lesion
Lymphadenopathy (Figure 6A) Local fibroproductive lesion
Miliary tuberculosis (Figure 6B) Tuberculoma
Tuberculoma Cavitation
Airway involvement Bronchogenic spread
Figure 4B: Interstitial pattern. Chest radiograph (PA view) demonstrates coarse Pleural effusion Miliary tuberculosis (Figure 6B)
reticulonodular opacities in bilateral lung fields. Bronchostenosis
Pleural disease
Pulmonary tuberculosis: The radiological features in pulmonary
tuberculosis have been divided into primary and post-primary Bronchogenic carcinoma
or reactivation TB. Bronchogenic carcinoma produces a wide range of radiological
appearances depending on histology (small cell vs non-small
Primary tuberculosis: Primary TB has two components:
cell), location (central vs peripheral) and stage of the disease
parenchymal lesion and extension of the lesion to the lymph
(Figures 7A and B). Usually peripheral bronchogenic carcinoma
nodes. Enlarged hilar or mediastinal nodes (right paratracheal,
is seen as an intrapulmonary mass. This may be quite small, an
subcarinal and aorto-pulmonary window) are the radiological
incidental finding on chest radiograph (solitary pulmonary
hallmark of this form. It may heal completely or leave a calcified
nodule) and poses a diagnostic challenge to the clinician and
focus. Atelectasis of a lobe or a segment is a frequent finding.
radiologist. Features that indicate malignancy include: size
Post-primary tuberculosis: Most common sites are apical and more than 4 cm; thick-walled (≥16 mm) cavity; associated hilar
posterior segments of the upper lobes and superior segments mass and lobulated, umblicated or shaggy outline (sunburst
66 of lower lobe. Parenchymal lesions are the hallmark of this form appearance). Plain radiographs have tremendous limitation in
 Conventional Radiology
Figure 6A: Primary tuberculosis in a 12-year-old female. Chest radiograph (PA
view) demonstrates right hilar and paratracheal adenopathy.

Figure 7A: Peripheral bronchogenic carcinoma in a 72-year-old male smoker.

Chest radiograph (PA view) shows ill-defined spiculated mass in the right upper
zone with destruction of anterior end of right 2nd and 3rd ribs.

Figure 6B: Miliary tuberculosis in a 24-year-old male. Chest radiograph (PA view)
shows miliary nodules (1-3 mm) involving bilateral lung fields.

detecting early manifestations of malignancy and lesions less

than 5 mm are not visualised on conventional radiographs.
Massive hilar or mediastinal adenopathy without lung lesion
is seen in small cell carcinoma whereas bronchioloalveolar Figure 7B: Central bronchogenic carcinoma with lung collapse in a 60-year-
carcinoma presents as solitary spiculated mass or as bilateral, old male. Chest radiograph (PA view) shows ill-defined spiculated left hilar mass
with collapse of the left upper lobe.
multiple ill-defined opacities resembling pneumonia.
Hilar Diseases enlarged. Hilar enlargement can be due to lymphadenopathy
Hilum as seen on chest radiograph comprises of proximal (Figure 8) or dilated pulmonary artery. Differential diagnosis
pulmonary artery, major bronchi, pulmonary veins and lymph of unilateral and bilateral hilar enlargement is mentioned in
nodes (Figure 1). Lymph nodes are not visualised unless Table 6.

67
 Table 6: Differential Diagnosis of Hilar Enlargement widening of the paraspinal soft tissues; apparent elevation of
the hemidiaphragm and poor visibility of the vessels behind
Unilateral Hilar Enlargement Bilateral Hilar Enlargement the diaphragm. Absence of air-bronchogram and visualisation
Lymphadenopathy Sarcoidosis (Figure 8) of the vessels differentiates pleural effusion from pulmonary
Infective (TB, Histoplasma, Lymphoma oedema and massive pneumonia.
Mycoplasma) Lymphangitis carcinomatosis
Carcinoma lung Infective (TB, Histoplasma)
Lymphoma Pulmonary artery dilatation
Pulmonary artery Pneumoconiosis (Silicosis)
Pulmonary embolus
Aneurysm
Post-stenotic dilatation

Figure 9: Pleural effusion in a 16-year-old male. Chest radiograph (PA view)

demonstrates right pleural effusion. Note the upper margin of the opacity is
concave and extends higher laterally than medially.

Pneumothorax
Pneumothorax is defined as the presence of air between
parietal and visceral pleura. Radiological features include
Figure 8: Sarcoidosis in a 30-year-old female. Chest radiograph (PA view) increased translucency with no intervening vessels, and
demonstrates bilateral hilar and right paratracheal adenopathy. Lung fields are underlying lung margin demarcated by visceral pleura (Figure
normal.
10). A small pneumothorax is best seen on expiratory film.
Inner margin is usually convex as compared to cysts, bulla or
Pleural Diseases
cavities which have concave margin towards the chest wall.
Pleural effusion Pneumothorax in supine film may show any of these signs;
Pleural effusion is one of the most common abnormalities of relative translucency, increased sharpness of the adjacent
the pleura. The radiographic appearances depend on the diaphragm or mediastinum, deep and tongue-like costophrenic
quantity of the fluid and posture of the patient. A minimum sulci, depression of the ipsilateral diaphragm and simultaneous
75 mL of fluid is required to see the fluid above the dome of visualisation of anterior sulcus and dome of diaphragm.
diaphragm on the lateral view; and a minimum of 175 mL is
Mediastinal Diseases
needed to obliterate costophrenic angle in upright erect film.
Lateral decubitus radiograph can detect 10 to 20 mL of fluid. A mediastinal mass has its base towards mediastinum, well-
defined margins and produces an obtuse angle with the
Pleural effusion produces a homogeneous opacity with concave
mediastinum. Air-bronchogram is absent. Boundaries of the
border facing the hilum producing characteristic meniscus sign.
mediastinum are shown in Figure 11 and common differential
The upper margin of the opacity extends higher laterally than
diagnosis in Table 7.
medially (Figure 9). Massive fluid obliterates the hemidiaphragm
and cardiac border. Further increase in fluid produces shift Table 7: Differential Diagnosis of Mediastinal Masses
of the heart and mediastinum, and even inversion of the hemi-
Anterior Middle Posterior
diaphragm. Supine radiographs are less sensitive in
demonstrating pleural effusion and the signs on a supine Lymphadenopathy Lymphadenopathy Neurogenic tumour
radiograph are a veil-like opacity over the lung with well (Lymphoma, TB) Carcinoma bronchus Paravertebral abscess
preserved vascular shadows; loss of outline of the ipsilateral Germ cell tumours Aortic aneurysm Dilated oesophagus
hemidiaphragm; blunting of the costophrenic angle; clear (Achalasia)
demarcation of the lateral lung margin from the chest wall; Thymoma Bronchogenic cyst
68
 Conventional Radiology
CARDIOVASCULAR SYSTEM
Conventional cardiac radiology is supplemented by 2D echo,
cardiac CT, catheter angiography or MRI. However, chest
radiographs are extremely valuable in demonstration of the
cardiac size, contour (individual chambers) and pulmonary
vascularity. Chest radiographs are also commonly used to follow
the progress of a disease and its treatment. The following
five points help in the diagnosis of the acquired or congenital
cardiac conditions. These are cardiac size, pulmonary conus, left
atrium, aortic knuckle and pulmonary vasculature. Meticulous
analysis of the above points gives some indication of the cardiac
abnormality in 60% to 65% cases.
The demonstration of the abdominal aorta and its branches was
usually done by digital subtraction angiography done through
transfemoral route. However now-a-days vascular tree, either
arterial or venous is well demonstrated either by CT angiography
or MR angiography.

GASTROINTESTINAL SYSTEM
Plain Radiograph
Plain abdominal radiographs are still commonly performed in
the clinical setting of acute abdomen or renal colic. A supine
Figure 10: Pneumothorax in a 40-year-old male. Chest radiograph (PA view)
abdomen and an erect chest can be regarded as the basic
shows increased right lung translucency with underlying lung margin standard radiographs in the work-up of acute abdomen. The
demarcated by visceral pleura (arrow). erect chest radiograph is superior to the erect abdominal view
for the demonstration of pneumoperitoneum (Figure 12).
Three to five fluid levels less than 2.5 cm in length may be
normally seen in an erect abdominal radiograph, particularly
in the right lower quadrant. However, more than two fluid levels
in a dilated small bowel (calibre greater than 2.5 cm) are said to
be abnormal, and usually indicate paralytic ileus or intestinal

Figure 11: Demarcation of the mediastinum. Line 1 extends along the back of
the heart and along anterior margin of the trachea. Line 2 connects a point
1 cm behind the anterior margin of the body of the dorsal vertebrae. Figure 12: Pneumoperitoneum in a 40-year-old male resulting from perforation
Mediastinum anterior to line 1 is anterior mediastinum, between lines 1 and 2 of a duodenal ulcer. Chest radiograph (PA view) demonstrates gas under both
is middle and posterior to line 2 is posterior mediastinum. domes of diaphragm.
69
 obstruction. Demonstration of a zone of transition between Table 8: Contrast Studies of Gastrointestinal Tract: Organs
dilated and normal/collapsed small bowel is an indicator of Evaluated and Common Clinical Indications
mechanical obstruction. Occasionally, plain radiographs can also
Contrast Organs Common Clinical
diagnose the cause of bowel obstruction, like obstructed
Study Evaluated Indications
inguinal hernia, sigmoid volvulus, etc.
Barium Oral cavity up Dysphagia, motility
Contrast Studies of the Gastrointestinal Tract swallow to fundus of disorder (achalasia),
The emergence of cross-sectional imaging techniques had a stomach carcinoma oesophagus,
dramatic impact on the imaging of gastrointestinal tract. hiatus hernia, extrinsic
However, a contrast examination still remains a valuable compression/
displacement
diagnostic test for evaluating the luminal and subtle mucosal
pathologies of the intestinal tract. Barium sulphate, an inert Barium Oesophagus, Epigastric pain,
UGI study stomach and dyspepsia, heart
contrast agent comes in a variety of suspensions designed for
duodenum, (single burn, unexplained
specific examinations depending on their density and viscosity. or double contrast weight loss,
Barium Examinations (Table 8) techniques) anaemia
1. Barium swallow: Barium swallow is the technique of choice Barium Stomach to Tuberculosis, Crohn’s
meal follow ileocaecal junction disease (Figure 14),
for symptoms of the dysphagia, odynophagia, atypical chest
through neoplasm, radiation
pain and gastro-oesophageal reflux. Barium swallow is
enteritis, diarrhoea,
complementary to endoscopy for oesophagitis and tumours. anaemia/gastrointestinal
2. Barium meal: Barium meal is rarely performed with the bleed, partial obstruction
advent of endoscopy. Barium studies are complementary Enteroclysis Duodenojejunal Partial small bowel
to endoscopy for most cases of dyspepsia and abdominal flexure to ileocaecal obstruction Crohn’s
pain (peptic ulcer and malignancy). However, they are junction disease-extent, Meckel’s
superior to endoscopy for evaluation of the functional diverticulum,malabsorption,
anomalies and submucosal lesions. tumours of small intestine,
occult gastrointestinal bleed
3. Small bowel follow-through: Indicated in subacute intestinal
Single contrast Colon Colon obstruction,
obstruction, chronic obstruction and inflammatory bowel
barium enema intussusceptions,
disease. fistula, uncooperative/
4. Barium enema: It is used for evaluation of the colonic debilitated patients
pathologies. Double contrast study is superior to single Double contrast Permits visualisation Inflammatory bowel
contrast for detection of small polypoidal lesions and small barium enema of mucosal detail disease (Figure 15), polyp
ulcerations.
Barium is contraindicated in suspected perforation (causes
5. Enteroclysis: It equires initial placement of a tube in the
peritonitis or mediastinitis). Suspected perforation is an
proximal jejunum prior to barium infusion (Figure 13).
indication for use of a water-soluble agent. Post-operative oral
Enteroclysis is preferred for evaluating subtle mucosal
abnormalities, focal small-bowel lesions or to determine the
cause of small-bowel obstruction.

Figure 14: Crohn’s disease in a 36-year-old male. Barium meal follow-through

shows pseudosacculation involving the jejunum (arrow), longitudinal ulceration
Figure 13: Normal enteroclysis. involving the mesenteric border (arrowhead).
70
 Conventional Radiology
Table 9: Features of Basic Patterns as Seen on Contrast Studies
of Gastrointestinal Tract
Patterns Features
Benign stricture Smooth tapering margin at both ends
Malignant stricture Irregular, abrupt narrowing, apple core
appearance, shouldering at one/ both ends
Extrinsic mass Intact mucosa, displaced lumen, obtuse
angle with luminal surface
Intramural Intact mucosa, right angle with
(Submucosal) mass luminal surface
Mucosal mass Irregular mucosa with ulcerations, acute
angle with luminal surface

Distinction between Small- and Large-bowel Dilatation

(Figures 16 and 17)
When a radiograph shows dilated bowel, it is important to
determine whether it is small- or large-bowel, or both (Table 10).

Table 10: Distinguishing Features between Small- and Large-

bowel Obstruction
Small-bowel Large-bowel
Obstruction Obstruction
Figure 15: Ulcerative colitis in a 30-year-old female. Barium enema shows
granular mucosal pattern and loss of haustration involving the entire colon. Number of loops More Less
Distribution of dilated loops Central Peripheral
Haustra Absent Present
contrast studies are also done with water soluble agents to look
Valvulae conniventes Seen in jejunum Absent
for suspected leaks and patency of anastomosis.
Diameter 3-5 cm ≥ 5 cm
Pattern Recognition in Gastrointestinal Radiology
Following a pattern approach on barium studies facilitates Ileocaecal (IC) Tuberculosis
diagnosis of wide spectrum of diseases affecting the alimentary IC TB is the most common form of alimentary tract TB (Figure 18).
canal (Table 9). Imaging features of ileocaecal TB are tabulated in Table 11.

B
Figures 16A and B: Small bowel obstruction: Supine (A) and erect (B) radiographs show dilated multiple bowel loops having central position and valvulae conniventes
suggestive of small-bowel obstruction. Erect radiograph demonstrates multiple air-fluid levels.
71
 Figure 18: IC tuberculosis in a 22-year-old male. Barium meal follow-through
shows narrowing involving the terminal ileum and IC junction, obtuse angle of
entry, contracted caecum and dilatation of terminal ileum.

Figure 17: Large-bowel obstruction in a 70-year-old male. Supine radiograph diagnosis of biliary obstruction and is used only as a prelude to
demonstrates gas filled distended large-bowel and caecum. Small-bowel is not percutanoeus transhepatic biliary drainage.
dilated due to competent IC valve.
MUSCULOSKELETAL SYSTEM
Table 11: Findings of Ileocaecal (IC) Tuberculosis on Barium Bone and joint radiographs require systematic analysis of bone
Examination density, alignment, cortex, medulla, joint space, soft tissue and
Spasm and hypermobility with oedema of the ileocaecal valve calcification, and periosteal reaction. The skeletal system may
Thickening of an incompetent IC valve with narrowing of terminal be involved in local (infection, primary tumours) and systemic
ileum (Fleischner sign) diseases (endocrine, metabolic marrow pathology, metastatic
Shallow ulceration
disease).
Napkin ring stenoses with a conical, shrunken caecum Metabolic/Endocrine Disease
Widely open IC valve with fixed and narrowed terminal ileum Endocrine disorders, such as osteoporosis, osteomalacia,
(Stierlin’s sign) hyperparathyroidism, acromegaly, hyper- or hypo-thyroidism,
Altered angle of entry of IC junction Cushing’s syndrome, pseudohypoparathyroidism, and
Contracted, pulled-up caecum haemoglobinopathies require skeletal survey. Diseases like
Skip areas of concentric mural thickening with luminal narrowing hyperparathyroidism and congenital hypothyroidism produce
in rest of bowel classical radiological changes depending upon the severity. For
detection of osteoporosis, bone mineral density by DEXA is the
HEPATOBILIARY SYSTEM ‘gold standard’. Osteomalacia is distinguished from osteoporosis
Conventional radiology has no role in the diagnosis of gall- by the presence of looser’s zones or insufficiency fractures.
bladder disease. Oral cholecystography has been replaced by Radiological features of common endocrine and metabolic
ultrasonography, CT and MRI. In liver diseases, ultrasonography, diseases are mentioned in Table 12.
CT, MRI are used to detect focal and diffuse liver diseases. In Avascular necrosis of the head of femur and other sites is known
pancreatic diseases, plain radiograph of abdomen is useful only to occur in steroid therapy, Cushing’s syndrome, atherosclerosis,
to demonstrate pancreatic calcification in chronic pancreatitis, pancreatitis, fat embolism, alcoholism, collagen vascular disease,
but this is also better done using CT. CT, transabdominal and Caisson’s disease, Gaucher’s disease and radiation therapy.
endoluminal ultrasound are most useful in imaging pancreatic Radiographs can detect avascular necrosis only late in the course
pathology and have virtually replaced conventional radiological of disease and MRI is the modality of choice for early diagnosis.
techniques. Magnetic resonance cholangiopancreaticography
shows intra- and extra-hepatic biliary radicals and pancreatic Primary Bone Tumours
duct and produces images analogous to Endoscopic retrograde Broadly bone tumours can be divided into two groups: benign
cholangiopancreatography ERCP. In majority of cases, ERCP is and malignant. Malignant tumours can be primary or secondary
done for therapeutic purposes only. Similarly percutaneous (metastatic). Radiographs are the primary imaging modality
72 trans-hepatic cholangiography is no longer used in the in diagnosis and characterisation of bone tumours. The
 Conventional Radiology
radiographic features that help in characterisation of bone
tumours are: site of the lesion (location in the skeleton and in
the individual bone); borders (also known as zone of transition);
matrix mineralisation (composition of the tumour tissue);
pattern of bone destruction (geographic, moth-eaten or
permeative); periosteal reaction; adjacent soft tissue, cortical
integrity; and multiplicity of the lesions. Benign tumours usually
produce well-defined, geographic lytic lesion with sclerotic
borders, narrow zone of transition, uninterrupted/solid
periosteal reaction, and no soft-tissue mass, whereas malignant
lesions demonstrate ill-defined, permeative lytic lesion with
wide zone of transition, interrupted periosteal reaction
(sunburst/onion skin/Codman triangle) and large soft tissue
component.

Table 12: Radiological Features of Common Endocrine and

Metabolic Diseases
Osteoporosis Osteopaenia (prominent in areas of the
skeleton rich in trabecular bone,
especially in the axial skeleton (vertebrae,
pelvis, ribs and sternum)
Low-trauma fractures (vertebrae, the
distal forearm and the proximal femur)
Hyperparathyroidism Subperiosteal erosions (radial aspects of
(Figures 19A to C) the middle phalanges of the index and
middle fingers, outer ends of clavicle,
symphysis pubis, sacroiliac joints)
Intracortical bone resorption
Chondrocalcinosis
Brown tumours
Osteosclerosis (seen in HPT secondary to
chronic renal impairment)
Metastatic calcification
Rickets Widening of the growth plate Figure 19A: Primary hyperparathyroidism in a 34-year-old male. Radiograph of
(Figures 20A and B) Cupping of the metaphysis hand shows subperiosteal resorption involving the radial margins of the
Rachitic rosary (expansion of the anterior proximal and middle phalanges.
ends of the ribs)
Deformities (genu valgum/varum, coxa
vara, Harrison’s sulcus, protrusio acetabuli
and tri-radiate deformity of the pelvis)
Osteomalacia Osteopaenia
(Figure 21) Looser’s zones or pseudo-fractures
(medial aspect of femoral neck, pubic
rami, lateral border of scapula and ribs)
Cushing’s disease Osteoporosis
Low-trauma fractures
Exuberant callus formation
Avascular necrosis of hip

Skeletal Metastasis/Myeloma
Skeletal metastases can be detected by skeletal survey and
sensitivity of conventional radiographs in the detection of
secondaries in skeletal system is about 60% to 70%. Isotope
scanning (99mTc-methyl diphosphonate) is more sensitive
but not specific. Osseous secondaries can be osteolytic or
osteoblastic. Majority of these are osteolytic; osteoblastic lesions
(Figures 22A and B) are mainly seen in the carcinoma of the
prostate in male and breast malignancy in female. Multiple
myeloma produces widespread involvement of the bones having
osteopaenia, punched out osteolytic lesions, endosteal scalloping
with sparing of the posterior elements and pedicles (Differential Figure 19B: Radiograph of left hand demonstrates subperiosteal resorption of
diagnosis secondary deposits).The usual sites are spine, skull, ribs, the proximal and middle phalanx and expansile lytic lesion (brown tumour)
involving the middle phalanx of the 4th digit.
pelvis, long tubular bones and distal ends of the clavicles. 73
 Figure 21: Osteomalacia in a 48-year-old female. Radiograph of pelvis shows
Figure 19C: Lateral skull radiograph demonstrates granular texture of the bone
reduced bone density and fuzzy trabecular pattern. Note the presence of
(salt and pepper pot appearance) with loss of definition of the both inner and
Looser’s zone (pseudo fracture) involving bilateral pubic rami (arrows).
outer table.

Arthritis
In rheumatoid arthritis small joints (metacarpophalangeal,
metatarsophalangeal and interphalangeal joints) are involved.
Imaging features include soft tissue swelling, regional/diffuse
osteopaenia, joint space narrowing, central or marginal erosions,
subluxation and deformities. In osteoarthritis, predominant
features are asymmetrical joint space narrowing, osteophytes,
subarticular sclerosis with cystic areas. In ankylosing spondylitis,
involvement of the bilateral sacroiliac joint is paramount with
ligamentous calcification (paraspinal as well as interspinous
ligaments). Disorganised joints, marked sclerosis, subluxation
and new bone formation are the classical features of neuro-
pathic joints which occur in syringomyelia, spinal dysraphism,
diabetes, leprosy and syphilis.

Osteomyelitis
Osteomyelitis can generally be divided into pyogenic and non-
pyogenic types. Radiographs are normal during the initial stage
of osteomyelitis and contrast enhanced MRI is the investigation
of choice. Later, radiograph demonstrates soft-tissue oedema,
loss of fascial planes, osteopaenia, metaphyseal lytic lesion and
fluffy periosteal reaction. In infants and adults metaphyseal
involvement with epiphyseal extension occurs, whereas in
children older than 18 months, metaphyseal involvement
predominates. Chronic osteomyelitis on radiograph
demonstrates dense involucrum (sheath of periosteal new
bone), sequestrum (dead bone), and cloaca (sinus tract). Brodie’s
abscess caused by Staphylococcus aureus is a well-demarcated
metaphyseal elongated lytic lesion surrounded by reactive
sclerosis.

Musculoskeletal Tuberculosis
Musculoskeletal TB accounts for about 1% to 3% of cases of
TB (Table 13). TB of the spine is the most common form and
accounts for approximately 50% of cases. Extra-spinal
Figures 20A and B: Rickets in a 4-year-old male child. (A) Radiograph of bilateral
wrist demonstrates diffuse osteopaenia. Growth plate of bilateral radius is manifestations are less common. Tuberculous spondylodiscitis
widened with metaphyseal cupping, fraying and splaying. (B) Chest radiograph has classical appearance of narrowing of the disc with
shows widening of the costochondral junction of the ribs suggestive of rachitic irregularities of the opposing vertebral endplates and
74 rosary.
paravertebral abscesses (Figures 23A and B).
 Conventional Radiology

Figures 22A and B: Sclerotic skeletal metastasis in a 72-year-old male with carcinoma prostate. Radiographs of anteroposterior view (A) and lateral view
(B) demonstrate sclerosis seen involving the L1, L3, L5 vertebrae and iliac bone.

Table 13: Imaging Features of Musculoskeletal Tuberculosis GENITOURINARY SYSTEM

Plain Radiography
Patterns of Common Bones/ Imaging Features
Involvement Joints Involved Plain abdominal radiography is routinely employed in the
evaluation of renal calculi and prior to intravenous urography
Tuberculous Mono-articular Narrowing of joint space
arthritis involvement (hip and Peripherally located erosions (IVU) to look for stones in the urinary tract.
knee–most common) Juxta-articular osteopaenia Intravenous Urography (IVU)
Tuberculous Small bones of hand and Poorly defined lytic lesion Current role of IVU (Figure 24) is in detection of the congenital
osteomyelitis feet–most common Periostitis
ureteric and renal anomalies, early changes of renal TB (Figure 25)
Tuberculous Upper lumbar/lower Reduction of intervertebral and papillary necrosis (Figure 26). It is complementary to
spondylitis thoracic vertebra with disc spaces
retrograde pyelography and CT in detection of the transitional
involvement of two End plate irregularities
contiguous vertebrae Collapse of vertebrae
cell carcinoma. IVP is alternative (suboptimal) to CT for
Paraspinal abscess evaluation of nearly all aetiologies of haematuria and flank pain
(calculi, tumour, infection and trauma). 75
 A B

Figures 23A and B: Pott’s Spine in a 22-year-old male patient. Radiographs of spine anteroposterior view (A) and lateral view (B) demonstrate reduction in the disc
space of L2-3 vertebrae, end-plate irregularity with lytic lesion involving body of L2-3 vertebra. Findings are suggestive of spondylodisitis.

Figure 25: Genito-urinary TB in a 40-year-old male. IVU shows fuzzy papilla

Figure 24: Normal IVU. Fifteen minutes IVU demonstrates normal contrast involving the left kidney with delayed contrast excretion and contracted bladder
excretion. Bilateral kidneys and ureters are normal. (thimble bladder).
76
 Conventional Radiology
Micturating Cystourethrogram (MCU)
MCU is very useful in demonstrating vesicoureteric reflux, bladder
abnormalities like diverticulum and filling defects. Obstructive
lesions in the urethra, like strictures, valves, diverticuli are readily
demonstrated.
Retrograde Urethrogram (RGU)
RGU gives excellent anatomical information concerning the
distal urethra as far as the distal sphincteric mechanism.
Hysterosalpingography (HSG)
HSG is a radiographic method for evaluation of the endometrial
cavity and the fallopian tubes following direct instillation of
contrast media. Current indications of the HSG include infertility,
recurrent abortions, detection of suspected uterine anomalies
and assessment of tubal patency and morphology.

RECOMMENDED READINGS
1. Adam A, Allison D. Grainger and Allison’s Diagnostic Radiology; 5th Ed.
Churchill Livingstone; 2007.
2. Felson B. A classical account of plain radiographic signs and differential
diagnosis. Chest Roentgenology, Saunders, Philadelphia; 1973.
3. Sutton D. Textbook of Radiology and Imaging; 7th Ed. Churchill Livingstone;
2008.
Figure 26: Papillary necrosis due to analgesic nephropathy. IVU demonstrates
4. Subbarao K, Banerjee S, Aggarwal SK, Bhargava SK. Diagnostic Radiology
characteristic egg-in-cup cavities. No focal cortical loss is seen.
and Imaging; 2nd Ed. New Delhi: Jaypee Brothers Medical Publishers; 2003.

77
 3.2 Ultrasound in Medicine

BS Rama Murthy

Ultrasound (US) has evolved into a first line imaging modality 5. Stroke/Transient ischaemic attacks
in the investigation of problems encountered in medical 6. Diabetes mellitus.
practice. Non-invasive cost-effective visualisation of the internal
organs without the use of radiation or contrast agents have FEVER OF UNKNOWN ORIGIN (FUO)
made US imaging readily accessible even in the remotest Fever under investigation may be due to infection, neoplasia or
regions of our country. The following paragraphs are an attempt collagen vascular disease. The US imaging can demonstrate the
to present a few situations in clinical medical practice and the focus of localised infection as a small liver/kidney abscess or a
possible US findings which aid in clinching the diagnosis or sub-diaphragmatic abscess (Figure 1). It should be emphasised
narrowing the differential diagnosis. US may give vital clues that US is an excellent modality, in demonstrating fluid
which can help make decisions for further imaging/laboratory containing space occupying lesions in solid organs. Extensive
investigations. tuberculous infection of the peritoneum in its ascitic or plastic
Apart from grey scale imaging which forms the bulk of basic forms can be well recognised by US (Figure 2). Loculated
US usage, one can use Doppler US to assess the vascular status peritoneal fluid collections traversed by flimsy fibrinous bands
of the organs or regions of pathology. Three-dimensional US are pathognomonic of ascitic form of peritoneal tuberculosis
gives the ability to view the region of pathology in multiple (TB). Omental and mesenteric thickening with adherence seen
planes simultaneously. as ‘sandwich sign’ is suggestive of plastic form of TB.
Special high frequency transducer (the hand-held probe which
emits US energy and receives the echoes) design enables the
study of superficial structures, such as the thyroid, testes etc. in
great detail.
Special transducer design enables intracavitary usage, such as
the vaginal, oesophageal, gastroduodenal or rectal routes.
US imaging employs sound waves that are beyond the range
of human hearing. Typically 3.0 to 5.0 Megahertz (MHz) is the
frequency used for abdominal imaging. Superficial part imaging
transducers are capable of producing US of upto 15 MHz. The
US energy propogates through the tissues underlying the
transducer. The tissue field produces reflections (echoes) which
reach the same transducer. These echoes are converted to
Figure 1: Liver abscesses in case of fever of unknown origin (FUO).
electrical impulses which after processing produce the image
on the monitor. The transducer has an array of piezoelectric
crystals which produce US on being deformed by an electric
impulse. The reverse process occurs when the echoes reach
the transducer.
A region which returns no echoes is termed anechoic. Clear
fluid containing structures as urinary bladder, gall bladder and
cystic lesions are anechoic. A region which returns echoes
similar to the liver is termed isoechoic. We also have the terms
hypo- and hyper-echoic signifying solid regions returning
lighter or darker echoes relative to the liver respectively.
Like all imaging modalities US interpretations have to be done
based on the clinical background.
Figure 2: Thickened omentum and loculated fibrinous ascites in peritoneal
For the purpose of discussion, the following clinical situations, tuberculosis.
are discussed:
Among neoplasia renal cell carcinoma and lymphoma can
1. Fever of unknown origin (FUO) present with fever. Abdominal or cervical lymph nodal
2. Jaundice enlargement can be demonstrated with US (Figure 3). Gut wall
3. Hypertension thickening especially in the ileocaecal region could be due to
4. Portal hypertension TB or lymphoma.
78
 Ultrasound in Medicine
Lymphoma is classically hypoechoic with increased vascularity Normal intra-hepatic biliary ducts beyond the right and left
on Doppler examination. main hepatic ducts are not visualised by US. Dilated intra-
hepatic ducts are seen as tubular cystic structures running
parallel to the portal radicles and produce the typical ‘double
barrel’ or ‘shot gun’ appearance.
The normal main bile duct (common hepatic and common bile
duct) can be consistently demonstrated by US and is less than
6 mm in caliber. Any diameter above 6 mm in a case with no
history of biliary surgery is indicative of dilatation. It must be
noted that there could be non-obstructive ectasia as in a
choledochal cyst or as in ectasia associated with advancing age.
The level of obstruction can be gauged by noting the presence
of gallbladder and/or pancreatic duct dilatation. The cause
of obstruction may often be demonstrated in the form of a
Figure 3: Splenic lesions and juxta-aortic lymph node enlargement in NHL. ductal calculus, cholangiocarcinoma, pancreatic mass or a
periampullary carcinoma (Figures 5A and B). In sclerosing
JAUNDICE cholangitis and human immunodeficiency virus (HIV )
cholangiopathy the main bile duct shows wall thickening.
Jaundice could be due to haemolytic, hepatocellular, cholestatic
or obstructive causes. Biliary ductal obstruction at any level
results in upstream dilatation. US imaging has a high sensitivity
for biliary ductal dilatation and can indeed stratify patients of
jaundice into obstructive versus non-obstructive groups. In
addition to recognising the presence of obstruction, US also
gives information about the level of obstruction and cause of
obstruction (Figures 4A and B).

Figure 5A: Intra-hepatic biliary ductal dilatation with gallbladder dilatation in

periampullary carcinoma (Figure 6).

Figure 4A: Intra-hepatic biliary dilatation in a case of common bile duct calculus
(Figure 4B) also note presence of gall bladder stone in the fundic region.

Figure 5B: Terminal CBD cut-off in periampullary carcinoma.

HYPERTENSION
In the setting of hypertension US plays two distinct roles.
1. To look for potential renal or adrenal causes in secondary
hypertension.
2. To assess renal status in chronic hypertension.
The renal conditions that can be identified as a possible cause of
hypertension include autosomal dominant polycystic renal
disease, post-inflammatory renal scarring (focal or global),
Figure 4B: Calculus in the intra-pancreatic segment of common bile duct. Calculi diabetic nephropathy, acute glomerulonephritis and other
are typically bright (hyperechoic) with an acoustic shadow.
parenchymal diseases (Figures 6 and 7). These are traditionally 79
 2. The segmental arteries are consistently seen by colour
Doppler and sampling of at least three of them serves as a
screening test. In the presence of main renal artery stenosis
the intra-renal Doppler spectral waveforms show ‘tardus
parvus’ nature (Figure 8B). This means that the systolic
velocities are attenuated with a slower acceleration of the
slope of the systolic upstroke. Acceleration time greater
than 70 milliseconds are indicative of main renal artery
haemodynamically significant stenosis.

Figure 8A: High systolic velocity in the origin of the right renal artery.

Figure 6: Right and left kidneys replaced by multiple cysts. Note the symmetrical
enlargement, in a case of autosomal dominant polycystic kidney disease.

Figure 8B: Tardus parvus intrarenal waveform (segmental artery) in the right
Figure 7: Focal lower pole chronic pyelonephritic scar of the right kidney. Note
kidney of the subject in Figure 10.
the presence of focal parenchymal thinning as well as the contour alteration.

In addition, the presence of low pulsatility in the intra-renal

classified as renal parenchymal causes and are diagnosed on the
arteries is indicative of better chance of reversal to normotensive
basis of B mode imaging.
state after stent placement or balloon angioplasty.
On the other hand, we have renal vascular cause as in renal artery
stenosis (atheromatous plaques or fibromuscular dysplasia). Adrenal cause which can be detected by US is a pheochromo-
cytoma or adrenal carcinoma (Figure 9).
Duplex Doppler US provides a non-invasive screening
technique. The B mode and Doppler findings include: PORTAL HYPERTENSION
1. High peak systolic velocity in the stenotic segment (greater In the clinical setting where portal hypertension is a potential
than 180 to 200 cm/sec) and an renal artery/aortic possibility (ascites, splenomegaly, haematemesis, dilated
ratio (RAR) of 3.5 or more are considered as markers of abdominal wall veins), US may help in answering the following
a haemodynamically significant (greater than 50% questions:
diameter reduction) main or accessory renal artery stenosis
(Figure 8A). The visualisation of the main renal artery is Is Portal Hypertension Present? What Is the Cause?
rather dependent on the body habitus, and the operator The splenomesentericoportal venous axis normally shows
expertise. Hence, it may not serve its ‘screening’ role to the an inspiratory increase and expiratory decrease in caliber.
80
expected level. Decrease or absent respiratory caliber change is a very
 Ultrasound in Medicine
Having obtained as much B mode findings as possible Doppler
is used to map the presence and direction of flow in the
splenomesentericoportal venous axis and the collaterals.
Hepatofugal flow in the portal vein has important clinical
implications. This is associated with decreased incidence
of variceal bleed but increased incidence of hepatic
encephalopathy. Porto-hepatic and porto-systemic collaterals
show hepatopetal and hepatofugal flow, respectively.
The cause of portal hypertension in terms of portal venous
Figure 9: Right adrenal solid mass. thrombosis (a portal cavernoma implies portal venous
thrombosis in the past), cirrhotic hepatic echopattern or IVC or
sensitive marker of portal hypertension (Figure 10). Upstream hepatic vein pathology may be identified.
dilatation of the splenomesentericoportal venous axis
occurs proximal to the site of pathology. For instance, in portal STROKE/TRANSIENT ISCHAEMIC ATTACKS
cirrhosis (hepatic cause of portal hypertension) upstream Stroke due to atherosclerotic disease is a leading cause
dilatation occurs in the splenic, superior mesenteric and portal of mortality and morbidity. Transient ischaemic attacks are
veins. harbingers of stroke. Vast majority of ischaemic strokes are
due to emboli. The source of emboli could be from the
carotid system or the cardia. It is well documented that the
embologenicity in the carotid system increases with the degree
of stenosis due to atheromatous plaques. The North American
Symptomatic Cartoid Endarterectomy Trial (NASCET) trial has
convincingly proved that carotid endarterectomy is more
beneficial than medical therapy in symptomatic patients with
70% to 99% internal carotid stenosis. This study has ensured
the future of carotid Doppler ultrasound as a screening tool.
The indications for carotid Doppler include TIA, stroke, carotid
bruit, amaurosis fugax and post-carotid endarterectomy/
stenting. The intima medial thickness is being used as a
Figure 10: Absent respiratory portal venous caliber change in portal
hypertension. Also note portal venous dilatation. predictor of the possibility of future cerebrovascular or
cardiovascular accident.
Portal vein is considered dilated when its caliber is more than 1.3 Carotid Duplex Doppler
cm. Dilatation of the portal or splenic veins is not as sensitive or Carotid duplex Doppler US enables us to assess the following:
specific compared to respiratory caliber change in the diagnosis
of portal hypertension. Identification of venous collaterals is a 1. The wall (atheromatous plaque) morphology: Plaque length,
strong confirmatory sign of portal hypertension. Collaterals may thickness, extent, echogenicity and surface characteristics
be porto-hepatic as in periportal (portal cavernoma) or peri- (Figures 12 and 13).
pancreatic collaterals (Figure 11). These collaterals bypass the 2. The patent luminal status is assessed in terms of
region of cause of portal hypertension and drain into the portal percentage diameter or area narrowing. This can be done
venous radicals in the liver. In contrast porto-systemic collaterals by direct visualisation or by velocity criteria. Velocity
drain either into the superior vena cava or inferior vena cava criteria include peak systolic ratio, end diastolic velocity
territories. Examples of the former include the dilated coronary and the velocity ratios (ICA/CCA systolic or diastolic ratios).
vein and short gastric collaterals. Examples of the latter include The velocity assessment of stenosis is based on the
splenorenal or splenoretroperitoneal collaterals and the principle of incremental acceleration of blood flow in the
recanalised umbilical vein. region of stenosis with increasing degree of stenosis.

Figure 11: Portal cavernoma and periportal collaterals. Figure 12: Carotid homogeneous, echogenic, smooth surfaced plaque.
81
 3. In terms of infective sequelae, we can identify emphy-
sematous cholecystitis/pyelonephritis.
We will now explore the role of US in the evaluation of various
organ systems.
i. Neonatal brain: Transfontanellar approach yields coronal
and sagittal images of the brain. Hypoxic ischaemic
sequelae, intracranial haemorrhage and congenital
malformations are assessed and followed-up.
ii. Neck: Thyroid, parathyroid, and cervical nodes may be
evaluated for enlargement, echopattern and nodules.

Figure 13: Internal carotid calcific plaque. iii. Chest: US is sensitive for detecting fluid in the pleural cavity.
Presence of loculation or fibrinous content may be assessed.
Large lung/mediastinal lesions may be characterised as
Haemodynamically significant stenosis implies more
being solid or cystic.
than 50% diameter reduction. Doppler assessment
can recognise only haemodynamically significant 4. Abdomen
stenoses. (a) Liver: Size may be assessed. The normal liver
Carotid duplex Doppler US screening is an excellent non- echopattern is homogeneous. In diffuse liver disorders,
invasive means of assessing stenosis. Useful information the echopattern is altered as happens in cirrhosis.
regarding the plaque morphology may be obtained. Presence of portal hypertension may be assessed. The
strength of US, however; is in its ability to demonstrate
DIABETES MELLITUS space occupying lesions of the liver and characterise
US has many roles to play in the context of diabetes mellitus. A them as solid or cystic.
few of them may be enumerated below: (b) Biliary system: US can demonstrate the biliary ductal
1. In terms of aetiology, chronic calcific pancreatitis may be dilatation in obstructive jaundice. The level and cause
demonstrated. Thinning of pancreatic parenchyma, of obstruction can be determined. Gall bladder disease
irregular ductal dilatation and ductular calculi are the in terms of calculi, cholecystitis, cholesterolosis and
defining features (Figure 14). malignancies may be demonstrated.
2. In terms of chronic sequelae, we could identify steatotic (c) Pancreas: Pancreatic swelling and intra- or peri-
infiltration of the liver (Figure 15), diabetic nephropathy, pancreatic fluid collections in acute pancreatitis and
and steno-occlusive atheromatous disease in the lower limb its sequelae may be demonstrated. Ductal dilatation
arterial axis. and calculi may be seen in chronic pancreatitis.
Pancreatic solid masses may be demonstrated.
(d) Kidneys: Abnormal location and/or absence of kidneys
may be assessed. Obstructive uropathy may be
demonstrated. The level of obstruction (pelviureteric or
ureterovesical or bladder outflow) may be ascertained.
Renal size and the parenchymal echopattern may be
evaluated in medical renal disease. Renal artery Doppler
may be used to evaluate potential stenosis.
(e) Adrenals: Adrenal mass lesions may be recognised and
described. Adrenal hyperplasia cannot be demon-
Figure 14: Chronic calcific pancreatitis. Echogenic calculi are seen in the diluted strated by US.
pancreatic duct.
(f) Bladder and prostate: Bladder volume, wall thickness
and presence of mural polypoid lesions can be
assessed. Post-void residue can also be estimated.
Prostatic weight and echopattern can be assessed by
transrectal ultrasonography.
(g) Female internal genitalia: Uterine size and presence of
fibroids or adenomyosis may be assessed. Ovarian
masses can be characterised. Ultrasound has an
indispensable role in infertility management.
Transvaginal ultrasonography has revolutionised the
pelvic imaging.
(h) Peritoneum: US is very sensitive for fluid in the
Figure 15: Patchy hepatic steatosis.
82 peritoneal cavity. Further, it can help in characterising
 Ultrasound in Medicine
whether the fluid is transudate or exudate. Thickened 5. Lower Limb Venous
peritoneum/omentum may be demonstrated as in Deep venous thrombosis may be mapped. Incompetency
peritoneal TB or metastasis. of the valves of the deep veins or communicating veins may
(i) Retroperitoneum: Retroperitoneal lymph node be evaluated.
enlargement and their distribution may be evaluated. 6. Abdominal
Retroperitoneal mass lesions may be described.
Doppler ultrasound contributes to the diagnosis of
(j) Abdominal wall: Hernial defects and wall masses can portal hypertension, renal artery stenosis, renal allograft
be delineated. vascularity, abdominal aortic aneurysm, and mesenteric
5. Perineal applications arterial insufficiency. Evaluation of an abdominal masses
Perianal sinuses and fistula can be delineated in terms of for the type of vascularity and main feeder and draining
extent and length. vessels.

6. Scrotal applications INVASIVE APPLICATIONS

Epididymorchitis, torsion, testicular tumours may be US-guided needle placements are now common place
recognised. procedures. Pleural taps, abscess drainages, renal and other
7. Musculoskeletal organ biopsies are all done successfully and non-safely under
Shoulder, wrist, knee, ankle applications. US guidance.

8. Orbital and ocular CONTRAST ENHANCED ULTRASONOGRAPHY

Anterior and posterior chamber applications. Ultrasonography contrast media are microbubbles which when
injected enhance the reflectivity of lesions. They have been
DOPPLER ULTRASOUND
particularly applied in liver space occupying lesions. Hepatic
1. Carotid and Vertebral haemangioma, primary tumour and metastatic lesions have
Atheromatous plaque morphology, luminal narrowing and/ their typical enhancement patterns.
or occlusion can be demonstrated in cases of transient
ischaemic attack or establisted stroke. ELASTOGRAPHY/FIBROSCAN
2. Transcranial Doppler Using US energy, the elastic properties of a tissue (e.g. liver)
It is used to evaluate the Willisian circulation in cases of or a lesion (e.g. breast carcinoma) can be qualitatively or
carotid occlusion. It is also used to evaluate the presence of quantitatively assessed. This technique holds promise to
spasm in subarachnoid haemorrhage. distinguish between benign and malignant lesions of the breast.
Assessment of the liver for diffuse parechymal diseases
3. Lower Limb Arterial (Fibroscan) is another area of promise.
Stenosis and/or occlusion can be demonstrated in cases of
intermittent claudication, rest pain or gangrene. Thus, we have seen a few situations in medical practice where
US plays an important role in investigation. However, there are
4. Upper Limb Arterial many other situations where US is indicated and where the
Evaluation of thoracic outlet syndrome and haemodialysis results have a bearing on the management of the individual
access fistula. case.

83
 3.3 Computed Tomography

Bhavin Jankharia,Nishigandha Burute

INTRODUCTION 2000 HU) appears white on the CT image. The differentiation

The discovery of computed tomography (CT) by Sir Godfrey between normal tissue and pathologies can, thus, be made by
Hounsfield, Senior Research Scientist in Middlesex, England and observing the difference in their shades of grey.
South African born Dr Alan Cormack in the 1970s has been a
milestone in the history of medical sciences and in the field of
radiology. CT literally means writing (graphien) slices (tomos)
of the human body with the help of a computation process. CT
has not only changed the understanding of many diseases but
also impacted the management of various disease processes.
Initially, it was called computerised axial tomography (CAT) or
computerised tomography, but computed tomography (CT) is
currently the preferred name worldwide.

BASIC PRINCIPLES OF COMPUTED TOMOGRAPHY

Working of the CT Scanner
The rays used in a CT scanner are X-rays. The basic principle
behind CT is that the internal structure of an object can be
reconstructed from multiple projections of the object. The ray
projections are formed by scanning a thin cross-section of the
body with a narrow X-ray beam and measuring the transmitted
radiation with a sensitive radiation detector. The detector adds
Figure 2: Differentiating tissues with the help of Hounsfield units.
up the energy of all the transmitted photons. The image is
formed by processing of the numerical data from the multiple EVOLUTION OF CT SCANNERS
ray sums by a computer (Figure 1).
CT scanners have gone through a number of design changes
since the technology was first introduced in 1971. The first
generation CT scanner used a single pencil beam of X-rays and
a single detector and used to take 25 to 30 minutes for a 5-view
study of the head. The second generation CT scanner used a
fan beam instead of a pencil beam with multiple detectors, with
a reduction in the scan time of a head CT to 1 to 2 minutes. The
X-ray tube and detector movements were both linear and
rotatory (translate-rotate) in the first and second-generation CT
scanners. In 1975, third generation CT scanners were introduced
in which the translation movement was completely eliminated
and only rotation was required with both the X-ray tube and
detectors rotating around the patient. A fan beam was
used and the unit could produce a head scan in a few seconds
(Figure 3A). The fourth generation CT scanner used a rotate-
fixed configuration of the X-ray tube and detector system, where
the detectors formed a ring that completely surrounded the
Figure 1: Working of a CT scanner. patient. The detectors did not move. The X-ray tube rotated in a
circle inside the detector ring (Figure 3B). The time required
CT Image for a CT head, thus, became 1 second.
The CT image is made up of a number of shades of grey. The The advent of spiral/helical CT scanners in 1989 has been
grey-scale of a tissue depends upon how much the tissue can considered a major technical advancement in body imaging. It
attenuate the X-ray beam. The unit of attenuation is called combines continuous gantry rotation with continuous table
Hounsfield unit (HU) (Figure 2). The degree of attenuation of feed, thus eliminating interscan delay (Figure 4). This enables
an X-ray beam by a particular tissue depends on its density. Air spiral CT acquisition to be much faster than conventional CT.
being the least dense (HU: 1000), it attenuates the beam the The spiral CT scanner has also matured from a single slice to a
least and appears black in colour; water being of medium 64-slice spiral CT scanner. The development of a dual source
84 density (HU: 0), it appears grey; dense cranial bone (upto multi-slice CT scanner is a recent development, in which two
 Computed Tomography
Contrast Related
The CT contrast medium is excreted by kidneys; hence,
deranged renal function is an absolute contraindication for
contrast-enhanced CT. Prior history of a serious reaction to CT
contrast agents is also a contraindication.

APPLICATIONS
Due to several recent technical innovations and improvements,
new CT applications continue to be added to an already long
list of indications. Both positive and negative results of a CT
improve the clinician’s understanding of the disease and assist
him in management decisions.
Head
Figures 3A and B: (A) In a third generation scanner, both the X-ray tube and CT is the modality of choice in head injury patients to look
detectors rotate around the patient. A fan beam is used. (B) A fourth generation for intracranial bleed, brain contusions and skull fractures
scanner has a rotating X-ray tube and a stationary array of detectors. A fan (Figure 5). It is also useful in acute cerebrovascular stroke
beam is used.
to differentiate haemorrhagic from non-haemorrhagic
tubes produce 64-slices together. A 256-slice spiral CT scanner stroke and to detect hypertensive bleeds. It is also helpful
is now commercially available. in detecting various other intracranial processes, such as
granulomas (tuberculomas, neurocysticercosis, etc),
hydrocephalous and tumours. CT is the modality of choice for
evaluating the bony anatomy of the skull base, temporal bone,
cranio-vertebral junction and paranasal sinuses (Figure 6).
High resolution CT (HRCT) of the temporal bone provides
exquisite details of the ear ossicles, middle ear cavity, mastoids
and bony labyrinth.
Neck
CT of the neck is used to detect the exact location and spread
of various disease processes involving the neck structures, such
as the nasopharynx, oropharynx, larynx, cricopharynx, salivary

Figure 4: A spiral CT scanner has continuous gantry rotation with continuous

table feed resulting in faster image acquisition.

CT CONTRAST MEDIA
Ionic/non-ionic contrast media are used intravenously in
appropriate doses for a contrast enhanced CT scan.These opacify
blood vessels and in turn the tissues that are supplied by them.
The degree of enhancement of a tissue depends on its vascularity
and capillary permeability. Thus, contrast media allow better
depiction of normal anatomy and help in differentiating normal
tissues from disease processes. Contrast media can cause allergic
reactions in some individuals. These may range from a simple
rash to the rare but fatal anaphylactic reaction.
Contrast media are also used to opacify the bowel loops during
abdominal imaging, as they enhance the contrast between
bowel loops and the surrounding viscera.

CONTRAINDICATIONS OF CT
X-ray Related
CT utilises X-rays for image production, hence, a CT is
contraindicated in the first trimester of pregnancy, which is the Figure 5: An axial CT of the brain shows haemorrhagic contusion in the right
85
temporal lobe (arrow).
period of organogenesis.
 Figure 6: Coronal high resolution CT of the paranasal sinuses shows mucosal
thickening (arrow) in the maxillary and ethmoid sinuses.

Figure 8: HRCT of the lung shows extensive cystic bronchiectasis.

Abdomen
CT is the modality of choice for detecting acute appendicitis,
cholecystitis, pancreatitis, acute ureteric colic, and intestinal
obstruction with or without perforation (Figures 9 and 10). It
is also used for the diagnosis, staging and pre-operative planning
of various gastro-intestinal and visceral malignancies and
benign neoplasms. It is also used for post-operative and post-
treatment follow-up of these malignancies.
Vessels
CT angiography, a logical application of spiral technology, is a
technique used to produce excellent images of the targetted

Figure 7: Axial contrast-enhanced CT of the neck shows a retropharyngeal

abscess (arrow).

glands, thyroid gland and parapharyngeal space lesions as well

as to detect cervical lymphadenopathy (Figure 7).
Thorax
CT is the modality of choice for evaluating lung pathologies,
such as benign and malignant neoplasms, infections, various
interstitial lung diseases (ILDs) and pneumoconiosis. In the
pleura, effusions, empyema, pneumothorax and tumours and
in the mediastinum, lymphadenopathy and neoplasm are well
assessed. HRCT is a technique used for evaluating exquisite
details of the lung parenchyma (Figure 8). HRCT can detect
pathologies, which are not apparent on plain chest radiographs
and has changed the management of patient with ILDs and Figure 9: Axial CT of the abdomen shows a bulky pancreas with extensive
calcification (arrow), suggesting acute on chronic pancreatitis.
86 airway pathologies.
 Computed Tomography
Figure 11: Axial cerebral angiography shows the arteries of the circle of Willis.

Figure 10: Coronal CT shows acute appendicitis (arrow).

arterial system.The images are displayed as thin collimation axial

images or 3D renderings using sophisticated reconstruction
techniques, like shaded surface display, maximum intensity
projection and multiplanar formats, or can be colour coded using
volumetric reconstruction images. Various applications of CT
angiography are given in Table 1.

Table 1: Applications of CT Angiography

1. Cerebral angiography for detecting lesions of the carotid,
vertebral and intracranial vessels, which include stenoses as well
as aneurysms and arteriovenous malformation (Figure 11).
2. Pulmonary angiography, which is now the ‘gold standard’ in
the evaluation of pulmonary thromboembolism.
3. Aortic angiography for aortic aneurysm, dissections and
stenosis (Figures 12A and B).
4. Renal angiography for detecting renal artery stenosis.
5. Mesenteric angiography for mesenteric ischaemia.
6. Peripheral angiography for assessing the peripheral circulation
of the upper and lower limbs. Figures 12A and B: Aneurysm. Maximum intensity projection (MIP) (A) and
7. Portal venography. volume rendered (VRT ) (B) images show a stented descending thoracic
aneurysm with another aneurysm in the lower abdominal aorta.
Musculoskeletal System
CT is the modality of choice for evaluation of the anatomy Cardiac CT
and pathology of the skeletal system. It has applications in Multi-detector CT coronary angiography is emerging as the
various congenital anomalies as well as infective, neoplastic most reliable non-invasive method for coronary artery disease
and traumatic conditions. The facility of retrospective (CAD) assessment. The newer ultra-fast cardiac CT holds the
reconstruction of thin sections and sophisticated 3D promise of replacing the standard invasive procedure of
evaluation techniques resulting in remarkably high quality conventional coronary angiography as well as nuclear stress
multi-planar reformats and shaded rendering is of immense thallium, especially in the setting of ‘to rule-out’. The standard
help (Figure 13). multi-slice CT that exquisitely produces coronary artery images
87
 Figure 14: Normal cardiac CT angiogram shows the left main (LM), left anterior
descending (LAD) and circumflex (CX) arteries.

Trauma
CT provides the high speed of data acquisition needed in
trauma patients and to plan triage. CT is the modality of choice
in an acute trauma setting for detecting internal bleeding, bone
fractures, vascular injuries affecting different systems of the
body, and for locating foreign bodies. Vertebral column injuries
are well depicted but for spinal cord injures, MRI is the modality
of choice. CT is also the modality of choice in patients with
metallic implants inside the body, such as metallic rods, plates,
fixation screws, etc (Figure 15).
Virtual Bronchoscopy and Colonoscopy
Using sophisticated software, it is now possible to get
bronchoscopic and colonoscopic views non-invasively. These
Figure 13: Sagittal CT of the spine shows gross osteopaenia and destruction of coloured pictures give better appreciation of the pathology.
the L2 vertebral body (arrow). Virtual bronchoscopy has a role in locating foreign bodies,
polyps, tumours, and strictures in the tracheobronchial tree.
is a 64-slice CT scanner, but 320-slice and dual-source scanners Virtual colonoscopy is used mainly in screening for polyps, some
are now available as well. All scans are gated to the of which may be pre-malignant lesions.
electrocardiogram (ECG) trace, which allows positioning the
3D Reconstruction
data acquisition accurately in specific phases (Figure 14). Using
such modality, one can perform calcium scoring, coronary artery With the advent of faster scanners, it is possible to achieve
imaging and assess function by reconstructing cine images. 3D images with enhanced spatial and temporal resolution.
Multi-planar reconstruction comprises reformatting of a CT
Paediatrics image in the axial, coronal and sagittal planes. Multi-planar
CT in children is often difficult due to motion artifacts and high reconstruction allows better localisation and delineation
respiratory rates. There is often a need to sedate or anaesthetise of structures. Curved planar reconstruction and maximum
babies. Multi-slice CT has overcome these problems with sub- intensity projection help better visualisation of tubular
second scans and improved image resolution. structures, such as blood vessels and ducts.
88
 Computed Tomography
Therapeutic Procedures
Pain management
CT-guided nerve blocks (lumbar sympathectomy,supra-clavicular
nerve block) are used for alleviation of pain (Figure 17).

Figure 17: CT-guided lumbar sympathectomy for pain management.

Radiofrequency ablation (RFA)

Radiofrequency ablation of osteoid osteoma and liver and lung
Figure 15: Coronal CT of the hip with orthopaedic hardware in situ, shows a malignancies is one of the newer applications of CT.
non-united fracture.
Vertebroplasty
Shaded surface display is useful in the setting of fractures, Transpedicular insertion of a bone biopsy needle in the diseased
dislocations and vascular trauma. Volume rendering offers vertebra under CT guidance, followed by delivery of bone
excellent anatomical details, and thus, enhances the cement into the body of the diseased vertebra is used for
visualisation of vessels and is also useful in cardiac imaging. management of painful vertebral pathologies.
CT-Guided Radiotherapy Planning
CT-GUIDED PROCEDURES
Radiotherapy treatment is usually planned in the axial planes.
Diagnostic Procedures CT has been extensively investigated as a method of providing
CT provides an accurate skin entry point and guidance for pre-treatment data for radiotherapy planning. CT not only
drainage of intra-abdominal and intra-thoracic collections provides accurate location and staging of the tumour but also
and abscesses. Under CT guidance, biopsies of mediastinal, calculates the volume of the tumour to be irradiated using
pulmonary and intra-abdominal lesions are possible (Figure 16). sophisticated software. It is also useful in successive follow-ups.
Liver Volume Estimation in Transplant Patients
CT enables accurate volumetric measurement of a donor liver
prior to transplant. This is essential in order to avoid small for
size grafts from living donors, which would compromise the
outcome of the liver transplant.

POSITRON EMISSION TOMOGRAPHY (PET)/COMPUTED

TOMOGRAPHY
The combination PET/CT scanner is a major advancement in
imaging technology and patient care. As the name implies, it
combines two scanners, the PET scanner, which shows
metabolism and the function of cells, and the CT which shows
detailed anatomy. The result is that doctors are now able to
get highly defined, 3D images inside the human body along
with functional information of the same (Figure 18).

SAFETY CONCERNS AND RADIATION ISSUES

Figure 16: CT-guided biopsy of an enlarged subcarinal node (black arrow), using With the tremendous increase in the use of CT in the past
an extra-pleural approach (red arrow).
decade, radiation exposure from CT have become a worrisome 89
 CT VERSUS MRI
The soft tissue resolution of CT is not at par with that of MRI,
especially in imaging of the brain and spine. However, CT scores
in imaging of the lung, bowel and skeletal structures. CT is the
modality of choice in acute and trauma settings due to shorter
scan times.

CONCLUSION
Although the discovery of CT was a major break-through in the
field of diagnostic radiology, the original model has undergone
many changes and developments. The list of applications
possible on a CT scanner is getting bigger and bigger as newer
applications get added.The currently used multi-detector, multi-
slice scanners offer sub-second scan times and provide true
volumetric data with exquisite 3D renderings. With a large
Figure 18: Axial PET/CT shows increased FDG uptake in a subcarinal lymph
increase in the use of CT, radiation issues are emerging as a
node. matter of concern, and need to appropriately be taken care of.

RECOMMENDED READINGS
issue. Recent studies have expressed concern over X-ray-
1. Berry M, Choudhary V, Suri S. Advances in Imaging Technology, Jaypee
induced cancer risk, especially in children. Proper adjustment Brothers Medical Publishers Pvt. Ltd; New Delhi 2003.
of scan parameters, using radiation doses as low as reasonably 2. Grainger and Allison‘s Diagnostic Radilogy; 4th Ed. Churchill Livingstone,
achievable and avoiding indiscriminate use of this modality pp 81-99.
are some of the ways suggested for lowering this radiation 3. Lee JKT, Sagel SS, Stanley RJ. Computed Tomography with MRI Correlation;
risk. 3rd Ed. Philadelphia: Lippincott Raven.

90
 3.4 MRI in Medicine

Raju Sharma, Ankur Gadodia

INTRODUCTION The process of the dephasing which occurs due to

Over more than two decades since its clinical inception, inhomogeneities in the nuclear magnetic environment
magnetic resonance imaging (MRI) has found widespread is known as T2 relaxation. The component of the net
application in nearly every area of medical practise. MR has had magnetisation vector in the transverse plane induces a current
major impact on medical diagnosis and has replaced, many in the magnetic coils (radiofrequency receiver coils). This
previous ‘gold standard’ invasive diagnostic procedures with current is known as the MR signal and is the basis for formation
safer and accurate alternative non-invasive imaging. of an image. By varying the time of application of the signal
(time to repetition or TR) or the time to acquiring the RF pulse
HISTORY (time to echo or TE) various image contrasts may be obtained.
The phenomenon of nuclear magnetic resonance was Advantages of MRI include lack of ionising radiation, true
discovered by physicists in the 1940s and was first utilised for multiplanar imaging, high soft tissue contrast and spatial
imaging the human body in the late 1970s. The process of resolution.
acquiring MR images was first illustrated by Lauterbur in 1973.
BASIC MR SEQUENCES
BASIC PHYSICS
There are two basic MR sequences that are frequently used for
MRI is based on excitation and detection of electromagnetic
MR imaging: spin-echo or gradient-echo techniques. Other
energy emitted by protons (H+). Hydrogen nuclei (1H), possess
sequences are modification of these basic sequences.
the strongest magnetic moment and are in high abundance
in the human body. Consequently, hydrogen is the most Spin Echo (SE) Sequences
widely used element for MR imaging. On application of Conventional spin echo pulse sequences are used to produce
electromagnetic radiofrequency pulses, these protons emit T1, T2 or proton density weighted images and are one of the
signal which is received and converted into an image. The most basic pulse sequences used in MRI. Spin echo sequences
greatest advantage is excellent soft tissue contrast resolution. are still considered the gold standard in that the contrast they
The physics of MRI is extremely complex and a full discussion produce is easily understood and is predictable. Spin echo
of the same is beyond the scope of this chapter and a brief sequences are versatile, available on all scanners, produce true
summary of the MR principles are discussed below. T2 weighting and are gold standard for image contrast and
The first step in MRI is application of a strong magnetic field. weighting. Disadvantage includes long scan times.
For this the patient is placed within a large magnet, either Fast Spin Echo (FSE) Sequences
permanent or superconductive. The nuclei adopt one of two
Fast spin echo (FSE) is a much faster version of conventional
possible orientations: parallel or antiparallel to the external field.
spin echo, but may show different contrast and demonstrate
A greater proportion of nuclei align in the parallel direction, so
decreased magnetic susceptibility effects. Fat appears bright
that the net vector of their alignment, and hence net magnetic
on both T1W and T2W images, muscles appear darker on T2
vector will be in the direction of the external field. Each nucleus
weighted images and haemorrhage may be missed on FSE
spins around the line of the field in a motion known as
sequences. However, ferromagnetic implants do not show as
precession. The frequency of this precession is given by the
much artefacts as other sequences. FSE sequences are usually
Larmor equation: F =γB 0 /2π where F is the precessional
used for brain, spine, joints, extremities and the pelvis.
frequency, B0 is the strength of magnetic field, and γ is the
Advantages include short scan times, high resolution imaging
gyromagnetic ratio of the nucleus.
and decreased magnetic susceptibility.
The net magnetisation vector from the nuclei inside the
magnet in its equilibrium state is static and does not produce Gradient Recalled (GRE) Sequences
a measurable signal. To obtain information from the spins, the GRE images should be called T2* weighted not T2 weighted
direction of the net magnetisation vector has to be altered. because of the effects of an imperfect magnetic field. Air
This is done by applying a radiofrequency (RF) pulse at the pockets (sinuses or intestines), dense bone (skull base), and
same frequency as the Larmor frequency. The RF pulse causes iron-rich blood breakdown products (methaemoglobin
the net magnetisation vector of the hydrogen atom to turn or or haemosiderin) all change the main magnetic field in their
flip towards the transverse plane, i.e. a plane at right angles to immediate vicinity, so tissues around such inhomogeneities will
the direction of the external magnetic field. Following the experience different magnetic fields. One area where the
cessation of the RF pulse, the extra energy is dissipated to prominent magnetic susceptibility artefacts on gradient
the surrounding chemical lattice in a process known as T1 recalled images can be used is in detection of haemorrhage.
relaxation. In addition, the RF pulse brings the precessing These sequences are typically shorter than routine sequences,
protons in phase, i.e. their spins are now in synchrony. and may yield significant image contrast. 91
 Inversion Recovery (IR) Sequences tumours, metastases, epidermoid cysts, etc. also show
Short inversion time restricted diffusion.
Short tau inversion recovery (STIR) sequence has very low signal Perfusion Weighted Imaging (PWI)
from fat but still has high signal from fluids. It is used in the Perfusion is a measure of the vascular supply to a tissue. Since
spine and musculoskeletal system to visualise marrow oedema, vascular supply and metabolism are usually related, perfusion
fractures, avascular necrosis, metastases, etc. can also be used to measure tissue activity. Perfusion imaging
Intermediate inversion time utilises a bolus injection of gadolinium administered
intravenously during ultrafast T2 or T2* acquisitions. This is
These are used in paediatric neurology to better visualise gray
used for evaluation of ischaemic disease or metabolic activity
white matter interface, to look for focal cortical dysplasia,
of tissues. On the cerebral blood volume (CBV) map, areas of
heterotopias, etc.
low perfusion appear dark (stroke) whereas areas of higher
Long inversion time perfusion appear bright (malignancies). Perfusion-weighted
Fluid attenuation inversion recovery (FLAIR) sequence uses MR imaging has applications in the evaluation of a number of
long inversion times (1,800-2,500 ms), depending on field disease states, including cerebral ischaemia and reperfusion,
strength, to null the signal from cerebrospinal fluid (CSF). FLAIR brain tumours, epilepsy, differentiation between radiation
is commonly used for neurological imaging to visualise necrosis and tumour recurrence and blood flow deficits in
periventricular lesions, white matter lesions. In addition, cortical Alzheimer’s disease.
changes which can also be hard to visualise with T2W sequences MR Spectroscopy (MRS)
are made more prominent (Figures 1A to C). Spectroscopy provides a frequency spectrum of a given tissue
Diffusion Weighted Imaging (DWI) based on the molecular and chemical constituents of that tissue.
Diffusion is a term used to describe moving molecules due Spectroscopy has now become routine part of MR imaging to
to random thermal motion. In normal tissues extracellular evaluate tissue metabolism. Proton spectroscopy has been used
water diffuses randomly whereas in ischaemic tissue, cells primarily for brain applications (Figures 2A to C) and recently
swell and absorb water thereby restricting diffusion. DWI for other organs, such as the liver, breast, prostate, and soft tissue.
should be interpreted in conjunction with apparent diffusion The use of spectroscopy expands the repertoire of anatomical
co-efficient (ADC) maps. Bright area on DWI should also be information by providing information on intracellular metabolites.
viewed on ADC maps. If the lesions appear bright on ADC, the The major metabolites detected in the CNS are N-acetyl aspartate
bright appearance on diffusion can be due to T2 shine through (NAA), a neuronal marker; choline, a marker for cellularity and
effect rather than true restricted diffusion, whereas lesions cell membrane turnover; creatine, a marker for energy metabolism;
and lactate, a marker for anaerobic metabolism. In addition to
which are dark on ADC map represent restricted diffusion. One
these metabolites, other metabolites that can be assessed
of the major uses for diffusion-weighted imaging sequence is
include alanine, glutamine, myoinositol, and succinate.
in the diagnosis of recent stroke where areas of decreased
diffusion represent infarction. DWI has also been used in the Functional Imaging
evaluation of other organs of the body such as liver, breast, Functional MR imaging (FMRI) is a rapid MR imaging technique
kidneys and prostate. Whole body diffusion imaging is used that acquires images of the brain during activity or stimulus
in oncology for delineation of metastatic disease and response and at rest. The two sets of images are then subtracted to
to treatment. Infarcts, encephalitis, abscesses, tightly packed depict regional cortical blood flow changes in space and time

Figures 1A to C: Axial T1W (A), T2W (B) and FLAIR (C) images of the cerebrum, mid ventricular level. CSF is hypointense on T1W and hyperintense on T2W images.
In FLAIR sequence image, static fluid signal is selectively suppressed.
92
 MRI in Medicine
MR Angiography (MRA)
The principle of MRA is to acquire images where the signal
returned from the flowing nuclei is high and the stationary
nuclei is low. Thus, contrast between vessel and background
tissue is achieved. MRA is used for non-invasive assessment of
many vascular abnormalities, including aneurysms, dissection,
stenosis, vessel anomalies, and coarctation. In many centers,
MRA has emerged as the imaging modality of choice in the
evaluation of the thoracic and abdominal aorta, and their major
branch vessels, including the carotid, renal, and mesenteric
arteries. It is also the modality of choice for getting an overview
of all major arteries in diseases like aortoarteritis.
MR Contrast Agents
The most commonly used, clinically approved contrast for MR
imaging, is a paramagnetic agent (atoms with unpaired
electrons in their outer shells) containing gadolinium, a T1-
shortening agent. Contrast enhancement is extremely useful
in evaluation of pathology like neoplasm, infection and
inflammation. Gadolinium has the ability to pass through the
breaks in the blood-brain barrier and thus is invaluable in
imaging the nervous system pathologies (Figures 3A and B).
Figures 2A to C: Tuberculoma in a 23-year-old male. Axial T2W image (A) shows In body imaging organs like liver, spleen, pancreas and kidneys
hyperintense lesion with central hypointensity seen involving the right
enhance immediately after contrast injection and thus, rapid
thalamus. On post-contrast image (B) thick nodular rim enhancement is seen.
Single voxel MR spectroscopy image (C) shows prominent lipid peak. These dynamic imaging is recommended for their evaluation.
findings are suggestive of tuberculosis.
MR HARDWARE
during performance of a particular task. An important clinical The hardware of a MRI machine consists typically of a cylindrical
application of FMRI is presurgical mapping where relation of superconducting magnet surrounding the patient to generate
the functional areas can be defined in relation to mass lesions, a large, static magnetic field; gradient coils through which
thus selecting the appropriate management strategy (surgical flowing current generates small changes in the magnetic field;
versus non-surgical) and avoid damage to vital neural tissues. radiotransmitter/receiver coils; electronics for radiofrequency
Other applications involve the understanding of brain functions, transmitting and receiving; and a computer to reconstruct the
evaluation of stroke, epilepsy, pain and cognitive problems. spatial image from the frequency spectra.

Figures 3A and B: Tuberculoma with meningitis in an 18-year-old male. Axial post-contrast images (A and B) show thick enhancing exudates involving the basal
cisterns with mild hydrocephalus. Also, note presence of homogenously ring enhancing lesions involving the right frontal and parietal lobes. These findings are
suggestive of tuberculosis.
93
 MR SAFETY AND CONTRAINDICATIONS HOW DO YOU DETERMINE THE SEQUENCE FROM THE FILM?
Any ferrous containing object is potentially dangerous within the When confronted with a series of MRI images, the first thing to
MRI scanning room and patients are always advised to remove do is identify known areas of fluid, for example, CSF, vitreous
all ferromagnetic substances. Hearing aids, jewellery, watches, chamber, the urinary bladder and renal pelvis. If these areas return
glasses, prostheses, credit cards and any type of implant should a high signal, then the image is T2W. If the fluid is bright and the
be removed before entering the scanner as they can potentially fat is dark then it is likely to be a fat suppressed T2 image/STIR
become a dangerous projectile. Current generation of image. If fat is bright and the fluid is dark then it is likely to be a
orthopaedic implants including prosthetic joints, rods, screws, T1W image. Contrast enhanced scans are usually labelled and
nails, clips, etc. are MR compatible and are not contraindications are usually T1W sequences with or without fat suppression. Fat
for MRI although they may significantly degrade image quality. in these cases will then be dark and the images are usually
compared with the pre-contrast T1W images to ascertain the
MR imaging is contraindicated for patients with metal implants
degree, if any, of enhancement. The way to differentiate a plain
or foreign bodies, such as intracranial aneurysm clips,
scan from a post-contrast study of the brain would be to look at
intraorbital metallic foci, cardiac pacemakers, or specific types
the nasal turbinates on T1W images. Post-contrast studies
of cardiac valves. In these instances, these objects may be
invariably show enhancement of the turbinates and bright signal.
dislodged or damaged by the magnetic field. MR imaging may
also be contraindicated for claustrophobic or uncooperative Second option is to look for the printed TR and TE on the film.
patients who may not respond to conscious sedation protocols. T1W images have short TR and TE (TR of the order of under
MRI examination poses almost no risk to the average patient 500-600 ms, while the TE is around 15-20 ms) whereas T2W
when appropriate safety guidelines are followed. sequences have longer TR and TE (TR of the order of more than
1,000 ms, TE over 80-100 ms). Inversion time (TI) is in the range
BASIC CONCEPTS IN MR INTERPRETATION of 100-180 ms in STIR and 1,800-2,500 ms in FLAIR images.
As mentioned previously, various sequences are used to obtain
image contrast. Most pathologies appear dark on T1 and bright CLINICAL APPLICATIONS
on T2 and FLAIR (or STIR) images. Neurological Disease
T1- and T2-Weighted Imaging Brain MR is the most commonly performed MR examination
in most institutions. Common indications include – multiple
The selection of TE and TR determines the resulting image
sclerosis, primary tumour assessment and/or metastasis
contrast. T1- and T2-weighted imaging are the most widely used
(Figures 4A to D), infections tuberculosis, toxoplasmosis,
sequences for soft-tissue delineation of anatomic structures and
HIV)(Figures 5A to D), infarction (cerebral vascular accident vs.
related pathologic conditions. On T1W images, tissues that have
transient ischemic attack), haemorrhage, visual disturbances,
short T1 relaxation times (such as fat) appear as bright signal
epilepsy, trauma and unexplained neurological symptoms or
(Table 1). Tissues with long T1 relaxation times (such as cysts,
deficit. Typically, most pathology appear hyperintense on T2W
cerebrospinal fluid and oedema) show as dark signal. On T2W
and hypointense on T1W images, but depending on the lesion
images, tissues that have long T2 relaxation times (such as fluids)
morphology, area of involvement (grey matter vs. white matter),
appear bright.
associated features (presence/absence of calcification,
Table 1: Signal Intensities Seen on T1- and T2-W Images haemorrhage) and enhancement patterns one can come to a
diagnosis. MR contrast agent (gadolinium) is required for
T1W T2W
assessment of tumours, infection and inflammation. Infectious
High Fat High free water (oedema, fluid, bile) process such as abscess shows intense thick nodular rim
signal Fatty marrow Proteinaceous tissue enhancement. Meninges enhance in infections (tuberculosis,
Methaemoglobin Blood products (oxyhaemoglobin pyogenic or viral meningitis) and leptomeningeal tumour spread.
Slow flowing blood and extracellular methaemoglobin) Contrast enhanced MR can also ascertain the age of the infarct.
Radiation change
Paramagnetic MRI with diffusion (DWI) and perfusion imaging (PWI) has an
contrast agents important established role in identification of hyperacute infarct
Proteinaceous fluid and ischaemia. An acute infarct shows on DWI as an area of
Melanin relatively high signal (Figures 6A to C). DWI is the most sensitive
Low Collagenous tissue Collagenous tissue (ligament, imaging test available for the diagnosis of hyperacute infarction.
signal (ligament, tendons) tendons) Perfusion weighted imaging can also be used to calculate the
High free water Cortical bone relative blood supply of the particular volume of the brain. By
(oedema, fluid, bile) Bone islands combining PWI and DWI methods, if PWI is larger than DWI, then
cortical bone, De-oxyhaemoglobin the area depicted may represent ‘at risk’ or penumbral tissue.
Infection Haemosiderin Evaluation of these tissue characteristics is important for the
Tumours Calcification targeting of therapeutic measures to optimise clinical
No Air Air outcomes. Thus, MR can accurately diagnose hyperacute infarct
signal Fast flowing blood Fast flowing blood and identify ischaemic penumbra.
Tendons Tendons
Cortical bone Cortical bone Owing to the relatively poor visualisation of acute haemorrhage,
Scar tissue Scar tissue time taken for the performance of examination and logistic
Calcification Calcification problem with monitoring equipment, MR has not been
94 recommended for the initial screening of acute head trauma. It
 MRI in Medicine
Figures 4A to D: Vertebral metastasis in a 68-year-old female. Sagittal T1W (A), T2W (B) MR images showing altered spinal signal intensity (hyperintense on T2W
and hypointense on T1W) involving the bodies of multiple vertebrae. Axial T1W (C and D) MR images showing involvement of the both anterior and posterior
elements of the vertebrae associated with soft tissue component extending into the spinal canal causing cord compression. Posterior vertebral margins of the
involved vertebrae are showing convex borders (arrow).

is most useful in non-acute situation of otherwise stable patient musculoskeletal neoplasms, the role of MR is to demonstrate
with an ongoing neurological/ cognitive deficit. In particular, the extent of the lesion prior to surgery rather than primary
MRI is highly sensitive for detection of diffuse axonal injury. characterisation for which plain radiographs are the investigation
of choice. MR evaluates compartmental involvement (e.g.
MRA may be used to image cerebral vessels (vascular stenosis,
extension of bone tumours into soft tissues and joints), skip lesions
aneurysms and vascular malformations). Sensitivity is similar
within the bone marrow and status of neurovascular bundle. Role
to catheter angiography for detection of aneurysm of 3 mm or
of intravenous contrast in musculoskeletal system is in evaluation
greater. MRA produces three dimensional images that can
of infection (bone, joint or soft tissues) (Figures 7A and B) and
be rotated, manipulated on a working station, allowing a highly
evaluation of post-operative spine to differentiate between scar
dedicated examination. MRA may also be useful in certain
tissue from non-enhancing residual disc.
clinical presentation with a high probability of cerebral aneurysm.
A common example is isolated third nerve palsy caused by Advanced musculoskeletal MR applications include MR
aneurysm of posterior cerebral artery. MRA has largely replaced arthrography. In MR arthrography joint cavity is distended by
conventional arteriographic studies for evaluation of intra-articular injection of dilute gadolinium. It is extremely
atherosclerotic disease, except in cases of critical stenosis (>70%). useful in demonstrating the glenoid and labral tears (shoulder
and hip) and in evaluation of the post-operative meniscus.
Musculoskeletal Applications
Applications in the musculoskeletal system include evaluation Hepatobiliary Applications
of internal derangement of joints (knee/hip/shoulder), soft MRCP uses heavily T2 weighted sequences such as HASTE (half
tissue injury/inflammation, ligaments and tendons, bone marrow Fourier acquisition with single shot turbo spin echo) or RARE
for marrow infiltration, bone infarcts or contusions. In (rapid acquisition with relaxation enhancement) to visualise 95
 Figures 5A to D: Tubercular spondylodiskitis lumbar spine in a 44-year-old male. Sagittal (A) and Axial T2W (B) image shows hyperintensity and irregularity
involving the end plate of two contiguous vertebras, intervening disc with small epidural component. Axial (C) and sagittal (D) post-contrast images demonstrates
intense enhancement of two contiguous vertebrae, intervening disc and extradural soft tissue. Also note presence of prevertebral abscess.

Figures 6A to C: Acute infarct in a 60-year-old male. Axial T2W (A) image shows hyperintensity seen involving the left parietotemporal lobes (MCA territory), with
mild mass effect. Diffusion weighted (B) image shows hyperintensity and ADC maps (C) show hypointensity in the corresponding area suggestive of restricted
diffusion (cytotoxic oedema).

static fluid in the biliary and pancreatic ducts as high signal bile duct diseases, post-surgical anatomic alterations, and
intensity. The heavy T2 weighting provides very high (bright) congenital anomalies of the biliary and pancreatic tract. A
signal of static fluid within the biliary and pancreatic ductal potential use of MRCP is the demonstration of aberrant bile duct
systems, while the background tissues have very low (dark) signal anatomy before cholecystectomy. MRCP is increasingly
(Figures 8A and B).These images look analogous to endoscopic becoming the initial imaging modality for the biliary system,
retrograde cholangiopancreatography (ERCP) images. with ERCP reserved for only therapeutic indications. MRCP can
MRCP is now the primary tool in the evaluation of biliary be combined with other sequences for the comprehensive
96 obstruction (calculi, intrinsic and extrinsic masses), intrahepatic evaluation of the liver, biliary tree and pancreas. In
 MRI in Medicine
Figures 7A and B: Tubercular arthritis left sacroiliac joint in a 26-year-old female. Axial T2W (A) image shows hyperintensity involving the left sacral ala and the iliac
bone, with joint widening and irregularities. Post-contrast (B) T1W image shows intense homogenous enhancement. Findings suggestive of infective sacroillitis.

Figures 8A and B: Chronic pancreatitis in a 37-year-old female. Axial T2W (A) and MRCP projectional (B) images show dilation of the main pancreatic duct (arrowhead)
and side branches with a pseudocyst (arrow in B) involving the tail of the pancreas. These findings are suggestive of chronic pancreatitis.

choledocholithiasis/cholelithiasis, calculi appear as dark

filling defects within the high-signal-intensity fluid. Benign
strictures due to sclerosing cholangitis are multifocal and
alternate with slight dilatation or normal-calibre bile ducts,
producing a beaded appearance, whereas in malignant
obstruction there is abrupt cut-off and eccentric wall thickening.
The current limitation of MRCP is its relatively low spatial
resolution.
Multiphasic contrast enhanced MR is the investigation of choice
for characterisation of focal liver lesions and to look for presence
of focal lesion in cirrhotic liver. In cirrhotic livers, MR can be
helpful in differentiating between regenerative, dysplastic
nodules and hepatocellular carcinoma. Hepatocellular
carcinoma enhances in the arterial phase, washes out in the
portal venous phase and shows capsular enhancement in
delayed phase. On the other hand peripheral nodular
Figures 9A to D: Liver haemangioma in a 43-year-old female. Axial T2W (A),
discontinuous enhancement of a lesion with delayed fill in is
post-contrast arterial phase (B), venous phase (C) and delayed phase (D) images
typical of haemangiomas (Figures 9A to D). Peripheral arterial show a well-defined mass lesion involving the right lobe of the liver. Mass is
phase enhancement and portal venous phase wash out is hyperintense on T2W images. Arterial phase image shows nodular
typical of metastases. MRI is considered a non-invasive discontinuous peripheral enhancement similar to signal intensity of the aorta.
Venous and delayed phases show progressive fill on the contrast in the lesion.
diagnostic tool for quantification of iron concentration in
haemochromatosis. Liver specific contrast agents (contrast
Findings are suggestive of liver haemangioma. 97
 agents specific to the hepatobiliary or the reticuloendothelial poor spatial resolution due to extremely low proton density of
system) add to the diagnostic capabilities of MR in problem normal lung and strong susceptibility artefacts induced by the
cases. multiple air—soft tissue interfaces within the lung, and the
consequences of cardiac and respiratory movement. The main
Gastrointestinal Applications
indications for chest MRI include characterisation of mediastinal
MRI of the bowel has been an under explored field of application lesions that are equivocal on CT, evaluation of superior sulcus
for years. High soft tissue contrast resolution, acquisition of tumours, particularly if brachial plexus involvement is suspected
multiplanar images and the possibility to obtain functional and posterior mediastinal masses.
information make MR a useful imaging technique to evaluate
small bowel pathology. Applications include MR enteroclysis, Cardiovascular Applications
MR colonography and MR virtual colonoscopy. The absence Technical advances in MRI have led to increased application of
of ionising radiation is an important advantage of MRI this modality for comprehensive evaluation of cardiovascular
examinations because inflammatory diseases such as Crohn’s diseases. Gradually, MRI has become the ‘gold standard’ for the
disease (CD) need to be followed up frequently, and are assessment of numerous cardiovascular conditions. Important
prevalent among young adults. MR enteroclysis (MRE) and MR clinical indications of cardiac MRI include heart failure, ischaemic
colonography are emerging techniques for the evaluation heart disease, myocardial viability, cardiac masses, congenital
(Figures 10A to C) of small and large intestinal diseases. heart disease, and diseases of the myocardium, pericardium,
valves and the entire vascular tree. Cardiac MR for ischaemic heart
disease shows higher spatial resolution and sensitivity compared
to stress thallium, particularly for subendocardial infarcts.
Disadvantages include: longer scanning time, need for general
anaesthesia, various contraindications including pacemaker.
Urological Applications
MRI is used as a problem-solving tool in renal imaging, to
characterise indeterminate masses on ultrasound and
computed tomography. MRI is an alternative to CT and is
particularly useful in paediatric or pregnant patients, and in
patients with renal insufficiency and when ionising radiation/
iodinated contrast is to be avoided. MR urography (MRU) is
clinically useful in the evaluation of suspected urinary tract
obstruction, haematuria, and congenital anomalies.
Pelvic Applications
Figures 10A to C: MR Enteroclysis demonstrating tubercular small bowel These include gynaecological conditions like pelvic pain or
stricture in a 20-year-old male. Tru-FISP (true fast imaging with steady-state pelvic mass, especially to differentiate between uterine and
precession) axial (A and B) and coronal (C) images show circumferential short adnexal masses, indeterminate adnexal masses on ultrasound,
segment wall thickening involving distal illeal loops.
detection of adenomyosis (blurring and thickening of
the junctional zone of uterus on T2 weighted images),
Chest Applications differentiation between uterine fibroids and focal adenomyosis
A
MRI does not substitute CT in the investigation of most thoracic (fibroids appear well defined and hypointense on T2 weighted
conditions requiring cross-sectional imaging. MRI in chest has images while focal adenomyosis/adenomyomas appear poorly

Figures 11A and B: Endometriosis in a 24-year-old female. Axial T1W (A) and T2W (B) images show left adenaxal mass lesion. Mass is hyperintense on T1W images and
shows mixed intensity (hyperintense upper part and hypointense lower part). These findings are suggestive of endometriosis.
98
 MRI in Medicine
A B
Figures 12A and B: Foetal MR showing corpus callosal agenesis with dorsal
interhemispheric cyst at 30 weeks gestation. T2W MR axial (A) and sagittal (B)
images show dorsal interhemispheric cyst with absence of corpus callosum
and dilatation of occipital horn (colpocephaly).

defined and may show intermediate to hyperintense speckling

on T2 weighted images). While both endometriosis and
dermoids might appear hyperintense (bright) on T1 and
T2 weighted images, endometriosis is identified on T1 fat-
saturated images as hyperintense due to haemorrhagic
contents (Figures 11A and B), while fat in dermoids is
suppressed. Another important application is the staging of
carcinoma cervix and endometrium.
An important application of MR in the male pelvis includes the
early detection of prostatic carcinoma using endorectal coils.
Unlike other malignancies, prostatic carcinoma appears
hypointense (dark) on T2 weighted images amidst the
Figures 13A and B: Takayasu’s arteritis in a 16-year-old female. Maximum
hyperintense peripheral zone. Early peri-prostatic spread, intensity projections of post-contrast MR angiogram (A) and invert image of A
neurovascular invasion or seminal vesicle invasion is well (B) demonstrates the narrowing of the proximal left subclavian artery, infrarenal
detected on MR. aorta, bilateral common iliac arteries and left renal artery.

Obstetric applications of MR include early detection of foetal

WB-MRI (Whole-Body MRI)
anomalies, especially when there is difficulty in sonographic
visualisation due to unusual lie of the foetus, complex Technical improvements in the MR sequences, the remote
congenital malformation or insufficient amniotic fluid. Foetal movement of the imaging table, and the use of specialised
MR is especially beneficial in evaluation of the sonographically surface coils have rendered whole-body screening with MRI a
occult or indeterminate and complex congenital malformations feasible method. Whole-body magnetic resonance imaging
(Figures 12A and B). Foetal MR has an established role in the is an accurate, safe and fast technique for the demonstration
evaluation of neurological and chest anomalies. of disease throughout the entire body. Whole-body MRI is
used to depict metastases in disseminated metastasis and
RECENT ADVANCES lymphoma. Whole-body MR angiography can be very helpful
MR at 3 Tesla for detecting vascular diseases (atherosclerosis, vasculitis) in
different anatomic regions of the body (Figures 13A and B).
Imaging at higher field strength (3.0-T MR) provides higher
resolution and has already proved superior to 1.5-T systems in RECOMMENDED READINGS
neuroradiologic and musculoskeletal applications. In the 1. Adam A, Allison D. Grainger and Allison’s diagnostic radiology. 5th Ed.
abdomen, 3.0-T MR imaging is beneficial for hepatic imaging, Churchill Livingstone, 2007.
MRCP, angiography, diffusion-weighted imaging, and 2. Sutton D. Textbook of Radiology and Imaging. 7th Ed. Churchill Livingstone,
colonography. 2008.

99
 3.5 Nuclear Imaging

BR Mittal

Nuclear Medicine is a field of medical practice where minute Edwards in 1963, but it was X-ray tomography introduced
quantities of unsealed radioactive substances, which rely on in 1973 by Hounsfield that had a tremendous impact in
the process of radioactive decay, are used for diagnosis, therapy diagnostic imaging. Practical application of SPECT came into
and clinical research. These procedures provide supportive existence only after the advent of the modern computers and
service to almost all branches of medicine. This unique ability availability of rotating gamma camera system. The most
of imaging and therapy is based on the cellular function and apparent advantage of SPECT is its ability to remove the
physiology rather than relying on the anatomy. Most diagnostic superimposition encountered in two-dimensional (planar)
radionuclides emit gamma rays while radionuclides emitting imaging leading to increased detection of lesions. The end
beta particles are used in therapeutic applications. result of the nuclear medicine imaging process is a “dataset”
Radionuclides for use in nuclear medicine are produced either comprising one or more images. Multi-image datasets may be
in nuclear reactors or in cyclotrons. The reactor produced dynamic, representing a time sequence (cine or movie), a cardiac
radionuclides usually have longer half-lives, whereas those gated time sequence, or a spatial sequence where the gamma
produced in cyclotrons have shorter half-lives. Radioisotopes camera is moved relative to the patient. The computer provides
are also generated by natural decay processes in dedicated quantitative information for each of the specific imaging
generators, e.g. molybdenum/technetium or strontium/ techniques.
rubidium. Radionuclides when combined with other chemical
Nuclear medicine images can be superimposed, using
compounds form radiopharmaceuticals which on being
software or hybrid cameras, on images from other modalities
administered to the patient, localise to specific organs or cellular
such as computed tomography (CT) or magnetic resonance
receptors. These radiopharmaceuticals emit gamma rays that
imaging (MRI) to highlight the part of the body in which the
are detected externally by sophisticated instruments such as
radiopharmaceutical is concentrated. This is called image fusion
gamma camera or PET scanners.This process is unlike diagnostic
or co-registration. Presently single photon emission computed
radiographs where external radiation is passed through the
tomography/computed tomography (SPECT/CT) and positron
body to form an image.
emission tomography/computed tomography (PET/CT)
Gamma camera is the basic equipment in nuclear medicine equipments are available as single units that are able to perform
imaging. The uses of computers in conjunction with cameras both imaging studies simultaneously. The fusion imaging
provide data and information about the area of body being technique allows information from two different studies to be
imaged. Planar studies provide a two-dimensional image correlated and interpreted on one image, leading to more
whereas tomography provides three dimensional view of precise information and accurate diagnosis. Nuclear medicine
physiological and biochemical processes. Tomography is the imaging procedures often identify abnormalities very early in
process of producing a picture of a section through an object. the course of a disease, long before some medical problems
It is performed either by transmitting X-rays through an object are apparent with other diagnostic tests. This early detection
(transmission computed tomography, as in CT scanning), by allows a disease to be treated early in its course when there
measuring proton density (magnetic resonance imaging) or by may be a more successful outcome.
tomographically detecting the distribution of radioactivity
Non-imaging procedures such as thyroid uptake tests,
in a patient (emission computed tomography). The two most
Glomerular filtration rate (GFR) estimations and haematological
widely used emission tomographic studies are Single Photon
tests also form part of nuclear medicine. Some of the non-
Emission Computed Tomography (SPECT ) and Positron
imaging functional studies like clearance studies, dilution
Emission Tomography (PET). The three major categories of
techniques are other forms of in vivo diagnostic methods.
emission imaging are projection, longitudinal and transverse
section imaging. Longitudinal tomography involves sampling Radioimmunoassay constitutes its in vitro application.
over a limited range of angles and usually involves motion of a Radioimmunoassay and radioimmunometric assay were
detector system parallel to long axis of the body. Transverse the first methods based on saturation analysis/competitive
section tomography involves rotation of the detector system limited reagent/radiolabelled analyte to measure picomolar
around the body with slices oriented perpendicular to the concentrations of biomolecules which otherwise is beyond
patient’s long axis. The transaxial data is then rearranged to get the reach of conventional chemistry. This laid the foundation
coronal, sagittal (slice parallel to the patient’s long axis) or of modern endocrinology. These assays are also used to
oblique algorithms. measure levels of hormones, vitamins and drugs in a patient’s
blood.
SPECT refers to tomography with standard nuclear medicine
radiopharmaceuticals that emit single photons upon decay. Beyond diagnosis, nuclear medicine also offers therapeutic
Though emission tomography was reported by Kuhl and applications. However, such applications are limited to a few
100
 MRI in Medicine
diseases like thyrotoxicosis, thyroid cancer, metastatic bone Table 1: The Commonly Used Intravenous Radionuclides in
pain, neuroendocrine tumours, rheumatoid arthritis and Nuclear Medicine
radio-immunotherapy for some cancers, etc.
Radionuclide Symbol Half-life Type of Energy
HISTORY (T½) Emission (Kev)
(Photon)
The origin of nuclear medicine stems from many scientific
Technetium-99m Tc99m 6.01 hours IT 140
discoveries, most notably the discovery of “X-rays” in 1895 123
Iodine-123 I 13.2 hours EC 159
and the discovery of radioactivity in 1896 and “artificial
radioactivity” in 1934. The first clinical use of artificial Chromium-51 51
Cr 27.7 days γ 320
radioactivity was carried out in 1937 for the treatment of a Indium-111 111
In 2.8 days EC, γ 171
245
patient with leukaemia at the University of California at 201
Thallium-201 Tl 73 hours EC 69-83*
Berkeley. The most fundamental principle of Nuclear Medicine
135
is the tracer principle, invented by George Hevesy for which 167
he received the Nobel Prize in 1944. Nuclear medicine gained Gallium-67 67
Ga 3.26 days EC, γ 93
recognition as a medical specialty in 1946 when a thyroid 185
cancer patient’s treatment with radioactive iodine caused 300
complete disappearance of the spread of the patient’s cancer. Fluorine-18 18
F 110 min β+ 511
Although, the earliest use of Iodine-131 was devoted to Rubidium-82 82
Rb 75 sec β+ 511
therapy of thyroid cancer, its use was later expanded to include
IT = Isomeric transition; EC = Electron capture; γ = Gamma; β+ = Positron decay;
imaging of the thyroid gland, quantification of the thyroid *Mercury X-rays.
function, and therapy for hyperthyroidism. Development of
rectilinear scanner by Benedict Cassen and scintillation Table 2: The Commonly Used Gaseous/Aerosol Radionuclides
camera (Anger camera) by Hal O. Anger broadened the in Nuclear Medicine
discipline of nuclear medicine into a full-fledged medical
Radionuclide Symbol Half-life Type of Energy
imaging specialty.
(T½) Emission (Kev)
Among many radionuclides that were discovered for (Photon)
medical use, none were as important as the discovery and Xenon-133 133
Xe 5.24 days γ and β– 81
development of technetium-99m. The development of 346 β–
generator system to produce Technetium-99m in the 1960s Krypton-81m 81m
Kr 13 sec IT 190
became a practical method for medical use. Today, Technetium-99m Tc99m 6.01 hours IT 140
Technetium-99m is the most utilised element in nuclear DTPA aerosols
medicine and is employed in a wide variety of nuclear Technetium 99m Tc99m 6.01 hours IT 140
medicine imaging studies. By the 1970s most organs of Technegas
the body could be visualised using nuclear medicine γ = Gamma; β– = Negative decay; IT = Isomeric transition.
procedures. The concept of emission and transmission
tomography, later developed into single photon emission CLINICAL APPLICATIONS OF DIAGNOSTIC
computed tomography (SPECT), was introduced by David E. NUCLEAR MEDICINE
Kuhl and Roy Edwards in the late 1950s. More recent
Nuclear Medicine scans may be used to diagnose a number of
developments in nuclear nedicine include the invention of
medical problems. Some of the more frequently performed tests
the PET scanner. Fusion imaging with SPECT and CT was
are highlighted below. This is not meant to be exhaustive, and
developed by Bruce Hasegawa from University of California
for a more detailed account the reader may refer to the standard
San Francisco (UCSF), and the first PET/CT prototype by D.W.
nuclear medicine text books, journals and periodicals. Positron
Townsend from University of Pittsburg in 1998.
Emission Tomography is discussed in a separate chapter of this
DIAGNOSTIC NUCLEAR MEDICINE IMAGING section.
A nuclear medicine study involves administration of a Endocrine Applications
radionuclide into the body by intravenous injection, ingestion Thyroid
while combined with food, inhalation as a gas or aerosol
Thyroid scintigraphy generates one or more images of the
(Tables 1 and 2). In some studies patient’s own blood cells
thyroid obtained after injection/ingestion of the tracer.
are labelled with a radionuclide (leucocyte and red blood cell
Common indications are:
scintigraphy). Following administration, the radiotracer is
distributed around the body and/or processed differently (a) Localisation of ectopic thyroid tissue (i.e. lingual) or to
where disease or pathology is present. Focal increase in determine whether a suspected thyroglossal duct cyst is
radiotracer accumulation results in a ‘hot-spot’ which the only functioning thyroid tissue present.
represents increased physiological function. In some disease (b) To evaluate a neck or substernal mass. Radionuclide
processes a ‘cold-spot’ may be visualised which represents non- scintigraphy may be helpful to confirm if the mass is
concentration of radiotracer. functioning thyroid tissue.

101
 (c) To assist in evaluation of congenital hypothyroidism.
(d) Differentiation of thyroiditis (i.e. subacute or silent) and
factitious hyperthyroidism from Graves’ disease and other
forms of hyperthyroidism.
(e) Functional evaluation of thyroid nodules and masses
(Figure 1 shows a case of cold nodule of right lobe of
thyroid gland).
(f) Distinguishing Graves’ disease from toxic nodular goiter,
a distinction of significance in determining the amount
of Iodine-131 to be given as therapy for hyperthyroidism.
(Figures 2 and 3).
(g) Post-operative assessment of differentiated thyroid cancer.
(h) Radioactive iodine uptake (RAIU) for calculating Iodine-131
therapy dose for treating hyperthyroidism.
(i) Perchlorate discharge test for identification of organification Figures 2A and B: 99m Technetium thyroid scintigraphy showing (A) enlarged
defects. thyroid gland with increased tracer uptake (B) technetium uptake calculated
by drawing ROIs showed 10% uptake (Increased) suggesting hyperthyroidism.
(j) Radioimmunoassay/radioimmunometric assay for
measurement of free and total T3, T4 and TSH.
Commonly used radiotracers for thyroid imaging are Tc99m
(pertechnetate), Iodine-123 and Iodine-131.
Thyroid evaluation is one of the most frequently performed
nuclear medicine procedure. Thyroid scintigraphy plays an
extremely important role in the classification of thyroid
pathology. The radiation dose to the thyroid is meagre with
Technetium-99m, but may be significant with Iodine-131. Hence,
lower doses of Iodine-131are utilised and imaging is not ideal
when this radioisotope is used.

Figure 3: 99mTechnetium thyroid scintigraphy showing tracer uptake in a nodule

in the right lobe of thyroid gland. Rest of the thyroid gland doesn’t show tracer
uptake. Findings are consistent with autonomously functioning toxic adenoma.

Parathyroid scintigraphy
(a) Localisation of hyperfunctioning parathyroid tissue
(adenomas) in primary hyperparathyroidism and in patients
with persistent or recurrent disease.
(b) Gamma probe guided surgery.
Thallium-201 or Tc99m-sestamibi are the tracers employed for
parathyroid imaging.
Over 90% of the primary hyperparathyroidism is caused by a
single parathyroid adenoma. Most of the parathyroid adenomas
are identified by scintigraphy (Figure 4) and hence allows
limited surgical approach rather than bilateral neck exploration,
reducing the morbidity and hospital stay of these patients.
Figure 1: 99mTechnetium thyroid scintigraphy showing a non-functional (Cold) Gamma probe guided surgery combined with intra-operative
nodule in the right lobe of thyroid gland. Rest of the thyroid gland shows PTH assay has the potential for reduced hospital stay and patient
homogenous tracer uptake.
102 morbidity. Parathyroid scintigraphy has lower specificity in the
 MRI in Medicine
Figure 4: Dual phase Tc99m sestamibi parathyroid scintigraphy shows focal tracer uptake in the region of the right lobe of thyroid. Tracer retention is noted in the
lesion at 1 hour. The findings are consistent with large right inferior parathyroid adenoma.

presence of thyroid adenomas. However, the use of subtraction Genitourinary Applications

scintigraphy allows reasonable differentiation of thyroid from Dynamic renal scintigraphy provides information about the
parathyroid adenomas. blood flow to the kidneys, parenchymal function and drainage
Ultrasonography has high specificity in the diagnosis of from the collecting system. Static cortical scintigraphy is useful
parathyroid adenomas but has insufficient sensitivity and inter- in evaluation of relative kidney function and morphological
observer variability. CT and MRI are also used in the evaluation abnormalities. Common indications of renal scintigraphy are:
of parathyroid disorders. (a) Diuretic renography for detecting urinary tract obstruction
(ureteropelvic or vesicourethral).
Adrenal medulla (b) Captopril renography to diagnose and prognosticate
The important tumours of the adrenal medulla are renovascular hypertension.
Pheochromocytoma and Neuroblastoma. (c) Evaluation of kidneys in prenatal Ultrasonography (USG)
The nuclear scan is usually performed with Iodine-123/Iodine- diagnosis of hydronephrosis.
131 labelled Metaiodobenzylguanidine (MIBG). Tc99m (d) Renal transplant evaluation.
HYNICTOC is also used for this. (e) Measure differential renal function in renal insufficiency.
Iodine-131 MIBG has a specificity of >95% in detection of (f ) Renal cortical scintigraphy for detecting pyelonephritis and
functioning neuro-endocrine tissue (Figure 5) and is mandatory cortical scars (Figure 6 shows cortical scars).
before considering radionuclide therapy with high dose Iodine- (g) Localisation of ectopic kidney and evaluation of anatomical
131 MIBG. However, sensitivity is lower because of the limited abnomalities.
spatial resolution and poor imaging characteristics of Iodine- (h) Radionuclide cystourethrography for vesico-ureteric reflux,
131. MRI is an excellent modality for the evaluation of adrenal (Figure 7 shows a case of right VUR).
medullary disorders but is incapable of providing the functional
(i) Measurement of GFR/effective renal plasma flow (ERPF).
status of the lesion. Further, whole body evaluation is possible
with scintigraphy. (j) Detect testicular torsion vs. epididymo-orchitis.
For most purposes the radiotracer used is Tc99m-DTPA or
Adrenal cortex
Tc99m-MAG3 or Tc99m- EC. For anatomical visualisation, the
Scintigraphy is useful in the evaluation of Cushing’s syndrome preferred radiotracer is Tc99m-DMSA though sometimes
and Conn’s syndrome. Tc99m-GHA may also be used if DMSA is not available.
Commonly used radiotracer for this is iodine-131 iodocho lestrol/ Renal scintigraphy has the advantages of providing functional
NP-59.With the advent of high resolution cross-sectional imaging parameters like cortical function and GFR. It plays an extremely
like CT and MRI, the role of nuclear medicine in the evaluation of important role in the follow-up of patients. The radiation dose
adrenal cortical pathologies has diminished. PET has an extremely delivered by renal scintigraphy is often lower than radiographic
important role in the evaluation of adrenal masses and has been procedure like micturating cysto-urethrogram (MCUG) and
shown to exceed CT/MRI in both sensitivity and specificity in intravenous pyelograms (IVP). Renal scintigraphy is also less
evaluation of adrenal masses in known/ suspected malignancies. traumatic to the patients.
103
 (a) Neoplastic disease: demonstration of skeletal metastasis from
various solid malignancies like breast, prostate (Figure 8
shows a typical case of widespread skeletal metastases).
(b) Early diagnosis of osteomyelitis (Figure 9).
(c) Evaluation of diabetic foot for osteomyelitis vs. Charcot’s
joint.
(d) Evaluation of prosthetic implant for infection or sterile
inflammation.
(e) Detection of bone graft viability.
(f ) Evaluation of metabolic bone diseases.
(g) Identify occult bone trauma (sports injuries like stress
fractures, occult fracture, shin splint).
(h) Diagnosing avascular necrosis of the femoral head.
(i) Evaluate arthritic changes and extent.
(j) Evaluation of chronic regional pain syndrome (CRPS) (Reflex
sympathetic dystrophy).
(k) Measure extent of certain tumours and localise sites for
biopsy in tumour patients.
(l) Evaluation of otherwise unexplained bone pain, especially
low backache.
(m) Identify bone infarcts such as in sickle cell disease.
(n) Distribution of osteoblastic activity before radionuclide
therapy for bone pain.
The commonly used radiotracer for bone scan is Tc99m-MDP.
Skeletal scintigraphy is extremely sensitive but lacks specificity.
With the advent of hybrid scanners, the information obtained
from CT is used to increase the specificity of bone scintigraphy.
To increase the specificity of bone scintigraphy, a second
imaging agent may be used e.g.; positive bone scan patient, in
a case of suspected prosthetic infection, may be subjected to
labelled WBC scan.
Cardiac Applications
Myocardial perfusion imaging (MPI), multigated radionuclide
Figure 5: Whole-body 131I MIBG scintigraphy obtained 48 hours after ventriculography (MUGA), first pass study are the common
administration of MIBG showing a focus of tracer uptake in the right procedures.
hypochondrium suggesting a functional neuro-endocrine tumour. The patient
had right adrenal pheochromocytoma. Myocardial perfusion imaging: MPI identifies areas of reduced
myocardial blood flow associated with ischaemia or scar. The
Ultrasonography is an inexpensive initial modality for relative regional distribution of perfusion can be assessed at
evaluation of the genito-urinary system. However, operator cardiac stress, rest or both. Imaging can also be performed
dependence and inability to differentiate dilated unobstructed during acute events such as in the coronary care unit or
systems from obstructed systems mandate further evaluation emergency department. Common indications include:
with scintigraphy. IVP requires bowel preparation and contrast
(a) Diagnosis of physiologically significant coronary artery
administration and doesn’t provide quantitative functional
disease (presence and severity). (Figure 10 shows a case of
parameters as scintigraphy.
ischaemia in the inferolateral wall).
Skeletal System Applications (b) Determine prognosis (risk stratification based on extent and
Bone scintigraphy evaluates the distribution of active bone severity of myocardial perfusion abnormalities and left
formation in the body. Whole-body bone scintigraphy produces ventricular function.
anterior and posterior planar images of the skeleton, both axial (c) Differentiate between coronary and non-coronary causes
and appendicular. Multiphase bone scintigraphy usually in patients with acute chest pain syndromes seen in the
includes blood flow images of the area of region of interest, emergency room.
immediate blood pool static planar images, and delayed images
at 3-4 hours. Delayed images may be limited to the areas of (d) Cardiac risk assessment for patients undergoing major non
interest or may include the whole body (planar or tomographic). cardiac surgery.
Common indications are: (e) Differentiate ischaemic from idiopathic cardiomyopathy.
104
 MRI in Medicine

Figure 6: Tc99m DMSA static planar (arterior and posterior) and pinhole images of the kidneys showing smaller right kidney with break in cortical outline in the
upper pole of right kidney suggestive of presence of a cortical scar.

(f) Assessment of viable myocardium overlying the infarction Multigated equilibrium radionuclide ventriculography: MUGA
to consider revascularisation. is a procedure where patient’s red blood cells (RBCs) are
(g) Evaluate the immediate and long-term effects of radiolabelled and ECG gated cardiac scintigraphy is obtained.
revascularisation procedures and medical or drug Parameters obtained from MUGA include (i) global ventricular
therapy. ejection fraction, (ii) systolic and diastolic function indices, (iii)
regional wall motion, (iv) ventricular volumes, (v) stroke volume
Myocardial perfusion imaging is a gate-keeper to invasive ratios. Common indications are:
coronary angiography. With the advent of CT coronary (a) Evaluation of known or suspected coronary artery disease.
angiography, there is an increase in the number of equivocal
coronary lesion whose physiological significance needs to be (b) Distinguishing systolic from diastolic causes of congestive
evaluated with MPI. MPI, apart from providing information heart failure (CHF) in patients with known or suspected CHF.
about the perfusion status, also provide various functional (c) Measure cardiac toxicity in patients undergoing chemotherapy.
parameters like ventricular ejection fraction, systolic and (d) Assessment of ventricular function in patients with valvular
diastolic volumes, myocardial mass and prognostic heart disease.
information. A normal stress MPI has less than 1% risk of (e) Monitoring response to surgery or other therapeutic 105
contracting any major cardiac event. interventions.
 Figure 7: Direct radionuclide cystography (DRCG) study showing left vesico-ureteric reflux. Tracer activity in the urinary bladder is noted refluxing into the left
ureter and renal pelvis during the voiding phase of the study.

First pass studies help to identify and quantify shunts and aerosol within the lungs. Pulmonary lung scintigraphy for
evaluation of right heart failure. pulmonary embolism assesses pulmonary perfusion and
often includes ventilation scintigraphy. The most common
Thallium-201, Tc99m-sestamibi, Tc99m tetrofosmin are the
indications are:
radiotracers for myocardial perfusion imaging. MUGA study is
performed with labelled erythrocytes. First pass study to (a) Determination of the likelihood of pulmonary embolism.
evaluate right heart function or shunts can be performed with (b) Quantify lung ventilation and perfusion as preoperative
any Tc99m labelled tracer. evaluation.
MUGA study is the current gold standard for the evaluation of (c) Evaluation of lung transplantation.
LV ejection fraction and is proving indispensable in the (d) Right-to-left shunt evaluation.
evaluation of patients undergoing cardio-toxic chemotherapy. (e) Detect pulmonary complications of AIDS.
Pulmonary Applications (f ) Detect inhalation injury in burn patients.
Perfusion scintigraphy measures the distribution of pulmonary Lung perfusion scan is performed with Tc99m-microspheres
arterial blood flow. Ventilation scintigraphy records the of albumin while ventilation scan is performed either with
106 bronchopulmonary distribution of an inhaled radioactive Xenon 133 or with Tc99m-DTPA aerosols/technegas.
 MRI in Medicine
(a) Evaluation of suspected acute cholecystitis.
(b) Evaluation of suspected chronic biliary tract disorders.
(c) Determine causes of jaundice and identify obstruction in
the biliary passage.
(d) Detection of bile extravasation.
(e) Evaluation of congenital abnormalities of the biliary tree.
(f ) Liver and gallbladder scans to evaluate liver and gallbladder
function.
(g) Liver (reticulo endothelial cells) scans for cirrhosis, non-
cirrhotic portal fibrosis (NCPF), tumours, space occupying
lesions, etc.
Scintigraphy suffers from limited anatomical resolution which
precludes detection of small lesion and to localise the exact sites
of biliary leaks. Some of the studies require many hours to complete.
Gastrointestinal tract motility studies
Gastrointestinal tract motility studies include oesophageal
transit, gastro-oesophageal reflux studies, gastric emptying
studies, intestinal and colonic transit studies. Gastrointestinal
bleeding scans are used to identify bleeding into the bowel.
Gastric emptying and motility: Radionuclide studies of gastric
emptying and motility are the most physiologic studies available
for studying gastric motor function. The study is noninvasive,
uses a physiologic meal (solids with/without liquids), and is
quantitative. Serial testing can determine the effectiveness of
therapy. Indications for gastric emptying include:
(a) Suspected gastroparesis
(b) Poor diabetic control
(c) Gastro-oesophageal reflux
(d) Following response to therapy for previously documented
motility disturbances
Gastric emptying time is the most physiological and the current
gold standard for the evaluation of gastric emptying. However,
various parameters like the content of the food, acceptability
of food to local population, etc. create variations and each centre
Figure 8: Tc99m-Methylene diphosphonate (MDP) bone scintigraphy showing
multiple foci of increased tracer uptake involving several bones. The findings needs to standardise the procedure.
are consistent with widespread skeletal metastasis.
Meckel’s diverticulum scintigraphy and gastrointestinal
bleeding:The indication for a Meckel’s scan is to localise ectopic
Inspite of the introduction of CT pulmonary angiography, gastric mucosa in a Meckel’s diverticulum as the source of
ventilation-perfusion (V/Q) scintigraphy has continued to have unexplained gastrointestinal bleeding (Figure 12). Scintigraphy
important role. V/Q scan delivers far less radiation to the female may be false negative in active bleeding and in those without
breast than CT angiography. V/Q scan also serves as a baseline adequate gastric mucosa in the diverticulum.
for the evaluation of response to anti-coagulants (Figure 11). Gastrointestinal bleeding scintigraphy is performed in patients
Of late, the utility of V/Q scintigraphy has also been studied in suspected of active gastrointestinal bleeding using Tc99m
parenchymal lung disease and asthma. One of the drawbacks labelled red blood cells (RBCs). Sites of active bleeding are
of V/Q scan is the large number of indeterminate scans but identified by the accumulation and movement of labelled red
with the advent of V/Q SPECT, the indeterminate scans have blood cells within the bowel lumen (Figure 13).Tc99m labelled
been reduced to <1%. In summary, V/Q SPECT performs equal red blood cells scintigraphy is the most sensitive of all the
to CT pulmonary angiography with far less radiation exposure. available investigations in the evaluation of gastrointestinal
Gastrointestinal Applications bleeding. Unlike invasive angiography, scintigraphy is non-
invasive, allows follow-up of patients for 24 hours, provides
Hepatobiliary scintigraphy
prognostic information and is not associated with risks of
Hepatobiliary scintigraphy evaluates hepatocellular function contrast administration and renal injury.
and patency of the biliary system by tracing the production and
flow of bile from the liver through the biliary system into the Neurologic Applications
small intestine. Sequential images of the liver, biliary tree and Brain perfusion scintigraphy reflects regional cerebral perfusion.
gut are obtained. The common indications are: Useful in: 107
 Figure 9: Three-phase MDP bone scintigraphy images of the legs showing increased blood flow and soft tissue pooling of tracer around the lower part of left tibia.
Bone phase image acquired at 3 hours shows increased tracer uptake in the same region. The findings are suggestive of active bony infection and inflammation.

(a) Detection and evaluation of cerebrovascular disease. The commonly used radiotracer for brain perfusion imaging
(b) Evaluating post concussion syndrome. is Tc99m-HMPAO, Tc99m-ECD. Brain tumour imaging may
(c) Evaluation of patients with suspected dementia (Alzheimer’s be performed with Tc99m-sestamibi/GHA or Thallium-201.
disease, multi-infarct dementia, AIDS dementia). CSF studies are performed with Tc99m-DTPA. The utility of
scintigraphy has diminished with the advent of conventional
(d) Presurgical localisation of epileptic foci (ictal and inter-ictal
scan). high resolution imaging modalities. Functional disorders like
seizures, psychiatric illness are identified with SPECT even when
(e) Evaluation of suspected brain trauma.
morphological imaging modalities are normal.
(f) Assess brain blood flow in patients suspected of brain death.
(g) Evaluation of patients for carotid surgery. Oncologic Applications
(h) Evaluation of brain tumours (Figure 14) especially follow- (a) Bone scan to evaluate primary bone tumours and to detect
up after surgery/radiotherapy. skeletal metastases from other malignancies.
(i) Cerebrospinal fluid studies for CSF leaks, hydrocephalous, (b) Scintimammography (breast scan) to accurately detect and
shunt patency, etc. locate cancerous tissue in the breasts.
108
 MRI in Medicine

Figure 10: Myocardial perfusion scintigraphy (MPS) performed at stress and rest with Tc99m-Tetrofosmin. Matched stress and rest images [short axis (SA)], vertical
long axis (VLA), horizontal long axis (HLA) show impaired tracer uptake in anterior septum and infero-lateral wall of the left ventricular myocardium indicative of
stress induced ischaemia.

(c) Sentinel lymph node mapping to localise the lymph nodes PET/CT has overcome many limitations of routine nuclear
before surgery in patients with breast cancer or melanoma. medicine procedures like the limited spatial resolution,
(d) MIBG and Octreotide scans for neuroendocrine tumours, sensitivity and quantification.
based on cellular receptors or functions. Other Applications
(e) Radio-immunoscintigraphy: These imaging tests use (a) Infection/inflammation detection using gallium-67/labelled
monoclonal antibodies. When combined with a radioactive leucocytes/ labelled ciprofloxacin.
tracer, they are quite useful for detecting various tumours,
especially those in the ovaries, colon or prostate. (b) Venography for deep venous thrombosis (DVT).
(f) Gallium scans to evaluate certain types of tumours. Determines (c) Lymphoscintigraphy.
the presence or spread of cancer in various parts of the body. (d) Salivary scintigraphy.
(g) PET/CT scans for initial staging, therapy monitoring and (e) Dacryo-scintigraphy.
follow-up. (f) Spleen scan.

109
 Figure 11: Lung perfusion scintigraphy performed with Tc99m-MAA (macro-aggregated albumin) showing improvement in the follow-up study. Initial perfusion
study shows large perfusion defect in the right lung. Follow-up study after treatment with heparin shows restoration of perfusion to the right lung. A small wedge
shaped defect in the left lung also improved.

THERAPEUTIC NUCLEAR MEDICINE structures. Most nuclear medicine therapies can be performed
as outpatient procedures since there are few side-effects from
Radionuclides are also used for therapy of malignant and non- the treatment and the radiation exposure to the general public
malignant conditions (Table 3). With the use of suitable radio- can be kept within a safe limit. Nuclear medicine therapies include:
pharmaceuticals targeted therapy is also possible. In nuclear
(a) Radioactive Iodine (I-131) for hyperthyroidism and thyroid
medicine therapy, the radiation treatment dose is also
cancer.
administered internally (e.g. intravenous or oral routes) rather
from an external radiation source as in radiotherapy. The (b) Iodine-131 MIBG (metaiodobenzylguanidine) for neuro-
ionising radiation emitted by therapeutic radionuclides endocrine tumours.
travels only a short distance, thereby minimising unwanted (c) Palliative therapy for metastatic bone pain using
110 side-effects and damage to non-involved organs or nearby Phosphorus-32 or Samarium-153 or Strontium-89.
 MRI in Medicine
Figure 13: Tc99m labelled RBC gastrointestinal bleed scintigraphy. Multiple
static images acquired shows abnormal tracer extravasation in the right iliac
fossa. Further imaging reveals further bleeding and antegrade peristalsis into
the transverse colon and splenic flexure.

Table 3: The Most Commonly Used Radionuclides for Therapy

in Nuclear Medicine
Radionuclide Symbol Half-life Type of Beta Energy
(T½) Emission (Max) (Mev)
Phosphorus-32 32
P 14.26 days β– 1.71
Strontium-89 89
Sr 50.5 days β –
1.492
Iodine-131 131
I 8.02 days β– 0.606
Yttrium-90 90
Y 2.67 days β– 2.3
Erbium-169 169
Er 9.5 days β– 0.34
Figure 12: 99mTechnetium Meckel’s scintigraphy. Multiple static images after
intravenous tracer injection shows a focus of tracer uptake in the right iliac Rhenium-186 186
Re 3.72 days β– and γ 1.071
fossa. The focus appears alongwith the stomach and shows increasing activity 0.93
as the study progresses. The findings suggest presence of heterotopic gastric Samarium-153 153
Sm 46.7 hours β– and γ 0.809
mucosa (Meckel’s diverticulum).
0.707
0.637
(d) Phosphorus -32 for polycythemia rubera vera. Lutetium-177 177
Lu 6.65 days β– and γ 0.176
(e) Radionuclides (Yttrium-90, Erbium-169, Rhenium-186) for 0.384
various arthritis like rheumatoid, psoriatic, haemophilic, etc. 0.497
(Radiosynoviorthesis). γ = Gamma; β– = Negative decay
(f) Iodine-131/Rhenium-186 lipoidal or yttrium-90
therapy using reporter probes. They also give early indications
theraspheres intra-arterial therapy for hepatocellular
about the efficacy and or toxic effects of a treatment plan, e.g.
carcinoma.
PET that provides information about tumour response to a
(g) Lutetium-177 peptide therapy for various neuroendocrine particular chemotherapy schedule; drug resistance in a tumour
tumours. and cardiotoxicity during adriamycin therapy.
(h) Radioimmunotherapy - Yttrium-90 Ibritumomab Tiuxetan
(Zevalin) and Iodine-131 Tositumomab (Bexxar) for low SAFETY OF NUCLEAR MEDICINE
grade refractory lymphomas. Nuclear medicine procedures are one of the safest diagnostic
imaging examinations available. A patient only receives an
Nuclear medicine can also guide the choice and extent of surgery extremely small amount of a radiopharmaceutical, just enough
not only by demonstrating metastases to the liver, lungs and to provide sufficient diagnostic information. It results in low
bones but also by demonstrating tumour limits and involvement radiation exposure, acceptable for diagnostic examinations.
of sentinel nodes by probe guided surgery. Nuclear techniques Thus, the radiation risk is very low compared with the potential
also portray biodistribution and pharmacodynamics/pharma- benefits. There are no known long-term adverse effects
cokinetics of conventional drugs; predict therapeutic abilities of from such low-dose exposure. Allergic reactions to radio-
non-radioactive biomolecules and the therapy effects of gene pharmaceuticals are extremely rare and are usually mild. 111
 Figure 14: Tc99m-GHA brain tumour imaging focal tracer uptake is noted in the right frontal region. The patient has high grade glioma. The uptake in the scalp
is physiological.

Women should always inform, if there is any possibility that mSv). The effective dose resulting from an investigation is
they are pregnant or if they are breastfeeding their baby. influenced by the amount of radioactivity administered in
Radiation Dose megabecquerel (MBq), the physical properties of the
radiopharmaceutical used, its distribution in the body and its
The amount of radiation from diagnostic nuclear medicine
procedures is kept within a safe limit and follows the ALARA rate of clearance from the body.
(As Low As Reasonably Achievable) principle. The radiation dose RECOMMENDED READINGS
from nuclear medicine imaging varies greatly depending on 1. Barry L Zaret, George A Beller. Clinical Nuclear Cardiology: State of the Art
the type of study. The effective radiation dose can be lower and Future Directions. Elsevier Mosby 2005.
than or compatible to the annual background radiation dose. 2. Martin P Sandler, R Edward Coleman, James A Patton, et al. Diagnostic
Nuclear Medicine. Vol 1 and 2. Lippincott Williams and Wilkins; 2002.
The amount of radiation from a nuclear medicine procedure is
comparable to, or often times less than, that of a diagnostic X- 3. Murray IPC, Ell PJ. Nuclear Medicine in Clinical Diagnosis and Treatment. Vol
1 and 2. Churchill Livingstone; 1995.
ray except that the dose is delivered internally rather than from
4. Peter J Ell, Sanjiv S Gambhir. Nuclear Medicine in Clinical Diagnosis and
an external source such as an X-ray machine. The radiation dose Treatment. Vol 1 and 2. Churchill-Livingstone, Edinburgh; 2004.
from a nuclear medicine investigation is expressed as an 5. Society of Nuclear Medicine Procedure Guidelines (http://interactive.
112 effective dose with units of sievert (usually given in milli sieverts, snm.org/index.cfm?PageID=772&RPID=10).
 3.6 Positron Emission Tomography

Rakesh Kumar, Varun Shandal

INTRODUCTION PET-CT IN ONCOLOGY

Positron emission tomography (PET) is a functional diagnostic The PET-CT imaging has revolutionised the approach and
imaging technique which can study metabolism of various management of cancer patients. It has proven benefit in all
biological processes like glucose, amino acid, phospholipids, stages of cancer, starting from detection of the lesion, its
receptors, etc. James Robertson and his associates in 1961 built characterisation, determining the extent of the tumour, initial
the first single-plane PET. staging, evaluating the therapy response and detecting the
recurrence of the disease. It has been also found useful for
Combined PET and computed tomography (CT) has better
monitoring the treatment response, re-staging of disease as well
specificity and sensitivity than either PET or CT alone, as it can
as prognostication of various cancers.
provide the functional and morphological details of the tissue
to be studied with better localisation, all-in-one procedure. Diagnosis
Although many radiotracers are used for PET and PET-CT but the Solitary pulmonary nodule (SPN) and bronchogenic carcinoma
most widely used radiotracer is Fluorine18-fluorodeoxyglucose
PET-CT provides additional functional information and is useful
(18F-FDG) which is an analogue of glucose. Since the neoplastic
as a non-invasive diagnostic test for SPN that differentiates
processes, infection foci, etc. have increased metabolism of
benign lesions from the malignant ones (Figures 1A to C). PET-
glucose, resulting in higher FDG accumulation which makes their
CT has low sensitivity in detecting low-grade tumours, like
visualisation better with PET-CT. For interpreting the images
bronchoalveolar carcinoma and bronchial carcinoid.
accurately, the knowledge of normal physiological distribution
of FDG is must. Tissues with higher metabolic rate such as skeletal Breast carcinoma
muscles, gut, brown fat, glandular breast, bone marrow, spleen, In breast cancer patients, mammography is the most readily
lymphoid tissues and urinary tract (normal excretion) accumulate used imaging technique for the diagnosis of primary tumour
more FDG which may sometimes interfere with image but it has lower sensitivity in women with radiographically
interpretation. There is a better quantitative way for evaluating dense breasts and patients with breast implants. PET-CT is
the images by measuring standardised uptake value (SUV) which found to be useful in patients with dense breasts and patients
directly correlates with FDG metabolism in the tissue. PET-CT is with breast implants (Figures 2A to C). PET has also been found
the one of the latest functional imaging modality with wide to be useful in detecting additional primary in contralateral
clinical applications in the fields of oncology, infectious diseases, breast in known breast cancer patients. However, magnetic
cardiology and neurology. As it is still in the early stages of resonance imaging (MRI) remains the gold standard for this
development, its applicability in other disease conditions are purpose.
still being explored. The major drawbacks of the PET-CT are the
limited availability, its high cost and sometime difficult Other malignancies
differentiation between infection and malignancy. In the PET-CT has the ability to differentiate pancreatic cancer from
following section major approved uses of the PET scan are benign lesions like cystic lesions, especially in patients with
discussed in brief. chronic pancreatitis. It has a higher accuracy of 94% in detecting

Figures 1A to C: A 52-year-old male, known smoker, presented with haemoptysis. Axial section of CT (A) and PET-CT (B)
show right lung upper lobe mass with intense FDG uptake. (C) Whole body PET projection image shows FDG uptake in
primary with no evidence of any distant metastasis.
113
 malignancy in cystic lesions than conventional CT (accuracy Colorectal cancer
80%). The 18F-DOPA whole-body PET-CT is highly sensitive and In colorectal cancer (CRC) patients, metastasis is usually present
specific for the detection of pheochromocytomas and in majority of them at initial presentation. CT is used as initial
paragangliomas and helps in detecting metastasis from investigation for staging but PET-CT is superior in detecting
malignant pheochromocytomas, especially when used after unexpected liver metastases and extra-hepatic lesions.
negative metaiodo-benzyl guanidine (MIBG) study. The FDG- Mucinous adenocarcinoma is one type in CRC which is less FDG
PET has excellent diagnostic performance in differentiating avid giving false negative results most of the time.
adrenal lesions detected on CT or MRI in patients with
known malignancies. PET-CT also has high diagnostic value Lymphoma
in endometrial carcinoma and gall bladder mass, but in rest of In patients with Hodgkin’s disease (HD) and non-hodgkin’s
the cancers it has less or no value for the purpose of diagnosis. lymphoma (NHL), PET-CT detects more lesions which change
Initial Staging the stage of the disease in almost 15% of patients when
compared to conventional imaging like CT (Figures 3A to C). For
Initial staging refers to assessing the extent of malignant neoplasms
histopathological examination of the lesion in HD and NHL, PET-
and in differentiating localised from disseminated disease.
CT can guide the biopsy from suitable and easily accessible site.
Bronchogenic carcinoma
Cancer of unknown primaries and other cancers
Non small cell lung cancer (NSCLC), which is the most frequent
Patients with head and neck cancers commonly present with
type of lung cancer, needs invasive procedures such as
thoracotomy, mediastinoscopy for nodal staging. Also, CT cervical lymph node metastasis from an unknown primary. Here,
and MRI are not useful in this condition if the tumour has PET-CT is a valuable tool in patients with an occult primary
involved less than 1 cm of area. PET-CT has overcome all these tumour in the head and neck region. PET-CT can identify
limitations by being a non-invasive investigation, giving the primary tumour in approximately 30% patients and allow
metabolic picture of all sites involved in one setting. It is accurate tumour and lymph node staging, that is essential for
important for the management aspect of NSCLC as the therapy treatment planning. PET-CT differentiates resectable and
to be used depends entirely on the extent of the disease. unresectable disease in oesophageal and gastric cancers and

Figures 2A to C: Axial sections of CT (A), PET (B) and PET-CT (C) showing focal areas of increased FDG uptake in outer quadrant of right breast in a 35-year-old
female with dense breasts. Biopsy of lesion revealed intraductal breast cancer.

Figures 3A to C: In a known case of Hodgkin’s lymphoma underwent PET-CT scan for initial staging. Coronal sections of CT (A), PET (B) and PET-CT (C) showing focal
areas of increased FDG uptake in the mediastinum and left axillary lymph nodes suggestive of active disease in these regions.
114
 Positron Emission Tomography
helps in avoiding futile surgeries. However, the detection of Treatment Response Evaluation
regional nodal metastases is limited due to the small volume PET-CT has emerged as a useful imaging modality that can
of the disease in some lymph nodes. The FDG uptake in evaluate the therapy response and differentiate responders
osteosarcoma correlates well with histological grading or from non-responders. As most of the chemotherapeutic drugs
tumour aggressiveness. In patients with ovarian cancers having are cytostatic, conventional imaging like CT and MRI has limited
raised serum CA-125, accurate staging is very important for value in evaluating the treatment response as they use the size
proper management. The PET-CT has high sensitivity and criteria. However, PET-CT as functional imaging modality can
specificity as compared to conventional imaging modalities show the treatment response earlier by determining the glucose
like transvaginal ultrasound (USG) and contrast enhanced uptake by tumour which decreases earlier than the size in solid
computed tomography (CECT ) in staging and detecting tumours. PET-CT performed after 1-2 cycles of chemotherapy can
metastases. PET-CT may reveal unsuspected and occult differentiate progressive disease from remission better than
metastases to the liver, bones, and lungs, those cannot be conventional imaging modalities in lymphoma, NSCLC, etc. and
detected by conventional imaging, and this can change the
can change the treatment plan accordingly (Figures 4A and B).
management protocol in patients with pancreatic cancer.

Figures 4A and B: A case of Hodgkin’s lymphoma who underwent pre-chemotherapy (A) and post-chemotherapy PET/CT (B) imaging. In pre-chemotherapy scan,
coronal sections of CT, PET and PET/CT are showing increased FDG uptake in multiple left axillary lymph nodes shown by arrows (upper row). In post-chemotherapy
scan, coronal sections of CT, PET and PET/CT are showing resolution of FDG uptake in left axillary lymph nodes (arrows) suggestive of complete response (lower row). 115
 In colorectal cancer patients, Delta SUVmax (absolute SUVmax localisation of infectious and non-infectious foci in soft tissues
change) and response index (RI), (per cent SUVmax change) is of primary importance. Whenever, the lesions of infectious
are best predictive parameters in response evaluation of and inflammatory disease cause changes in local anatomy,
neoadjuvant chemotherapy. capillary permeability, or tissue water content, the conventional
imaging like USG, CT, and MRI are effective in detecting
In breast cancer patients, PET-CT detects metabolic changes
inflammation. Scintigraphic techniques are best used to localise
much earlier than conventional imaging and clinical
inflammatory foci when normal anatomic landmarks are lost
examination after initiation of chemotherapy. There is strong
or obscured. FDG-PET-CT is also useful to detect infection and
correlation between the quantitative changes in SUV and
inflammatory foci. The enhanced uptake of FDG in activated
overall clinical assessment of response of skeletal metastases
inflammatory cells, such as lymphocytes or macrophages, is
to therapy and changes in tumour markers in breast cancer
related to significantly increased levels of glycolysis as a result
patients. In patients with oesophageal carcinoma, PET-CT is
of increased numbers of cell surface glucose transporters,
more specific than CT and endoscopic USG for loco-regional
particularly after cellular stimulation by multiple cytokines. PET-
lymph node metastasis and response evaluation to neoadjuvant
CT is useful in the diagnosis, treatment response evaluation of
chemotherapy.
infectious and inflammatory diseases, to find out recurrence/
Around two-third of patients with HD and 50% of patients with residual disease in case of chronic disorders and in pyrexia of
NHL show persistent mass lesion on conventional imaging unknown origin (PUO).
modalities after treatment. However, PET-CT readily shows
Diagnosis
absent metabolic activity in these lesions and lower incidence
of relapse in these patients proving its efficacy in treatment PET-CT has shown its usefulness in diagnosing various difficult
response monitoring in lymphoma. to diagnose infectious and inflammatory conditions. It has
been successfully used in the diagnosis of tuberculosis (TB),
CT is the imaging modality of choice in gastrointestinal stromal sarcoidosis, osteomyelitis, vasculitis, human immunodeficiency
tumours (GIST), which can locate a mass lesion, contiguous virus (HIV) infection and infections in organ transplant.
organ invasion and distant metastases. Since the introduction
of imatinib mesylate, PET-CT is being used widely in GIST. PET- Tuberculous lesions show variable FDG uptake according to
CT may show significant decrease in FDG uptake early after the grade of inflammatory activity and they do not show any
imatinib therapy, while on conventional morphological imaging, characteristic pattern. PET-CT helps in detecting unsuspected
tumour size may remain constant for a significant time. distant foci of infection (Figure 5). For the diagnosis of TB,
Therefore, PET-CT accurately separates responders from non- biopsy and histopathological examination are essential
responders at an early stage, and is helpful during follow-up. many a times. Here, PET-CT is useful in guiding biopsy from
However, in the assessment of the solid tumours, the role of metabolically active lesions. In another granulomatous disease
PET-CT is yet to be determined. sarcoidosis, although, PET-CT shows FDG uptake by sarcoid
granulomas but it cannot distinguish sarcoidosis from HD or
Restaging/Recurrence and Prognosis NHL and even from TB. However, PET-CT can assess the extent
Most of the cancers relapse or recur even after the successful and degree of the disease once the diagnosis has been
therapy. PET-CT is becoming standard of care in evaluating established.
the recurrence of various cancers and in determining the
In chronic osteomyelitis, PET-CT is highly sensitive in the
prognosis. PET-CT has proven role in assessing the prognosis
detection of the disease, even in patients treated with antibiotics
of NSCLC, pancreatic cancer, lymphoma, cervical cancer and
before FDG-PET imaging. When chronic osteomyelitis is
other cancers as discussed below. In colorectal cancer, CT is
suspected in complicated fractures, PET-CT appears to be the
frequently used to localise the site of possible recurrence,
study of choice as FDG uptake normalises in less than 2 to 3
which has lower sensitivity and specificity. In a meta-analysis
months whereas bones scintigraphy remains positive for longer
conducted on 577 patients, the sensitivity and specificity of
periods following complicated fractures reducing the false
FDG-PET for detecting recurrent colorectal cancer was found
positive results. Diagnosing osteomyelitis in diabetic foot using
to be 97% and 76%, respectively. In head and neck cancers,
conventional imaging poses a challenge as findings of acute
PET-CT is sensitive and specific in detecting residual and
osteomyelitis may be similar to those of acutely evolving
recurrent lymph node metastasis and this can detect the
neuropathic osteo-arthropathy on CT, MRI which frequently
complete metabolic response, and thus, predicting overall
coexist in diabetic patients. Here, the precise anatomic
survival; it changed radiotherapy planning technique in 29%
localisation of increased FDG uptake provided by PET-CT
and altered TNM staging in 34% of the patients. PET-CT has
enables accurate differentiation between osteomyelitis and
been shown to be useful in malignant melanoma, ovarian
soft-tissue infection. In diagnosing the infected prosthesis,
cancer, recurrent cervical cancer, hepatocellular carcinoma
studies have shown variable results on the role of PET-CT.
(HCC), prostate and cancer of the bladder.
More studies are needed to confirm the role of PET-CT in the
PET-CT IN INFECTIOUS AND INFLAMMATORY DISEASES evaluation of periprosthetic infections or inflammation.
Infectious diseases are the major cause of morbidity and PET-CT is useful in early diagnosis and establishing the extent of
mortality in developing countries and the incidence of both the vasculitis in patients with several types of vasculitis such as
community and hospital acquired infections is on the rise. Most giant cell arteritis, polymyalgia rheumatica, Takayasu’s arteritis,
of the times, focus of infection remains undetermined. For periaortitis due to Wegener’s granulomatosis, aortitis, unspecified
the successful management of patients with presumed or large vessel vasculitis and infectious vasculitis. PET-CT is helpful
116 established inflammatory and septic diseases, the detection and in demonstrating giant cell arteritis in arteries exceeding 4 mm
 Positron Emission Tomography

Figure 5: Patient is a case of extensive tuberculosis. Coronal (upper row) and axial sections (middle and lower row) of CT, PET and PET/CT are showing multiple
focal areas of increased FDG uptake in left supraclavicular, mediastinal lymph nodes and right lung mass suggestive of active disease.

in diameter; however, in very small vessels it cannot replace the inflammatory bowel disease (IBD), detection of disease and
need of arterial biopsy for making the diagnosis. its extent can be assessed with PET-CT enteroclysis and good
correlation has been demonstrated between the degree of
In HIV-infected patients with central nervous system (CNS) inflammation and the uptake of FDG.
lesions PET-CT has a major role in their management. PET-CT
demonstrates activated lymphoid tissue in the head and neck Pyrexia of Unknown Origin (PUO)
region during acute stages, a generalised pattern of peripheral PUO diagnosis is still a challenge for the internists. The
lymph node activation at the mid-stages, and abdominal lymph infections are the most common cause of PUO, followed by
node involvement during the late disease. PET-CT imaging neoplasm and noninfectious inflammatory diseases. For
has been reported to be more accurate than CT or MRI in improving the management in patients with PUO, the accurate
differentiating a malignant CNS lymphoma from non-malignant localisation and characterisation of the underlying cause is of
CNS aetiologies, such as toxoplasmosis, syphilis, and progressive paramount importance. Because of high sensitivity of PET-CT
multifocal leucoencephalopathy. in detecting malignant lesions, infections, and various
inflammatory processes, PET-CT has the potential to play a role
In organ transplantation cases, PET-CT can distinguish infection in the diagnostic protocol and management of patients with
from rejection and hence, this non-invasive and repeatable test PUO but there are some disadvantages also in some cases. PET-
could reduce the number of biopsies required during the CT cannot exclude cerebral disease or meningitis, because
follow-up period of patients after organ transplantation. In physiological uptake in the cerebral cortex in most cases 117
 obscures any pathological uptake. Normal activity in the PET-CT IN NEUROLOGY
kidneys and the bladder severely hampers the delineation of The PET-CT is increasingly being used in neurology in the
the disease in these organs. With the development and the evaluation of epilepsy, brain tumours, dementias and
introduction of several new PET radiotracers, it is expected movement disorders, although due to increased functional
that PET-CT will secure a major role in future in the management uptake of FDG by cerebral cortex the evaluation of meninges
of patients with inflammatory and other benign disorders. and cortical tissue is difficult. The PET-CT imaging of the brain
Treatment Response Evaluation allows non-invasive quantification of cerebral blood flow,
In infectious and inflammatory diseases, PET-CT has the ability metabolism, and receptor binding. In epilepsy, surgical removal
to monitor the response to therapy when baseline PET-CT study of epileptogenic foci results in significant control of the seizures
is available before the commencement of the therapy. It is and the quality of life. Although, MRI identifies the focus of the
mainly true for chronic granulomatous diseases. PET-CT can also seizure in most of the patients, but still a normal MRI has been
detect residual/recurrent disease in some cases. PET-CT is useful reported in 20% to 30% of potential surgical candidates. PET-
in follow-up of patients with known TB, for monitoring response CT in ictal period shows an increase in glucose metabolism and
to treatment; however, more studies are needed to confirm cerebral blood flow in epileptogenic focus whereas, in post-ictal
its role, especially in spinal TB. With our own experience, we feel period the increased glucose uptake gradually returns to
that PET-CT can be useful for detecting suspected recurrence baseline. Interictally, there is hypoperfusion and decreased
and residual disease activity in patients treated previously. glucose metabolism in epileptic focus.
Similarly PET-CT will also be useful in assessing treatment In brain tumours, higher FDG uptake as compared to the normal
response in patients with sarcoidosis. The PET-CT has been also brain correlates with the higher histologic grade. PET-CT also
used in IBD for the early diagnosis, assessing the extent of the prognosticates the shorter survival period in case of higher glucose
disease and evaluating treatment response and disease activity metabolism. In disorders with dementia such as Alzheimer’s disease
in various stages of the disease. (AD), PET-CT shows decrease in glucose metabolism in the
PET-CT IN CARDIOLOGY temporoparietal lobes. In AD, a new PET tracer has been employed
to target amyloid saline plaques and neurofibrillary tangles which
PET-CT has demonstrated its usefulness in patients with
shows prolonged retention in affected areas of the brain. Similarly
cardiac diseases. PET-CT quantifies the in vivo physiologic and
newer tracers (2-carbomethoxy-3-(4-chlorophenyl)-8-(2-18F-
pathologic processes including myocardial perfusion
fluoroethyl) nortropane (18F-FECNT) and F-DOPA) are being used in
(coronary blood flow) and metabolism without disturbing
movement disorders,which allow assessment of the integrity of pre-
their physiological properties. This very property of PET-CT
synaptic dopaminergic neurones and are able to diagnose
is the basis for it being used as a clinical imaging tool for
Parkinson’s disease and other movement disorders, identify the
the quantitative assessment of myocardial perfusion and for
speech and sensory-motor areas to minimise post-operative
the characterisation of tissue viability in patients with
morbidity. It is also being used to measure the pharmacokinetic and
advanced coronary artery disease (CAD). Cardiac PET-CT helps
in selecting the patients with CAD and left ventricular pharmacodynamic effects of drugs of abuse on the human brain.
dysfunction that would benefit from coronary artery RECOMMENDED READINGS
revascularisation. PET-CT also characterises the viability of 1. Alavi A. PET Imaging I. Radiologic Clinics of North America. 2004; 42: 983-
myocardium which can prognosticate the outcome of the 1200.
patients after revascularisation in patients with ischaemic 2. Kumar R, Nadig M, Chauhan A. Positron emission tomography: clinical
cardiomyopathy and chronic left ventricular dysfunction. application in oncology: Part I. Expert Rev Anticancer Ther. 2005; 5: 1079-94.
PET-CT also aids in assessing the presence and stability 3. Kumar R, Basu S, Torigian D, et al. FDG-PET imaging for assessing
of plaques; however, it is not used routinely for the detection inflammation and infection. Clin Microbiol Rev. 2008; 21: 209-24.
of any vascular disease. PET-CT is also used in the evaluation 4. Pelosi E, Pregno P, Penna D, et al. Role of whole-body [18F]
of cardiomyopathies, post-cardiac transplant evaluation fluorodeoxyglucose positron emission tomography/computed
tomography (FDG-PET/CT) and conventional techniques in the staging of
and cardiac receptor evaluation for the regulation of patients with Hodgkin and aggressive non-Hodgkin’s lymphoma. Radiol
cardiovascular functions. Med. 2008; 113: 578-90.

118
Section 4
Clinical Pharmacology
Section Editor: B.B. Thakur
4.1 Introduction and Scope of Clinical Pharmacology 120
Ranjit Roy Choudhury, Urmilla Thatte
4.2 Rational Use of Drugs 123
Sangeeta Sharma
4.3 Adverse Drug Reactions and Pharmacovigilance 125
M.C. Gupta
4.4 Prescribing in Special Situations 128
Uma Tekur
4.5 New Drug Development 133
Sadhna Joglekar
4.6 Pharmacoeconomics 135
Gurudas Khilnani
 4.1 Introduction and Scope of Clinical Pharmacology

Ranjit Roy Choudhury, Urmilla Thatte

INTRODUCTION PHARMACOKINETICS
Clinical pharmacology is the study of drugs in relation to Pharmacokinetics is the quantitative analysis of the time course
clinical sciences and deals mainly with the effects of medicines of drug absorption, distribution, metabolism and excretion or
in human beings. Apart from giving a scientific basis for drug to put in simple terms deals with ‘what the body does to the
use, clinical pharmacology also includes drug development, drug’. This knowledge forms the scientific basis for deciding
especially in man. For a physician, awareness of clinical the dose and dosage regime of a medicine. Modifications can
pharmacology (and therefore the knowledge of drug behaviour be made in the dosage form or in the chemical structure of a
in man) is necessary to guide rational therapeutics. drug to influence individual pharmacokinetic parameters,
thereby assisting in optimising dosing regimen (e.g. slow
Although the genesis of pharmacology (Greek pharmakos,
release formulations will delay the absorption, while
medicine or drug; and logos, study) is not very distinct, it is
modifications in lipid solubility of an injectable drug will change
known that experimental demonstration of drug action began
the distribution, metabolism and excretion, and thereby the
as far back in 1809, when François Magendie demonstrated, in
duration of action). Knowledge of pharmacokinetic principles
dogs, that the spinal cord was the site of the convulsant action
also assists in the development of new drugs, especially while
of Nux vomica (a strychnine-containing plant drug). Later in
selecting drug doses.
1842, Claude Bernard discovered that curare acted at the
neuromuscular junction to interrupt the stimulation of muscle Information related to the absorption, distribution, metabolism
by nerve impulses. However, pharmacology emerged as a and excretion of a drug allows for calculating the initial loading
separate science only in 1847, when Rudolf Buchheim was as well as maintenance doses to achieve and maintain target
appointed as the professor of pharmacology at the University levels at the site of expected action (Figure 1). The route of
of Dorpat in Estonia. It was his student Oswald Schmiedeberg administration (e.g. oral, ocular, inhaled, etc.) as well as several
(1838–1921), who has established pharmacology as a special drug-related factors (including the formulation and this is
discipline and was also responsible for the pre-eminence of the where pharmaceutics plays a crucial role), and the site of drug
German pharmaceutical industry up to World War II. His student, absorption, including vascularity (e.g. muscles are very vascular
John Jacob Abel, became the first chairman of pharmacology and therefore allow good absorption) influence how much of
in the USA. a drug is absorbed into the systemic circulation. As the drug
absorption is variable, an important parameter that is used
The seeds of modern clinical pharmacology were sown as far
to compare the availability of a drug at the site of action is
back as 1937 when Harry Gold (who is considered the father
bioavailability. This is defined as ‘the rate and extent to which
of modern clinical pharmacology) described in the JAMA, the
the active substance is absorbed from the pharmaceutical form
double-blind trial design. The formal subject ‘Clinical
and is available at the site of action’. A study of bioavailability is
Pharmacology and Therapeutics’ was introduced in the USA
a useful tool to compare formulations (e.g. conventional to slow
only in 1960 by Gold. Then there was surge of knowledge in
release) or generics. Comparative studies in animals or humans
this field which established clinical therapeutics firmly.
(clinical trials) are done only if entirely justified. When the
SIX STEPS TO RATIONAL THERAPEUTICS bioavailability of two drugs, when administered in equimolar
doses, is similar, these are considered to be bioequivalent and
When drug treatment is rationally approached, six simple steps
it can be assumed that their clinical effects would be
need to be taken. These have been summarised in Table 1. In
comparable.
this algorithm, the cornerstone for optimal therapeutics is an
appreciation of the clinical pharmacology, i.e. the pharmaco- After absorption, a drug is rapidly distributed. For most drugs,
kinetics and pharmacodynamics of a drug. distribution is characterised by a rapid mixing into one

Table 1: Six Steps to Rational Therapeutics

1. Making the correct diagnosis and defining each patient’s problems.
2. Identifying the need and targets for drug therapy.
3. Understanding the clinical pharmacology of the medicines from which a rational choice can be made.
4. Selecting the appropriate medicine for that patient: Here the safety, tolerability, efficacy and price (STEP) of the drugs are good guidelines
for making a choice when there is one [either between groups (e.g. alpha-blockers or ACE-inhibitors, or between drugs of the same
group, e.g. enalapril or ramipril or lisinopril, or even between pharmaceutical brands of each medicine)].
5. Monitoring the treatment: Here the choice of the correct endpoint for both effect and safety is important as well as appropriate time
points for modulating and individualising therapy. It is crucial to monitor for unexpected drug interactions and appropriately counselling
the patient.
6. Developing a rapport with the patient to ensure complete and correct compliance.
120
 Introduction and Scope of Clinical Pharmacology
regimes. Prescribing in special conditions is discussed in chapter 4
in this section.
A certain amount of the drug is cleared from the body in unit
time. The time taken to clear 50% of a drug from the body is
defined as the ‘half-life’ (t1/2). Most drugs follow first order
(exponential) kinetics and these drugs have a fairly constant
t1/2 (when rate of clearance depends on the concentration of
the drug). However, some drugs follow zero order or saturation
kinetics where the clearance processes get saturated at a point
in time, thus leading to a fixed amount of the drug getting
cleared rather than a fixed proportion. Thus, the t1/2 now varies
according to the concentration and can contribute to toxicity.
Phenytoin is a good example, where as the dose increases, the
clearance shifts from being exponential to a saturation type,
making it important for close monitoring.
A useful clinical application of the knowledge of pharmacokinetics
is applied in therapeutic drug monitoring (TDM) which is the
measurement of drug levels in body fluids (mostly blood or
plasma, and sometimes saliva, urine or cerebrospinal fluid)
at intervals to minimise toxicity and maximise effect. Drugs
that have a narrow therapeutic window, poor or no physiologic
or therapeutic endpoints to guide dosage, and whose
pharmacokinetics varies widely between individuals, are good
Figure 1: Fate of a drug in the body. All the parameters are influenced by various
host- and drug-related factors (some of the key factors are indicated in brackets).
candidates for TDM. Further, if there is a critical need to monitor
adherence, TDM is a useful tool.
compartment consisting of blood volume and other tissues.
PHARMACODYNAMICS
This distribution depends on the molecular weight, lipid
solubility, protein binding and active transport. Some other Pharmacodynamics deals with ‘what the drug does to the body’
drugs (like diazepam) are initially distributed into a small central and is the study of the biochemical and physiological effects of
compartment [consisting of the well-perfused tissues like the drugs on the body and their mechanisms of action. Knowledge
brain (contributing to a rapid onset of action with minimal side- of pharmacodynamics helps in intelligent drug development
effects), blood and heart]. From this, these drugs are rapidly and also forms the basis of rational drug therapy. Most drugs
redistributed to a larger peripheral compartment (consisting act by altering body’s control systems by different mechanisms,
of poorly perfused tissues like adipose) leading to a rapid e.g. by binding to receptors, interfering with transport processes,
reduction in the plasma concentration followed by a slower inhibiting enzymes, etc. Coupled with the body’s homeostatic
reduction which occurs due to renal clearance. responses to the primary actions of the drug, a composite
therapeutic effect occurs, which finally leads to well defined and
Clearance is the ability of the body to remove the drug from
desired clinical endpoints.
circulation and is clinically the most relevant in determining
dosage (especially maintenance dose and intervals).The liver is
ADVERSE EFFECTS OF DRUGS
responsible for biotransformation (although some drugs may
be excreted via the bile) while the kidney excretes the drug or Unwanted effects are an integral part of drug use. It has been said
metabolites and may also be responsible for some metabolism. by Mathew Prior (1664-1721) ‘Cur’d yesterday of my disease, I died
The hepatic microsomal enzyme system (CYP or cytochrome last of my physician!’ Complete information regarding known
P450) which has been now studied in great detail is one of the adverse reactions as well as a knowledge of how to recognise and
major contributors to variability in drug clearance and the study manage unexpected adverse reactions to medicines is an integral
of how an individual’s genetic inheritance affects the body’s part of rational therapeutics. Chapter 3 in this section deals with this
response to drugs is called pharmacogenomics (discussed in a important part of clinical pharmacology.
subsequent chapter of sec. 6, chapter 9). Thirty CYP gene families Among the adverse reactions to drug, allergic reactions
have been identified in humans and the categories are based are clinically the most challenging for both diagnosis and
upon protein sequence homology. Most of the drug- management. Allergic reactions are generally of four types: type
metabolising enzymes are in the CYP 1, 2 and 3 families. The I (immediate, anaphylactic, e.g. penicillin), type II (antibody
activity of CYP enzymes can be influenced by genetic and dependent cytotoxic reactions, penicillin induced haemolytic
environmental factors [nutrition, alcohol, other drugs anaemia), type III (immune complex mediated) and type IV
(cimetidine is an inhibitor while phenobarbitone induces these (lymphocyte medicated delayed reactions, contact dermatitis).
enzymes) and smoking] thus influencing drug metabolism. Characteristically, allergic reactions do not show a correlation
Apart from this, several other factors influence clearance with the pharmacological properties of a drug, lack a linear
including many host and drug factors, influencing to a large relationship with the dose (i.e. a very small dose can precipitate
extent,therapeutic decisions about the choice of drug and dosing a reaction), are rare and unpredictable, can recur on re-exposure,
121
 usually disappear on withdrawal of drug and reappear on physician reaches the decision that the patient requires
reintroduction of drug. Taking history of drug allergy is crucial medicine, a prescription results (Table 1). Perhaps the most
before starting therapy as a rule, as allergic reactions, although crucial aspect of drug therapy is that of compliance which is
common with some drugs, can occur with any medicine. defined as ‘the extent to which a person’s behaviour coincides
with medical advice’. Noncompliance to medication can lead
DRUG INTERACTIONS to serious problems for the patient as well as to the community.
Drug interactions are common in today’s rampant practice of It is impractical to expect ‘perfect’ compliance, but useful
polypharmacy and if they go unrecognised, can lead to fatal to define what would be ‘adequate’ compliance in a given
outcomes. The true incidence of drug interactions is difficult to patient during therapy. Supervised therapy [as in directly
determine. Drug interactions can be pharmacodynamic (due observed treatment, short-course (DOTS)] assists in improving
to interactions at the receptor) or pharmacokinetic (related to compliance. Improved communication to convince the patient
absorption, distribution, metabolism or elimination of the drug). of the need for compliance and simplifications of the regimes
Pharmacodynamic interactions occur due to additive, are some other methods reported to improve compliance. In
synergistic, or antagonistic effects from co-administration of fact, no drug can substitute for effective communication
two or more drugs (e.g. synergistic actions of antibiotics, additive between a doctor and a patient.
effects of ethanol and benzodiazepines, or antagonistic effects, An important aspect of drug therapy and response to medicines
like anticholinergic effects of drugs such as amitriptyline with is the placebo effect and the physician needs to be aware of
acetylcholinesterase inhibitors). and exploit this phenomenon to the maximum. An essential
Pharmacokinetic interactions are also common. Interference part of a therapeutic decision is an assessment of the cost-
with absorption of drugs by food is the most common benefit assessment (see chapter on Pharmacoeconomics).
example (e.g. Indinavir is rapidly absorbed in a fasted state INTRODUCTION OF NEW DRUGS
and absorption is reduced by 80% with a high calorie/fat/
protein meal while the absorption of saquinavir is increased New drugs are introduced into the market regularly by
significantly when given with a high fat meal. Chelation in the pharmaceutical companies and this is associated with
stomach (tetracycline or dairy products) is another cause for aggressive marketing. After extensive preclinical and clinical
interaction. Alteration in gastrointestinal motility or pH research (described in the section on drug development), a drug
also influences drug absorption (e.g. antacids, omeprazole, is marketed for an approved condition for which it has been
H2-blockers may decrease absorption of ketoconazole developed. When a drug is used for an indication or in an
and itraconazole). Competition between drugs for protein indication that is not approved this is called ‘off-label’ use and
or tissue-binding sites can increase free (unbound) the responsibility for use rests on the physician alone. There
concentrations leading to enhanced pharmacological effects has to be sufficient scientific justification for the off-label use.
(e.g. oral hypoglycaemic agents and nonsteroidal anti- Research on the other hand for ‘off-label’ indications, new routes
inflammatory drugs). Drug metabolism interactions are very of administration or new formulations including fixed drug
common and occur by co-administration with CYP inducers combinations require regulatory clearance. In India, drug
or inhibitors. Drugs can inhibit a specific CYP even though choices are wide because of the variety of drugs approved.
they are not metabolised by that isozyme, e.g. quinidine is a Additionally, each drug has several generics and to make a
potent CYP2D6 inhibitor but is itself metabolised primarily by rational choice between these requires skill and a clear
CYP3A4. Cimetidine, erythromycin, ketoconazole, ritonavir, understanding of principles of clinical pharmacology.
fluoxetine, paroxetine (CYP2D6) and nefazodone (CYP3A4) An interesting feature of therapeutics in India is the widespread
are the common CYP inhibitors while drugs like rifampin, popularity of ‘alternative’ systems of medicine among patients.
carbamazepine, phenobarbital or phenytoin induce CYP. Many Ayurveda, Siddha, Unani, Yoga, Naturopathy and Homeopathy
medicinal plants have been shown to interact with drugs are officially recognised by the Government of India and most
through interference of metabolism (the concentrations of clinicians will come across patients, especially those with
indinavir are decreased in the presence of St John’s Wort as it chronic diseases like asthma or arthritis using alternative
induces CYP3A4 while grapefruit, by inhibiting CYP3A4 can systems of medicine. A physician must be aware and recognise
increase concentrations of saquinavir, benzodiazepines or that the medicines from alternative systems used by the
calcium channel blockers). patients may have an impact (favourable or unfavourable) on
For a clinician, recognising drug interactions is very crucial so therapy including the occurrence of adverse reactions and drug
as to manage the patient appropriately. A patient showing interactions.
exaggerated toxicity or drug effects or treatment failure should
RECOMMENDED READINGS
trigger a high index of suspicion. When a drug interaction is
1. Bennett PN, Brown MJ. Clinical Pharmacology; 9th Ed. Edinburg: Churchill
suspected, the physician must study the time course of the Livingstone; 2003: pp 529-38.
interaction, investigate whether it is a drug class effect and
2. De Vries TPGM, Henning RH, Hogerzeil HV, et al. Guide to Good Prescribing:
assess if the interaction is clinically significant. A Practical Manual. Geneva: World Health Organization, Action; 1994. WHO/
DAP/94.11.
Understanding and applying these principles of clinical
3. Melmon K, Nierenberg D. Introduction to clinical pharmacology and
pharmacology form the basis rational therapeutics. However,
rational therapeutics. In: Carruthers G, Hoffman B, Melmon K, Nierenberg
an important principle of therapeutics that must be remembered D, editors. Melmon and Morrelli’s Clinical Pharmacology; 4th Ed. McGraw Hill
is ‘Drugs cannot work if patients do not take them!’ When the Medical Publishing Division; 2000: pp 3-62.
122
 4.2 Rational Use of Drugs

Sangeeta Sharma

The availability of essential drugs is minimal and capacity of  Failure to provide available, safe and effective drugs/
the facilities is grossly inadequate. The private sector is the vaccines.
most important source of health care in India, providing  Under-use of life-extending drugs for illnesses, such as
approximately 80% of the services. Patients have to shell out of hypertension, heart disease, asthma, and other chronic
their pocket payments for seeking private health services at the illnesses.
cost of other essential expenditure.The pharmaceutical industry
has witnessed tremendous transformation since the 1950s but Massive Detrimental Effects of Irrational Use of Medicines
at the same time irrational, non-essential and hazardous drugs 1. Lack of access to medicines and inappropriate doses results in:
have flooded the market.  Serious morbidity and mortality, particularly for child-
hood infections and chronic diseases, such as hyper-
Access to essential medicines, high expenditure on medicines
tension, diabetes, epilepsy and mental disorders.
and irrational combinations are the three problems people face
and public systems are challenged to respond to. Other concerns  Overuse of medicines leading to wastage of meagre
are the rising health care costs, increasing medicine costs, newer resources resulting in significant patient harm in terms
products and technology, over-dependence on investigations, of poor patient outcomes and adverse drug reactions.
diseases of old age, rising incidence of heart disease, cancer, 2. Rising anti-microbial resistance:
increased expectations and reducing health budgets. Overuse of antimicrobials is leading to increased anti-
DRUGS: A CRITICAL INPUT microbial resistance (AMR) and non-sterile injections to the
transmission of hepatitis, HIV/AIDS and other blood-borne
Drug expenditure is the most critical aspect of the financing of
diseases. AMR is one of the world’s most serious public
health services. Lack of drugs can block the operation of the health
health problems resulting in prolonged illness and
care system. Credibility, effectiveness and attendance at health hospitalisation, which are costly and the use of drugs other
services, depend on a large extent on patient being able to obtain than first-line drugs may increase cost 100-fold, making
relevant drugs at the right time. A good diagnosis is not much use them unaffordable.
if the patient cannot obtain the necessary treatment.
Development and spread of anti-microbial resistance is
RATIONAL USE OF MEDICINES due to:
Patients receive medications appropriate to their clinical needs,  Overuse, misuse, and irrational use by doctors.
in doses that meet their own individual requirements, for an  Non-compliance and self-medication by patients.
adequate period of time, and at the lowest cost to them and
 Non-human use of antibiotics in animal husbandry,
their community. Unfortunately, worldwide more than 50% of
aquaculture and agriculture.
all medicines are prescribed, dispensed or sold inappropriately
and 50% of patients fail to take their medicines correctly. 3. Irrational overuse of medicines can stimulate inappropriate
Inadequate consulting time, very short dispensing time and patient demand, and lead to reduced access and loss of
incorrect use by patients is of great public health concern too. patient confidence in the health system.
Global Epidemic of Irrational Use of Medicines The first step to correcting irrational use of medicines, i.e.
Problems of irrational use of drugs and non-availability of drugs promoting rational use of medicines, is to understand:
are often similar in many countries including India. Common  Types and amount of irrational use of medicines, so that
types of irrational medicine use are: strategies can be targeted towards changing specific
 The use of too many medicines per patient (polypharmacy). problems.
 Choice of more expensive drugs when less expensive drugs  Monitoring the reasons why medicines are used
would be equally or more effective. irrationally, so that appropriate, effective and feasible
strategies can be chosen. People often have very
 Inappropriate use of antimicrobials, often in inadequate
rational reasons for using medicines irrationally. Causes
dosage, for non-bacterial infections—common cold,
of irrational use include lack of knowledge, skills or
diarrhoea, etc.
independent information, unrestricted availability of
 Overuse of injections when oral formulations would be medicines, overwork of health personnel, inappropriate
more appropriate. promotion of medicines and profit motives of selling
 Failure to prescribe in accordance with clinical guidelines. medicines.

123
 Table 1: Twelve Core Interventions to Promote More Rational Policies to Promote Rational Use of Medicines
Use of Medicines Based on the available evidence, WHO has developed
1. A mandated multi-disciplinary national body—to co-ordinate
recommendations for twelve core national policies and structures
medicine use policies. that are needed to promote rational use of medicines (Table 1).
2. Evidence-based clinical guidelines—to aid prescribers on how Essential medicines are those that satisfy the priority health care
to treat patients. needs of the population.These can be selected with due regard
3. Essential medicines list based on treatments of choice—to be to disease prevalence, evidence on efficacy, safety and
followed in procurement and distribution of medicines. comparative cost-effectiveness. Therefore, these should be
4. Drugs and therapeutics committees—to monitor quality of available at all times in adequate amounts, in the appropriate
care in the hospitals. dosage forms, with assured quality, and at a price the individual
5. Problem-based pharmacotherapy training in undergraduate and the community can afford. No public sector or health
curriculum—to better equip future doctors in how to prescribe. insurance system can afford to supply or reimburse all
6. Continuing in-service medical education as a licensure medicines that are available in the market. Lists of essential
requirement—in order to ensure that prescribers remain up- medicines also guide the procurement and supply of medicines
to-date with new treatments/guidelines.
in the public sector, schemes that reimburse medicine costs,
7. Supervision of health care workers, audit of prescribing and etc. Careful selection of a limited range of essential medicines
feedback to prescribers—in order to help prescribers use
results in a higher quality of care, better management of
medicines more appropriately.
medicines, and more cost-effective use of health resources.
8. Provision on independent information (drug bulletins) on
medicines—in order to make sure that prescribers have Clinical Guidelines or Standard Treatment
sufficient unbiased information on medicines. These guidelines is consist of systematically developed
9. Public education about medicines to try and reduce statements to help prescribers make decisions about
inappropriate self-medication and demand for medicines and
appropriate treatments for specific clinical conditions. These are
also to increase awareness about the importance of adherence.
an effective tool for assisting health professionals to choose the
10. Avoidance of perverse financial incentives such as prescribers
most appropriate medicine for a given condition. Essential
earning money from the sales of medicines which encourage
medicines list together with standard treatment guidelines
over-prescription of medicines.
are the most powerful tools for promotion of rational use of
11. Appropriate and enforced regulation, particularly concerning
medicine promotional activities by the pharmaceutical
medicines.
industry, licensing of drug outlets (pharmacies, hospitals) and
RECOMMENDED READINGS
healthcare workers, and the availability of prescription-only
1. World Health Organization. Promoting Rational Use of Medicines: Core
medicines without prescription.
Components. WHO Policy Perspectives on Medicines No. 5. Document
12. Sufficient government expenditure to ensure availability of WHO/EDM/2002.3. Geneva: World Health Organization 2002. Available at
medicines and staff. URL: http:/www.who.int/medicines.
Adapted from WHO, 2002. 2. World Health Organization. The Rational Use of Drugs. Report of the
Conference of Experts. Geneva: World Health Organization; 1985.

124
 4.3 Adverse Drug Reactions and Pharmacovigilance

MC Gupta

INTRODUCTION product, which does not necessarily have a causal

Drugs have the potential to do good which may be trivial to relationship with this treatment.
lifesaving. Drugs, used appropriately, can improve both the 2. An adverse event may or may not be due to the drug, while
quality and longevity of life, but drugs also have the potential an adverse drug reaction is always due to the drug.
to cause harm which may be trivial to death. No drug can be 3. Adverse event is more relevant to the new drugs where
considered to be totally devoid of causing any harmful effects nothing is known of the adverse drug reactions of the
to the recipient. The principle of appropriate treatment entails molecule under trial.
making a balance between the benefit and the harm in such a
way that the benefit always outweighs the harm. 4. An adverse event can eventually become the ADR of the
drug, if it is proven with some certainty that it is because of
ADVERSE DRUG REACTIONS the drug only.
Magnitude of the Problem of Adverse Drug Reactions
PHARMACOVIGILANCE
In USA and Canada, adverse drug reactions (ADRs) are the fourth
World Health Organization (WHO) defines pharmacovigilance
leading cause of death. Over one million Americans suffered from
as ‘the science and activities relating to the detection,
ADRs in 2009. Worldwide also, the ADRs are the sixth leading
cause of death. Monetary costs involved in the management of assessment, understanding and prevention of adverse effects
these ADRs are astronomical, a staggering US dollar 75 to 180 or any other drug-related problems’.
billion which may almost be adequate to meet the cost of Food and Drug Administration defines it as, ‘all the post-
managing the cardiovascular diseases ($120 to 150 billion) or approval scientific and data gathering activities relating to the
cancers ($130 to 195 billion). Responsibility of drug-induced detection, assessment and understanding of adverse events’.
injury raises important issues affecting medical practise, not only
pertaining to development of drugs, but also of regulatory laws Why Pharmacovigilance?
especially in view of the Consumer Protection Act (CPA) in India. The information on the safety, collected during the
premarketing phase of a medical drug, is inevitably incomplete
The overall objective of drug development is to ensure that
with regard to the possibility of adverse reactions. Following
medicinal products being produced are of acceptable quality,
are the important reasons as to why the pharmacovigilance
good efficacy and safety with a minimum possibility of causing
activities should be routinely carried out.
serious adverse effects. All the hazards of drug use cannot be
known before it is marketed; neither tests in animals nor clinical 1. Tests in animals are insufficiently predictive of human
trials will reveal all the possible side-effects of the drug. These safety.
may only be known when the drug has been administered to a 2. Limitations of the premarketing phases of clinical trials
large number of patients over a considerable period of time.  Failure to detect rare and delayed adverse drug
Definition reactions.
Adverse drug reaction (ADR) is a response to the drug which is  Conducted in strictly controlled conditions and not in
noxious and unintended, and which occurs at doses normally an actual clinical scenario.
used in man for the prophylaxis, diagnosis, or therapy of disease,  Do not provide data
or the modification of physiological function. – In children, elderly, seriously ill, pregnant and
ADRs have been classified into two broad categories: type A and lactating patients
type B. Type A (augmented) reactions are common, predictable, – Patients with other diseases
dose-dependent reactions that account for at least 80% of total – Patients receiving other drugs
reactions and are produced by known pharmacologic actions of – Patients from various populations
the drug. Type B (bizarre) reactions, on the other hand, are
uncommon and unpredictable, usually having an immunologic 3. Aggressive marketing strategies of the pharmaceutical
basis and occur only in susceptible individuals. More recently, companies.
further classes of ADRs have been defined. These include type C 4. Fast changing physician and patient preferences.
(continuous), which are dose related and time related, type D 5. Easy accessibility to drugs.
(delayed) which are time-related and type E (end of use) which
are seen after withdrawal of a drug. Pharmacovigilance is needed in every country, because there
are differences between countries (and even regions within
ADVERSE EVENT countries) in the occurrence of adverse drug reactions and
1. Adverse event is any untoward medical occurrence that other drug related problems. This may be because of
may present during treatment with a pharmaceutical differences in: 125
 1. Disease and prescribing practices 6. Intensive hospital monitoring.
2. Drug production distribution and use (e.g. indications, dose 7. Record linkage schemes by computer.
and availability). 8. Population statistics.
3. Pharmaceutical quality and composition (excipients) of 9. Meta-analysis
locally produced pharmaceutical products.
Spontaneous Reporting of Adverse Drug Reactions
4. Genetics, diet and traditions of the people.
Spontaneous reporting is currently the major source of information
5. The use of non-orthodox drugs (e.g. herbal remedies) may
in pharmacovigilance. This is a sensitive, powerful and a cost-
pose special toxicological problems, when used alone or in
effective system.It is expected now that all the prescribing clinicians
combination with other drugs.
should take the professional responsibility of reporting the adverse
Data derived from within the country or region may have events causing a risk to the patient to the pharmacovigilance
greater relevance and educational value and may encourage centre of their state/region, and thus, contributing to the NPP. The
national regulatory decision-making. Information obtained in advantages of the spontaneous reporting are:
a certain country (e.g. the country of origin of the drug) may 1. It can cater to large population.
not be relevant to other parts of the world, where circumstances 2. It can cover all types of medicines including the herbals.
may be different.
3. It is possible to do both in hospital and outpatients.
The WHO International Drug Monitoring Programme may 4. It may generate rapid alerts.
provide information on possible safety issues which may not 5. It is least likely to influence prescribing behaviour.
yet have emerged within the country’s data. 6. Low set-up and recurring costs.
Aims of Pharmacovigilance The system has some disadvantages also like under-reporting
Pharmacovigilance is needed for the prevention of drug- by the clinicians, difficulty in detecting ADRs, number of the
induced human suffering and to avoid financial risks associated exposed unknown patients and there may be a bias in reporting
with unexpected adverse effects. the ADRs.
Major aims of pharmacovigilance are: Who can report?
1. Early detection of hitherto unknown adverse reactions and 1. Professionals working in health care are the preferred
interactions. source of information in pharmacovigilance, e.g. family
2. Detection of an increase in frequency of known adverse practitioners, medical specialists and pharmacists.
reactions. 2. Dentists, midwives and nurses.
3. Identification of risk factors and possible mechanisms 3. Pharmaceutical manufacturers should ensure that suspected
underlying these adverse drug reactions. ADRs must be reported to the competent authority.
4. Estimation of quantitative aspects of benefit/risk analysis 4. ADRs may be reported directly by the patients to the
and dissemination of information needed to improve drug national or local ADR monitoring centres. It is important
prescribing and regulation. to communicate with their physicians for additional
The ultimate goals of pharmacovigilance are: information and data verification.
1. The rational and safe use of medical drugs. What to report?
2. The assessment and communication of the risks and In the early stages of any pharmacovigilance system, reports
benefits of drugs in the market to the clinicians. on all suspected ADRs, known or unknown, serious or non-
3. Educating and informing the patients. serious are encouraged, because it is necessary to create a
‘notification or reporting culture’. All serious adverse events
4. Making the appropriate regulatory decisions as and when should be reported. A serious ADR entails, hospitalisation,
required. disability, congenital abnormalitis or death.
Methods of Pharmacovigilance 1. For new drugs (up to 5 years): All suspected reactions,
A number of methods have been employed for the including minor ones, should be reported.
pharmacovigilance activities, the spontaneous reporting being 2. For established drugs: Serious or unusual suspected adverse
the most common, effective and cheap in terms of costs. Globally reactions are to be reported. If an increase in frequency of
also, this method has the best acceptability. The various methods a given reaction is suspected, then this is also reported.
which can be used for the pharmacovigilance activities are: 3. Special fields of interest are drug abuse and drug use in
1. Case reports and case series. pregnancy and lactation.
2. Spontaneous reporting, e.g. yellow card system in UK, blue 4. Lack of efficacy and suspected pharmaceutical defects is
card system in Australia, Med watch in USA and National recommended.
Pharmacovigilance Programme (NPP) in India. 5. Adverse reactions to cosmetics.
3. Prescription event monitoring. 6. All suspected ADRs associated with drug-drug, drug-food
4. Comparative observational studies, e.g. case control and or drug-food supplements interactions.
cohort studies. 7. Suspected ADRs associated with the drug withdrawals.
126 5. Pharmacy based postmarketing surveillance studies. 8. ADRs occurring from overdose or medication error.
 Adverse Drug Reactions and Pharmacovigilance
Pharmacovigilance is primarily concerned with the pharma- Pharmacovigilance Scenario in India
ceutical medicines (including radiological contrast media, The status of the pharmacovigilance activities in India has been
vaccines and diagnostics) but adverse reactions associated with dismal. A fresh effort is being made again to revive this
drugs used in traditional medicine (e.g. herbal remedies) should programme by the Government through Drug Controller
also be considered. General of India (DCGI). The revised National Pharmacovigilance
The pharmacovigilance programme in general has not taken Programme has now chosen 24 centres for this all over the
off very well in most countries really because of some country with a nodal center at New Delhi. With such a large
misconceptions on the part of the clinicians, such as: population using the drugs and a vast amount of expertise,
the National Pharmacovigilance Programme in terms of
1. All serious ADRs are documented by the time, a drug is
implementation and an acceptable outcome should not be a
marketed.
problem, if all cooperate and report.
2. It is difficult to determine if a drug is responsible.
Good pharmacovigilance practices
3. ADRs should only be reported if absolutely certain.
The pharmacovigilance is an important tool in the lifecycle of a
4. One reported case is not going to make a difference.
drug starting from the beginning of the clinical trials and going
5. One can have legal complications if he reports an ADR. into the post-marketing phase with the sole motive of making
The general attitude of the prescribers which does not really the drug treatment safe for the patient. The various ingredients
help the cause of pharmacovigilance programme is amply of these practices are as follows:
shown by the ‘seven deadly sins’, i.e. indifference, ignorance, 1. Education, training and access to reliable information for
financial incentives, legal hurdles, complacency, diffidence and the clinicians and the patient.
lethargy. 2. Good pharmacovigilance regulations.
Stakeholders in pharmacovigilance 3. Development of a national pharmacovigilance database.
The stakeholders who can help in pharmacovigilance are the 4. Good pharmacovigilance communication.
users (patients), prescriber (the clinician), supplier (pharma 5. Good culture of spontaneous reporting by the clinicians
industry) and the Government. Media can also play an and the patients.
important role.
6. Proactive industry initiatives.
Communication tools 7. Provision of convenient system of submission and feedback
The main reason for poor success of the pharmacovigilance on reported ADRs.
programmes all over the world has been a poor communication. 8. Better patient care through better safety information.
It is required to use well-defined tools for an effective
communication within the various participants of any such CONCLUSIONS
programme. Following are some of the proposed tools which The clinicians have to be aware of the harmful potential of the drugs
are likely to help: and to be ready to detect the ADRs at the earliest and correlate
them with the drug therapy and if so to manage them as best as
Vehicle Issued by
possible to serve the best and safe interest of the patients which
“Dear Doctor” letters Pharmaceutical manufacturers will go a long way for the success of the NPP. This will surely need
Medicine alerts National health authorities the active and willing participation of all the stakeholders.
Media statements National health authorities/
pharmacovigilance centres RECOMMENDED READINGS
1. Gad SC. Clinical Trial Handbook; New Jersey: John Wiley and Sons, Inc; 2009.
Patient information leaflets National health authorities/
pharmacovigilance centres/ 2. Gad SC. Drug Safety Evaluation; 2nd Ed. New Jersey: John Wiley and Sons,
Inc; 2009.
pharmaceutical manufacturers
3. Mann RD, Andrews EB. Pharmacovigilance; 2nd Ed. West Sussex: John Wiley
Newsletters National pharmacovigilance and Sons, Inc; 2007.
centres and WHO
4. Waller P. An Introduction to Pharmacovigilance. Sussex: Wiley-Blackwell; 2010.

127
 4.4 Prescribing in Special Situations

Uma Tekur

INTRODUCTION avoided in pregnancy. Other antiemetics that may be safely

Inter-individual and intra-individual variation in drug response used in pregnancy are, promethazine, cyclizine and
is a well known phenomenon. It is, therefore, imperative that prochlorperazine.
the health care providers are aware of the sources of such Anaemia
variations. This knowledge will help physicians prescribe drugs
Due to increased demand of growing foetus anaemia occurs
more effectively and safely.
commonly. Folic acid and iron should be given routinely
The variations in the drug response may be: during pregnancy. Folic acid should be started as soon as
1. Pharmacokinetic variations are chiefly due to alteration pregnancy is diagnosed whereas iron may be started in
in the absorption, distribution, metabolism or excretion second trimester. The risk of neural tube defects is significantly
of drugs in an individual patient leading to an alteration reduced with supplemental folic acid. This is in addition to a
in the concentration of drug available at the site of its healthy diet that should be recommended throughout the
action. These variations may be seen in malabsorption pregnancy.
syndrome; heart failure, nephrotic syndrome (due to Pregnancy induced hypertension
altered absorption); renal or hepatic impairment or in
It can present as pre-eclampsia or eclampsia. Apart from
meningitis (variation in distribution, metabolism or
increase in blood pressure, eclmapsia manifests as seizures.
excretion).
Alpha methyldopa is the drug of choice for the management
2. Pharmacodynamic variations due to difference in response of hypertension whereas magnesium sulphate is used for the
to a drug. These may be seen in Myasthenia gravis, nephro- treatment of eclampsia.
genic diabetes insipidus, familial hypercholesterolaemia, Pre-term labour
precocious puberty, etc.
Atosiban (oxytocin receptor antagonist), calcium channel
The human body undergoes constant physiological changes blockers, terbutaline like drugs can be used for delaying the
throughout one’s life. Definitive changes are observed in labour. In addition, dexamethasone can be administered to
childhood, old age, and in women during pregnancy and accelerate foetal lung maturation.
lactation.
Placenta praevia
The present chapter will briefly discuss the drugs use: (i) at the
Drugs do not play much role in the management of this
times of physiological changes seen in pregnancy, childhood
condition.
and old age, and (ii) in hepatic and renal impairment.
Rh isoimmunisation
DRUGS IN PREGNANCY To a mother with Rh negative blood group, if a baby is born
There is a two-fold problem that should be taken care of while with Rh positive blood group, anti-D (anti-Rh immunoglobulin)
administering drugs during pregnancy, viz: (i) alteration in drug should be administered within 72 hours of delivery to prevent
response due to variation in physiology, and (ii) the teratogenic erythroblastosis foetalis that may occur during subsequent
effects of drugs. pregnancy.
A pregnant woman will require drug treatment primarily under Medical Conditions Complicating Pregnancy
two circumstances. General guidelines to be followed are:
1. For the management of pregnancy related (obstetrical) 1. As a general rule, drugs should be avoided during
conditions, and pregnancy.
2. For the management of medical conditions unrelated to 2. The drugs having the best safety record over time should
pregnancy. be used if necessary.
Obstetrical Conditions 3. Newer drugs should be avoided unless safety is clearly
The common obstetrical problems encountered during established.
pregnancy are: 4. The drugs should be used at lowest effective dose and for
shortest period.
Nausea and vomiting
5. Over-the-counter drugs cannot be assumed to be safe in
These symptoms are seen in early pregnancy and usually do
pregnancy.
not require any drug therapy. However, hyperemesis gravidarum
may be treated with doxylamine (anti-histaminic) alone or in The following is a list of drugs that may be given during
combination with pyridoxine. Metoclopramide should be pregnancy if necessary.
128
 Prescribing in Special Situations
1. Analgesics: Paracetamol and ibuprofen (at low doses) are feeding while prescribing drugs to a lactating female. It is
safe during pregnancy. Other nonsteroidal anti-inflammatory inappropriate to discontinue breastfeeding while on drug
drugs (NSAIDs) and opioids should be avoided during treatment or to continue breastfeeding while taking drugs that
pregnancy. are contraindicated.
2. Anti-allergics: Older anti-histaminics like chlorpheniramine Two factors to be considered are:
and promethazine are considered safe during pregnancy. 1. Are these drugs indicated by themselves in children, e.g.
Second generation agents like cetirizine should be avoided. penicillins?
3. Anti-microbials: Penicillins, macrolides and cephalosporins 2. Is there any risk to the infant in the concentration present
are considered safe during pregnancy. Tetracyclines, in the milk?
aminoglycosides and fluoroquinolones should be avoided.
Safety Assessment of Some Frequently Used Drugs
4. Anti-tuberculosis drugs: Rifampicin and isoniazid are safe
during pregnancy. Streptomycin should not be used in Analgesics
pregnancy. Analgesics such as paracetamol, ibuprofen, naproxen and
5. Anti-parasitic and anti-protozoal drugs: Diloxanide codeine are considered to be ‘safe’, due to low transfer into
furoate (anti-amoebic) drug is safe during pregnancy breast milk. Aspirin is best avoided due to the theoretical
whereas metronidazole should be avoided. risk of Reye’s syndrome. Sumatriptan has a short half-life of
approximately 2 hours and infant exposure can be almost
Chloroquine and proguanil are safe antimalarials; and
completely avoided by expressing and discarding breast milk
piperazine and niclosamide are preferred for worm
for approximately 8 hours after dosing. Tramadol has a low
infestations.
transfer into breast milk (insufficient data) therefore is to be
6. Anti-hypertensive drugs: Methyldopa, hydralazine, avoided. Morphine is usually considered ‘safe’ because of low
labetalol, clonidine and prazosin are safe during pregnancy. transfer into milk, and high first-pass metabolism.
Angiotensin converting enzyme (ACE)-inhibitors and
angiotensin receptor blockers are absolutely contra- Anti-helminthics
indicated during pregnancy. There does not appear to be any data on the transfer of
7. Anti-diabetic drugs: Insulin is safe to be used during mebendazole or pyrantel embonate into human breast milk
pregnancy whereas oral anti-diabetic drugs should be although these agents are generally considered to be ‘safe’ due
avoided. to poor absorption from the gastrointestinal tract.
8. Hormones: Inhaled and topical corticosteroids can be safely Antibiotics
used during pregnancy. Oral steroids like prednisolone in low  Antibiotics such as penicillins, cephalosporins and
doses may be given. However, high-dose and prolonged use macrolides are considered to be compatible with
of oral corticosteroids are not indicated. Thyroxine can be breastfeeding although there are theoretical risks of
used safely for the treatment of hypothyroidism and alterations to infant bowel flora and allergic sensitisation.
propylthiouracil is used for hyperthyroidism.
 The safety of metronidazole is controversial.
9. Drugs for central nervous system (CNS) disorders:
 The transfer of tetracyclines into breast milk is low but are
Haloperidol (anti-psychotic drug) is safe. Fluphenazine,
avoided due to the possible risks of inhibiting bone growth
clozapine should be avoided during pregnancy. Lithium is
or causing dental staining.
contraindicated. Amitryptyline, imipramine and fluoxetine
are safe anti-depressants whereas other SSRIs should be  Fluoroquinolones have been reported to cause
avoided. arthropathies in immature animals and hence avoided.
10. Anti-coagulants: Heparin and low molecular weight  Sulphonamides such as sulphamethoxazole are avoided in
heparins are considered safe during pregnancy whereas infants with hyperbilirubinaemia or glucose-6-phosphate
oral anti-coagulants like warfarin should be avoided. dehydrogenase deficiency.
11. Asthma: Inhaled bronchodilators like salbutamol, and Anti-coagulants
ipratropium, inhaled corticosteroids like beclomethasone Heparins (unfractionated and low molecular weight) are
and mast cell stabilisers like cromoglycate are safe drugs
considered ‘safe’ since do not cross into breast milk to a
during pregnancy. Theophylline and oral corticosteroids
significant extent. Warfarin is also considered to be compatible
should be avoided.
with breastfeeding as transfer is low, and adverse effects and
12. Laxatives: Dietary fibre, lactulose and Ispaghula are changes in prothrombin time have not been detected. However,
considered safe laxatives during pregnancy. it would be prudent to monitor the infant’s prothrombin time
13. Anti-diarrhoeals: Oral rehydration salts should be used to during treatment.
prevent and treat the dehydration. Use of loperamide and Anti-convulsants
diphenoxylate are unsafe.
Carbamazepine, phenytoin and sodium valproate are generally
Breastfeeding and Drugs considered to be compatible with breastfeeding although the
Many drugs are secreted in the breast milk. However, all the infant should be observed for evidence of central nervous system
drugs do not necessarily cause harm to the baby. The clinician depression. Lamotrigine and gabapentin are best avoided during
must determine the risk-benefit ratio of the continued breast- breastfeeding.
129
 Anti-depressants therapeutic index. The physiologic changes decrease renal
Selective serotonin reuptake inhibitors (SSRIs) transfer into elimination of the drugs. Creatinine clearance (measured by the
breast milk to varying extents. Paroxetine is the preferred SSRI Cockcroft-Gault formula) is used to guide of dose excreted by
in breastfeeding women. Fluoxetine along with its active the kidneys.
metabolite, norfluoxetine transfers to a greater extent and, has [140 – age (yr)] [body wt (kg)]
Clcreat (mL/min) = -------------------------------------------
a long half-life of one to two weeks and may accumulate in a (72) [serum creatinine (mg/dL)]
breastfed infant. Tricyclic anti-depressants are considered to be
compatible with breastfeeding. Moclobemide considered For women, the calculated values are multiplied by 0.85.
compatible with breastfeeding.
EFFECT OF AGE ON PHARMACODYNAMICS OF DRUGS
Anti-histamines
Increased sensitivity due to ageing must be considered with
Promethazine, dexchlorpheniramine and diphenhydramine drugs like morphine, pentazocine, warfarin, ACE-inhibitors and
are considered to be safe although it would be prudent to diazepam (especially when given parenterally) and tolbutamide,
monitor for evidence of sedation or irritability in the infant. glyburide and beta-blockers should be used with caution
Loratadine and fexofenadine are likely to be safe due to low because of serious dose-related toxicity.
transfer into milk.
For effective and safe sedation, the dose of midazolam should
Benzodiazepines be decreased by 30% in elderly patients because of
Sporadic use of midazolam and temazepam ( short half-life) are pharmacodynamic changes associated with age.
safe. Diazepam (having long half-life) may accumulate and is
Principles of Drug Therapy in Elderly
associated with lethargy, poor suckling and reduced weight gain.
Efficacy and safety are important considerations when
Recreational agents prescribing drugs in the elderly. Therefore, use drugs with
These have particular problems because the dose and pattern documented efficacy and lowest toxicity.
of usage are uncontrolled. In addition most have relatively high
Dose must often be reduced in the elderly. In general, the
infant doses. Alcohol consumption should be minimised during
starting doses of drugs are about one-third to one-half the usual
lactation (e.g. by withholding breastfeeding for about two hours
adult doses.
after ingestion of a standard alcoholic drink). Caffeine exposure
may lead to restlessness and irritability in infants. Smoking is Complexity of drug regimens (e.g. multiple drugs, frequent
best avoided by breastfeeding mothers. dosing, and variable doses) increases the risk of non-
compliance. If a patient has more than one disorder, e.g.
DRUGS IN GERIATRICS
hypertension and angina then treat both conditions with a
Ageing alters pharmacokinetics and pharmacodynamics, single drug like a beta-blocker or calcium channel blocker.
affecting the choice, dose, and dosing frequency of many drugs. Wherever possible choose long-acting or slow-release
The elderly have many chronic disorders and consequently use preparations for better compliance.
more drugs than any other age group. Safe, effective pharmaco-
therapy is one of the greatest challenges in clinical geriatrics. Cost of drugs can impose a major financial burden, hence least
Appropriate use of drug requires an evaluation of potential expensive drug with comparable efficay should be considered.
benefits and risks. Drug Therapy in Children
EFFECT OF AGE ON PHARMACOKINETICS OF DRUGS Children are not small adults. It cannot be assumed that a child’s
dose is proportional to an adult’s dose (i.e. a 5 kg child requires
Absorption and Distribution 1/10 the dose of a 50 kg adult).
Absorption and distribution of drug tend to be trivial and
Pharmacodynamic Considerations
clinically inconsequential. The relative decrease in total body
water leads to higher blood (and often tissue) concentrations Children have increased risk with certain drugs because of
of some water-soluble drugs. differences in pharmacokinetics or because of drug effects on
growth and development. Although the adverse effects are
Hepatic Metabolism similar to those seen in adults, but children are at high-risk of
Decreased hepatic blood flow significantly affects hepatic accidental poisoning. Infants are at risk of toxicity from drugs
elimination of drugs. Hepatic cytochrome p450 enzymes is used by adults.
reduced. In the elderly, the initial doses of, labetalol, propranolol,
verapamil should be reduced. Drugs with active metabolites Common drugs with unique or higher risk of adverse effects in
lihe diazepam, chlordiazepoxide, amitriptyline, imipramine, children are presented in Table 1.
chlorpromazine, thioridazine, risperidone, and morphine, Drug dosing
meperidine, propoxyphene, may accumulate and have
increased risk of toxicity. The maintenance doses of these drugs In children, less than 12 years is always a function of age, body
should be reduced. weight, or both. This approach is practical but not ideal; even
within a population of similar age and weight, drug requirements
Renal Elimination may differ because of maturational differences in absorption,
Clinical implications depend on the contribution of renal metabolism, and elimination. Thus, dose adjustments should be
elimination to total systemic elimination and on the drug’s based on plasma drug concentration, wherever possible.
130
 Prescribing in Special Situations
Table 1: Drugs Manifesting Unusual Toxicity in Children 3. Lipid-lowering medications: HMG-CoA reductase inhibitors
(statins) and nicotinic acid (niacin).
Drug Adverse effect
4. Anti-hypertensives: Labetalol, hydralazine, antiarrhythmics,
Local anaesthetics Cyanosis due to conversion of amiodarone, procainamide.
(e.g. benzocaine, mixture of haemoglobin to methemoglobin
5. Antibiotics: Erythromycin, estolate, isoniazid, nitrofurantoin,
lidocaine and prilocaine)
sulphonamides, tetracycline.
Sulphonamides Kernicterus in neonates
6. Anti-fungal medications: Fluconazole, itraconazole,
Diphenoxylate Respiratory depression and death as
ketoconazole.
an overdose syndrome, usually in
children < 2 years 7. Anti-convulsant medications: Valproic acid, carbamazepine.
Fluoroquinolones Cartilage toxicity suspected based on 8. Psychotropic medications: Bupropion.
animal studies, but adverse effects in 9. Tricyclic anti-depressants: Chlorpromazine.
humans are not proved
10. Hormonal medications: Tamoxifen, testosterone.
Chloramphenicol Grey Baby syndrome in neonates
11. Miscellaneous medications: Halothane, methotrexate
Prochlorperazine Extrapyramidal effects, opisthotonus
etretinate, protease inhibitors.
and bulging fontanelles. Febrile and
dehydrated infants especially at risk Hepatic Disease Affecting the Drug Pharmacokinetics and
SSRIs Increased incidence of suicidal Dynamics
ideation in children and adolescents Liver is a metabolic factory of the body which controls and
Tetracycline Discolouration and pitting of tooth regulates the body physiology. A large proportion of drugs are
enamel. This adverse effect is metabolised and their pharmacological properties are regulated
restricted to children < 8 years by the liver. In disease states of the liver, the metabolism of these
drugs may significantly change and therefore these drugs may
DRUGS AND LIVER DISEASE
have enhanced action even bordering toxicity. Therefore, use of
Pharmacotherapy in liver disease can be discussed under two these drugs should either be reduced or stopped totally. Drugs
broad headings: excreted through the bile namely azithromycin, tetracycline,
1. Drugs causing hepatotoxicity. rifampicin and fusidic acid have a reduced excretion in cases of
2. Hepatic disease affecting the drug pharmacokinetics and intrahepatic and extrahepatic obstruction.
dynamics. Hypoalbuminaemia associated with marked liver dysfunction
Drug-Induced Hepatotoxicity is associated with impaired metabolism of drugs which bind to
albumin in the body. One of the examples is Phenytoin and the
The liver plays a central role in transforming and clearing
toxicity of such drugs is increased manifold. The effect of drugs
chemicals and is susceptible to the toxicity from these agents.
like alcohol, opioids, sedatives or hypnotics may be prolonged
Major mechanisms of drug-induced hepatotoxicity include:
and enhanced significantly in liver disorders.
1. Interference with bilirubin transport and conjugation
occurs, e.g. rifampicin. Similarly, action of anti-coagulants may enhance mainfold
in patients of advanced liver disease. The risk of bleeding
2. Use of paracetamol and isoniazid cause cytotoxic damage.
also increases in patients with liver disease especially on NSAIDS
3. Cholestasis occurs with orally active anabolic and androgenic and the bleeding may occur in areas like brain, kidney and
agents and oral contraceptives, phenothiazines like subcutaneous tissue.
chlorpromazine, trifluoperazine, promazine, pecazine, etc.
In liver disease, there are no clear cut guidelines available
4. Mixed cytotoxic/cholestatic injury occurs with chlorpromazine.
like that in CKD about the change in dosage schedule in
However, p-aminosalicylic acid may cause mixed hepatocellular
cases of liver dysfunction. Therefore, the drugs may have to be
liver injury.
reduced or stopped altogether.
5. Fatty liver (steatosis) occurs with the use of tetracycline.
6. Chronic active hepatitis, cirrhosis and subacute necrosis is DRUGS AND RENAL DISEASE
seen with alpha-methyldopa, nitrofurantoin and isoniazid. Pharmacotherapy in renal disease can be discussed under two
Long-term administration of the antituberculosis drug broad headings:
(isoniazid) may lead to hepatic dysfunction. 1. Drugs causing nephrotoxicity.
7. Liver tumours: Anabolic steroids have been implicated as 2. Renal disease affecting the drug pharmacokinetics and
responsible for primary hepatocellular carcinomas and dynamics.
adenomas.
Drugs Causing Nephrotoxicity
8. Non-specific changes: Certain hypotensives, vasodilators, Many drugs can cause renal dysfunction.
anti-inflammatory agents and oral contraceptives cause a
transient increase in transaminase levels. Drugs causing prerenal damage
Nonsteroidal anti-inflammatory drugs (NSAIDs),even in short course,
List of Hepatotoxic Drugs
can cause acute renal failure; ACE-inhibitors can also cause a
1. Analgesics: NSAIDs, acetaminophen. deterioration in renal function. Care should be taken when an ACE-
2. Anti-diabetic agents: Acarbose, pioglitazone, sulphonylureas inhibitor and NSAIDs are prescribed together as this combination
(e.g. Glyburide). may precipitate an acute deterioration in renal function. 131
 Drugs causing intrarenal damage Renal Disease Affecting Drug Pharmacokinetics and Dynamics
Drugs that cause glomerulonephritis include penicillamine, An accurate estimation of renal function, or glomerular filtration
gold, captopril, phenytoin penicillins, sulphonamides and rate, requires sophisticated techniques. In practise, the serum
rifampicin. creatinine concentration is used for day-to-day assessment of
renal function. Creatinine clearance can be calculated using
Drugs that may cause interstitial nephritis include penicillins,
Cockcroft-Gault formula.
cephalosporins, sulphonamides, thiazide diuretics, frusemide,
NSAIDs and rifampicin. Dose Alteration in Renal Impairment
Aminoglycosides, amphotericin and cyclosporine can cause Generally dose adjustment is needed when the creatinine
acute tubular necrosis. clearance is below 60 mL/min. Adjustments can be achieved
by a reduction in dose, or an extension of the dosing interval,
Drugs causing postrenal damage (urinary tract obstruction) or both. List of some commonly prescribed drugs that require
High-dose sulphonamides, acetazolamide or methotrexate dose alteration in renal impairment are given in Table 2.
may cause crystalluria and could therefore cause obstruction.
Tricyclic antidepressants, and alcohol may cause urinary tract CONCLUSION
obstruction due to retention of urine in the bladder. The dosage of drugs is based on the half life of the drug, age and
Other nephrotoxic drugs weight of the individual. This dosage may need to be adjusted in
special situations like, liver disease, kidney disease, pregnancy.
Cephalosporins: Cephaloridine, one of the first cephalosporins This is important so that the function of that organ is not
has been associated with direct renal toxicity but third compromised further and due to poor excretion. The toxicity of
generation cephalosporins, e.g. cefixime, have very rarely been drugs may ensure at therapeutic dosages due to retention in the
reported to cause nephrotoxicity. body. In pregnancy the issue of medicine producing teratogenic
Analgesics: NSAIDs may cause acute renal failure. Analgesic effects and crossing the placental barrier may induce damage to
nephropathy has been most commonly seen with combination the foetus.
analgesic that contain aspirin and/or paracetamol. Analgesic Therefore this chapter has discussed some of important issues
nephropathy is one of the few preventable causes of chronic in drug usage in such situations. Adjustment of drug dosages
renal failure. Discontinuation of the abused drugs often results has been highlighted. It is important for a clinician to know
in stabilisation or even improvement in renal function Lithium the pharmacology and metabolism of the drug along with the
levels consistently above the therapeutic range have been integrity of functional capacity of various organs where drug
associated with development of a nephrogenic diabetes is metabolised or excreted and defects of various enzyme
insipidus. systems.

Table 2: Commonly Prescribed Drugs that Require Dose Adjustment in Renal Impairment
Class Examples
Antibiotics/anti-fungals Aminoglycosides (e.g. gentamicin), vancomycin, ceftazidime, cefepime, cephazolin, ciprofloxacin,
fluconazole, piperacillin, carbapenems (e.g. meropenem), sulphamethoxazole
Anti-virals Famciclovir, acyclovir, valacyclovir, valgancyclovir, gancyclovir
Anti-coagulants Low molecular weight heparins (e.g. enoxaparin)
Cardiac drugs Digoxin, sotalol, atenolol
Diuretics If creatinine clearance is less than 30 mL/min: avoid potassium-sparing diuretics due to risk of
hyperkalaemia-thiazide diuretics have limited efficacy
Opioids Morphine, codeine, pethidine (due to risk of accumulation of active or toxic metabolites)
Psychotropics/anti-convulsants Amisulpride, gabapentin, lithium, levetiracetam, topiramate, vigabatrin
Hypoglycaemic drugs Metformin, glibenclamide, glimepiride, insulin
Drugs for gout Allopurinol, colchicine
Others Lamivudine, methotrexate, penicillamine

132
 4.5 New Drug Development

Sadhna Joglekar

INTRODUCTION PRE-CLINICAL/NON-CLINICAL TOXICOLOGY

Pharmaceutical medicine is a relatively new discipline, but is AND PHARMACOLOGY
growing very rapidly. It deals with the discovery, development, Initiation of non-clinical toxicology studies marks the end of
evaluation and monitoring of drugs and devices, as well as with the discovery or research phase and the beginning of the
medical aspects of their commercial promotion. development phase. Animal toxicology studies can be
categorised into the following:
THE PROCESS OF DRUG RESEARCH AND DEVELOPMENT
1. Acute toxicity: single dose and repeat dose
The research and development (R and D) process for a new drug 2. Subacute toxicity
can be subdivided into the following phases: discovery (basic
3. Chronic toxicity
chemical or structural research); preclinical R and D; clinical
development and regulatory development. 4. Special toxicological studies

In addition, two other processes contribute to the life-cycle of Single dose studies are an important first step in establishing
a drug, once it is marketed. These are pharmacovigilance and the safety profile of a new chemical entity, the aim being to
life-cycle management (which includes development of new test a range of doses, from those that produce no effect to those
or improved uses of the drug or new delivery systems). that produce some level of exaggerated effect. The results of
these studies guide dose selection for the repeat dose studies,
DISCOVERY in which animals are provided continuous exposure to test drug
In the early 50s and 60s, new drugs were discovered primarily to identify safe levels of the drug. Generally, animals are exposed
through random screening and serendipity played a very to higher doses of the drug for longer duration than that
crucial role. Structure-activity relationship (SAR) was a planned in clinical studies. An important aspect of these studies
rudimentary science then. The 70s and 80s saw the process of is pharmacokinetic correlation called ‘toxicokinetics’.
pharmaceutical discovery evolve into a fine science of protein The duration of chronic studies depends to a large extent on
chemistry and enzyme elucidation. Combinatorial chemistry, the intended duration of therapy in clinical usage. It varies from
genomics and high-throughput screening have characterised 6 months to 9-12 months in rodent and non-rodent species.
the 90s with a resultant drug discovery targeted at molecular
and disease mechanism level. Special studies include reproduction and teratogenicity studies,
carcinogenicity studies and mutagenicity studies. It was the
Today, the starting point for the R and D activity is the thalidomide disaster which highlighted the need to evaluate
identification of an unmet medical need. This is followed by new drugs in reproductive toxicology studies. Carcinogenicity
the identification of specific molecular targets (e.g. cellular studies involve exposure of rodents to the new chemical entity
enzymes or receptors) with the help of protein biochemistry, for 18-24 months and are usually required for drugs intended
immunology (antibody targeting), pharmacology and to be used clinically for 6 months or more. Apart from these,
molecular biology. One of the latest entrants on the scene of special studies could also include neurotoxicity studies,
target identification is the use of genomics and linkage metabolic studies, etc.
analysis. A classic example of the success of this technique is
the identification of apolipoprotein E (ApoE) as an important All preclinical studies intended to support further clinical work
causative factor in Alzheimer’s disease. Once a molecular or marketing applications need to be conducted in compliance
target is identified, it is validated. If results of validation with good laboratory practices (GLP) and ICH (International
experiments appear promising, drug screens or assays are Conference on Harmonisation) guidelines, wherever applicable.
established to identify new chemical entities. An assay In addition, local national regulations stipulate different types
essentially integrates a biological system with chemical of studies.
compounds that may become tomorrow’s drugs. The sources CLINICAL DEVELOPMENT
of starting material for drug screens are chemical libraries,
The successful culmination of in vivo animal data, receptor
natural products, computationally designed drugs and drugs
binding studies and in vitro functional assays, is a progression
derived from medicinal chemistry which are modified using
of the new chemical entity to clinical testing. The clinical
combinatorial chemistry.
development programme is divided into four phases.
Besides evaluation and validation of a new chemical entity, the Although in earlier times, the testing of a drug used to progress
drug discovery programme also includes cytotoxicity from one phase to the next one in a step-wise manner, the
evaluation. Only compounds with good activity in ‘in vitro’ assays temporal distinction between these phases has significantly
with no cytotoxicity progress to animal testing. blurred in recent times, due to evolving regulatory

133
 environment, financial considerations and a need to expedite patients are prescribed this drug in a real-world, uncontrolled
drug development. Definitions of phases of clinical trials are environment. Specific studies are conducted after a medicine
therefore purely functional and an investigational medicine is is marketed in order to provide additional information on
often evaluated in two or more phases simultaneously. It must efficacy or safety, or drug interactions or comparisons with other
be highlighted here that all clinical trials with drugs are marketed drugs. Phase IV studies are distinct from post-
regulated in India by the Schedule Y of the Drugs and Cosmetics marketing surveillance, which are observational or non-
Act, 1945 (http://cdsco.nic.in). Further, the Indian Council of experimental in nature.
Medical Research (ICMR) has issued guidelines for ethical
conduct of biomedical research (http://www.icmr.nic.in/ CLINICAL STUDY DESIGNS
human_ethics.htm) and it is expected that all individuals While designing clinical studies, different methods are used to
conducting clinical research would follow these guidelines. enhance the accuracy of the data and to reduce bias and effect
of nondrug factors. Some of these techniques are given below.
Phase I (First in Human) Studies
Phase I studies are the first opportunity for extrapolation from Blinding
animal data to human exposure. These are initial safety studies, This technique is employed to reduce observer bias and
usually conducted in normal volunteers, the notable exception patient bias by concealing the identity of the treatment being
being oncology drugs which are evaluated in cancer patients administered. If either the investigator or the patient is unaware
even at Phase I level. The aim of these studies is to establish a of the treatment, the study is termed as ‘single-blind’ study. If both
dose range tolerated by volunteers for single and multiple these parties are unaware, the study is termed as ‘double-blind’.
doses. Additionally, pharmacokinetic studies are usually
Placebo-Controlled Study
considered as Phase I studies, regardless of when these are
conducted during a medicine’s development. In addition to the specific effects of the drug, the final patient
response is often affected by non-specific factors such as
Phase II (First in Patients) Studies patient’s personality, attitude of the medical staff, appearance
These are studies in a selected group of patients, with an aim to of the drug and the feeling of being looked after. To distinguish
assess safety and identify the tolerable effective dose of the new the pharmacological effect from non-specific effects, a pseudo
drug. Phase IIa generally refers to pilot studies which may assess drug, identical in appearance but pharmacologically inert
dose response, frequency of dosing, type of patient, etc. Phase (placebo), is administered.
IIb, also termed as ‘pivotal studies’, are well-controlled trials, usually
Randomisation
representing the most rigorous demonstration of a drug’s efficacy.
Studies in this phase are usually exploratory in nature. In a comparative study, allocation of patients to different groups
must be done by random assignment. Randomisation ensures
Phase III Studies random distribution of uncontrolled variability factors and
These are aimed at generating additional efficacy and safety ensures that patient assignment to treatment groups cannot
data in relatively large number of patients in both controlled be predicted.
and uncontrolled trials. Special population groups such as the
Finally, one must be cognizant of the fact that the R and D
elderly or those with renal failure are also studied during this
process is fraught with inherent risks and is an expensive and
phase.
time-consuming process. It is estimated that the end-to-end
Phase III trials are often subdivided into IIIa (prior to regulatory process can take upwards of 10 years and cost on an average in
submission of New Drug Application) and IIIb studies (after excess of US $800 million in the US before a chemical is
regulatory submission of New Drug Application but before its marketed as a ‘medicine’.
approval). Phase III studies are generally aimed at being
confirmatory studies. RECOMMENDED READINGS
1. Fletcher AJ, Edwards LD, Fox AW, et al. Principles and Practice of
Phase IV Studies Pharmaceutical Medicine. UK: John Wiley and Sons Ltd; 2002.
New drug development does not stop when regulatory 2. Spilker B. Guide to Clinical Trials. USA: Raven Press; 1991.
approval comes in. As a matter of fact, the true test of a new 3. Spriet A, Simon P. Methodology of Clinical Drug Trials. Switzerland: S Karger
drug begins once it is available in the market and millions of AG; 1985.

134
 4.6 Pharmacoeconomics

Gurudas Khilnani

INTRODUCTION
The health expenditure is increasing day-by-day due to increasing
cost of medicines and other health services. The expenditure is
further escalated by increased life-expectancy, technological
upgradation and increased demand due to increased awareness.
Therefore, there is a need for optimal allocation of limited
resources. Pharmacoeconomics is a subset of health economics
that identifies, measures and compares the costs of medicines/
treatments with outcomes. It helps us to make therapeutic
choices among the alternatives. It should not be viewed merely
as cost cutting academic exercise because it is an important
aspect of rational therapeutics and enhancing patient care.
Pharmacoeconomic analysis is also increasingly incorporated in
clinical protocols for the evaluation of new drugs.

COMMON TERMS USED IN PHARMACOECONOMIC ANALYSIS

Efficacy
It is the utility of treatment in ideal (trial conditions) settings.
Clinical effectiveness is the effect of treatment in clinical settings
than in ideal settings.
Incremental Analysis
It finds out the superiority and benefit of new treatment over
Figure 1: Cost-effectiveness analysis.
and above existing one. This is done by calculating additional
cost of new treatment for treating one extra patient or how much
extra cost is needed to discharge a patient one day earlier to the effective and less costly, it is to be ascertained by cost-
existing treatment. This is called as incremental or marginal cost, effectiveness analysis that existing medicine/therapy be
which is how much cost is changed with a small change in retained or not.
outcome. Incremental analysis is usually done for cost-effective
analysis. Perspective
Since overall cost reduction affects society at large, therefore
Cost Effectiveness societal perspective is considered in most of the pharma-
It compares natural units of beneficial outcome (e.g. reduction coeconomic analyses.
in HbA1c, life years gained, etc.) with the cost of treatment.
Cost of a drug may be lower than the alternative available and METHODS OF PHARMACOECONOMIC EVALUATION
therefore, total cost of treatment is considered. An example Utilising the basic fundamentals of economics, the cost is
is use of low molecular weight heparin (LMWH) versus considered as one factor and is compared with benefit accrued
conventional heparin (CH). The cost price of CH is less than from the use of medicine or treatment as another variable.
that of LMWH, but CH use requires frequent injections (nursing Therefore, cost outcome analysis is an integral part of
charges included) and monitoring by activated partial pharmacoeconomics. The data for analysis can be collected by
thromboplastin time (aPTT) test, which also has some cost. prospective or retrospective studies. Another method is the use
Thus, LMWH may become more cost-effective in certain of ‘modelling’ such as decision analysis tree to make value based
situations. Figure 1 gives four possible outcomes found in decisions.
such a analysis.
Cost
It is obvious that a therapy, which is less costly and more This includes direct, indirect and intangible costs.
effective, should be preferred. If a newer medicine or treatment
is more costly but less effective, it should be discarded. When Direct cost
new treatment is more effective but more costly then cost- It is the cost of procurement of medicines and treatment.
effectiveness analysis may provide quantitative data (how many It includes price of medicines, nursing, hospitalisation,
life years are gained and is it worth to spend more?) for rational transportation and drug administration. These are measured
selection of new therapy. If new medicine/treatment is less easily.
135
 Table 1: Types of Pharmacoeconomic Analysis
Type of analysis Measurement Example Advantages Disadvantages
Cost minimisation Differences in costs with Generic versus branded Simple, useful when Cannot be used when
equal benefits drug use: Use of medicine outcomes are similar outcomes are different
Excess cost of branded by two different routes of
drug administration
Cost effectiveness Health benefits in natural Use of heparin versus low Magnitude of benefit Cannot be used for
units (life years saved, heart molar heparin in acute of two treatments direct comparisons of
attacks prevented, strokes myocardial infarction: (defined outcome) is outcomes between the
prevented and costs in effect on mortality measured with treatments of different
monetary units monetary units conditions
(rupees) Cost per (unit)
patient saved
Cost utility Measures utility units, Reduction in mortality Can compare two Utility units are not easily
degree of well-being and morbidity. treatments for different defined and fixed.Measured
achieved. Measures Quality adjusted life conditions values vary with time and
qualitative and quantitative years (QALYs)* disease perspective
change Cost per QALY
gained
Cost benefit Costs and benefits are Comparison of surgical Dissimilar treatments Difficulty in quantifying health
measured in monetary treatment with drug (outcomes) can be benefit in monetary terms
terms (Rupees) treatment of chronic compared (Rupee value) Intangible
Benefit: Cost ratio simple glaucoma benefits are usually ignored

* One QALY is living for one year in perfect health or living in half perfect health for two years and so on.

Indirect cost minimisation and cost-effectiveness analyses are commonly

It is the cost of loss of work output and earnings due to patient’s used for evaluation of newer medicines and therapies. Cost-
illness and family members’ attendance during illness. These utility analysis requires a comprehensive analysis. Cost-benefit
are difficult to measure. analysis is useful to compare the cost of different therapies in
dissimilar disorders.
Intangible cost
It is a cost due to pain, distress and suffering affecting quality of USES OF PHARMACOECONOMIC ANALYSIS
life. It is measured for cost-utility analysis. In addition, there is an Pharmacoeconomic studies increase cost consciousness among
opportunity cost which is the benefit foregone in opting for an the medical fraternity and health administrators. Pharmaco-
alternative therapy or drug. For example, diversion of some of economic methods are utilised to assist hospitals, insurers,
limited funds for procurement of a new anti-platelet drug may and health care professionals in making important decisions
put constraint on the treatment of outdoor patients on antibiotics. such as selecting medicines for hospital formularies, settling
Benefit insurance claims of treatments from different hospitals, and
It is the outcome which is measured in physical (natural) units formulating and implementing preventive health policy
such as number of strokes prevented, life years gained or it can respectively. It assists clinicians to prepare standard treatment
be in utility units such as quality adjusted life years gained guidelines and to prescribe cost-effective medicines and
(QALYs) which involves quality and quantity both. The benefit therapies.
may also be measured in monetary units as in cost-benefit
analysis. In ascertaining benefit or outcome, one has to make RECOMMENDED READINGS
assumptions and these assumptions may be varied in sensitivity 1. Drummond MF, Sculpher MJ, Torrance GW, et al. Methods for Economic
Evaluation of Health care Programmes; 3rd Ed. London: Oxford University
analysis. There are four major types of PE analyses which are
Press; 2005: p. 379.
used in making decisions. Table 1 shows the advantages and
2. Jana S, Mondal P. Pharmacoeconomics: The need to sensitise
disadvantages of these types. undergraduate medical students. Indian J Pharmacol 2005; 37: 277-8.
3. Rascati KL. Essentials of Pharmacoeconomics; 1st Ed. Baltimore: Lippincott
TYPES OF PHARMACOECONOMIC ANALYSES Williams and Wilkins; 2008: p. 250.
The four common types of pharmacoeconomic analyses, their 4. Walley T, Haycox A. Pharmacoeconomics: basic concepts and terminology.
advantages and disadvantages are given in Table 1. Cost- Br J Clin Pharmacol 1997; 43: 343-8.

136
Section 5
Immunology
Section Editor: Sita Naik

5.1 An Overview of the Immune System 138

Sita Naik
5.2 General Concepts of Immunoinflammatory Disorders 146
Ramnath Misra
5.3 Immunology of Infectious Diseases 149
Sita Naik
5.4 Primary Immunodeficiency Disorders—A Clinical Approach 151
Surjit Singh
5.5 Laboratory Investigations in Immune-Mediated Diseases 155
Amita Aggarwal
5.6 Pharmacological Manipulation of the Immune System 159
Mitali Chatterjee
5.7 Immunology of Organ and Haematopoietic Stem Cell Transplantation 164
Narinder K. Mehra, Jamshaid A. Siddiqui
 5.1 An Overview of the Immune System

Sita Naik

The immune system deals with a wide variety of organisms activated by locally produced cytokines and in turn secrete a
that are encountered in the environment, by preventing the variety of cytokines which are important for activation of the
establishment of infection and eliminating infections that gets adaptive immunity. The ingested pathogen is broken down in
established. The immune system has evolved to selectively phagolysosomes and antigenic fragments are transported to the
destroy only foreign molecules and cells with little collateral cell surface in a form that can be recognised by antigen-specific
damage to the host’s own normal cells. The system is unique in T lymphocytes, and hence, the name ‘antigen-presenting cell’
its ability to retain a memory of each attack, allowing it to respond (APC). These macrophages carry specialised plasma membrane
more efficiently to subsequent attacks by the same invader. Hence, glycoproteins called major histocompatibility complex (MHC)
individuals rarely suffer more than once from the same infectious class II molecules.The density of MHC antigens on the cell surface
disease such as chicken pox, mumps, or whooping cough. is increased following activation, thus increasing their antigen
presenting capability.
The immune response consists of two broad overlapping sets
of events, the early or first-line of defence that occurs within
minutes to hours of encounter with foreign antigen, the innate
or non-specific immunity and a delayed response, which
occurs within days, called adaptive or specific immunity. The
recognition of events constitute the afferent arm and the
effector arm functions either through cells (cell-mediated
immunity) or antibodies (humoral immunity).

CELLS AND ORGANS OF THE IMMUNE SYSTEM

Granulocytic Cells
The granulocytic cells are neutrophils, eosinophils and basophils.
Neutrophils are the first cells to reach the site of infection. They
engulf foreign particles in a membrane bound vacuole, the
phagosome which fuses with neutrophil granules to form
phagolysosomes. The enzymes within these granules digest the
Figure 1: Macrophages bear several receptors (pattern recognition receptors
contents of the vacuole either by oxygen-dependent mechanism or PRR) that recognise the PAMP on microbes and ingest them.
(respiratory burst) or oxygen independent mechanism.
Eosinophils are phagocytic cells that participate in allergic Dendritic Cells (DCs)
responses. Allergens and parasites stimulate an immunoglobulin These are morphologically distinct cells with membranous or
(IgE) antibody response and IgE coated antigen is recognised spine-like projections, which are located in the interstitium of
by the receptor for Fc portion of IgE on eosinophils. This results most organs, except the brain, and are abundant in the T-cell-
in release of its enzymatic contents which can destroy many rich areas of lymph nodes and spleen. Immature DCs are efficient
parasites. Basophils are non-phagocytic cells which mediate phagocytes and are abundant at locations where external
immediate hypersensitivity responses. Mast cells are analogous antigens enter the body, namely skin, alveoli, gut mucosa, etc.
to the circulating basophils and reside at various tissue sites. They ingest newly entering antigens, undergo maturation, lose
These cells are rich in granules containing histamine and other their phagocytic capability and become efficient APCs. Follicular
mediators of immediate hypersensitivity. dendritic cells (FDC) are located in the germinal centres of lymph
Mononuclear Phagocytes nodes, spleen and mucosa-associated lymphoid tissues. These
are not of bone marrow origin, are unrelated to the interdigitating
These cells have a common lineage from haematopoietic
DCs, do not bear cell surface MHC molecules and cannot act as
precursors in bone marrow and enter the circulation as
APCs. They display ‘trapped’ antigens on their cell surface for
incompletely differentiated monocytes. They migrate into
recognition by B lymphocytes.
tissues to become mature macrophages such as microglial cells
of central nervous system, Kupffer cells lining the vascular Lymphocytes
sinusoids in liver, alveolar macrophages in lung, etc. They ingest Lymphocytes mediate the adaptive immune responses and are
antibody coated antigens very efficiently through the large of three types, T cells, B cells, and natural killer (NK) cells.
number of specialised Fc receptors they bear (Figure 1), a
mechanism termed opsonisation. Neutrophils and other cells B lymphocytes (B cells)
produce cytokines,which are low molecular weight proteins B cells develop in the bone marrow and are characterised by
that regulate the intensity and duration of the immune the presence of membrane-bound immunoglobulin (Ig)
138 response by acting on other cells and tissues. Macrophages are molecules which are the receptors for antigens. Following
 An Overview of the Immune System
Figure 2: Maturation of B cells into plasma cell. Each B cells bears a unique surface immunoglobulin molecule, which is termed ‘B cell receptor’ (BCR). It arises from
a population of undifferentiated stem cells and becomes committed to producing only one species of antibody molecule.

receptor binding to specific antigen, the cell divides and Natural killer cells
progeny differentiate into terminally differentiated, antibody These large granular lymphocytes are part of the innate immune
producing plasma cells that cannot divide (Figure 2). response and do not have membrane markers of T cells (CD4 or
T lymphocytes (T cells) CD8) or B cells (sIg) but bear CD16 and CD56. They can kill a wide
range of tumour cells and some virus and lyse them; this is termed
T cells develop and mature in the thymus and acquire their
antibody dependent cellular cytotoxicity (ADCC). Hence, ADCC
specific cell surface receptor for antigen recognition, the T cell
can occur only after the innate immunity is activated and
receptor (TCR). TCR recognises the modified antigenic
antibodies are produced. NK cells have surface receptors with
fragments or peptides presented by the MHC antigens on APCs.
stimulatory and inhibitory functions (Figure 3). However, body’s
MHC molecules are genetically diverse glycoproteins that are
own cells are protected from NK-mediated killing because the
of two types, class I molecules expressed on almost all nucleated
ligands for the inhibitory receptors (killer Ig like receptor or KIRs)
cells and class II molecules expressed on APCs. TCR engagement
are MHC class I molecules which are present on all nucleated cells.
with MHC-peptide is followed by cell division and generation
Down regulation of MHC expression due to virus infections or
of effector T cells. These are of two types, CD4 expressing T
malignant transformation makes these cells susceptible to NK
helper cells ( T H cells) and CD8 expressing cytotoxic T
cell-mediated killing through the stimulatory receptors. NK cells
lymphocytes (CTLs of TC cells). TH cells are activated by MHC class
mediate cytotoxicity through enzymes present in their granules
II bearing professional APCs leading to activation of other
namely perforins that assemble within the membrane of the
lymphocytes that are specific for the same antigen. CTLs
target cell to form transmembrane channels and granzymes
recognise antigenic fragments along with class I MHC on cells
that enter the perforin channels and activate caspases. Caspases
infected with viruses, bacteria, yeast, protozoa, and parasites and
are proteolytic enzymes that initiate the programmed death
kill them. They also are the principle mode of elimination of
pathway.
tumour cells. Cells are recognised by the CD nomenclature
which refers to the monoclonal antibodies that react with a The bone marrow, thymus, lymph nodes, spleen and various
particular membrane molecule that are grouped together as a mucosa-associated lymphoid tissues are involved in the
cluster of differentiation or CD. development of an immune response. Cells move freely
139
 Table 1: Pattern Recognition Receptors of the Innate Immune
System
Receptor (location) Target (source) Effect
Complement (blood- Microbial cell wall Complement
stream,tissue fluids) components activation,
opsonisation, lysis
Mannose-binding Mannose containing Complement
lectin (blood-stream, microbial activation,
tissue fluids) carbohydrates opsonisation
(cell wall)
C reactive protein Phosphatidylcholine, Complement
(CRP) (blood-stream, pneumococcal activation,
tissue fluids) polysaccharide opsonisation
(microbial membranes)
Lipopolysaccharide Bacterial Delivery
(LPS) receptor, lipopolysaccharide to cell
Figure 3: NK cells bearing activating and inhibitory receptors.
LPS-binding (Gram-negative membranes
protein (LBP) (blood- bacterial cell walls)
stream, tissue fluids)
between organs and this permits immediate activation of the
Toll like receptors (cell Microbial components Induces innate
immune response at any site of entry of a foreign agent. All the
surface or internal not found in host responses
cells originate in the bone marrow, except follicular dendritic
components)
cells. ‘Clonal selection’ of T lymphocytes, takes place in thymus
NOD family receptors* Bacterial cell wall Induces innate
resulting in the generation of mature T lymphocytes that
(intracellular) components responses
recognise only non-self antigen.
Scavenger receptors Many targets; Gram- Induces
INNATE IMMUNE RESPONSES (SR) (cell membrane) positive and Gram- phagocytosis or
negative bacteria, endocytosis
Unlike the adaptive immunity, innate responses lack antigen
apoptotic host cells
specificity and the same set of defence mechanisms acts against
*Nucleotide-binding oligomerisation domain
all pathogens. The earliest barriers to pathogen entry are
physical and chemical ones such as ciliary action of bronchial
mucosa, enzymes in saliva and sweat, acidity of the stomach, Table 2: Toll-like Receptors and their Ligands
etc. Pathogens that breach these barriers are recognised by the TLRs Ligands Target microbes
innate immune system by specialised receptors that help to
TLR 1 Triacyl lipopeptides Mycobacteria
discriminate the invading organism as non-self. These molecular
TLR 2 Peptidoglycans Gram-positive bacteria
sensors that recognise broad structural, highly conserved motifs
GPI-linked proteins Trypanosomes
within microbial species that are not present in the host and Lipoproteins Mycobacteria
are termed pathogen associated molecular patterns (PAMPs). Zymosan Yeast and other fungi
These are various combinations of sugars, some proteins,
TLR 3 Double-stranded RNA Viruses
particular lipid-bearing molecules and some nucleic acids, (dsRNA)
which are part of invading bacteria or viruses. The cellular
TLR 4 LPS Gram-negative bacteria
receptors for PAMPs are the soluble and cell-bound pattern F-protein Respiratory syncitial virus
recognition receptors (PRRs). Soluble PRRs bind to and
TLR 5 Flagellin Bacteria
promote phagocytosis and complement-mediated lysis
(Table 1). TLR 6 Diacetyl lipopeptide Mycobacteria
Zymosan Yeast and fungi
The most important cellular PRR is the toll-like receptor (TLR) TLR 7 Single-stranded RNA Viruses
present predominantly on immature DCs and macrophages (ssRNA)
(Table 2). The members of this family are type 1 membrane TLR 8 Single-stranded RNA Viruses
proteins that bear a common structural element. In the (ssRNA)
extracellular domain consisting of repeating segments of 24 to TLR 9 CpG unmethylated Bacterial DNA
29 amino acids called leucine-rich repeats (LRR). A subset of the dinucleotides
LRRs recognise the ligand and the cytoplasmic Toll/IL-1 (TIR) Dinucleotides
domain binds to adaptor proteins and activates signalling Herpes virus infection Some herpes viruses
pathways. Each TLR detect a repertoire of conserved pathogen TLR 10, 11 Unknown Unknown
molecules and the complete set of TLRs can detect a wide
variety of viruses, bacteria, fungi and some protozoa. Another cellular PRR, NOD (nucleotide-binding oligomerisation
Interestingly, TLRs that recognise extracellular ligands are domain) 1 and NOD2 are present in the cytoplasm and recognises
present on the cell surface (TLR 1, TLR2, TLR4, TLR5, TLR6) while products of peptidoglycans of Gram-positive bacteria. The cell
those that recognise intra-cellular ligands (TLR 3, TLR 7, TLR 8, surface scavenger receptors (SR) internalise Gram-positive and
140 TLR 9) are found within the cell. Gram-negative bacteria and apoptotic cells.
 An Overview of the Immune System
TLRs are widely expressed on DCs, macrophages, neutrophils also leads to generation of C3a which acts as an opsonin and
but not NK cells and are activated through a common pathway. C5a which is an anaphylatoxin and vasodilator.
This culminates in the production of a number of important pro-
The functions of the complement system include: (i) lysis of
inflammatory cytokines and the important anti-viral cytokine, invading bacteria, viruses and cells, (ii) opsonisation of
interferon-α. DCs are predominantly involved in acting as a link organisms and promotion of their ingestion, (iii) clearance of
between adaptive and innate immunity while neutrophils and immune complexes, and (iv) binding to specific complement
macrophages ingest the invading organism and destroy them. receptors on immune cells and triggering their specific cell
COMPLEMENT SYSTEM functions including the secretion of immunoregulatory
molecules. Persons with absence of one of the alternative
The complement system consists of about 20 serum proteins pathway proteins, late components (C3-C9) or one of the control
and is an important constituent of innate immunity. It is activated proteins (H or I) are susceptible to severe infections with
sequentially with amplification stages to ensure that single pyogenic organisms, particularly Gram-negative bacteria,
molecule can trigger generation of thousands of terminal particularly N. meningitides. Classical pathway deficiencies (C1,
effector molecules. The three pathways of complement C4, and C2) are associated with increased risk of infection,
activation are the classical pathway activated by antigen- though not as frequently as with the alternative pathway or
antibody complexes, the alternate pathway activated by late component deficiencies. Bacteria that cause recurrent
polysaccharides from yeasts and Gram-negative bacteria and infections in these patients include, but are not limited to
the mannan-binding lectin pathway activated by the mannose Streptococcus pneumoniae, Haemophilus influenzae and
containing proteins and carbohydrates on microbes (Figure 4). Staphylococcus aureus.
Activation of any of these pathways culminates in activation
of C3 and generation of C3 convertase. This enzyme, via a final ACUTE INFLAMMATION
common pathway leads to assembly of C5-C9 complexes Acute inflammation is the early response of the body to
(membrane attack complex or MAC). The MAC forms invading organisms and is characterised by vasodilatation and
transmembrane pore on the cell surface and death by osmotic increased local blood flow resulting in redness and warmth and
lysis. MAC has a similar structure as perforin which is released extravasation of fluid into the extravascular space resulting in
by NK cells to mediate killing. Normal host cells also bear a swelling and pain. In a few hours, leucocytes migrate into tissue
number of complement regulatory proteins on their surface spaces to phagocytose the invading organisms. These cells
[complement receptor (CR) and decay accelerating factor (DAF)] release pro-inflammatory cytokines, TNF-α, IL-1, IL-6, G-CSF and
which inhibit C3 convertase generation and prevent progression GM-CSF. TNF-α and IL-1 cause increased expression of E-selectin
of complement activation. These molecules protect self cells on endothelial cells and neutrophils which bear L-selectin bind
from complement lysis while at the same time causing lysis of to the endothelium, thus slowing their flow. The stable bond
microbes which lack these molecules. Complement activation formed between LFA on the neutrophils and ICAM-1 on the

Figure 4: The complement activation pathways.

141
 endothelium and the released chemoattractants of host MHC class I molecules. The MHC–peptide complex moves
(interleukin-8, leukotriene B4 and complement 5a) and bacterial through the biosynthetic pathway to reach the plasma
origin (FMLP) helps the neutrophils to move out of the vascular membrane where the peptide is displayed for recognition by
compartment into spaces (Figure 5). These cells phagocytose the TCR of CD8+ T cells (Figure 6).
and clear the pathogen. While G-CSF and GM-CSF stimulate the
production of large numbers of leucocytes in the bone marrow,
the vasodilators and anaphylatoxins, C3a and C5a, cause release
of additional inflammatory mediators, including histamine from
mast cells. The sluggish local blood flow and increased
permeability of vessels allows a fresh supply of complement,
coagulation and other proteins from the circulation to permeate
into the inflamed tissues to maintain the inflammation. TNF-α,
IL-1 and IL-6 also act at distant sites, particularly the liver, to
induce synthesis of acute phase proteins such as C-reactive
protein (CRP).This is widely used in clinical practice as a biomarker
of the acute phase response. CRP can bind polysaccharides on
the surface of pneumococci and phosphorylcholine on many
other bacteria to act as an efficient opsonin.

Figure 6: Processing of exogenous and endogenous antigens.

CD4 and CD8 molecules are expressed on mutually exclusive

subsets of T cell and bind to a non-polymorphic site on the
MHC II and MHC I molecules respectively. Thus, T helper
functions of CD4+ cells is strictly dependent on recognition
of the CD4 molecule by the class II molecule on APCs, a
phenomenon termed ‘restriction’. This stimulates antibody
production, which is useful to neutralise or lyse extracellular
organisms by a variety of mechanisms. The cytotoxic function
of CD8+ T cells is class I ‘restricted’ and the endogenous
pathway delivers peptides to MHC class I molecules which are
recognised by cytotoxic CD8+ cells that kill the presenting
cell. This is beneficial to the host since this is the only way
intracellular antigens can be eliminated. Also, viruses can infect
Figure 5: The multi-step cascade of leucocyte extravasation. The blood-borne
cell makes transient contact with endothelial cells, which leads to the cell rolling any cell in the body and it is advantageous that class I
along the vascular lining. If the cell gets activated, it subsequently adheres to molecules are present on all nucleated cells. The distinct
the endothelium, seeks out inter-endothelial junctions and migrates through compartmentalisation of the exogenous and endogenous
the basement membrane into the tissue. pathways for presentation of antigen to CD4 and CD8 cells
respectively is a clever strategy to increase efficiency of
ANTIGEN PROCESSING AND PRESENTATION dealing with infectious agents.
MHC class II bearing APCs process endocytosed antigens. The MATURATION OF T AND B LYMPHOCYTES
endocytic vesicles bearing antigen fuse with endosomes
Autoreactive lymphocyte clones are deleted during
(Figure 6) and hydrolytic enzymes within the endosomes degrade
development of T and B cells in the thymus and bone marrow
foreign antigens into small peptide fragments of 10-20 amino
respectively. Progenitor T cells from the early sites of
acid length.These fragments bind to MHC class II molecules. MHC
haematopoiesis migrate to the thymus, undergo proliferation
class II molecules are synthesised within the endoplasmic
and begin to express their TCR; cells that fail to express their
reticulum (ER) and move along the biosynthetic pathway into an
TCR die by the process of apoptosis. A process that is unique to
endosome or lysosome. To meet the peptide and form the MHC-
T and B-lymphocytes, gene rearrangement, generates TCRs by
peptide complex. This gets transported to the cell membrane for
a totally random phenomenon and has an estimated potential
recognition by the T cell receptor of CD4+ T cells.
to produce over 1015 kinds of T cell receptors. Being a random
Endogenous antigens that originate within the cells of the host process, rearrangement generates TCRs with equal frequency
organism also trigger immune responses. For example, cells that and affinity for foreign and self-antigen. To ensure that only
have become infected by a virus usually manufacture foreign T lymphocytes bearing TCRs for foreign antigens exit the thymus
proteins encoded by viral genes. Fragments derived from the and all those that can react with self-antigen are eliminated
viral proteins or from altered self-antigens as in the case of (Figure 7), interaction of immature thymocytes with cortical
cancer cells (endogenous proteins) are degraded into short epithelial cells rescues all T cells whose TCRs can recognise self-
peptides of 8-10 residues by proteases that are part of a MHC molecules from apoptosis (positive selection). These cells
multimeric complex called proteasome. The peptides are interact with DCs and macrophages in the thymic medulla where
142 transported into the ER where they bind to newly synthesised all lymphocytes that bear TCR for self-MHC alone or self-antigen
 An Overview of the Immune System
plus self-MHC undergo apoptosis (negative selection). This is receptors on T and B lymphocytes recognise even subtle
achieved by a unique arrangement in which, all self-antigens get differences between antigens. Due to the huge diversity of these
expressed in the thymic medulla. This occurs under the control receptors, the immune system can respond to an extremely
of the autoimmune regulator (AIRE) gene and genetic defects wide range of antigen specificities. After each successful
in this gene leads to the human autoimmune disease known immune response, memory for the specific antigen is retained
as autoimmune polyendocrinopathy candidiasis-ectodermal for long periods of time and it allows the body to respond more
dystrophy (APECED). A third subpopulation of cells, FoxP3 rapidly to subsequent encounter with the antigen.
positive T regulatory cells, also develop in the thymus and play
an important role in maintaining the balance within the immune ACTIVATION OF THE CELLULAR RESPONSE
system. Adaptive immunity, develops over 2-3 days, and following
transport of antigens from the site of infection to the secondary
lymphoid organs. Antigens are transported by DCs from the
periphery to the lymph node, from blood to the spleen and from
the mucosae to the mucosa-associated lymphoid tissues. As
described earlier, at the site of inflammation, DCs are activated
and become potent APCs bearing upregulated chemokine
receptors. Lymphoid tissues constitutively express chemokines
and DCs home to lymphoid tissues where they come in contact
with the T lymphocytes. T lymphocytes are in continuous
circulation throughout the body, taking 1-2 days to complete their
sojourn. The large number of T cells that traffic through lymph
nodes come in contact with the DCs bearing the processed
antigen within the MHC class II. After a series of hit and trials,
T cell bearing the correct TCR is found and TCR-MHC-peptide
interaction, results in immediate activation of the T cell. Without
interaction of the TCR with its cognate antigen, T cells remain
quiescent and may recirculate through lymphoid tissues for many
Figure 7: Thymic selection.
months or years.The TCR consists of an α and a β chain complexed
with γ, δ, ε and ξ chains of the CD3 molecule (Figure 8). The α
Thus, all T cells that leave the thymus recognise foreign antigen
and β chains bind to the MHC/peptide complex and CD3ξ chain
with self-MHC and do not recognise self-antigen. Less than 2%
transduces intracellular signals that result in activation of a
of the thymocytes that enter the thymus survive this rigorous
number of genes, including a variety of cytokine genes.
selection exercise.
Unlike T lymphocytes, B lymphocytes recognise conformational
epitopes on antigens through the B cell receptor (BCR); there
is no antigen presentation or an MHC analogous molecule
in BCR engagement. Hence, there is no requirement for a
round of positive selection; however, negative selection of self-
reactive B cells occurs in the bone marrow. As in the thymus, more
than 90% of immature B cells are eliminated through negative
selection.
Although the developmental process is aimed at providing
an immune repertoire that can recognise and deal with
all external antigens without any self-directed responses,
many low-affinity anti-self T and B cells escape and survive.
Self-reactive T cells and low titre autoantibodies can be
demonstrated in most individuals if adequately sensitive
methods are used and their frequency increases with age.
Fortunately, autoimmune disease develop in only a small
proportion of the population because peripheral tolerance Figure 8: The T cell receptor–CD3 complex.
mechanisms keep these autoreactive cells in an inactive state
through T cell anergy. T cell activation only occurs following In addition to signalling through the TCR-CD3 complex,
an initial pro-inflammatory response and upregulation of co- additional signalling through co-stimulatory molecules is
stimulatory molecules on APCs. required, failing which T cell activation is abortive for generating
effector cells. Such T cells either get anergised or undergo
ADAPTIVE IMMUNITY programmed cell death. The most important co-stimulatory
The unique features of the acquired immune response are molecule is CD28, a homodimeric glycoprotein on T cells that
specificity, diversity and memory. The response is specific to the interacts with two receptors, CD80 and CD86, expressed on
structural components of complex protein, polysaccharide and APCs. While CD86 is expressed constitutively at low levels and
other antigens termed epitopes or determinants. The unique CD80 is not expressed on professional APCs like DCs, but
143
 get rapidly upregulated following activation by the pro- its tertiary and quaternary structure. This is in contrast to the
inflammatory cytokines. This is the critical role of innate immune recognition of linear peptides by the TCR. The five types of
responses, since failure to upregulate these molecules leads to H chains (γ, μ, α, ε and δ) can each combine with either of the
anergised T cells. It also ensures that the effector arm is activated two L chains (κ, λ) to form the molecules of IgG, IgM, IgA, IgE
only when there is a genuine need to deal with overwhelming and IgD (Table 3).
antigen load. CTLA4 or CD152 on T cells, is structurally related
to CD28 and binds to CD80 and CD86 with higher affinity than
to CD28. However, its engagement along with the TCR results
in negative signalling.
Activated T cell expands clonally to produce large number of
progeny which home back to the site of inflammation, guided
there by tissue-specific adhesion molecules. However, all the
activated cells do not leave the lymph node and some remain
as central memory cells.

CELLULAR EFFECTOR RESPONSE

The effector T cells are of CD4+ helper (Th) and CD8 +cytotoxic
(Tc) type and CD4 effector response diverges to either a Th1 or
a Th2 type. The Th1 response is characterised by the cytokines
TNFα, IL-2 and IFN-γ and Th1 expansion results in appearance
of cell mediated immunity involving generation of specific CTLs
and activated macrophages. Th2 cells make IL-4, IL-5 and IL-13
that are critical for induction of humoral immunity and
eosinophilia. It is not clear what determines whether a particular
response will be Th1 or Th2 in type. A new subset of T cells, the
Th17 cells, secrete IL-17 and are involved predominantly in the
maintenance of the inflammatory response. The mechanism of Figure 9: The arrangement of immunoglobulin.
target cell lysis by CD8+ cells is same as NK cells, except that
unlike NK cells, CTLs release these enzymes only on antigen
stimulation. Table 3: Immunoglobulin Classes and their Functions
IgG IgA IgM IgE IgD
THE HUMORAL RESPONSE
Molecular weight 150,000 150,000- 900,000 190,000 150,000
Immunoglobulins or antibodies neutralise toxins, prevent
600,000
organisms adhering to mucosal surfaces, opsonise bacteria for
Heavy chains γ1, γ2, α1, α2 μ ε δ
phagocytosis and sensitise infected cells for lysis by antibody
γ3, γ4
mediated cellular cytotoxic attack by NK cells while antigen-
Normal serum 13.5 3.5 1.5 0.0003 0.03
antibody complexes activate the classical complement cascade.
levels (mg/ml)
B lymphocytes reside primarily in lymphoid tissues with little
recirculation. They recognise native antigen, through the BCR, In vivo serum 23 6 5 2.5 3
half-life (days)
which is a membrane-bound immunoglobulin.
Activate classical ++ – ++ – –
Immunoglobulins complement
There are five classes of immunoglobulins (Ig), namely IgG, IgM, pathway
IgA, IgE and IgD. They have a common structure consisting of Crosses placenta + – – – –
two identical light (L) chains of approximately 22,000 Da and Present on – – + – +
two identical heavy (H) chains of 55,000 Da or more (Figure 9). membrane of
Each light chain is bound to a heavy chain by disulphide bonds mature B cells
and other non-covalent interactions and each set of H+L Binds to Fc ++ – ? – –
chains is bound to the other by similar bonds to form the four receptor on
chain structure (H-L) 2 . The numbers and position of the phagocytes
disulphide bonds vary among the different classes of Ig. Each Mucosal transport – ++ + – –
H and L chain is made of variable (V) and constant (C) regions, Induces mast cell – – – + –
with each light chain having one variable (VL) and one degranulation
constant (CL) unit and heavy chains having one variable region
(VH) and 3 to 4 constant regions (CH). The first 110 amino acids Effector Functions of Antibodies
of the VH and VL chains show a great degree of variability The first immunoglobulin produced during an immune
(hypervariable regions) and form the region by which antigen response is IgM. Th2 derived IL-4, IL-5, IL-6 and IL-13 help in the
is recognised. This, the antigen combining site, binds to the antibody response. These cytokines also upregulate CD40
conformational epitopes on the antigen, which is formed by ligand (CD40L) on T cells which interacts with the constitutively
non-contiguous regions of the antigen and is dependent on expressed CD40 on B cells and APCs, an essential interaction to
144
 An Overview of the Immune System
switch the cell from IgM to IgG production. Most of the effector antigen elimination deprives the antigenic stimulus. The
responses are most efficiently carried out by IgG and as the contraction occurs leaving behind long-lived memory cells
immune response matures IgG molecules undergo somatic for CD4, CD8 and B cell memory. These reside in secondary
hypermutation, a process by which the quality of the antibody lymphoid organs, to be recalled for immediate and accelerated
to fit the antigen is improved. It is also evident that, the help responses on subsequent exposure to the antigen.
provided by T cells is crucial for antibody production and most
The counter-regulatory mechanisms include negative
antigens are thus T-cell dependent. A few antigens especially
signalling in T cells by CTLA-4, and T regulatory cells (Treg) which
polysaccharides, having a repeating structure can cross-link
actively downregulate activated T cells. Tregs are CD4+ T cells
multiple BCRs and stimulate IgM response. However, this is not
that express cell surface CTLA4 and CD25 and have a
followed by affinity maturation or isotype switch and such
characteristic transcription factor, FoxP3. Tregs are important
responses wane rapidly. These are called T-cell-independent
for maintaining tolerance to self-antigens.
antigens.
CONCLUSION
REGULATION OF THE IMMUNE RESPONSE
The immune system is an extremely fine-tuned orchestra that
An efficient immune response is characterised by augmentation responds efficiently to external challenges only to the exact
of innate (antigen independent) response by the products of quantum that is required to deal with that challenge. Diseases
the adaptive (antigen specific) response. Pro-inflammatory are a consequence of failures of the development of the system
cytokines, upregulate numerous cytokine receptors on T cells (primary immunodeficiency), failures of the normal control
which bind with T-cell derived cytokines setting up paracrine mechanisms (autoimmunity and cancer) or excessive efforts
and autocrine mechanisms for amplification of the immune and to deal with the foreign challenge of chronic infections like
inflammatory processes. A Th1 response deals with intracellular tuberculosis.
pathogens while Th2 response favours antibody production (IL-
4 favours class switching and IgE production, IL-5 eosinophilia); RECOMMENDED READINGS
IL-4 provides stimuli for feedback amplification of the Th2 1. Abbas AK, Licchtman AH, Pillai S. Cellular and Molecular Immunology; 6th
response and dampening of the Th1 response. Ed. Philadelphia: WB Saunders and Co.; 2009.
2. Abbas AK, Lichtman AH. Basic Immunology: Functions and Disorders of the
This cascade is exquisitely orchestrated and immune response Immune System; 3rd Ed. Canada: Elsevier; 2008.
is generated that is adequate to control this challenge. However, 3. Kindt TJ, Goldsby RA, Osborne BA. Kuby Immunology; 6th Ed. New York: WH
the expansion of the effector response is not uncontrolled; Freeman and Co.; 2007.

145
 5.2 General Concepts of
Immunoinflammatory Disorders
Ramnath Misra

Understanding cellular and molecular basis of inflammation consequence of the immune response generated against the
and immunology has helped to develop targeted therapy in pathogen. For example, in acute rheumatic fever, cellular and
several immunoinflammatory diseases, such as rheumatoid humoral responses against the Streptococcus M protein cross-
arthritis (RA), psoriasis, inflammatory bowel disease, ankylosing- react against myocardial tissues causing carditis. However, cross-
spondylitis, juvenile idiopathic arthritis, systemic lupus reactive microbial antigens have not been found even after
erythematosus (SLE), inflammatory myositis, vasculitis, etc. extensive search in the classical autoimmune diseases, like
Immunoinflammatory diseases result from an aberrant immune juvenile diabetes, RA and SLE.
response and a heightened inflammation process consequent
Altered Self-Antigen Presentation
to generation of effector T- or B-cells. Though the precise trigger
for the inflammation is not understood, the cells and molecules In animal models of autoimmune diseases, it has been
that cause the tissue damage have been elucidated in great shown that autoimmune response to one antigenic epitope
detail in these conditions.Therefore, biological therapy directed at (part of the protein seen by the antibodies or T-cells) may
inhibiting key molecules or dysregulated cells have been successful spread to involve other epitopes which are normally not
in limiting tissue damage and increase the quality of life. seen by lymphocytes. These later epitopes could be self-
antigens.
While hypersensitivity is an inappropriate immune response to
antigens (allergens), autoimmunity is directed against self- Polyclonal B-Cell Activation
antigens. Both situations result in inflammation that causes Many infectious agents, such as gram-negative bacteria,
tissue damage by various mediators of inflammation. Epstein-Barr virus and cytomegalovirus cause polyclonal
activation of B-cells. A wide spectrum of antibodies is
THE NORMAL IMMUNE RESPONSE AND THE produced in patients with AIDS and infectious mononucleosis
IMMUNOLOGICAL BASIS OF AUTOIMMUNITY as part of the diseases process. A persistent stimulation of T
Immune response is mediated by the T-cells causing the cellular lymphocytes may also lead to polyclonal stimulation of B cells.
and B-cells producing antibodies. These cells work in Some of these antibodies may be directed against self-
collaboration helping each other in a coordinated way. There is antigens.
a tight control over these T- and B-cells reacting against self-
Autoimmune diseases are polygenic in nature with a number
antigens in cells or tissues called the ‘self-tolerance’. During the
of genes contributing to the causation of the disease. They
embryonic maturation of these lymphocytes, most self reacting
result from a multi step process, probably triggered by an
lymphocytes are removed by apoptosis (negative selection). A
environmental factor, in a genetically susceptible individual.
protein called autoimmune regulator (AIRE), is believed
The risk of developing autoimmune diseases is higher
to stimulate expression of several peripheral antigens to
among monozygotic twins than dizygotic twins and familial
the thymic epithelial cells. Mutations in the AIRE gene can
clustering is often seen. Unaffected healthy family members
cause polyendocrinopathy in experimental animals. Those
of patients have higher incidence of autoantibodies
lymphocytes that escape this central deletions are kept under
than normal healthy population. The susceptibility to
control by peripheral mechanisms, such as lack of B7 by (APCs)
autoimmune disease differs between two sexes with SLE, RA,
to interact with CD28, repeated stimulation by self-antigen
and scleroderma affecting predominantly the females. This
causing activation induced cell death and suppression by CD4+,
difference has been attributed to hormonal differences and
CD25+ regulatory T-cells.
the effect of circulating foetal cells in maternal blood during
HOW DOES AUTOIMMUNITY DEVELOP pregnancy.
Several hypothesis have been proposed.
BASIS OF HYPERSENSITIVITY AND AUTOIMMUNE DISEASES
Sequestration of Self-Antigens Autoimmune diseases are classified as organ specific and
During thymic development, lymphocytes are not exposed to systemic non-organ-specific (Tables 1 and 2). The immuno-
those self-antigens which are not expressed by the thymic logical basis of hypersensitivity and autoimmune diseases
epithelial cells. These include, but are not limited to, the lens have been described as Types I , II, III and IV reactions by Gell
protein, sperms or ova or myelin basic proteins (protected by and Coombs.
the blood-brain barrier in the central nervous system). Later, an
inadvertent exposure of the antigens, leads to development of Hypersensitivity is the inappropriate host response to an
autoimmunity. antigen which results in tissue damage of variable severity and
even death. The hypersensitivity may be ‘immediate’ in which
Molecular Mimicry symptoms manifest within minutes to hours of exposure to the
Several host proteins and proteins of pathogens (bacteria, antigens or ‘delayed’, due to delay in the onset of symptoms up
146 virus, etc.) share structural similarity and autoimmunity is a to days after the exposure to antigen.
 General Concepts of Immunoinflammatory Disorders
Table 1: Organ Specific Autoimmune Diseases that are Caused to bronchoconstriction and abdominal cramps and diarrhoea.
by Antibodies Directed against Autoantigens In severe cases death occurs due to shock and vascular collapse.
The reaction usually takes 15 to 30 minutes from the time of
Diseases Antibodies directed Effect
exposure to the antigen, although sometimes it may have a
against cells/tissues
delayed onset (10 to 12 hours).
Type 1 Diabetes Beta cells Cell lysis
The diagnosis is mainly clinical and in cases confirmation is
Grave’s disease TSH receptor Stimulating
thyrocytes needed, intradermal challenge with allergens may be done with
caution.
Myasthenia gravis Acetylcholine receptor Blocking Ach
Autoimmune Red cell surface Fc receptor Type II Hypersensitivity Reaction
haemolytic anaemia antigens mediated Type II hypersensitivity is mediated by IgG or IgM antibodies
phagocytosis directed against cell-bound antigens. Antibodies binding to
Autoimmune Platelet GpIIb-IIIa Fc receptor cell surface antigens, activates the complement cascade
thrombocytopaenic mediated and deposits of complement products C3b and C4b facilitates
purpura phagoctyosis their ingestion and destruction by Fc receptor bearing
by splenic
macrophages. Preformed antibodies may cause transfusion
macrophages
reactions following incompatible blood transfusion,
Goodpasture’s Alpha 3 chain of Complement
erythroblastosis foetalis due to placental transfer of maternal
syndrome collagen mediated
inflammation
antibodies to the foetus with destruction of foetal red blood
of the blood cells and autoimmune haemolytic anaemia.
vessels in kidney The diagnosis of type II hypersensitivity diseases is made
and lung
by demonstration of circulating or tissue-bound antibodies
Wegener’s Serine proteinase 3 Neutrophil to target antigens. Some examples are Coombs test for
granulomatosis damage haemolytic anaemias, antibodies to Ach receptor in
myasthenia gravis, antibodies to glomerular basement
Table 2: Systemic or Non-Organ-Specific Diseases with their
membrane in Goodpasture’s syndrome. However, antibodies
Respective Target Cells/Tissues
are not of clinical importance, such as antibodies to platelet
Disease Self-antigen glycoprotein and glutamic acid decarboxylase (GAD) in type 1
Systemic lupus DNA, nucleosomes, Sm, histones, DM. Here the diagnosis is dependent upon the manifestation
erythematosus RNP, Ro, La lymphocytes, platelets of organ damage, such as purpura and hyperglycaemia,
Rheumatoid arthritis IgG, cyclic citrullinated peptide, respectively.
synovium, cartilage
Type III Hypersensitivity Reaction
Sjögren’s syndrome Salivary glands, epithelial cells,
kidneys
In this type, immune complexes containing antigens and
antibodies to auto or bacterial antigens are deposited in the
Polymyositis Myocytes
capillaries and small blood vessels, causing complement
Type I Hypersensitivity Reaction activation, neutrophil activation and release of proteolytic
enzymes leading to inflammation and tissue damage. SLE is
This is also known as immediate or anaphylactic hypersensitivity.
a prototype example of type III hypersensitivity disease.
IgE antibodies are generated in the first exposure to antigen
Circulating antibodies to anti-nuclear antibodies (Figure 1)
(allergens) and during the subsequent exposure binds to the Fc
which are directed against a variety of nuclear constituents
receptor for IgE which is expressed abundantly on mast cells and
basophils. A subsequent exposure to the same allergen cross-
links the cell-bound IgE and triggers the release of various
biologically active primary (preformed) and secondary mediators
(Table 3). The preformed mediators are responsible for
immediate reaction, such as local oedema, increased secretion
and bronchospasm.The secondary mediators are responsible for
delayed phase reactions, and act by recruiting inflammatory cells
which amplify the reactions. Of the recruited cells, eosinophils
are particularly important and are preferentially expanded under
the influence of (Th)2 derived cytokines, such as IL-3, IL-5 and
GM-CSF. These mediators act on the surrounding tissues and
cause vasodilatation and smooth muscle contraction.The clinical
picture may vary from a mild local reaction to a severe systemic
anaphlyaxis, which may be fatal. Systemic anaphylaxis may result
from penicillin and administration of foreign proteins, such as
antisera, intravenous immunoglobulins and monoclonal Figure 1: Anti-nuclear antibodies detected by indirect immunofluorescent assay.
antibodies of murine origin. The clinical manifestations are skin Circulating anti-nuclear antibodies with its antigens, such as dsDNA,
nucleosomes gets deposited in the blood vessels to activate complement
urticaria, rhinorrhoea, rhinitis, conjunctivitis, angioneurotic
mediation inflammation and subsuequent damage.
oedema, respiratory stridor due to laryngeal spasm, asthma due 147
 Table 3: Primary and Secondary Mediators in Hypersensitivity Reaction
Mediators Effects
Primary (pre-formed) Histamines Smooth muscle constriction, vasodilatation, increased
glandular secretions
Enzymes (chymase, tryptase) Generation of kinins and activated complement C3
Secondary mediators Leukotrienes C4,D4 Vasoactive
Lipid mediators Leukotrienes B4 Chemotactic for neutrophils and eosinophils
Prostaglandin D2 Bronchospasm
Platelet activating factor Platelet aggregation, histamine release
Cytokines TNF, IL-1, IL-3, IL-4, IL-5, IL-6 Mediate inflammation at the local site

(such as nucleosomes, DNA, Sm, U1RNP, Ro or SS-A, La or SS-B) produced and markedly influence the cell composition at
get deposited at various sites giving rise to malar rash, the inflammation site and the reparative process that follow.
photosensitivity, arthritis, glomerulonephritis, serositis and For example, in RA, antibodies to cytokine targets have shown
central nervous system involvement. Immunofluorescence excellent results for controlling the signs and symptoms of
microscopy of kidney biopsy reveals deposits of IgG, IgM and the disease. The putative triggering agent in the synovial
complement components C1q and C3. Other examples are compartment activate the synovial macrophage which
serum sickness and primary Sjögren’s syndrome. produce as key mediator of inflammation tumour necrosis
Type IV Hypersensitivity Reaction factor TNF-alpha which has pleiotropic effect both locally
as well as systemically. These include release of other
Also known as delayed type hypersensitivity (DTH), it is proinflammatory cytokines (IL-1, IL-6, IL-18, IL-23 and GM-CSF),
mediated by effector T-cells which have been earlier exposed activation of endothelial cells and upregulation of adhesion
to the same antigen. These cells accumulate at the site of entry molecules E-selectin and VCAM1, chemokine release (Rantes,
of antigen, and get activated releasing cytokines that cause MCP1, SDF1) causing leucocytes influx, induction of acute
accumulation of monocyte/macrophage cells from the phase response in liver, chondrocytes and osteoclast
peripheral blood. A typical example is Mantoux test. This type activation causing cartilage and bone loss, and upregulating
of hypersensitivity is an important defence mechanism against
and maintenance of class II expression. These cytokines
parasites and intracellular organisms. When pathogen is not
activate cells of the adaptive immune system, especially naive
cleared within a week or so, a granuloma may form at the
CD4+Th cells which are driven to Th1 and the recently
site which releases proteolytic enzymes and destroys the
described Th17 cells. IL17, in turn, activates synovial fibroblast
surrounding tissue. Such pathology of hypersensitivity is seen
to produce RANK L and in synergism with IL-1 and TNF
in sarcoidosis and other granulomatous conditions.
activates osteoclast precursor cells to osteoclast causing bone
DTH can be measured by injecting the antigen intradermally resorption. IL17 has also been shown to be an important
and measuring the local reaction at 24 to 48 hours. Contact cytokine in psoriasis skin and joint lesions.
dermatitis and Bacillus-Calmette Guerin skin test are examples
The elaboration of cytokine pathways has made it possible to
of DTH reaction. Histology reveals lymphocytes, monocytes,
develop monoclonal antibodies directed against TNF-α, IL-1,
macrophages at the site of reaction. The granuloma seen in
Th17, IL-6 to downregulate the proinflammatory process in
tubercular and in non-tubercular cases occurs after 21 to 28
RA, Crohn’s disease, ankylosing spondylitis and psoriatic
days of antigen exposure and is also an example of DTH
arthropathy with effective control of signs and symptoms of
reaction.
the disease.
CYTOKINES—KEY MEDIATORS OF INFLAMMATION RECOMMENDED READINGS
Although the triggering factor for an autoimmune disease is 1. Brian KL. Autoimmunity. In: Edwards HD, editors. Kelly’s Textbook of
not known, much is understood about the sequence of events Rheumatology. Philadelphia: Elsevier Saunders; pp260-75.
that follow. Studies in experimental models for autoimmune 2. Goldsby RA, Kindt TJ, Osborne BA, Kuby J. Immunology; 5th Ed. New York:
diseases have shown that cytokines are the key mediators of WH freeman and Company; 2003: pp 361-89.
inflammation. They activate the cells from which they are 3. Macky RI, Rosen FR. Autoimmune diseases. N Engl J Med. 345; 5: 340-50.

148
 5.3 Immunology of Infectious Diseases

Sita Naik

The earlier chapters have discussed how the immune response activation of a ribonulease that degrades viral RNA. Other genes
has evolved to protect the host from external infectious agents. that contribute to the antiviral activity are also activated,
The diversity seen in the T cell and B cell receptors have probably including dsRNA-dependent protein kinase (PKR), a dsDNA
evolved over time to deal with the diversity of the infectious dependent protein kinase that causes inactivation of protein
agents. The organisms, however, constantly evolve mechanisms synthesis, and thus, viral replication. Many other cell types such
to evade immune recognition and the effector immune as macrophagges, monocytes and fibroblasts produce IFNs and
response. Some of these will be discussed later in this section. interleukin (IL)-12 is an important cytokine produced during
Each new effort by the organism is reciprocated by the host the innate response. This is a potent activator of NK cells which
response making the required adjustments. This constant are efficient killers of virus infected cells.
evolutionary battle has given us the system as we know it today.
Antibodies have a limited but important role in limiting acute
For an infection to establish itself in a susceptible host, it has infection. Both humoral and cellular responses are important
to overcome the combined efforts of the innate and adaptive for viral immunity. Antibodies that neutralise viral surface
immune systems to eliminate it. The earliest barriers, which molecules involved in cell entry can prevent establishment as
try to prevent the establishment of the infection, includes the well as cell to cell spread of the virus. Secretory immunoglobulin
physical one provided by the epithelial lining itself. The (IgA) has an important role in this regard as in the case of
epithelial layer also provides specialised barriers, such as the attenuated oral polio vaccine. Further in the course of infection,
ciliary processes of the lining epithelium of nasal passages and antibodies can also agglutinate viral particles and function as
production of anti-bacterial peptides at many locations. The an opsonising agent to facilitate Fc or C3b-receptor mediated
acidic pH of the stomach forms an effective barrier for any phagocytosis of viral particles.
ingested agent as do the normal flora of the gastrointestinal,
Most of the vaccines against viruses that are in use act by
genito-urinary and respiratory tracts which competitively
generating neutralising antibodies (HBV, polio). Antibodies
inhibit the binding of pathogen to host cells.
also help in activating the complemet pathway leading to virus
Although, there has been a significant decline in the morbidity lysis. However, once infection is established, cellular
and mortality caused by infectious diseases in much of the mechanisms are required and the infected cell has to be lysed.
developed world, they continue to be a major killer in our Both CD4+ and CD8+ cells play important roles in antiviral
country. The understanding of the immune response to immunity. The activated CD4+ cells secrete numerous
infectious agents is also important in the context of new and cytokines, of which IFN-γ can induce an antiviral state in the
emerging pathogens like severe acute respiratory syndrome cell, IL-2 helps in the maturation of precursor CTLs to a mature
(SARS) and the challenges posed by the old and well established effector population and both IL-2 and IFN-γ activate NK cells
ones like influenza virus. These have not spared any region of which are important in killing infected cells in the initial days
the world. In recent times, the major challenge has been posed of the infection. In established infections, CTLs are probably
by an infectious disease, caused by human immunodeficiency the most important effector mechanism with CTL activity
virus (HIV ) pandemic and the resultant re-emergence of peaking 7 to 10 days following infection. Elimination of
tuberculosis (TB), leishmaniasis, and other opportunistic infected cells ensures that no virus infects new cells and
infections. perpetuates infection. Failure of CTL activity results in
dormancy or chronicity of the infection.
VIRAL INFECTIONS
Viruses establish infection by entering cells often through Viruses have developed a variety of mechanisms to subvert
specific cell surface receptors. They use the host cell machinery the immune effector mechanisms directed against them, and
for their replication and in many instances this replication thus, ensure their survival. For instance, hepatitis C virus can
machinery is error prone, allowing many mutated forms to overcome the anti-viral effects of type I IFNs by interfering
emerge. It is beneficial to the infecting virus not to kill the host with the action of PKR. Herpes simplex virus (HSV)-1 and HSV-
cell. Viruses adopt various survival strategies, such as prolonged 2 inhibit the antigen presentation by MHC class I, thus
latency (HIV) or rapid transmission to a new host (influenza). escaping CTL mediated target lysis. CMV, HIV and measles
The innate immune response plays a crucial role in viral downregulate class I expression, thus interfering with efficient
elimination. Viral nucleic acids are recognised by the toll like antigen presentation. Vaccinia virus secretes a protein that
receptors leading to the activation of interferon responsive binds to C4b and inhibits classical pathway, while herpes
elements and production of type 1 interferons (IFN-α and IFN- simplex glycoprotein binds C3b and inhibits both classical and
β). These cytokines bind to the type 1 IFN receptors and activate alternate pathways. Many viruses cause a generalised
the JAK-STAT pathway which in turn activates several genes immunosuppression (mumps, measles, EBV, CMV, HIV ) by
including 2’-5’-oligo-adenylate synthetase. This leads to various mechanisms.
149
 Viruses constantly change their antigenicity as a strategy for against tubercular antigens. The immune effort is successful in
evasion from immune mediated elimination. The classical restricting multiplication of the bacilli in the majority of cases.
example is of influenza virus where this strategy leads to Failure to contain multiplication, leads to continuing tissue
emergence of new strains and the failure of previously necrosis with eventual rupture of the granuloma and release
generated immunity to protect against fresh infections. HIV also of mycobacteria. This leads to the miliary lesions in the lung
uses this strategy, with an estimated mutation rate 6.5 times and establishment of infection at various extrapulmonary sites.
faster than influenza. This has led to the difficulties in generating
vaccines against these infections. PARASITIC INFECTIONS
Diseases caused by protozoa and helminths account for
BACTERIAL INFECTIONS considerable part of the disease burden in developing countries.
Most bacterial infections are extracellular and specific Protozoa are mainly unicellular eukaryotes that live and multiply
antibodies bind and lyse these by activating the complement intracellularly. Of these, malaria and leishmania are of particular
cascade on the bacterial cell wall leading to membrane pore relevance to our country. The host does mount an immune
formation. Gram negative bacteria also act as opsonins and thus response to malarial parasite, and anti-malarial antibodies can
facilitate phagocytosis and intracellular killing within the be demonstrated in those who have been infected. However,
phagocyte. Many bacteria also release harmful toxins that are the parasite has a multi-stage life cycle in which it resides within
neutralised by the specific antibody as in the case of diphtheria. erythrocytes as sporozoites and gametocytes, and within
However, cell-mediated immunity is important in the case of hepatocytes as merozoites. These are antigenically distinct
intracellular bacteria. stages and the immune response to these stages is not well
understood. This has proved a challenge for the development
Many bacteria too have evolved strategies to evade the host
of a malaria vaccine.
immune response. Many bacteria (Neisseria gonorrhoeae,
Haemophilus influenzae, Neisseria meningitidis) secrete The immune response to leishmania has been better sudied.
proteases that cleave secretory IgA at the hinge region, and While leishmania major causes predominantly a cutaneous
thus, abrogate their ability to agglutinate these organisms. N. disease that is not seen in India, the visceral form of the disease
gonorrhoeae can change its surface antigens, thus evading the that is endemic in parts of eastern India is caused by L. donovani.
neutralisation by IgA. Streptococcus pneumoniae surface Those who resist infection have a robust TH1 response, while
polysaccharide can prevent phagocytosis effectively while S. those who develop the disease have a TH2 biased response.
pyogenes do so by its surface M protein. The long side chains Although these distinctions are more clearly seen in murine
on the lipid A moiety of the cell wall core polysaccharide of models of the disease, there appears to be a role for cellular
Gram negative bacteria help resist complement mediated lysis. immunity in protection against this parasite. However, leishmania
The elastase secreted by Pseudomonas inactivates C3a and C5a also has two distinct antigenic forms, the infective promastigote,
anaphylotoxins, and hence, decreases local inflammation. In and the amastigote form which resides within the protected
some instances, the disease and symptoms are caused by the environment of the phagosome. The protective immunity is still
immune response against the pathogen and not the pathogen far from clear and a vaccine is not on the horizon.
itself. In fact, pathogen induced cytokine production, usually
TNF and IL-1, is responsible for septic shock and toxic shock FUNGAL INFECTIONS
syndromes. It also contributes to some of the pathology seen These are caused by entry of the fungal organism through
in tuberculosis. inhalation or through sites of injury. They are often restricted
at the site of entry by the barriers provided by the innate
Intracellular bacteria can survive within the protected
immune system. They are also restricted by phagocytosis by
environment of cells for long periods. The examples are L
neutrophils and by the activation of the complement system.
monocytogenes and more importantly, Mycobacterium
The important role of the immune system is evident from the
tuberculosis. The sustained antigenic stimulation results in
fact that non-pathogenic commensal fungi can cause disease
activation of CD4+ cells and the characteristic delayed type
in the immunocompromised host. The best example of this is
hypersensitivity response. The activated CD4+ cells secrete
the Candida albicans which can cause a serious systemic illness
cytokines which attract large number of macrophages and
in acquired immunodeficiency syndrome patients.
these differentiate into epithelioid cells and sometimes coalesce
to form multinucleated giant cells. The localised accumulation RECOMMENDED READINGS
of lysosomal enzymes released by the activated macrophages 1. Abbas AK, Lichtman AH. Basic Immunology: Functions and Disorders of the
leads to extensive tissue necrosis, seen as the caseous Immune System; 3rd Ed. Canada: Elsevier; 2008.
material at the centre of the this accumalation of lymphocytes, 2. Abbas AK, Licchtman AH, Pillai S. Cellular and Molecular Immunology; 6th
epithelioid cells and giant cells. Thus, the characteristic Ed. Philadelphia: WB Saunders and Co.; 2009.
‘granuloma’ which is considered to be pathagnomonic of 3. Kindt TJ, Goldsby RA, Osborne BA. Kuby Immunology; 6th Ed. New York: WH
tuberculosis is the outcome of the intense immune response Freemna and Co; 2007.

150
 5.4 Primary Immunodeficiency Disorders—
A Clinical Approach
Surjit Singh

The large majority of children who appear to have had ‘frequent’ 5. Congenital defects of phagocytic cells, e.g. congenital
or ‘very frequent’ infections in infancy are completely normal neutropaenia. Affected children may present with life-
when examined clinically. A small minority, however, who need threatening bacterial or fungal infections
further investigations can be identified clinically. In these 6. Defects of innate immunity relating to monocyte and
children, possibility of an underlying primary immunodeficiency dendritic cell function
disorder (PID) should be seriously considered. Of course, the more 7. Autoinflammatory disorders, e.g. periodic fevers
common secondary causes of immunodeficiency [e.g. human 8. Complement deficiencies. Affected children may have a
immunodeficiency virus (HIV) infection] and conditions which clinical presentation like, that of XLH. Further, children with
may mimic an immunodeficiency (e.g. cystic fibrosis, α-1- C2 and C4 deficiency may present with an autoimmune
antitrypsin deficiency, Kartagener’s syndrome and gastro- disease mimicking lupus
oesophageal reflux disease) should be excluded.
Based on the clinical experience from various centres which
PIDs are a heterogenous group of conditions with the majority may not necessarily reflect the true epidemiological situation,
of cases presenting in infancy and early childhood and some 60% to 70% of PID cases are due to humoral immunodeficiencies,
conditions, e.g. common variable immunodeficiency (CVID) 15% to 20% due to cellular immunodeficiencies, 10% to 15% due
manifesting in late childhood or even in adult life. PIDs are not to phagocytic cell defects and 10% to 20% due to miscellaneous
as rare as is often believed and if immunoglobulin (Ig) subclass causes.
deficiency and IgA deficiency are included, the prevalence
rate may be as high as 1/250 - 1/1000 population. However, there APPROACH TO A CHILD WITH SUSPECTED PID
is a spectrum of illness and majority of children with ‘minor’
Clinical History
immunodeficiencies may not develop clinically symptomatic
diseases. A PID should be suspected when a child has two or The age of presentation is important and earlier the age of onset
more of the following signs: in children, the more severe is the immunodeficiency.
Appearance of recurrent/serious infections before the age of 6
1. Four or more new ear infections within a year
months is suggestive of a severe combined immunodeficiency
2. Two or more serious sinus infections within a year
or a neutrophilic disorder. Children with XLH usually present
3. Two or more months on antibiotics with little effect after the first 6 months of life while the usual age of presentation
4. Two or more cases of pneumonia per year of CVID is the second decade of life.
5. Failure of an infant to gain weight or grow normally
Type of Infection
6. Recurrent deep skin or organ abscesses
The type of infection may suggest a specific immunodeficiency
7. Persistent thrush in the mouth or elsewhere on the skin in
syndrome (Table 1).
children more than 1 year old
8. Need of intravenous antibiotics to clear infections Family History
9. Two or more deep-seated infections, like meningitis or The inheritance pattern provides some leads to diagnosis. For
cellulitis instance, ataxia telangiectasia and certain forms of chronic
10. A family history of immunodeficiency granulomatous disease (CGD) and SCID have an autosomal
recessive inheritance while XLH, XLPS, Wiskott-Aldrich
CLASSIFICATION OF PIDs syndrome, hyper-IgM syndrome, SCID and CGD have an X-linked
PIDs are classified based on the affected component of the recessive inheritance.
immune system. The International Union of Immunological
Physical Examination
Societies has suggested one such classification system which
is enumerated below: Generally, children with a serious immunodeficiency usually fail
to thrive and conversely an underlying serious PID is unlikely in
1. Severe combined immune deficiencies in which both T-
a well-looking school going child even if there is a history of –
and B-cells are defective, e.g. severe combined immuno-
‘frequent’ infections. Some PIDs have an associated syndrome
deficiency (SCID)
which can be picked up on physical examination (Table 2).
2. Predominantly antibody deficiencies, e.g. X-linked
hypogammaglobulinaemia (XLH) Investigations
3. Other well-defined immunodeficiency syndromes in A broad diagnosis of the PID group can be made based on history
which there are non-immunological features, e.g. ataxia- and findings. Investigations should be done with a specific PID
telangiectasia (AT) in mind since these only serve to confirm the clinical suspicion.
4. Diseases of immune dysregulation, e.g. X-linked lympho- HIV infection should be excluded before embarking on
proliferative syndrome (XLPS) investigations for a PID.
151
 Table 1: Type of Infection and Associated Possible Table 3: Screening Tests
Immunodeficiency Syndrome
Investigation Clinical correlate
Type of infection Likely immunodeficiency
Haemogram
Viral, fungal, mycobacterial/bacterial SCID Haemolytic anaemia CVID
infections starting within a few Lymphopaenia Cell mediated immunodeficiency
weeks of birth
Neutropaenia Agranulocytosis
Recurrent pyogenic bacterial infections Humoral immunodeficiency
Marked polymorhonuclear CGD, leucocyte adhesion molecule
(e.g. Streptococcus pneumoniae, syndrome (e.g. XLH)
Haemophilus influenzae) starting complement deficiency leucocytosis deficiency
from early infancy Thrombocytopaenia Wiskott-Aldrich syndrome, CVID
Recurrent pyogenic bacterial infections CVID Peripheral blood smear
(e.g. Streptococcus pneumoniae, Giant granules in neutrophils Chediak-Higashi syndrome or variants
Haemophilus influenzae)
starting late in childhood Quantitative serum Several humoral and cellular PIDs;
Recurrent Staphylococcal ‘cold Hyper-IgE syndrome IgG, IgA, IgM levels to be interpreted in the
abscesses’ and respiratory infections context of the clinical diagnosis
(especially with pneumatocoeles) Chest radiograph
Recurrent Giardia lamblia infection IgA deficiency; Persistent pneumonia Chronic granulomatous disease
other humoral Pneumatocoeles Hyper-IgE syndrome
immunodeficiencies Absent thymic shadow SCID
Cryptosporidiosis in early childhood SCID
T- and B-cell markers Absent or low T- and B-cells in SCID;
Recurrent (Staphylococcal) skin CGD (CD3; CD19) B cells absent with normal T-cells
infections, persistent fungal in XLH
pneumonia, recurrent Staphylococcal
pneumonia, multiple liver abscesses persist even at 18 to 24 months (and sometimes longer), a
Disseminated Bacillus-Calmette SCID condition known as transient hypogammaglobulinaemia of
Guerin (BCG) infection
infancy (THI).
Recurrent mycobacterial infections Defect in interferon γ,
interleukin-12 receptor Confirmatory Tests
pathway
If the clinical findings and screening tests suggest a PID, more
Recurrent Neisseriae infections Late complement
detailed investigations are necessary (Table 4). If antibody
deficiencies
deficiency is suspected on clinical grounds and serum
Table 2: Symptoms and Clinical Features with Associated immunoglobulin level is normal, an IgG subclass deficiency or
Immunodeficiency Syndromes a functional antibody defect should be suspected.
Clinical features Likely immunodeficiency
Table 4: Confirmatory Tests
Failure to thrive since early infancy, SCID
diarrhoea, rash, atrophic tonsils and Detailed analysis of lymphocyte
lymph nodes subsets by
Failure to thrive, recurrent respiratory XLH Flow cytometry CD3: T- cell marker
infections in a boy with onset after CD19, CD20: B-cell marker
6 months CD16, CD56, CD57: natural
Recurrent respiratory infections CVID killer (NK) cell marker
starting later in childhood, diarrhoea, CD4: Marker for helper-inducer
hepatosplenomegaly subset of CD3 lymphocytes
Infantile eczema (often atypical), Wiskott-Aldrich syndrome
CD8: marker for suppressor
recurrent infections since early infancy
cytotoxic subset of CD3
and bleeds(due to thrombocytopaenia)
in a boy lymphocytes
Typically coarse facial features with Hyper-IgE syndrome Lymphocyte proliferation using Functional assessment
history of recurrent Staphylococcal mitogen, phytohaemagglutinin of T- cells
infections
Slowly progressive ataxia, recurrent Ataxia-telangiectasia Complement component assays For complement deficiency
bacterial infections (especially Nitroblue tetrazolium dye Useful and simple test for
pneumonia), bulbar/facial telangiectasia reduction test diagnosing CGD

Screening Tests IgG subclasses by nephelometry A child with deficiency of one

or ELISA (G1, G2, G3, G4) subclass may have a normal
Screening tests should include a complete blood count and level of total IgG because of
peripheral smear examination, quantitative serum immuno- compensatory over-production
globulin assay, chest radiograph and markers for T (CD3) and B of other subclasses
(CD19) cells (Table 3). Hypogammaglobulianaemia is diagnosed
IgE Levels are frequently above
if the serum immunoglobulin levels are below -2 SD of the age
2000 IU/mL in the hyper-IgE
related norms. The physiological hypogammaglobulinaemia in syndrome
152 the first 3 to 6 months of life, may get abnormally prolonged to
 Primary Immunodeficiency Disorder—A Clinical Approach
Prenatal Diagnosis infections with opportunistic organisms soon after the
As the genetic defect is now known for several of the PIDs, many neonatal period and in the first 6 months of life. Typical
of these disorders can be diagnosed prenatally using chorionic presenting features include failure to thrive, rash, diarrhoea,
villus sampling, cultured amniotic cells or foetal blood sampling. pneumonia and oral thrush. Physical examination may show
Prenatal diagnosis has been successfully carried out for XLH, absence of tonsils and impalpable lymph nodes. Live vaccines
some forms of SCID and the Wiskott-Aldrich syndrome. Further, must be avoided.
under special circumstances sex determination by ultra- X-Linked Hypogammaglobulinaemia (XLH)
sonography can be used to exclude X-linked PIDs. Affected boys usually remain well during the first 3 to 6
TREATMENT months of life due to the presence of maternally acquired IgG.
After this, they present with serious and recurrent bacterial
Prevention of infection is an integral part of the management infections. Laboratory investigations reveal a panhypogamma-
of children with PIDs. This is achieved using prophylactic globulinaemia with normal numbers of T-cells but absent or
antimicrobials, judicious use of vaccines and early treatment very low numbers of B-cells in the peripheral circulation. The
with appropriate anti-microbials after exposure. If a blood genetic defect is at the level of the tyrosine kinase gene located
product has to be transfused, the donor should be screened on the X chromosome.
for cytomegalovirus infection. For cell-mediated immuno-
deficiencies, the blood should be doubly irradiated to prevent Common Variable Immunodeficiency
development of graft-versus-host disease. CVID is a group of disorders characterised by hypo-
gammaglobulinaemia and a normal B-cell number. Many
Intravenous immunoglobulin (IVIG) given in doses of 400-
patients also have a T-cell defect but this is more difficult to
600 mg/kg every 3 to 4 weeks has improved the outlook for
document and characterise. Low levels of lymphocyte
children with humoral PID. Replacement immunoglobulin
proliferation following mitogen stimulation may be
can now also be given subcutaneously (100 mg/kg weekly),
demonstrable. A number of mutations in different genes have
but such preparations are yet to be marketed in our country. been identified, all causing the same phenotype. Patients usually
Haematopoietic cell transplantation (with peripheral blood become symptomatic after the first decade of life and
stem cells or bone marrow) is the treatment of choice for associated autoimmune features (e.g. leucopenia, haemolytic
cellular immunodeficiencies and since children with severe anaemia, arthritis) are commonly seen. Hepatosplenomegaly
forms of SCID cannot reject the donor stem cells, pre- and lymphadenopathy are prominent clinical features. Patients
transplantation chemotherapy is not required in many cases. with CVID need to be closely monitored for the development
Gene therapy using viral vectors has been successfully used of lymphoreticular malignancies.
in patients with adenosine deaminase activity (ADA)-
deficient SCID, X-linked SCID and in the Wiskott-Aldrich Immunoglobulin A Deficiency
syndrome. IgA deficiency is the most common form of PID with prevalence
of 1:350-1:650. IgA deficiency is diagnosed if the serum IgA level
PROGNOSIS is less than 5-10 mg/dL or if the level is below -2SD of the age
With timely diagnosis and appropriate treatment, children related normal value. While majority of the patients may remain
with several of the PIDs can lead a normal life. Most patients asymptomatic throughout life, some do have an increased
with a humoral immunodeficiency disorder can survive to incidence of respiratory and gastrointestinal infections and
adulthood with replacement immunoglobulin. Disorders, like allergic disorders. A small proportion of these patients may have
hyper-IgE syndrome, chronic granulomatous disease and IgG an associated deficiency of one of the IgG subclasses (e.g. IgG2,
subclass deficiency can be successfully managed with pro- IgG4). Autoimmune diseases associated with IgA deficiency
phylactic anti-microbials. In the case of ataxia-telangiectasia, include lupus, rheumatoid arthritis and chronic active hepatitis.
the immunodeficiency is usually not severe but these Some patients with IgA deficiency may develop anti-IgA
patients succumb to other complications (e.g. malignancies). antibodies and this may lead to unfavourable transfusion
Haematopoietic stem cell transplantation carried out reactions if the patient is given blood products.
expeditiously, is the only treatment option for severe forms
IgG Subclass Deficiency
of cellular immunodeficiencies (e.g. SCID, Wiskott-Aldrich
syndrome). Long-term survival rates of matched haemato- IgG subclass deficiency, a condition with undetermined clinical
poietic stem cell transplantation for PID are now upwards of significance, is the most common form of PID seen in clinical
90%. practise. One may suspect the condition if a patient presents
with the clinical phenotype of a humoral immunodeficiency
SPECIFIC IMMUNODEFICIENCIES has normal (or, at times, even elevated) levels of serum
Severe Combined Immunodeficiency immunoglobulins. The disorder can present in early childhood
or later.
This group of PIDs is characterised by the absence of T- and B-
cell (and sometimes natural killer cell) function. The Wiskott-Aldrich Syndrome (WAS)
inheritance pattern is either autosomal recessive (e.g. ADA WAS, an X-linked recessive immunodeficiency disorder, is caused
deficiency SCID) or X-linked recessive (e.g. X-linked SCID), the by a mutation in the gene encoding a cytoplasmic protein,
latter being the more common. Other types of autosomal Wiskott-Aldrich syndrome protein. WAS is expressed in
recessive SCID include Janus kinase 3 deficiency (T-B+NK-) and haematopoietic cell lineages and controls the assembly of actin
IL-7Rá deficiency (T-B+NK+). Affected children develop severe filaments. Children present with eczema, recurrent serious 153
 bacterial infections and thrombocytopaenia, characterised congenital cardiac defects (e.g. truncus arteriosus, transposition
by small sized platelets. Children with WAS present in early of great vessels). Patients have a typical facies characterised by
infancy and have impaired immunological responses to the low-set ears, micrognathia, shortened and upturned philtrum of
polysaccharide antigens. They are especially susceptible to the upper lip and hypertelorism. Patients with milder degrees of
infection with Streptococcus pneumoniae, Haemophilus immunodeficiency may be given only supportive management
influenzae and Neisseria meningitidis. Serum IgM levels are low, while those with more severe forms of the disease are candidates
while IgE may be elevated. The clinical phenotype is variable for haematopoietic stem cell transplantation.
ranging from a very fulminant course with repeated infections
Chronic Granulomatous Disease (CGD)
to milder forms in which children survive childhood. Long-term
complications include development of lymphoreticular CGD is a group of disorders characterised by defects in
malignancy. superoxide radical generation due to reduced activity of the
NADPH oxidase. Both denovo mutations, and X-linked
Ataxia-Telangiectasia recessive (mutations in the X-chromosome gene encoding
Ataxia-telangiectasia is an inherited disorder of DNA repair gp91phox) or autosomal recessive (mutations in the gene
mechanism with characteristic susceptibility to radiation- encoding p47phox on chromosome 7) inheritance occur, X-
induced chromosomal damage. Serum IgA levels are low with linked being the most frequent. Patients present with
IgG subclass deficiency. Patients present with progressive recurrent life-threatening infections often starting very early
cerebellar ataxia that becomes evident around 2 to 3 years of in life. Infections are caused by catalase-positive bacteria (e.g.
age. Affected children may have recurrent respiratory infections Staphylococcus aureus, Serratia spp.) or fungi, especially
that are less severe than seen in WAS. The telangiectasia Aspergillus. Typical clinical findings include a persistent non-
become apparent around 4 to 6 years of age and may be first resolving pneumonia, prominent lymphadenitis and multiple
noted over the lateral aspect of bulbar conjunctiva. Most liver abscesses. Osteomyelitis of the small bones of hands and
children need to be supported with prophylactic antimicrobials. feet is also characteristic. Long-term prophylaxis with a
There is a risk of development of lymphoproliferative combination of trimethoprim-sulphamethoxazole and
malignancies later in life. Bone marrow transplantation is not a itraconazole has resulted in significant reductions of morbidity
treatment option in this condition. and mortality in this condition.
DiGeorge Syndrome
RECOMMENDED READINGS
DiGeorge syndrome is a T-cell deficiency disorder of varying 1. Primary immunodeficiency diseases: an update. Clin Exp Immunol 2003;
severity which is associated with abnormal embryogenesis of the 132: 9-15.
3rd and 4th pharyngeal pouches. The phenotype includes severe 2. Singh S. Immunodeficiencies. In: Ghai OP, Gupta P, Paul VK, editors. Essential
neonatal hypocalcaemia causing tetany,hypoparathyroidism and Paediatrics, 6th Ed, New Delhi: CBS Publishers & Distributors; 2004: pp 187-9.

154
 5.5 Laboratory Investigations in
Immune-Mediated Diseases
Amita Aggarwal

Immune-mediated diseases occur either because of lack of Anti Citrullinated Peptides Antibody (ACPA)
an appropriate immune response as in immunodeficiency ACPA are a set of antibodies directed against citrullinated self
states or an abnormal response like in allergic diseases and peptides and are highly specific for a diagnosis of RA. Anti-cyclic
autoimmune disease. Laboratory investigations play an citrullinated peptide (anti-CCP) is the most often used test and
important role in diagnosis of patients with such immune has a specificity of 95% and a sensitivity of 65-70%. In contrast
disorders. The available tests need to be used judiciously in to RF, it is rarely seen with other connective tissue diseases and
order to provide a cost-effective and efficient approach to infections. In early arthritis, presence of anti-CCP antibodies
diagnosis. increases the likelihood of RA.
AUTOANTIBODIES IN SYSTEMIC AUTOIMMUNE DISEASES Antinuclear Antibody (ANA)
Autoantibodies directed against self-antigens are present ANA is a heterogenous group of autoantibodies directed
in many autoimmune diseases. These may be directed to against components of nucleus including deoxyribonucleic
any constituent of cell, be it cell membrane, cytoplasm, acid, ribonucleic acid (RNA) associated proteins (nRNP, Sm, La,
deoxyribonucleic acid and other proteins in the nucleus. Ro), nucleolar proteins, centromere, etc.
Although their pathogenetic role is not clear, they are good The ‘gold standard’ for ANA detection is indirect immuno-
diagnostic markers due to their frequent association with fluorescence (IIF) assay using Hep2 cells (Figures 1A and B).
specific diseases. However, the mere presence of an auto-
antibody is not equivalent to disease and absence of an
autoantibody does not exclude a disease. The common
antibodies used in clinical practise are given in Table 1.

Table 1: Autoantibodies that are Commonly Used and their

Disease Association
Antibody Associated disease
Rheumatoid factor Rheumatoid arthritis, Sjögren‘s syndrome
Anti-nuclear antibody Systemic lupus erythematosus (SLE),
systemic sclerosis, inflammatory myositis,
Sjögren‘s syndrome (Figures 1A and B)
Anti-dsDNA SLE
Anti-proteinase 3 Wegener’s granulomatosis
Anti-myeloperoxidase Microscopic polyarteritis nodosa, Churg-
Strauss syndrome
Anti-cardiolipin Anti-phospholipid syndrome, SLE

Rheumatoid Factor
Rheumatoid factor (RF) is an antibody directed against the Fc
portion of immunoglobulin (IgG) and is usually of IgM type. RF is
detected by latex agglutination, nephelometry or enzyme linked
immunoassay and the results should always be expressed in
International Unit (IU) for ease of comparison between different
laboratories or methods. Presence of RF in a patient with joint
disease increases the probability of diagnosis of rheumatoid
arthritis (RA). It is present in 75% to 85% of patients with RA
and in 10% of children with juvenile arthritis. In a patient with
established RA, its presence suggests a more aggressive disease.
It is also present with lesser frequency in infections like malaria,
leprosy and tuberculosis, malignancies and other autoimmune
diseases like Sjögren‘s syndrome, SLE, etc. The prevalence of RF
increases with age and geriatric population have a prevalence of
approximately 20%. Thus, in elderly patients with vague joint Figures 1A and B: Antinuclear antibody positivity on Hep2 cells by
pains, presence of RF should not lead to a diagnosis of RA. RF immunofluorescence microscopy. (A) Homogeneous pattern suggestive
titres correlate poorly with activity of disease in RA, and therefore, of antibodies to dsDNA and (B) Centromere pattern suggestive of
155
there is no utility in repeating the test. limited systemic sclerosis.
 The recently developed ELISA tests are inferior to IIF both in anti-prothrombin antibodies may be used as a substitute for
sensitivity and specificity. The IIF test also has the advantage lupus anticoagulant assay but it has low sensitivity. Antibodies
that the fluorescence pattern can give an indication regarding against other phospholipids, like phosphotidylserine, annexin-
the target antigen against which the antibody is directed. For V, are not useful clinically.
instance, rim pattern suggests antibodies to dsDNA and is
Antibodies to Neutrophil Cytoplasmic Antigens
suggestive of SLE, while a centromere pattern is typical of
patients with limited systemic sclerosis (Figure 1B). ANA is used Anti-neutrophilic cytoplasmic antibodies (ANCAs) are
as a screening test and its detection increases the likelihood of serological markers of severe necrotising vasculitis affecting
the diagnosis of a connective tissue disease in a patient with the small vessels and are seen in patients with Wegener’s
multisystem involvement. Further investigations, like anti- granulomatosis, Churg-Strauss syndrome and microscopic
dsDNA antibodies, anti-Sm antibodies are needed to establish polyarteritis nodosa. ANCA is detected using IIF assay with
the specificity of the ANA present in the sera. ANA is also positive human neutrophils as substrate. Two patterns of staining are
in other conditions, such as infection, malignancy, RA and recognised namely cytoplasmic (cANCA) and perinuclear
juvenile idiopathic arthritis. (pANCA) (Figures 2A and B). The antigenic target of cANCA
is proteinase 3 (PR3) which has specificity of 85-90% for
Antibodies to dsDNA diagnosis of Wegener’s granulomatosis. pANCA is mainly
Antibodies to dsDNA are a hallmark of SLE. They are detected
by IIF using Crithidia luciliae, Farr assay (liquid phase radio-
immunoassay) or ELISA. Crithidia luciliae is a protozoan parasite
of Leishmania family which has a prominent kinetoplast made
of dsDNA. Anti-dsDNA titre is raised in about 60% of patients
with SLE and has a good correlation with presence of lupus
nephritis. Serial measurement can help in monitoring of the
disease activity. However, a rise in the antibody titre alone does
not warrant a change in the treatment which should be made
in the context of clinical parameters.
Antibodies to Extractable Nuclear Antigens
Antibodies to extractable nuclear antigens (ENAs) comprise
of antibodies to various RNA associated proteins. Each
antibody has a specific disease phenotype associated with it
and variable prevalence (Table 2). ENAs are detected using
ELISA or immunoblotting. Since antibody titres do not
correlate with disease activity, qualitative assays like
immunoblot or line assays are as useful as quantitative assays
like ELISA.

Table 2: Antibodies to Nuclear Target Antigens

Antibody Disease Prevalence
Anti-Sm SLE 30%
Anti-nRNP SLE 40%
Mixed connective tissue disease 100%
Rheumatoid arthritis 15% to 20%
Anti-Ro Primary Sjögren‘s syndrome 60%
SLE 30%
Anti-La Primary Sjögren‘s syndrome 30%
SLE 15%
Anti-centromere Limited systemic sclerosis 50%
Anti-Scl 70 Diffuse systemic sclerosis 45%

Antiphospholipid Antibodies
Presence of antibodies to phospholipids is mandatory for the
diagnosis of antiphospholipid (APL) syndrome. Cardiolipin is
the most commonly used substrate. IgG and IgM antibodies are
measured by ELISA and the results are expressed as mild,
moderate and marked elevation. IgA antibodies to cardiolipin
can also be detected, but have less diagnostic value.
Anti-beta 2-glycoprotein 1 antibodies which are directed
Figures 2A and B: ANCA positivity on neutrophil smear showing:
against a co-factor required for binding of cardiolipin are more
(A) pANCA pattern; (B) cANCA pattern.
156 specific for diagnosis and are detected by ELISA. Detection of
 Laboratory Investigations in Immune-Mediated Diseases
directed against myeloperoxidase (MPO) and is present in tetanus toxoid, Candida, Trichophyton) and chest radiograph
60% of patients with microscopic PAN. pANCA or an atypical for thymic shadow for T-lymphocyte defects; phagocyte
staining pattern is also positive in other diseases, like morphology, IgE levels and NBT reduction test for neutrophil
ulcerative colitis, RA, SLE, etc. However, the antigenic targets function defects; and CH50 and serum C3, C4 levels for
are variable (cathepsin G, lactoferritin, BPI, elastase, etc). complement defects.
Antibodies to MPO and PR3 are usually detected by ELISA
Second Level Tests
and quantitative measurement of antibodies to PR3 is helpful
in monitoring disease activity in patients with Wegener’s If an underlying immunodeficiency is suggested or there is high
granulomatosis. ANCA is not useful in a patient with classical index of suspicion, additional tests are performed. The tests
polyarteritis, Takayasu’s arteritis, etc. include iso-haemagglutinin titres, antibody response to tetanus
toxoid for B-lymphocyte defects; lymphoproliferative assay to
ORGAN-SPECIFIC AUTOANTIBODIES mitogen and recall antigens for T-lymphocyte defects;
chemotaxis, superoxide production and bactericidal assay for
The characteristic autoantibodies found in the organ-specific
neutrophil function defects; and AH50 for defects of complement
autoimmune diseases along with their prevalence is given in
function.
Table 3. Most of these can be detected by IIF assays using
appropriate tissue substrates or by ELISA. Quantitative titres are Advanced Tests
not useful in the management of these conditions and the IIF These are performed to establish the exact cause of the
tests have adequate sensitivity to assist in diagnosis. In many immunodeficiency disease. The exact genetic defect has been
of these diseases, detection of antibody only suggests an auto- identified in many conditions, such as mutations in btk, CD40
immune aetiology and is not required for diagnosis. For and CD40L gene in B-cell defects, interleukin (IL)-2 receptor
instance, the diagnosis of Graves’ disease is based only on clinical gamma chain, and TCR signalling molecules in T-cell defects. in
findings and hormone levels. Antibodies to insulin, GAD65 and NADPH oxidase system in neutrophil defects and serum
IA-2 though present years before onset of type 1 diabetes complement C5-9 complex in complement deficiencies and
mellitus are not useful in diagnosis. gene mutation analysis can provide an exact diagnosis.

Table 3: Organ-Specific Autoantibodies

Disease Antibodies Prevalence
Hashimoto’s thyroiditis Thyroid microsomal antibodies, antibodies to TPO 85% to 90%
Graves’ disease Antibodies to TSH receptor 90% to 95%
Type 1 diabetes mellitus Antibodies to Islet cells, insulin, GAD65, IA2 75%
Pernicious anaemia Antibodies to parietal cells 85% to 90%
Chronic active hepatitis Antibodies to smooth muscle (actin) Type I CAH
Antibodies to liver-kidney microsomes Type II CAH
Primary biliary cirrhosis Antibodies to mitochondria (pyruvate dehydrogenase) 90%
Coeliac disease Anti-endomysial antibodies, antibodies to tissue transglutaminase 95%
Immune thrombocytopaenia Antibodies to platelets (GpIIb/IIIa) 80% to 90%
Autoimmune haemolytic anaemia Antibodies to RBCs (Rh antigen) 95%
Myasthenia gravis Antibodies to acetylcholine receptor 70% to 75%
Goodpasture’s syndrome Antibodies to basement membrane 60% to 70%

INVESTIGATION FOR IMMUNODEFICIENCY DISEASES All these tests need to be performed using appropriate age-
Immunodeficiency diseases are broadly classified into T-cell matched controls, especially for cellular assays as the immune
defect, B-cell defect, complement deficiency or phagocytic system has different maturity at different ages. The normal
defect. Laboratory investigation of a patient with immuno- reference values of immunoglobulins for all age groups should
deficiency is a step-wise process: be established for each population group. Table 4 provides a
guideline for evaluating immunoglobulin results, since antibody
 Exclusion of secondary causes
deficiency is present in more than half the children with
 Screening tests to detect common diseases immunodeficiency.
 Second level tests to confirm an immunodeficiency disease
Tests for Allergic Diseases
 Advanced test for diagnosis of rare immunodeficiency
diseases. Although allergic reaction is mediated by IgE and, total IgE levels
are elevated in patients with allergic diathesis, this is not of
Screening Tests diagnostic value. Antigen-specific IgE measured by radio-
These are simple, easily available tests that help in excluding allergosorbent assay helps to identify the specific offending
a major immunodeficiency state. These include: immuno- allergens. The skin or prick test is commonly used for
globulin levels and B-cell count for B-lymphocyte defects; identification of the offending agent in allergy prone
lymphocyte count and CD4/CD8 numbers by flow cytometry, individuals. A large number of probable allergens are injected
delayed type hypersensitivity test with multiple antigens (PPD, intradermally along with saline as a negative control and 157
 histamine as a positive control. The immediate wheal and flare proteins are separated, based on their size, is helpful in their
response is observed and allergens giving positive reaction are diagnosis. Normal serum shows five distinct bands, of albumin,
used for de-sensitisation programme. α1 globulin, α2 globulins, β globulins and γ globulin of which
albumin has the fastest mobility. The normal γ globulin band
Table 4: Immunoglobulin (Ig) Levels as Clue to Diagnosis of is replaced by a single sharp band called the M peak in
Immunodeficiency Diseases multiple myeloma. Other diseases, like primary amyloidosis,
Ig Levels Diagnosis Waldenstrom’s macroglobulinaemia and monoclonal
Levels of all immuno- X-linked agammaglobulinaemia, severe gammopathy of uncertain significance can also give an M
globulins reduced combined immunodeficiency, intestinal band.
lymphangiectasis, common variable In 10% to 15% of cases of multiple myeloma no M peak is seen
immunodeficiency
as only light chains are produced and immunofixation has to
Only IgA reduced Selective IgA deficiency
be performed. Immunofixation can also help in typing of
IgM: normal or increased X-linked hyper IgM syndrome
paraprotein.
IgA, IgG: reduced
IgG, IgA, IgM: normal Selective deficiency of IgG subclass In conclusion, a wide array of tests are available for evaluation
IgG subclass reduced of immunological diseases. However, they should be used
Transient reduction in Transient hypogammaglobulinaemia of judiciously in the appropriate clinical setting to get best help
IgG, IgA infancy from the tests.

The patch test in which allergen is applied to the skin is useful RECOMMENDED READINGS
for identifying cases of contact dermatitis. All provocative tests 1. Agarwal V. Laborator y tests in rheumatology: rational use and
should be done under close supervision as sometimes they can interpretation. In: Syngle A, Deodhar S, editors. Rheumatology: Principals
and Practice; 1st Ed. Jaypee Brother Medical Publisher: New Delhi; 2010:
aggravate the symptoms. pp 40-6.

PRESENCE OF ABNORMAL IMMUNOGLOBULIN 2. Detrick B, Hamilton RG, Folds JD. Manual of Molecular and Clinical Laboratory
Immunology, editors; 7th Ed. American Society of Microbiology; 2006.
OR PARAPROTEIN
3. Naik S, Aggarwal A. Investigations for immunodeficiency. In: Sengupta PC,
A malignant clone can produce hypergammaglobulinaemia editor. Clinical Immunology; 1st Ed. Oxford University Press: New Delhi;
in some B-cell malignancies. Serum electrophoresis, in which 2003: pp 233-40.

158
 5.6 Pharmacological Manipulation
of the Immune System
Mitali Chatterjee

Diseases with an immunological basis occur as a result of transplantation. However, due to the narrow therapeutic range
aberrations of the immune response. Therefore, an effective coupled with high intra- and inter-patient variability of CsA, it was
drug for these diseases should have the ability to modulate the replaced by a newer calcineurin inhibitor, tacrolimus, which also
immune response by inducing immunosuppression, tolerance inhibits IL-2 but is 10 to 100 times more potent than CsA. The
or immunostimulation. Such manipulations are used to prevent antiproliferative effect of calcineurin inhibitors is mediated by its
allograft rejection, boost the immunosurveillance against binding to an immunophilin (cyclophilin for cyclosporine and
cancers and treat allergic conditions. FKBP12 for tacrolimus); they block phosphatase activity, prevent
induction of cytokine genes, importantly IL-2 and halt cell cycle
INDUCTION OF IMMUNOSUPPRESSION TO LIMIT GRAFT progression of T cells.These compounds are hydrophobic in nature
REJECTION and easily penetrate plasma membranes. The introduction of these
Drugs that induce immunosuppression and result in an effective agents caused dramatic alterations in the outcome of renal
organ transplant can act at one or multiple steps involved in transplantation and has brought down the frequency of acute
T cell activation and proliferation pathways. rejection episodes from 85% to 50%. The occurrence of post-
transplant diabetes mellitus, especially when combined with
Corticosteroids
steroids and associated nephrotoxicity, are important compli-
The advent of corticosteroids in the 1960s revolutionised cations associated with both tacrolimus and cyclosporine.
the arena of organ transplantation. Steroids are classical
immunosuppressants that form the mainstay of treatment. Sirolimus (Rapamycin)
They act to dampen antigen presentation by APCs. Steroids bind This is another fungal metabolite, which is structurally related
to steroid receptors, are transported to the nucleus and bind to FK-506 and binds to same proteins. However, its mechanism
to the glucocorticoid response elements to regulate the differs from that of FK-506, since it prevents phosphorylation
transcription of many genes. Their effects on the immune of a p70 kinase in the CD-28 co-stimulatory and IL-2R signal
system include blocking of T cell activation cascade, transduction pathway. Rapamycin blocks T cell proliferation
downregulation of interleukin (IL)-1 and IL-6 genes, and through during late G1 and pre-S phase of the cell cycles. Thus, rapamycin
indirect mechanisms IL-2 production. Glucocorticoid receptor inhibits late signals in T cell activation while cyclosporine and
complexes also increases Ικβ expression, curtailing NF-κβ which FK-506 inhibit an early signal in T cell receptor signal transduction
causes enhanced apoptosis of activated T cells. Since long-term pathway and these compounds have synergistic effect when
steroids administration has serious adverse effects, which may given together.
even be life-threatening, introduction of newer agents and
Anti-Lymphocyte Globulin
steroid-sparing protocols have been developed.
More general immunosuppression is achieved by use of anti-
Azathioprine, Mizoribine and Mycophenolic Acid lymphocyte globulin, which has an overall lymphocyte
Antiproliferative agents such as azathioprine inhibit de novo depleting property. This has been licensed for a long time and
purine biosynthesis, prevent mitosis and consequently was widely used prior to the availability of the more specific
proliferation of rapidly dividing cells, including T and B agents like OKT3 and anti-IL 2R antibodies. A disadvantage of
lymphocytes. The purine salvage pathway in lymphocytes is using polyclonal ATG is the general recommendation to
less active than in other rapidly dividing cells. Hence, these cells administer the medication via central venous access.
are more dependent on the de novo synthesis of DNA and RNA
building blocks. Inhibition of de novo nucleoside synthesis BLOCKING THE T CELL RECEPTOR AND CO-RECEPTOR
achieves a milder immunosuppression than with cyclosporine The OKT3 was the first mouse antibody licensed for use in
A (CsA) or rapamycin and it also inhibits many other cell types. humans; it is directed against the CD3 antigen that is closely
Newer anti-proliferative agents are mycophenolate mofetil and associated with the T cell receptor. The principal mechanism of
rapamycin. Mycophenolate mofetil selectively prevents action of OKT3 is inhibition of cell-mediated immunity by
proliferation of activated T lymphocytes by inhibiting purine binding to CD3 and promoting phagocytosis or complement
synthesis and non-competitive inhibition of the type II isomer mediated lysis of CD3+ T cells. Anti IL-2 receptor antibody
of inosine monophosphate dehydrogenase (IMPDH). prevents T cell activation by blocking the binding of IL-2 to
Rapamycin inhibits graft rejection by blocking IL-2 activation activated T cells. This approach would prevent T cell activation
and phosphorylation of 70 S6 kinase inhibiting progression of and a monoclonal murine IgG2 directed against the ε chain of
cells from G to S phase. the pentapeptide CD3 complex (OKT3) has been approved for
human use. However, it needs to be administered in large doses
Cyclosporine and Tacrolimus (FK 506) to achieve effective T cell silencing and at this dose the toxicity
The introduction of CsA, a calcineurin inhibitor which inhibits is considerable. Hence, this drug is only used to treat acute
normal T cell signal transduction was a great leap forward for rejection. 159
 Another approach is the use of humanised monoclonal MONOCLONAL ANTIBODIES
antibodies against the IL-2 receptor (anti-CD25), such as Monoclonal antibodies can cause death of tumour cells both
daclizumab and basiliximab. These target only activated T cells, directly by apoptosis and blocking of growth factor receptors
while sparing resting T cells. Targeting costimulatory receptor/ or indirectly by antibody-dependent cell-mediated cytotoxicity.
ligand pairs is a viable alternative for triggering immuno- An example of antibody-dependent cell-mediated cytotoxicity
suppression. Antibodies to the CD40/CD40 ligand have been is that of rituximab, a chimeric antibody targeting CD20 that
shown to induce long-term graft survival by inhibiting release is expressed in B cell malignancies. The antibody binds to
of Th1 cytokines interferon (IFN)-gamma, IL-2 and IL-12 and CD20 on B cells and to Fc receptors present on monocytes,
concomitant up-regulation of Th2 cytokines. Inducing blockade macrophages, and natural killer cells leading to tumour cell
of the B7/CD28 costimulation pathway using CTLA-4 Ig which destruction. Monoclonal antibodies may also bind complement
binds to CD28 also prevents activation of T cells. A long-term and trigger the complement cascade, causing complement-
goal in transplantation research is to develop therapies that dependent cytotoxicity. The end result is a membrane attack
would induce graft-specific tolerance for which alloreactive complex that literally perforates the cell membrane, causing cell
T cells would be targeted, leaving other T cells competent to lysis and death.
function effectively.
Successful therapy with monoclonal antibodies is handicapped
ROLE OF IMMUNOTHERAPY IN CANCER by the qualitative and quantitative heterogeneity in distribution
In contrast to the graft situation, immunotherapy in cancer of antigens on malignant cells. The poor blood flow to tumours
involves stimulation of the immune system for the elimination may not permit adequate concentrations of the systemically
of residual tumour. It has been proposed that cancers evolve delivered antibodies to reach tumour cells. The presence of high
from a chronic inflammatory environment which suppresses interstitial pressure within the tumour also prevents binding of
the cell-mediated immunity and encourages tumour monoclonal antibodies. Since most monoclonal antibodies are
angiogenesis. The immune response directed at the tumour can of rodent origin, there exists the possibility that the host will
be enhanced by a variety of approaches including vaccines, mount an immune response to these antibodies. This response
infusion of T cells, or cytokines. These approaches either not only decreases the efficacy of monoclonal antibody therapy,
increase the number of effector cells and/or increase but also eliminates the possibility of re-treatment. Despite these
production of soluble mediators, such as lymphokines. obstacles, there has been tremendous success in the clinical
application of monoclonal antibodies in haematological
VACCINES malignancies and solid tumours (Table 1).
Specific tumour antigens can be administered as vaccines.
CYTOKINES
However, the inability of these antigens to stimulate a strong
T cell response limits the utility of such vaccines. The Cytokines regulate the innate immune system and function in
immunogenicity of these antigens can be augmented by a cascades. Thus, clinical trials of individual cytokines have rarely
variety of immunological approaches that are not being been found effective. Some of the individual cytokines that
discussed here. In fact dendritic cell vaccines using monocyte- have been tested and found to be beneficial are mainly for the
derived DCs pulsed with tumour antigens have been evaluated treatment of haematological malignancies or immunogenic
in early clinical trials using HER-2/neu peptide in case of tumours and include IL-1 β, Interferon-α, IL-12 and GM-CSF.
metastatic breast carcinomas and gp100, MART-1 and MAGE-3 Interferon
antigens in stage IV melanomas. In melanomas, heat shock
IFN-α is a family of molecules that up-regulate genes for MHC
protein gp96, gp100, tyrosinase, and MAGE have been used as
class I, tumour antigens, adhesion molecules and is additionally
vaccines with adjuvants such as BCG. Responses have been
an anti-angiogenic agent. It promotes B and T cell activity,
modest with some instances of complete or partial remissions
stimulates macrophages, dendritic cells and upregulates Fc
or prolongation of survival. The immunogenicity of tumours is
receptors. The benefit of IFN-α therapy in renal cell carcinoma
also enhanced by infecting irradiated tumour cells with viruses
is small but consistent and it is now considered as second-line
transduced with genes expressing cytokines (e.g. IL-2) and
therapy. It is also effective in metastatic melanoma where it
granulocyte-macrophage colony-stimulating factor (GM-CSF),
enhances disease-free and overall survival. However, toxicity
or genes for HLA molecules or co-stimulatory molecules. These
remains a major problem and patients have to be adequately
injected tumour cells undergo apoptosis or are destroyed by
hydrated and given treatment for the associated depression and
inflammatory responses and the shed antigens are processed
decreased energy levels.
by dendritic cells and presented to T cells. The disadvantage of
tumour cell-based vaccines are that antigen is prepared from Interleukin-2
tumour cells extracted from surgical resection or biopsy
IL-2 is a T cell growth factor that binds to a specific tripartite
specimens and, hence, has to be individualised for each patient.
receptor on T cells. Patients treated with high doses of IL-2 have
Viral vectors and naked DNA in the form of plasmids encoding shown clinical responses in renal cell carcinoma and melanoma.
tumour antigens are administered to muscle cells. A prime boost IL-2 has also shown activity in non-Hodgkin’s lymphoma,
approach has been applied where the patient is first immunised leukaemias and lymphomas, post-stem cell transplant. However,
with vaccinia virus, encoding the gene for carcinoembryonic high-dose therapy with IL-2 results in severe toxicity akin to a
antigen (CEA), followed by CEA protein. Clinical responses have state of septic shock. Hypotension, low systemic vascular
been limited, but various modifications of these strategies resistance, high cardiac output, grade 3/4 haematological,
continue to be explored. hepatic and renal toxicity, and pulmonary oedema have all been
160
 Pharmacological Manipulation of the Immune System
Table 1: Monoclonal Antibodies Approved for Cancer Therapy
Name Target site Indications
Alemtuzumab CD52 CLL
Bevacizumab VEGF (receptor for vascular endothelial growth factor) Metastatic colorectal cancer; non-small cell lung
cancer, pancreatic cancer, breast and ovarian cancer
Cetuximab HER1, receptor for epidermal growth factor (EGFR) Colorectal, head and neck cancers
Edrecolomab Glycoprotein 17-1 A Colorectal cancer
Epratuzumab CD22 Indolent, aggressive non-Hodgkin’s lymphoma
Gemtuzumab ozogamicin CD33 Relapsed AML
Ibritumomab tiuxetan CD20 (conjugated with Indium-111 or Yttrium-90) Non-Hodgkin’s lymphoma
Panitumumab receptor for epidermal growth factor Colorectal cancer
Pertuzumab Inhibits dimerisation of HER-2 with EGFR Lung cancer, metastatic breast carcinoma
Rituximab CD20 Lymphomas
131
Tositumomab CD20 (conjugated with I ) Non-Hodgkin’s lymphoma
Trastuzumab HER2, receptor for epidermal growth factor Metastatic breast carcinoma
Vitaxin Vascular integrin α(v)beta(3) Solid tumours

documented but are nearly always reversible. A similar scenario response to ubiquitous and generally innocuous environmental
was recently reported in a phase I trial of the anti-CD28 MAb antigens which cause disease in atopic individuals. Immediate
RGN 1412; CD28, a superagonist and activator of T cells triggered phase responses are usually followed by the development of
by a cytokine storm resulting in a ‘systemic inflammatory late phase reactants and eosinophilic inflammatory processes
response syndrome’ or SIRS. driven by the production of Th2 lymphocytes of IL-4, IL-5, IL-9
and IL-13.
Granulocyte Macrophage Colony Stimulating Factor
(GM-CSF) Conventional treatment of allergic conditions includes
GM-CSF has been approved for use in stem cell and bone antihistaminics and anticholinergics to relieve symptoms along
marrow transplantation to aid reconstitution of the myeloid with corticosteroids to suppress the allergic inflammatory
series. In patients with stage III and IV melanoma, chronic, processes. However, while this approach effectively controls
intermittent GM-CSF following surgical resection improved symptoms, discontinuation of these medications results in
long-term survival and treatment was well tolerated. reappearance of symptoms on re-exposure to the offending
allergens. Therefore, these therapies have a limited capacity to
Interleukin-12 (IL-12) alter the natural course of allergic diseases and the underlying
IL-12, a heterodimeric protein that promotes NK and T cell immunological processes remain uncorrected.
activity, is a growth factor for B cells. IL-12 given alone has
Current therapies for allergic conditions are aimed at
minimal therapeutic benefit but has shown utility as a vaccine
neutralising the allergic response. Allergen-based immuno-
adjuvant as it can induces a strong T helper 1 response. IL-12
therapy aims at inducing a shift in helper T cells from Th2
boosts the response to peptide vaccines in patients with
cytokines (IL-4 and IL-5) towards production of Th1 cytokines,
resected stage III and IV melanoma.
IFN-γ and IL-12, which control IgE production. It is accompanied
FLt3L Ligand (FLt3L) by induction of T-regulatory cells via an enhanced release of
FLt3L stimulates progenitor cells in the bone marrow resulting IL-10 which induces long-term hyporesponsiveness to the
in an increase in DCs. Patients with HER-2/Neu overexpressing allergen. The IgG blocking antibodies that develop, compete
breast or ovarian cancers were administered FLt3L which with IgE for binding to allergens and prevent aggregation of
showed evidence for enhanced HER-2/Neu T cell response, IgE complexes with the α chain of the high affinity IgE receptor
indicating its immunomodulatory potential. on mast cells. Collectively, this prevents release of mediators of
inflammation from mast cells and basophils, prevents infiltration
Immunotherapy may be the next great hope for cancer by inflammatory cells, and decreases the number of mast cells.
treatment. While monoclonal antibodies, cytokines, and
vaccines have individually shown promise, it is likely that the Another approach is to induce allergic specific tolerance so that
best strategy to combat cancers would be a multipronged exposure to a particular allergen fails to produce symptoms.
approach since cancers have multiple mechanisms of Immunotherapy involves administering increasing concent-
preventing the activation of and evading an immune response. rations of extracts of allergens; this induces hypo-sensitisation
Through these concerted efforts, our ultimate achievable goal or desensitisation and attenuates symptoms for several years
may be a durable anti-tumour immune response that can be even after being discontinued. The potential risk involved of
maintained over the course of a patient’s life-span. fatal anaphylaxis, particularly during the up-dosing phase,
necessitates that allergen immunisation should always be
TREATMENT OF ALLERGIC DISEASES conducted in a hospital setting. To overcome this problem,
Allergic diseases including asthma are emerging public health ‘hypoallergic naturally occurring’ allergens prepared from plants
problems. They are characterised by an abnormal immune and trees have been tested and found to be effective in
161
 minimising the risk of anaphylaxis. An alternative approach is IMMUNOTHERAPY FOR AUTOIMMUNE DISEASES
administration of ‘recombinant’ allergens, wherein the cysteine Conventionally, treatment for autoimmune diseases was
residues have been removed by site directed mutagenesis. based on therapies that reduced inflammation and induced
Allergen immunisation is carried out by various approaches. By non-specific immunosuppression. However, as autoimmune
subcutaneous immunotherapy (SCIT), wherein patients are diseases are chronic, prolonged use of anti-inflammatory
sensitised to one or more environmental allergens, for 3 to drugs such as non-steroidal anti-inflammatory drugs, or
5 years of SCIT, can give long-term remission for 3 to 5 years corticosteroids, translates into a shorter life expectancy and
following discontinuation of SCIT. The alternative approach, a poor quality of life. The improved understanding of the
sublingual immunotherapy (SLIT), has the advantage of routé immunopathogenesis of autoimmune diseases has led to
of administration but unlike SCIT, long lasting immuno- a shift towards targeting specific signalling molecules
modulating effects are yet to be established. SLIT simply helps associated with the adaptive immune response. The growing
to reduce incidence of rhinitis and medication usage. A third number of targeted therapeutics now includes monoclonal
approach is DNA vaccines which induce a strong Th1 response. antibodies, soluble receptors and molecular mimetics.
This can be further enhanced by administration of immuno- Possibly the greatest success story has been neutralising
stimulatory sequence of CpG motifs, such as GACGTC, which is TNF-α by infliximab, the humanised monoclonal antibody
the ligand for Toll like receptor-9 on dendritic cells. This leads against TNF-α in the treatment of rheumatoid arthritis. This
to activation of signalling pathway of MAPK, NF-kappaB, principle of TNF-α blockade has also been extended for
cytokines (IFN-α, IFN-β, IL-10, IL-12) along with co-stimulatory Crohn’s disease, ankylosing spondylitis, psoriatic arthritis and
molecules (e.g. CD409, B7); collectively this helps to shift away psoriasis and has also led to the development of other
from a Th2 pro-allergic response towards a Th1 response. Fusion TNF-α blockers (Table 2). Although the long-term safety
proteins, e.g. IL-12 fused with the prototype allergen OVA also is satisfactory, it must be kept in mind that anti-TNF-α
potentiate Th1-based immune response and reverse treatment has been associated with an increased incidence
established allergic responses. Other alternatives include of tuberculosis, production of anti-nuclear and anti-double
blocking IgE or its synthesis and interruption of the Th2 stranded DNA antibodies.
dependent allergic cascade. This has been achieved using
omalizumab, a recombinant humanised monoclonal antibody Targeting B cells decreases production of autoantibodies and
against IgE, which not only neutralised IgE, but also inhibited IgE also depletes B cells, thereby decreasing the proportion of
production in B cells and decreased expression of FceR1 on antigen presenting cells. Rituximab is a human-mouse chimeric
basophils. Importantly, it did not permit activation of mast cells, antibody specific for CD20, a B cell antigen that rapidly depletes
basophils or monocytes rendering it non-anaphylactogenic. B lymphocytes. It was initially approved for the treatment of
Inhibition of IL-4 and IL-5, and treatment with soluble recombinant B cell lymphomas but has been effectively applied in patients
IL-4 receptor has been reported to improve severe atopic asthma. with idiopathic thrombocytopaenic purpura, autoimmune

Table 2: Monoclonal Antibodies that are Approved or Being Evaluated for Use in Autoimmune Diseases
Disease Biological effect Antibody Binding epitope
Rheumatoid arthritis Auto-antibodies, immune complexes Denosumab Nuclear factor kappa B
Infliximab TNF
Lenercept Soluble TNF p55 receptor
Etanercept Soluble TNF p75 receptor
Alemtuzumab CD52
Abatercept CTLA-4Ig
Anakinra IL-1RA
Rituximab CD20
Anti-IFNg IFN-γ
Type 1 diabetes mellitus Decreased insulin production Anti-CD3 (OKT3) CD3
Systemic lupus erythematosus Auto-antibodies cause complement Rituximab CD20
mediated lysis, Type-III hyper- Anakinra IL-1RA
sensitivity reactions BG9588, IDEC 131 CD154
CD154
Multiple sclerosis Myelin destruction Alemtuzumab CD52
Natalizumab Alpha-4 integrin
Psoriasis Activation of T cells in dermis Infliximab TNF
Alefacept LFA3-Ig
Efalizumab CD11a
Juvenile rheumatoid arthritis Damage of synovium Etanercept Soluble TNF p75 receptor
Anakinra IL-1RA
Tocilizumab IL-6
Crohn’s disease Damage of intestinal mucosa Infliximab TNF
Natalizumab Αlpha-4 integrin
ND = Not defined; IFN = Interferon-gamma; TNF = Tumour necrosis factor; IL = Interluekin.
162
 Pharmacological Manipulation of the Immune System
haemolytic anaemia, vasculitis, dermatomyositis, rheumatoid Taken together, our enhanced understanding of the immune
arthritis, Sjogren’s syndrome and systemic lupus erythematosus. system in the last two decades has led to the availability of a
However, there are reports of progressive multifocal leuko- large number of novel treatments and strategies to tackle
encephalopathy following its use. Other biologicals targeting immune based diseases. However, our inability to date, to
CD20 include MAbs ocrelizumab, ofatumumab, hA20 and TRU- achieve complete success by immunotherapy indicates the
015 that also act by depleting B cells. An alternative approach complexities of the immune response that cannot be tackled
to B cell depletion is modulation of B cell function by targeting by a single agent but instead by adopting a multipronged
CD22, thus, preventing B cell activation. Antibodies to CD3 are approach.
also being tried to induce immune tolerance to both allo- and
autoantigens, the goal being to achieve self-tolerance. The CD3 RECOMMENDED READINGS
antibodies are showing promising results in type 1 diabetes 1. Bhardwaj N. Harnessing the immune system to treat cancer. J Clin Invest
2007; 117: 1130-6.
(Table 2).
2. Broide DH. Immunomodulation of allergic disease. Annu Rev Med 2009; 60:
The limitation of the targeted therapies is that despite their 279-91.
high selectivity for immune cell subsets or receptors, they need 3. Chatenoud L. Immune therapies of autoimmune diseases: Are we
approaching a real cure? Curr Opin Immunol 2006; 18: 710-7.
to be applied at multiple intervals to retain their effectiveness.
4. Kaur J, Badyal DK, Khosla PP. Monoclonal antibodies: Pharmacological
The risk of excessive immunosuppression remains a concern.
relevance. Indian J Pharmacol 2007; 39: 5-14.
Therefore, it is currently recommended that for long-term
5. Spagnoli GC, Ebrahimi M, Iezzi G, Mengus C, Zajac P. Contemporary
improvement, targeted therapy should be coupled with immunotherapy of solid tumors: From tumor-associated antigens to
conventional anti-inflammatory agents. combination treatments. Curr Opin Drug Discov Devel 2010; 13: 184-92.

163
 5.7 Immunology of Organ and
Haematopoietic Stem Cell Transplantation
Narinder K Mehra, Jamshaid A Siddiqui

Transplantation is the treatment of choice for functional failure alleles and its multi-peptide binding ability making it an
of many organs. The success of transplantation depends on the important immune response control system. The major clinical
degree of histocompatibility between donor and recipient, role of HLA testing remains in the area of donor selection in
among other factors. The genetic difference between recipient organ and stem cell transplantation.
and the donor is determined by a set of immune response genes
GENETICS OF HLA
clustered together as human leucocyte antigen (HLA) system.
These antigens play an important role in immune discrimination The human MHC gene cluster contains three distinct groups
between self and non-self (foreign) molecules. of loci, a centromeric ‘class II region’ which has HLA-DP, DQ and
DR loci, a telomeric ‘class I region’ that contains the classical
MAJOR HISTOCOMPATIBILITY COMPLEX HLA-A,B,C and a central ‘non-HLA’ or ‘class III region’ which
The blood group system (A, B, O), the major histocompatibility contains genes whose products are involved in the
complex (MHC) and the minor histocompatibilty antigens complement cascade (C2, C4 and properdin factor Bf) and
(mHA) that include the male specific H-Y antigen system various non-immunological functions (Figure 1). Both class I
constitute the histocompatibility system in humans. The MHC and II gene products show important differences in structure,
of man, the HLA system, is located on the short arm of function and tissue distribution. Matching donors and
chromosome 6 extending over approximately 4 megabases of recipients for HLA-A, B and C for haematopoietic stem cell
DNA. The MHC molecules bind peptide fragments derived from transplantation (HSCT) loci of class I and of HLA-DR/DQ loci in
protein antigens (viruses, bacterial peptides, mismatched the class II region during organ and bone marrow
transplant antigens, etc.) and display them on the surface of transplantation is critical to the survival of a graft.
antigen presenting cells (APCs) evoking effector responses HLA Class I Genes
upon recognition by the T-cell receptor (TCR).
HLA class I molecules are expressed on all nucleated cells. Of
The four inherent features of the MHC are the extraordinary the 35 loci that have been described so far, HLA -A, -B and -C
high polymorphism of its genes at the population level, tight are the most important. Using tools of molecular biology and
linkage among its various loci, non-random association of HLA DNA typing methods, 238 alleles have been identified in locus

Figure 1: Human major histocompatibility complex (MHC) with chromosomal location and gene map showing multiple genes on the short arm of chromosome
6 (6p21.3). The two way array shows the genetic distance covered by the respective regions on the chromosome. The circled loci are highly polymorphic and are
important for donor-recipient matching in the transplantation context. Note that MICA (MHC class I related chain A) is situated in close proximity to the HLA-B
locus.
164
 Immunology of Organ and Haematopoietic Stem Cell Transplantation
Figure 2: Schematic view of HLA class II and class I molecular structures showing the peptide binding cleft formed between α1 and β1 domains in case of class II and
α1 and α2 domains in case of class I molecules. The membrane proximal domains (α2, β2 of class II and β2m and α3 of class I) are conserved and non-polymorphic.

A, 451 in locus B, and 238 in locus Cw. These molecules are HLA-A*02010101 is designated as HLA-A*02:01:01:01, where
heterodimeric glycoproteins consisting of an MHC encoded the first 2 digits following the star sign represent the HLA allele
alpha or heavy chain and non-MHC encoded light chain (beta- family, which often corresponds to broad serological HLA
2 microglobulin) (Figure 2). The extracellular portion of the antigen (in this case HLA-A2). The 3rd and 4th digits correspond
heavy chain is folded into three globular domains, α1, α2 and to the order in which the sequences were determined, 5th
α3 and associates noncovalently with the β2 microglobulin and 6th digits the synonymous substitutions in coding region
(β2m). X-ray crystallography of class I molecule has revealed and 7th and 8th digits the variations in introns or untranslated
that the region distal from the membrane is formed by regions.
α1 and α2 domains which take part in antigen binding.
POLYMORPHISM AND INHERITANCE
Functionally, MHC class I molecules bind to CD8 co-receptor
molecules on the T-cells and therefore, present non-self- An individual inherits two alleles of each of the above loci, one
antigens to CD8+ T-cells. MHC class II molecules bind to CD4 each from either parent. A complete set of alleles on the same
co-receptors molecules on T-cells and hence, they present chromosome is usually inherited (a haplotype) and the two
antigen to CD4+ helper T-cells. HLA haplotypes in an individual derived after family testing
constitute the genotype; the total HLA antigen profile is the
HLA Class II Genes phenotype. Siblings in a family have a 25% chance of being HLA-
The HLA-class II region of the human MHC has at least six identical, 50% chance of being HLA-haploidentical (sharing one
subregions termed DR, DQ, DO, DN, DM and DP. They are parental haplotype only) and 25% chance of being HLA-
expressed as heterodimers on the cell surface and are composed unidentical (Figure 3).
of an α (alpha) gene and a β (beta) chain that traverse the plasma
membrane (Figure 2). Their tissue distribution is restricted to
specific cells of the immune system involved in antigen
presentation (APCs), namely B lymphocytes, macrophages,
monocytes, epithelial cells, dendritic cells, Langerhan’s cells and
Kupffer cells. Currently, 438 DRB1, 71 DQB1 and 59 DPB1 alleles
can be recognised using DNA typing methods of polymerase
chain reaction and oligonucleotide probes.
Class III Genes (Central Genes)
At least 39 genes have now been located in a 1000 kb stretch
of DNA within the class III region interposed between class I
and class II regions. This includes the complement genes C2,
C4 and Bf (factor β), the TNF-α and TNF-β genes and the Hsp 70
(heat shock protein) genes. Figure 3: Segregation of HLA haplotypes in a family. The sibs inherit one
haplotype from each parent and accordingly four different haplotypic
NOMENCLATURE OF HLA combinations are possible. In this case, the patient is HLA-identical with her
In HLA nomenclature system colons (:) are introduced into the younger brother, HLA-unidentical with her younger sister and shares only one
haplotype (haplo-identical) with her elder brother and sister.
allele names to act as demiliters of separate fields. Thus, the allele
165
 SELECTION OF OPTIMAL DONORS 7.8 years for cadaver donor grafts which are generally mis-
The MHC is the major barrier in selection of HLA matched matched. There has been no significant improvement in
donors for patients requiring solid organ or HSCT. The the half-life of grafts even following introduction of highly
probability of finding a 100% matched donor is higher among effective immunosuppressive agents including tacrolimus
the family members, because of the haplotypic inheritance and sirolimus.
pattern of the MHC. Four main donor categories are considered
ALLORECOGNITION
for HSCT: (1) HLA-identical sibling; (2) family donors other than
siblings-defined by extended family testing, and who share Allorecognition refers to T-cell recognition of genetically encoded
HLA-A,B,C,DR and DQ alleles; (3) HLA-identical cord blood polymorphism between members of the same species. CD4+
following antenatal testing; and (4) the unrelated HLA matched recipient T-cells recognise donor alloantigens through either the
donors obtained through marrow registries. direct pathway in which host T-lymphocytes recognise native
MHC molecules expressed on graft-associated APCs or the
The best HSCT results are seen in patients with a genotypically indirect pathway, in which donor alloantigen-derived peptides
HLA-identical sibling. The probability of finding such a donor is are recognised in the context of self MHC molecules expressed
approximtely 30% to 35%; about 30% of remaining patients are on recipient APCs (Figures 5A and B). The direct pathway is of
successful in finding a matched, unrelated voluntary donor particular relevance during acute rejection. Donor derived APCs
through unrelated donor marrow registries. Large global, expressing donor alloantigens rapidly migrate from the graft and
American and European registries have been established; enter the secondary lymphoid tissues, where they can encounter
however, Asians-Indians are poorly represented in them. An and prime the allospecific T-cells. Cytotoxic T-lymphocytes, B-cells,
Asian-Indian Donor Marrow Registry (AIDMR) has been macrophages and natural killer cells are recruited in a graft
established at the All India Institute of Medical Sciences, New undergoing rejection. The main mechanisms implicated for graft
Delhi since 1994 and has close to 5000 registered voluntary destruction are cell-mediated cytotoxicity, delayed type
Asian-Indian donors. hypersensitivity and antibody-dependent-cellular cytotoxicity.
Matching strategies for renal transplantation consider only HLA-
GRAFT REJECTION
A, HLA-B and HLA-DR loci. In renal and other solid organ
transplantation, a direct relationship exists between graft Efforts are always made to ensure that patient and donor are
survival and the level of matching. Four types of donors are matched for HLA gene loci as completely as possible. However,
generally available for renal transplantation. Family donors this is difficult to achieve and immunosuppressive drugs are
include parents, siblings and offspring and their match status given to control the host immunity caused by HLA disparity.
is determined by the parental haplotype inheritance and The aim is to prevent or control rejection and allow the recipient
whether they share one, both or no HLA haplotypes (Table 1). to develop long-term acceptance (or tolerance) of the graft.
In HSCT, the level of HLA matching is much more critical than Rejection can be mediated by antibodies, lymphocytes or both
solid organ transplants and is limited to HLA-identical sibling and can manifest as hyperacute (in the early post-transplant
donors. This is because of the risk of graft versus host diseases period, within hours), acute (occur at any time) and chronic
(GVHD) where T-cells in the stem cell graft react against rejection (slowly developing process with progressive decline
allogeneic host HLA molecules expressed on all tissues. in graft function).

Table 1: Donor Categories for Renal Transplantation and Probability of HLA Match
Donor category Match probability Match designation
Family donors
Parents 50% match or one haplotype match Haploidentical
Siblings 25% chance of full match HLA identical
50% chance of one haplotype match Haploidentical
25% chance of no haplotype match HLA unidentical
Offsprings 50% match or one haplotype match Haploidentical
Cadaver donor Generally poor Expressed as mismatch (mm) for the number of HLA antigens shared
in HLA– A, B, and DR loci: for example, full house match (0/6 mm) or
grades of 1 to 6 antigen mm
Spousal donor Generally poor
Unrelated donor Generally poor

HLA = Human leucocyte antigen

Most grafts from unrelated donors are mis-matched at several Hyperacute rejection is caused by preformed donor specific
HLA loci. The 10 year graft survival of 70% seen in the HLA- alloantibodies in a presensitised recipients. Humoral
identical sibling grafts is significantly reduced to 50% for the presensitisation may be caused by a previous transplant, blood
HLA haploidentical parental donor grafts and < 40% for those transfusions or pregnancy. The alloantibody-mediated rejection
involving poorly matched cadaver donors as is seen in the is initiated by activation of the complement cascade leading to
long-term renal graft survival compiled by the UCLA registry release of various inflammatory mediators and the initiation of
(Figure 4). The ‘half-life’ (the period at which at least half the the coagulation and fibrinolytic systems. Hyperacute rejection
grafts are still functioning) is 25 years for well-matched is manifested by rapid vascular constriction, oedema and
166 HLA-Id sibling grafts, 11.5 years for parental donors and only thrombotic occlusion.
 Immunology of Organ and Haematopoietic Stem Cell Transplantation
Figure 4: University of California Los Angeles (UCLA) data involving large series of kidney transplants showing the HLA matching effect followed for at least a
10-year period. The HLA-identical sibling donor transplants have 70% graft survival compared to 50% for haplo-identical parental grafts and < 40% for mismatched
cadaver donor grafts. The half-life of the HLA-Id grafts is 25 years which drops significantly to 7.8 years (1987-95 block) and 9.3 years (1996-2006 block) for the
cadaver donors.
Source: Kaneku et al 2006.

Figures 5A and B: The pathways of allorecognition that cause problems in organ transplantation as a result of HLA mismatching. (A) Direct pathway. The alloreactive
responses of recipient T-cells to donor APC expressing incompatible antigens. (B) Indirect pathway. Allogeneic HLA antigens are taken up and processed by the
recipient APCs and presented in the context of autologous (self) HLA molecules to recipient T-cells. Antigen-presenting cell trigger CD4+ and CD8+ cells, and as a
result local and systemic immune response develops. Cytokine recruitment and activation of specific T-cells, NK cells and macrophage-mediated mechanisms lead
to cytotoxicity and finally the allograft destruction.
MHC = Major histocompatibility complex; HLA = Human leucocyte antigen.

The injury in acute rejection (AR) is caused by T-cells (T-cell exert a direct cytotoxic effect on graft parenchymal cells, and
mediated rejection) and antibodies (humoral rejection), either mediate a delayed type hypersensitivity (DTH) response.
alone or together. It typically appears during the first 1-6 weeks
after transplantation and declines sharply after the first Chronic rejection, affects most long-term transplant survivors
6 months. The allograft vascular endothelium is the primary and is characterised by vasculopathy, fibrosis and a progressive
target of the initial stage of cellular rejection and lymphocytes loss of the organ function. Chronic rejection is mediated by low- 167
 grade, persistent DTH response and activated macrophages CONCLUSION
secrete mesenchymal cell growth factors leading to fibrosis. Recent advances in immunological techniques promise
Persistent viral infections also induce cellular immune improved management of transplant patients by predicting
responses. The donor-specific alloreactive T-cells and the rejection episodes before the onset of irreversible and terminal
chronic ischaemia secondary to injury of the blood vessels damage. HLA matching is beneficial in both short as well as
by antibody or cell-mediated mechanisms also contribute. long-term survival of the renal allograft and in live related as
Vascular occlusion may occur as a result of smooth muscle cell well as deceased donors. The poor match status between donor
proliferation in the intima of the arterial walls. and recipient is frequently associated with more vigorous
antibody response. Molecular approaches for clinical
PRE- AND POST-TRANSPLANT ANTIBODY SCREENING
monitoring of the post-transplant immune status and
A meticulous ‘crossmatch test’ for possible occurrence of anti- identifying the best functionally matched donor before the
donor antibodies is always performed before any transplantation. transplant procedures are among the key areas of futuristic
This is similar to the direct crossmatch done prior to blood research in the area of clinical transplantation. Continuing
transfusions; donor lymphocytes instead of red cells are tested progress in understanding molecular mechanisms of graft
with patient serum. Several improved cross-match assays have rejection may lead to the ultimate goal of long-term acceptance
been developed to increase the sensitivity and specificity of organ allograft through tolerance induction.
of the test and include the anti-human globulin test (AHG),
flow cytometry, and solid phase assays like enzyme linked RECOMMENDED READINGS
immunosorbent assay and luminex systems. Serum treatment 1. Abbas AK, Lichtman AK Pillai S. Cellular and Molecular Immunology.
with dithiothreitol is used to distinguish clinically less relevant Philadelphia: WB Saunders; 2007.
IgM type antibodies. 2. Marsh SGE, Albert ED, Bodmer WF, et al. Nomenclature for factors of the
HLA system, 2010. Tissue Antigens 2010; 75: 291-455.
HLA antibodies that develop de novo post-transplantation and
3. Mehra NK, Kaur G, McCluskey J, Christiansen FT, Class FHJ. The HLA Complex
not necessarily donor specific, are associated with poor graft in Biology and Medicine: A Resource Book. New Delhi: Jaypee Brothers
survival. It is, therefore, advisable to monitor routinely the post- Medical Publishers (P) Ltd; 2010.
transplant development of such antibodies, as a predictive 4. Terasaki PI. History of HLA. Ten Recollections 1990; Los Angeles, CA: UCLA
marker for allograft function. Tissue Typing Laboratory, USA.

168
Section 6
Medical Genetics
Section Editor: Shyam Swarup Agarwal
6.1 Introduction to Medical Genetics 170
Shyam Swarup Agarwal
6.2 Mendel and Beyond 173
Ratna Dua Puri
6.3 Clinical and Molecular Cytogenetics 180
Ashutosh Halder
6.4 Genetic Tests 189
Ashwin Dalal
6.5 Inborn Errors of Metabolism 193
Madhulika Kabra
6.6 Molecular Genetics, Human Genome Project and Genomic Medicine 201
Girisha K.M.
6.7 Gene Therapy 206
Rita Mulherkar
6.8 Genetic Counselling and Prenatal Diagnosis 209
Shubha R. Phadke
6.9 Pharmacogenomics and Personalised Medicine 215
C. Adithan
6.10 Cancer Genetics 217
Rajiv Sarin
 6.1 Introduction to Medical Genetics

Shyam Swarup Agarwal

DEFINITION cystinuria and pentosuria—the inborn errors of metabolism—

Genetics is the science of study of genes, a field devoted to identified by Sir Archibald Garrod in 1909. As a parallel activity,
understanding principles and mechanisms of heredity and around the same time (1879 onwards), diploid nature of the
variation. Gene—a segment of deoxyribonucleic acid (DNA) that chromosomes in eukaryotic cells and mitotic and meiotic cell
codes one polypeptide chain—is the basic unit of inheritance divisions were delineated that provided the physical basis for
that transmits characters from generation to generation. Mendelian inheritance (Sutton 1902). The correct number of
Collectively genes are responsible for uniqueness of each human chromosomes, however, was not known until 1956 (Tjio
species as well as each individual. Studies in genetics deal with and Levan 1956).
decoding the structure, function and transmission of genes that Next major milestone in genetics was the study of variation in
determine the development and differentiation of a single cell Drosophila melanogaster, the fruit fly, which led to identification
zygote into a whole human being, and also, the functioning of of spontaneous mutations and their induction by radiation and
various organs and systems of the body from conception to chemicals (Muller and Morgan). Studies on fruit flies also led to
death. In addition, genetics also includes the study of genesis
the discovery of linear arrangement of genes on a chromosome,
and selection of variation which determines survival of the
the linkage of closely located genes on the same chromosome,
fittest, and thus, evolution. Classically, genetics had dealt with
and mechanism of determination of sex and meiotic
study of one gene at a time, both for sake of simplicity and lack
re-combination. The first inkling about the biochemical
of tools to study multiple genes or the genome as a whole. It
functioning of genes came from the studies of Beadle and
needs to be appreciated that the normal structure (anatomy)
Tatum (1941) on auxotrophy in the fungus neurospora. It led to
and function (physiology) of genes that determines health
the hypothesis of ‘one gene-one enzyme (polypeptide chain)’
(Genetics in Medicine) is as important as the study of their
as the basis of inheritance. The chemical nature of genetic
aberration that leads to genetic disease (Medical Genetics as a
material was discovered by Avery, Macleod and McCarty in 1944
speciality).
who showed that the ‘transforming principle’ of pneumococcus
GENETICS AND GENOMICS was DNA [in some organisms the genetic material was later
With recent advances in molecular biology leading to successful shown to be ribonucleic acid (RNA) instead of DNA].
completion of the Human Genome Project in 2003, and Subsequently, in quick succession, the molecular structure of
emergence of technologies enabling study of whole genome, DNA was delineated by Watson and Crick in 1953, and the
transcriptome, proteome and metabolome of the cell, in one processes of DNA replication, transcription and translation were
go, a new era of medicine has dawned. In the words of Victor delineated leading to unravelling of the genetic code. The holy
McKusick, “… Biomedical research in the future would be trinity of DNA-RNA-Protein became the gospel truth of life, until
progressively more integrated and integrative; that families of Baltimore and Temin discovered the enzyme ‘reverse
genes, not single genes, and physiologic systems, not single transcriptase’ in onco-RNA viruses providing a mechanism for
reactions will be the objects of study…. ”. This approach when reverse transcription of RNA into DNA, that gets integrated into
applied to the study of genes in health translates into host genome.
“Integrated Systems Biology”, and in patient care to “Genomic
Medicine”. Literally, genomics can be defined as the study of A totally new chapter in the field of human/medical genetics
the ‘genome’ as a whole, the sum total of all the genes and non- has been written with the advent of genetic engineering in
coding genetic material as well. This includes study of gene- 1970s. The discovery of restriction endonucleases (Smith 1968)
gene and gene-environment interaction. enabled cutting and pasting of different DNAs leading to
engineering of ‘new’ DNA. The ‘new’ DNA can be cloned in
HISTORY plasmids giving rise to millions of copies of the desired DNA
Although occurrence of familial disorders (such as, haemophilia, (unique single copy genes). Combined with the technique of
colour blindness, polydactyly, etc.) and resemblance of children DNA sequencing, genetic engineering has paved the way for
to their parents was known for a long time, it was Mendel’s the Human Genome Project (1995-2003) that led to mapping
classic experiments in 1865 on transmission of discrete and sequencing of the entire human genome. The completion
characters in sweet-pea plants that laid the foundation of of the Human Genome Project in 2003 is likely to be as
genetics (the term ‘genetics’ was coined by William Bateson in revolutionary as the discovery of Mendelian principles of
1906). It was remarkable that Mendel deduced the laws of inheritance at the turn of last century.
inheritance much before the discovery of chromosomes. The
contributions of Mendel remained unnoticed till the turn of the MAJOR DIVISIONS OF THE FIELD OF GENETICS
19th century when they were independently rediscovered by Genetics as a whole encompasses a wide field of study. It has
de Vries, Tschermak and Correns. But very soon the application many sub-divisions. On basis of tools used for the study, there
170 of Mendelian laws was found for alkaptonuria, albinism, are four classical sub-divisions of genetics, viz., (1) Mendelian or
 Introduction to Medical Genetics
pedigree genetics, (2) cytogenetics, (3) biochemical genetics, Online Mendelian Inheritance in Man (OMIM) database which
and (4) molecular genetics. To this list, another specialised area collectively affect approximately 2% to 3% of all births
of statistical genetics, bioinformatics and computational (excluding congenital malformations which account for another
genetics has been added in recent years which is going to 1.5% to 2.5% of all live births). The genetic defect acquired in
dominate the scene of genomic medicine in the years to come. somatic cells may give rise to malignant transformation (leading
The above terms are self-explanatory and are covered in to cancer), or senescence, without being transmitted to the next
separate chapters under this section. With regards to the area generation.
of study, the discipline of genetics can be divided into the
The studies in medical genetics include understanding of the
following categories: (1) human genetics, (2) medical genetics, pathophysiology of genetic diseases, i.e. how the abnormal
(3) clinical genetics, and (4) community genetics. These are gene gives rise to disease. The most classical example is of sickle
interrelated areas which run into one another. A brief cell disease where substitution by ‘T’ for ‘A’ at codon 6 of beta
description of each follows, giving some idea about the scope globin gene leads to substitution of glutamic acid by valine
of each domain. In addition, there are other areas of application resulting in formation of a slow-moving haemoglobin (Hb S).
as well, such as developmental genetics, population genetics, The latter, under hypoxic conditions, gives rise to sickling of red
evolutionary genetics, and forensic genetics, etc. cells which are responsible for all the manifestations of sickle
Human Genetics cell disease. This knowledge allows for definitive diagnosis of
Human genetics may be broadly defined as study of the role of the disease, antenatal diagnosis, as well as screening of the
genes in health and normal variation. While identity of all the disorder in newborns for better prevention of various
genes has been unravelled with successful completion of the complications. Efforts are also being made to correct the defect
Human Genome Project, their detailed function—giving rise by gene therapy, and designing of pharmacophores for
to the ultimate phenotype—still remains to be delineated to a treatment of genetic diseases.
large extent (Functional genomics and Phenomics). Even more Besides causation of disease, the genetic make-up of an
importantly, we need to understand regulation of temporal and individual may also modify its response to drugs – both safety
spatial expression of genes, gene-gene interaction and gene- and efficacy (Pharmacogenomics), toxins (Toxicogenomics) and
environment interaction. Some examples include production nutrients (Nutrigenomics). This information can be used for
of different haemoglobins during embryonal, foetal and adult personalising therapy as well as for prevention of disease.
life; regulated secretion of insulin and other hormones to
Clinical Genetics
achieve glucose homoeostasis—after and in-between meals;
regulation of reproductive cycles from puberty to menopause; Clinical genetics deals with application of the knowledge of
senescence and even life span, characteristic of each species. It genetics to patients with genetic disorders in the clinic and at
needs to be realised that the basis of life has now been reduced the bedside. It includes diagnosis, management and prevention
from cell to molecule, and we have to understand the entire of genetic disorders. To begin with, the role of genetic clinic
anatomy, physiology, pathology and pharmacology at the was limited to genetic counselling. With the development of
molecular level—the so called “Molecular Medicine”. the technique of amniocentesis in the 1960s to obtain foetal
cells, antenatal diagnosis could become possible, providing the
Human genetics deals with not only understanding of normal couple an opportunity to choose reproductive options in a child
structure and function, but also of normal variation such as at risk of genetic disorder. Simultaneously, the development of
height, weight, colour of the skin and eyes, intelligence, etc. Guthrie’s technique for newborn screening of phenylketonuria
Unravelling of the human genome sequence has led to and other inborn errors of metabolism on one hand, and diets
identification of millions of SNPs, CNVs and STRs among normal for treatment of these disorders on the other, has revolutionised
healthy individuals, some of which may contribute to the treatment of genetic disorders to the extent that screening
quantitative variation—giving rise to characteristic Gaussian of newborns has been made mandatory by law in a number of
distribution curve for these genetic traits. countries in the developed world. With the advent of DNA
Human genetics is as relevant to medicine, as anatomy, diagnostic tests, the scope of antenatal diagnosis has expanded
physiology and biochemistry are. to cover several hundred disorders. In addition to antenatal
diagnosis and newborn screening, several other interventions
Medical Genetics have been developed for management of patients with genetic
Medical genetics is an extension of human genetics. It deals disorders. This includes replacement therapy such as AHG in
with the study of the role of genes in causation of the disease. haemophilia, high-dose vitamin therapy in homocystinuria,
In this context, genes play a dual role. On one side chromosomes, bone marrow transplantation for thalassaemia and others. More
genes and DNA constitute the ‘genetic system’ in anatomical recently, recombinant DNA technology has allowed large scale
sense that is the site of lesion for genetic disease, and on the manufacture of enzymes for enzyme replacement therapy for
other, the gene acts as an aetiological agent contributing to lysosomal storage disorders, though the cost of treatment
causation of disease. In the latter context, genetic make-up of remains high. There is also a ray of hope that gene therapy and
the individual determines susceptibility/resistance to other forms of molecular and cellular therapies may develop
environmental pathogens, giving rise to complex, multifactorial for some genetic disorders in the future. All theses
polygenic disorders. The defects of nuclear DNA, because of developments have necessitated that the speciality of clinical
their presence in gametes, follow Mendelian segregation, genetics be developed for the benefit of patients with genetic
whereas mitochondrial DNA defects follow maternal disorders and primary care physicians (PCPs) be knowledgeable
inheritance. More than 3,000 genetic disorders are listed in the to suspect, counsel and refer these patients to speciality centres. 171
 The core competencies required by PCPs have been published medical colleges in India do not have any teaching-training
by the National Coalition for Health Professional Education in programme in human and medical genetics at present, mainly
Genetics. because of lack of trained medical faculty in this discipline. As
mentioned above, we now need to tune ourselves to the
Community Genetics
molecular basis of health and disease. As far as clinical practice
Community genetics is an extension of clinical genetics for the is concerned, there has been some introduction of services in
public at large. One of the earliest examples was the screening this area as a by-product of clinical research programmes in this
of Ashkenazi Jews for Tay-Sachs disease carrier state and the field. However, its penetration is limited mainly due to absence
offer of antenatal diagnosis to the couple at risk. Application of of adequate diagnostic laboratory facilities. There is an urgent
the same principle to thalassaemia screening in the Cyprus need to establish quality assured laboratories, with adequate
island has virtually eliminated the birth of even a single counselling support, to provide to our people (at least to those
thalassaemic child in that country. It is one of the most radical who can afford) what is already available elsewhere. Since
and successful implementation of primary prevention of clinical genetics is still largely a preventable programme, it
genetic disorders. In more recent years, periconceptional folic would be better to take it up in the public health, national
acid supplementation has led to marked reduction in the birth programme mode. As far as research is concerned, we are better
of children with open neural tube defect. Likewise, identification than the other two areas. Most of our biomedical research labs
of several high-risk markers for Down’s syndrome and other have adequate infrastructure and expertise to be competitive
chromosomal disorders has led to universal counselling and in this field. What is needed is innovation in our approach and
screening of all pregnancies (irrespective of maternal age) with competition in spirit to make use of the opportunity. This will,
triple/quadruple test. For many of the strategies of antenatal however, require well-defined clinical material for exploration
diagnosis, it is desirable that the couples at risk should seek as well as validation which also needs to be addressed.
genetic advice before conception. It is strongly recommended
that obstetric care should commence with preconception RECOMMENDED READINGS
clinics. Cost-benefit analyses have shown that many of the
1. Gene Tests. Available at www.ncbi.nlm.nih.gov/sites/GeneTests .
screening programmes deserve to be taken up as national Accessed on 2010-05-04.
public health programmes. One of the new areas that are
2. Genomic Science Program: Human Genome Project Information–
emerging is that of cancer genetics. Association of BRCA1/ Education. Available at http://genomics.energy.gov. Accessed on
BRCA2 gene mutations with familial breast-ovarian cancer, and 2010-05-04.
APC/MSH mutations with familial colon cancer have shown the 3. Lutherville MD. National Coalition for Health Professional
utility of predictive screening for prevention of cancer. With Education in Genetics; 2008. Available at www.nchpeg.org.
increasing recognition of genetic markers for various polygenic- Accessed on 2010-05-04.
multifactorial disorders, such as diabetes, hypertension, 4. National Human Genome Research Institute – Health, Education
coronary artery disease, etc., community genetics is bound to and Issues in Genetics. Available at www.genome.gov. Accessed
become a major component of public health programmes. on 2010-05-04.
5. Public Health Genomics. Available at www.cdc.gov/genomics/.
CURRENT STATUS AND FUTURE PROSPECTS: INDIAN Accessed on 2010.
SCENARIO
6. The Family Medicine Genetics Program. Available at
It needs to be considered under 3 headings, viz., teaching, www.mountsinai.on.ca/care/family-medicine-genetics-program
practice and research. As far as teaching is concerned, most Accessed on 2010-05-04.

172
 6.2 Mendel and Beyond

Ratna Dua Puri

INTRODUCTION genomic imprinting, instability of triplet repeats, mitochondrial

The roots of understanding of genetics can be traced back to gene structure, function and phenomenon of homo-
1865 when the Augustinian monk Gregor Mendel described heteroplasmy, uniparental disomy, epigenetic modulation of
the principles of inheritance based on his meticulous and pain- gene expression, etc. our appreciation of the Mendelian
staking cross-breeding experiments with the sweet pea (Pisum principles of inheritance has enhanced rather than diminished.
sativum) plants which he grew in his monastery garden in Brno. The next challenge is to unravel and understand the
After 8 years of tedious experimental work with hybrid plants, phenomenon of polygenic inheritance. Interestingly, even the
Mendel proposed the basic principles of inheritance which are monogenic disorders are greatly influenced by multiple genes-
enumerated in Table 1. so called modifier genes. There is a growing realisation that no
gene functions in isolation. The effect of every gene may be
Table 1: Basic Principles of Mendelian Inheritance influenced by gene-gene interaction and gene-environment
 Each individual inherited trait, including its alternate form, is interaction. The fuzziness will give way to more clarity as we
determined by a pair of factors, later called genes by Wilhelm know more.
Johannsen in 1909.
As a clinician, to identify individuals at risk for a genetic disorder,
 Each member of the pair of factors is inherited from one parent and to counsel the families with a child suffering from genetic
(the members of the pair segregate during gametogenesis—
disease, it is important to ascertain the mode of inheritance.
so that each gamete contains only one factor).
This requires recording of the family history. The following
 The gene determining the alternative form of the trait is called discussion of the art of pedigree drawing and then its analysis
‘allele’. The genes may be dominant or recessive, depending on
to deduce the pattern of inheritance of the disease under
their expression in the hybrid state. In the F1 hybrid only the
dominant form is expressed. The recessive gene is neither lost, consideration is of great importance.
nor blended. It remanifests in the F2 generation in a ratio of 3:1.
PEDIGREE DRAWING
 Genes determining different traits (now identified to be located
on different chromosomes) segregate independently of each The initial step in any genetic consultation is the collection of
other. relevant family data. A pedigree or a family tree is a
diagrammatic representation of the relationships amongst
The observations of Mendel are summarised in two laws which family members and record of relevant medical information
form the basis of inheritance of unifactorial traits. about each of them by employing a combination of
The Law of Segregation internationally accepted symbols and lines. The index case, or
proband, is the affected person who brings the family to notice
For any particular trait, the pair of alleles of each parent separate
during meiosis so that the gamete receives only one allele. Only and his position in the pedigree is depicted by an arrow. From
one allele passes from each parent to an offspring. this start point the brothers/sisters, parents, offspring and
maternal and paternal relatives are recorded using the symbols
Principle of Independent Assortment as shown in Figure 1.
This law states that different pairs of alleles determining By convention, a three-generation pedigree is used in clinical
different traits are passed to offspring independently of each
practice. More extended family trees may be drawn if needed.
other. Today, we know this is true only for those genes which
are located on different chromosomes, or quite far from each The importance of the pedigree chart is to record concisely and
other if located on the same chromosome. The genes located pictorially complete family history with names and dates of
close to each other are inherited together (linkage). birth, their health and disease status, etc. from which the mode
of inheritance of the disorder can be deduced. For example, limb
A Mendelian trait is one which is controlled by a single gene, girdle muscular dystrophy can be inherited as an autosomal
follows Mendel’s laws of inheritance, and mutation in the gene dominant or recessive trait and this can be differentiated by
leads to altered/diseased phenotype. pedigree analysis. It can also be used to identify the risk of
Life is not simple, and so is the relationship of phenotype to the transmitting an inherited condition to the offspring, to identify
genotype. Heterogeneity of genetic disorders, both intra-family family members at risk of the disorder, or carriers of the disorder.
and inter-family, is the rule rather than an exception. This led to
invocation of the phenomenon of ‘penetrance’ and ‘expression’. MENDELIAN INHERITANCE/SINGLE GENE DISORDERS
The next challenge was to account for anticipation and various This refers to a group of disorders occurring as a result of a
anomalous patterns of inheritance. At first, the very validity of defect/mutation in one or both alleles of a gene. Autosomal
the Mendelian laws was challenged, but with better pattern of inheritance is due to a mutation of a gene on an
understanding of the molecular basis of gene function, such as autosome and in sex-linked inheritance/trait, the relevant gene
173
 CONCEPT OF DOMINANCE AND RECESSIVENESS
Dominance is defined in terms of expression of the gene (disease
or trait) in the heterozygous state. This occurs as a result of gain
of function mutation where the abnormal gene product (even
in the presence of normal product of the other gene) is sufficient
to lead to altered state, e.g. Huntington chorea, Charcot-Marie-
Tooth disease. Oncogenes are classical example of dominant
genes. On the other hand, a recessive gene manifests as loss of
function. It gives rise to disease/trait only when both the copies
of the gene are knocked out, i.e. in homozygous state, e.g.
thalassaemia. A dominant negative mutation results in a gene
product that is non-functional, but it interferes with the function
of the normal allele, so that it manifests even in the heterozygous
state, e.g. osteogenesis imperfecta.
Autosomal Dominant Inheritance
The disorder occurs due to a mutation in one copy of a gene
present on autosomes. Hence, these disorders manifest in the
heterozygous state where the affected individual has one
abnormal (mutated) and one normal allele (Figures 2 and 3).
The characteristics of autosomal dominant inheritance are
listed in Table 2.

Figure 2: Autosomal dominant inheritance.

Figure 1: Pedigree symbols.

is on the X or Y chromosome. An individual with identical alleles

of the gene is homozygous, and one whose alleles are not Figure 3: Punnett square showing segregation of alleles in a family with an
identical is heterozygous. autosomal dominant disorder.
174
 Mendel and Beyond
Table 2: Characteristics of Autosomal Dominant Inheritance changes, neurofibromas, short stature, mental subnormality
and Lisch nodules in the eyes.
 Vertical mode of transmission with expression in more than one
generation Onset
 Males and females are equally affected The onset of genetic disorders can be variable, e.g. Huntington
 Father to son transmission present chorea, spinocerebellar ataxias, etc. In these disorders, it is
 The risk to the offspring of an affected individual is 50% in each difficult to counsel at what age a person will develop the disease,
pregnancy or the quantum of risk of transmitting the disorder to the
 Family members, who are unaffected, themselves do not offspring if the person has not developed symptoms yet. In
transmit the disorder majority of these diseases, this dilemma may be overcome by
Examples: Huntington disease, achondroplasia, autosomal dominant polycystic the availability of DNA diagnostic tests.
kidney disease, facioscapulohumeral dystrophy, neurofibromatosis I and II,
tuberous sclerosis. New mutations
In some autosomal disorders, an affected person may be born
It is not unusual to see deviations from the typical characteristics to normal parents and there may be no history of similar disease
of autosomal dominant pattern of inheritance described above. in previous generations. In this clinical situation a new change
These have significance while counselling families. in the gene (de novo mutation during gametogenesis) is
responsible for the disease phenotype. The affected offspring
Penetrance
would have 50% risk of transmitting the disease gene, but the
In some disorders, the individual who carries the mutant gene risk to siblings will be nil, e.g. achondroplasia, Marfan’s
does not manifest any sign or symptom of the disease, i.e. the syndrome. It is important to exclude variable expression/non-
gene is non-penetrant. This phenomenon may result in penetrance and non-paternity as other possible reasons for an
skipped generation in the pedigree chart (Figure 4). For apparent new dominant mutation. In some cases there may be
disorders that show incomplete penetrance, the unaffected gonadal mosaicism—where the risk of recurrence cannot be
individual cannot be completely reassured that his or her excluded. De novo mutations are more likely to occur if paternal
children will not be affected unless molecular tests are done, age is more than 45 years.
e.g. hereditary non-polyposis colorectal cancer, acute
intermittent porphyria. Homozygosity in an autosomal dominant disorder
In some autosomal dominant disorders, the severity of the
disease increases in homozygotes, e.g. homozygosity for
mutation causing achondroplasia may result in severe skeletal
dysplasia that is lethal in the intrauterine or perinatal period.
There is a 25% risk of lethal achondroplasia in the offspring if
both the parents are affected with achondroplasia.
Recurrence risks
If one parent is affected by an autosomal dominant disorder
and the other is normal, the risk of recurrence for their offspring
in each pregnancy is 50%. Each pregnancy is an independent
event and the probability remains the same with every
conception, independent of the disease status of any previous
Figure 4: Autosomal dominant inheritance with non-penetrance. children (Figure 3).
If both parents are affected by an autosomal dominant trait,
Variable expression and pleiotropy then the risk of an affected child is 75% in each pregnancy. There
is a 25% chance that they will have a child with both alleles
Individuals in the same family who carry an identical mutation
mutated, e.g. achondroplasia.
can have varying clinical features and severity of the disorder,
e.g. tuberous sclerosis—a mildly affected parent with only Autosomal Recessive Inheritance
minor skin lesions can have a child with severe infantile spasms These disorders manifest when both alleles of a gene present
and mental retardation. Such intra-familial variability is difficult at a locus are mutated. This disorder manifests only in the
to explain on the basis of monogenic inheritance, as all the homozygous state. Most metabolic disorders due to enzyme
affected members in the family carry the same mutation. But deficiency follow the autosomal recessive mode of inheritance.
now it is understood that no gene functions in isolation and This is because; being a catalyst, even half the product in a
the disease manifestations may be modified by interaction person with mutation in only one copy of the gene (carrier) is
with other genes and the environment. Now, more and more sufficient for the normal functioning of the cell (Figures 5 and 6).
information about genes which modify the phenotype of The characteristics of autosomal recessive inheritance are
so-called monogenic disorders is becoming available. summarised in Table 3.
The phenomenon of gene-gene interaction is known as
epistasis. Pleiotropy refers to multiple effects of a single Recurrence risks
gene/mutation in several tissues or organs of the body, In each pregnancy, carrier parents have a 25% risk of having an
e.g. neurofibromatosis type 1 can cause skin pigmentary affected child.
175
 Figure 5: Autosomal recessive inheritance.

Figure 7: X-linked recessive inheritance.

Table 4: Characteristics of X-linked Disorders

 No father to son transmission
 All daughters of an affected male have the mutant gene, hence,
are carriers
 Unaffected males never transmit the disease to their offspring
 Carrier women will transmit the disease to 50% of their sons
 Carrier women transmit the mutant allele to 50% of their daughters
Examples: Haemophilia A and B, Duchenne’s muscular dystrophy, G6PD
deficiency, X-linked ichthyosis, X-linked agammaglobulinaemia.

chromosome, carrier female marrying an affected male giving

Figure 6: Punnett square of gametes and offspring for autosomal recessive birth to a daughter with mutation on her both X chromosomes,
inheritance. skewed inactivation of the X chromosome, and X-autosome
translocation.

Table 3: Characteristics of Autosomal Recessive Disorders There are some X-linked recessive disorders where a
heterozygous female can manifest a mild phenotype in the
 Horizontal mode of transmission. All affected individuals are in absence of above situations, e.g. Fabry’s disease, X-linked
one generation
hereditary nephrogenic diabetes insipidus, fragile-X mental
 Parents of an affected individual are obligate, unaffected carriers retardation.
 The risk of recurrence to the siblings of an affected individual
with carrier parents is 25% in each pregnancy Recurrence risks
 Healthy siblings of an affected individual have a two-third risk In each pregnancy,a woman with a mutation in one X chromosome
of being a carrier has a 50:50 chance of having an affected son, and a 50:50 chance
 Consanguinity among parents is more common in these disorders to have a daughter who carries the mutation. In the situation of
Examples include beta-thalassaemia, sickle cell anaemia, Wilson’s disease, cystic marriage between an affected father and a non-carrier spouse, all
fibrosis, Fanconis anaemia, autosomal recessive polycystic kidney disease, sons are normal whereas all daughters are carriers.
oculocutaneous albinism.
In mating between a carrier female with an affected male, 50%
X-linked Disorders daughters are affected, and 50% are carriers; whereas 50% sons
These disorders occur due to mutations in genes present on the are affected and 50% are normal.
X chromosome. X-linked disorders can be recessive with X-linked dominant inheritance
expression only in males, or dominant with expression in both
Looks similar to an autosomal dominant pedigree with both
the sexes. The characteristics of X-linked disorders are listed in
males and females affected (Figure 8). Differences are
Table 4.
summarised in Table 5.
X-linked recessive inheritance
Y-linked Inheritance
Only males manifest the disease and it is transmitted through
Only males are affected as these disorders are due to genes on
healthy female carriers (Figure 7).
the Y chromosome. An affected male will transmit the trait to
Rarely, manifestations in a carrier female of an X-linked recessive all his sons but none to his daughters, e.g. hairy ears. Genes
disorder can occur in the following situations:Turner’s syndrome involved in spermatogenesis are present on the Y chromosome,
176 with 45, X karyotype and mutation in a gene on the X but as they are associated with infertility, the inheritance
 Mendel and Beyond
Figure 9: Mitochondrial inheritance.

Figure 8: X-linked dominant inheritance. Table 6: Characteristics of Mitochondrial Disorders

 Maternal transmission as mitochondria are exclusively maternal
Table 5: Differences of X-linked Dominant Inheritance in origin
 Affected males transmit the disorder to all daughters but none  Both males and females are affected
to their sons  Offspring of affected male will not manifest the disorder
 Some of these disorders are lethal in males (hemizygous state),  All offspring of the affected female have the risk of being affected
thus showing false predominance of affected females
 Homoplasmy and heteroplasmy: In a cell with two populations
 No direct father to son transmission of mitochondria, with wild type DNA and mutant mitochondrial
 Females (being heterozygotes) may be less severely affected DNA, during cell division the proportion of wild type and mutant
Examples of X-linked dominant disorders are Rett syndrome, X-linked type mitochondria may drift towards a pure type, either wild or
hypophosphataemic rickets, incontinentia pigmentii. mutant (homoplasmy), or may remain mixed (heteroplasmy)
 Threshold expression: When the mutant mitochondrial DNA
pattern, may only come to light with the use of modern assisted crosses a threshold level, phenotypic expression results. This
reproductive techniques like intracytoplasmic sperm injection. accounts for the variability in the clinical manifestations of
mitochondrial disorders in different individuals and also the
NON-MENDELIAN PATTERNS OF INHERITANCE tissues affected in one individual
These are disorders due to mutations in single genes but they Examples of mitochondrially inherited disorders are Leber hereditary optic
do not conform to the above Mendelian patterns of inheritance. neuropathy, Leigh disease, MELAS (mitochondrial encephalopathy, lactic acidosis,
stroke), MERRF (myoclonic epilepsy, ragged red fibres), Kearns-Sayre syndrome.
Mitochondrial Inheritance
Each cell has several copies of mitochondrial DNA which is early embryogenesis in a predetermined fashion. Lyonisation
capable of replicating independently of the nuclear genome. of one of the two X chromosomes in females is an example of
Mutations in the mitochondrial genome, and some nuclear genes the same.
controlling mitochondrial function, result in mitochondrial Genomic Imprinting and Uniparental Disomy (Table 7)
disorders (Figure 9). The pedigree of mitochondrial disorders is Parent-of-origin-dependent transmission of some diseases,
peculiar—both sexes are affected but the disease is exclusively such as Prader-Willi and Angelman syndrome was first
transmitted through females. The division of mitochondria from described in the 1980s.
parent to daughter cells during cell division is random, giving
rise to wide variations in wild type and mutant type mitochondria Table 7: Genomic Imprinting
in different cells, different tissues, and at different times
Salient features of the imprinting are:
(heteroplasmy). Due to this unique behaviour of mitochondria,
 It occurs before fertilisation
these diseases display extensive phenotypic variability (Table 6).
 It confers transcriptional silencing
Epigenetics  It is stably transmitted through mitosis in somatic cells
Epigenetics refers to modifications in the genetic material that  It is a reversible process during passage though the opposite
do not change the nucleotide sequence, but result in functional parental germline so that the sex appropriate imprint can be
changes in the DNA molecule. It is a heritable change, as far as established
somatic cells are concerned, and may lead to alterations in gene
For every gene on a chromosome there are two copies, one
expression. As a result of this, the phenotype can vary even
inherited from the father and the other from the mother. Usually
though the nucleotide sequence does not differ. The common
both copies are active and used for protein synthesis. However
epigenetic changes occur as a consequence of cytosine
for some genes, their expression in the cells depends on the
methylation of DNA and histone modifications. DNA methylation
parent of origin. This is referred to as genomic imprinting
occurs in the cytosine residue of the CpG islands which are most
whereby the parent of origin of the gene is stamped on it and
commonly located in the promoter region of protein coding
the phenotype of the disorder depends on the parent of origin
genes. This process causes alteration in gene transcription.
of the allele. For this group of genes, a functional hemizygous
A special category of genes called imprinted genes are subject state is normal, with expression of only the paternal or maternal
to epigenetic re-programming during gametogenesis or during allele. A gene is maternally imprinted if the allele derived from 177
 the mother is inactive, and paternally imprinted if the allele from
the father is inactive. Best examples of imprinting are Prader-
Willi syndrome and Angelman syndrome which can also occur
due to deletion of chromosome 15q11-13 region, or uniparental
disomy (UPD).
Uniparental disomy is the condition where both copies of a
particular chromosome are inherited from one parent and
none from the other. Usually UPD has no clinical consequence
unless the involved chromosome has one or more imprinted
genes. The disease phenotype in UPD occurs as a result of loss
of the normally functioning gene where both chromosomes
are inherited from the parent where the gene is imprinted,
and hence, non-functional. In Prader-Willi syndrome
(hypotonia, mental retardation, obesity, hyperphagia, and
characteristic facies), the paternal allele is the active gene and
the maternal counterpart is normally inactive. Any condition
resulting in the absence of the active paternal allele results in
the disease. This could occur as a result of microdeletion of
the gene on the paternally inherited chromosome, or both
chromosomes being inherited from the mother (maternal
uniparental disomy). The reverse situation occurs in Angelman
syndrome characterised by hypertonia, inappropriate
laughter, mental retardation and seizures. The active allele in
this case is present on the maternal chromosome, hence
maternal 15q 11 deletion, or paternal uniparental disomy
results in the disorder (Figures 10A and B).
Other disorders due to genomic imprinting are Beckwith-
Wiedemann syndrome, Russell-Silver syndrome, neonatal
diabetes mellitus, etc. Majority of these disorders are sporadic
with negligible risk of recurrence.
Dynamic Inheritance/Trinucleotide Repeat Sequence
Mutation–Anticipation
Some genetic disorders express a more severe phenotype,
and an earlier age of onset in successive generations. This
phenomenon is called anticipation. It is observed in many
autosomal dominant neurological disorders like myotonic
dystrophy, spinocerebellar ataxias, and Huntington disease, Figures 10A and B: Uniparental disomy and genomic imprinting.
etc. Spinobulbar muscular dystrophy and fragile-X mental
retardation are X-linked triplet repeat disorders.
In myotonic dystrophy, an autosomal dominant disorder, the
Genes of the above disorders carry trinucleotide repeats (e.g. mildest form manifests as cataract in late life, but as the repeat
CGG, CAG) in them. When the number of repeats increases number increases in successive generations, neuromuscular
beyond a critical size threshold, the repeat sequence becomes manifestations like myotonia and dystrophic features occur at
unstable with a tendency for repeat numbers to increase in each an early age. At the most severe end of the spectrum, the disease
successive generation. This phenomenon is known as dynamic manifests at birth and presents with respiratory distress,
mutations. Premutation(s) are intermediate sized alleles, hypotonia and mental retardation. This usually occurs when the
between alleles with normal range of trinucleotides and larger mutation is transmitted from an affected mother.
ones (mutation) which is associated with the disease Somatic/Gonadal Mosaicism
phenotype. The premutation is the harbinger of full mutation
during meiosis. The presence of two genetically different cell lines, derived
from a single zygote in an individual is called mosaicism. This
For some disorders the sex of the transmitting parent can be present in somatic, gonadal, or both cells. Somatic
influences the degree of expansion of the repeat, and thus, mosaicism usually results in a milder and partial phenotype.
the occurrence of the disease in the offspring, e.g. fragile-X Gonadal mosaicism does not lead to any phenotypic
mental retardation is usually transmitted through a female abnormalities in the individual, but may be responsible for a
with mutation developing during oogenesis, whereas clinically unaffected individual to have two or more affected
Huntington disease is more often severe if transmitted offspring, e.g. facioscapulohumeral dystrophy, Duchenne’s
through an affected father. muscular dystrophy, osteogenesis imperfecta type II.
178
 Mendel and Beyond
Digenic Inheritance CONCLUSION
In digenic inheritance mutations in two different genes Pedigree analysis is a very useful tool for elucidation and
together give rise to the affected phenotype. Disease does not interpretation of family history. It should be incorporated as a
occur when the individual carries mutation only in one gene, standard practice in clinical medicine and should be learned by
e.g. Bardet-Biedl syndrome, retinitis pigmentosa, sensorineural all clinicians. Besides its role in genetic counselling, it can greatly
hearing loss, Hirschsprung disease. help in making the diagnosis, e.g. haemophilia in a child with
bleeding, and also as a tool for risk assessment in familial disorders,
Polygenic-Multifactorial Inheritance
like diabetes, hypertension, autoimmune disorders, etc.
This includes conditions where multiple genes, and also the
environment, play a role in expression of the disease phenotype. RECOMMENDED READINGS
In these disorders the pedigree chart usually shows familial 1. Antonarakis SE, Beckmann JS. Mendelian disorders deserve more attention.
aggregation but the disease phenotype does not segregate in Nature reviews. Genetics 2006; 7: 277-82.
Mendelian proportions. The risk of recurrence in these disorders 2. Bennette RL. The Practical Guide to the Genetic Family History. New York:
Wiley-Liss; 1999: pp. 1-12.
is derived empirically from population studies, and is influenced
3. Eichers ER, Lewis RA, Katsanis N, Lupski JR. Triallelic inheritance: a bridge
by the number of affected individuals in the family. Also, closer between Mendelian and multifactorial traits. Ann Med 2004; 36: 262-72.
the relation of the individual at risk to the proband, higher is 4. Harper PS. Trinucleotide repeat disorders. J Inher Metab Dis 1997; 20: 122-4.
the risk of recurrence. It has to be kept in mind that familial 5. Heyningen VV, Yeyati PL. Mechanisms of non-Mendelian inheritance in
aggregation may also occur simply due to sharing of the same genetic disease. Hum Mole Genet 2004; Review Issue 2.
environment. 6. Kaufmana L, Herbert M. Genetic resources for the neonatologist. Semi Foetal
Neonatal Med 2005; 10: 291-8.
Examples of polygenic inheritance: congenital malformations
7. Nadeau JM. Listening to the background noise. N Engl J Med 2005; 352:
like neural tube defects, pyloric stenosis, etc., and complex 1598-9.
multifactorial disorders like hypertension and coronary artery 8. Wattendorf DJ, Hadley DW. Family history: the three-generation pedigree.
disease, etc. Am Fam Phys 2005; 72: 441-8.

179
 6.3 Clinical and Molecular Cytogenetics

Ashutosh Halder

INTRODUCTION banding techniques practiced are quinacrine banding, reverse

Cytogenetics is a branch of genetics that is devoted to the study banding, C-banding, nucleolar organising region staining, etc.
of structure and function of cellular constituents concerned High-resolution banding involves analysing chromosomes
with heredity. A chromosome, as seen at metaphase, consists during prophase or early metaphase (prometaphase), wherein
of two identical strands of chromatids. The chromatids are the number of bands increases from about 300 to 800. Analysis
joined at the centromere, which appears as a constriction. The of banded chromosomes is done under a microscope by a
centromere divides the chromosome into a short arm (p), and trained cytogeneticist. Generally, 20 metaphases are analysed
a long arm (q). Individual chromosomes differ in size. Depending from each individual (enough to rule-out mosaicism at clinical
on the position of the centromere, chromosomes are significance). The results are reported as per the guidelines of
categorised as metacentric (at the centre), submetacentric an International System for Cytogenetic Nomenclature (ISCN).
(slightly away from the centre), acrocentric (near the end) and
NUMERICAL ABNORMALITY
telocentric (at the end). Human chromosomes are classified into
different groups, viz., Group A (chromosome 1-3), Group B Normal chromosome complement of 46 (46, XX in female and
(chromosome 4-5), Group C (chromosome 6-12, X), Group D 46, XY in male) is known as diploid, while one set of 23
(chromosome 13-15), Group E (chromosome 16-18), Group F chromosomes seen in gametes (23, X in female or 23,Y and 23,
(chromosome 19-20) and Group G (chromosome 21-22,Y). X in male) is known as haploid. Error in segregation of
Chromosomes of Groups D and G are acrocentric and their chromosomes during cell division leads to gain or loss of
p arms do not contain important genes. Chromosomes 1-22 chromosome, which is called aneuploidy. It includes missing of
are in pairs (autosomes). Chromosome X and Y are sex a member of the pair (monosomy) or presence of more than
chromosomes. A karyotype is a full set of chromosomes from two chromosomes in a pair (trisomy for 3 numbers, tetrasomy
an individual (Figures 1A and B). Homologous chromosomes for 4 numbers, etc). Errors in mitosis result in mosaicism, i.e. two
(members of each pair) in meiosis (cell division during types of cells originated from single cell. Sometimes an
gametogenesis) exchange (recombine) DNA segment at individual may have an additional set of haploid (triploidy; 69)
crossing-over. It is responsible for genetic variation. or diploid (tetraploidy; 92) chromosomes.

Chromosomal study is carried-out from living nucleated cells STRUCTURAL ABNORMALITIES

through in vitro culture methods using cell culture medium In structural abnormality, the appearance (morphology) of the
containing growth-stimulating agents. A mitotic inhibitor chromosome is altered. Structural anomalies are classified into
(colchicine) is added to stop cell division at mitosis. The cells the following types:
are then treated with a hypotonic solution to swell the cells and
then fixed in Carnoy’s fixative (3:1 methanol to acetic acid). The Deletion
cell suspension is then dropped onto slides, air-dried and A portion of the chromosome is missing, resulting in loss of
banded using trypsin and Giemsa stain. Other chromosome- genetic material.

Figure 1A: Metaphase cell. Figure 1B: Karyotyped chromosomes.

180
 Clinical and Molecular Cytogenetics
Duplication (21q21-22) of extra chromosome 21 leading to over expression
A portion of the chromosome is duplicated, resulting in extra of chromosome 21 genes (amyloid beta A4 precursor protein,
genetic material. microRNAs, etc). It is characterised by mental sub-normality,
developmental disability, facial dysmorphism (round face,
Translocation epicanthic fold, up-slanting palpebral fissures and macroglossia;
A portion of one chromosome is transferred to another Figure 2), cardiac malformations, and often duodenal atresia,
chromosome. There are two main types of translocations, i.e. thyroid dysfunction and early onset of Alzheimer’s disease.
reciprocal and Robertsonian. In reciprocal translocation, Fertility is reduced; males are usually unable to father children.
segments from two (or more) different chromosomes are Majority of cases of DS are due to trisomy 21 where the risk of
exchanged. In Robertsonian translocation, the long arm of one recurrence in the siblings is negligible. About 4% cases are due
acrocentric chromosome is translocated to the long arm of to translocation. The risk of recurrence in translocation cases
another acrocentric chromosome with loss of short arms of both varies depending on the chromosomes involved and sex of the
the chromosomes, resulting in one chromosome, derived from carrier parent (more if mother is the carrier and may be up to
two chromosomes. Translocations can be balanced (no gain or 100% with chromosome 21:21 translocation). Birth of a child
loss of genetic material) or unbalanced. with DS is preventable through maternal serum screening,
prenatal diagnosis and selective termination of pregnancy.
Inversion
Parental age at conception, in particular maternal age above
A portion of the chromosome breaks, flips around and rejoins, 35 years, increases the risk of DS.
resulting in change of orientation (physical position) of the
genetic material.
Ring
Chromosomal ends break (near the tip) and rejoin each other
to form a ring. This can happen with or without the loss of
genetic material.
Isochromosome
Isochromosome is an abnormal chromosome with two identical
arms, i.e. either two short (p), or two long (q) arms. It is formed
by faulty chromatid separation during segregation.
Polymorphism
Chromosome polymorphism is a normal variation in
appearance (heterochromatin, satellite, etc.) which occurs
frequently (5%). It does not give rise to any phenotypic or
reproductive problems.

OTHER ABNORMALITIES
Chromosomal Breakage/Instability/Fragility
It is characterised by spontaneous/induced chromosomal
instability, breakage, constriction or fragility.
Figure 2: Facial profile in Down’s syndrome.
Uniparental Origin
Normally, each member of the pair of chromosomes is derived
from each parent. Sometimes, both members of the pair (part Trisomy 18 (Edward Syndrome)
or whole) of chromosome may be derived from one parent. It is the second most common autosomal trisomy in live births
Occasionally the entire set of chromosomes may derive from (1 in 3,000). It is more in female births. The incidence increases
one parent as in molar pregnancy. with maternal age. The affected newborns have a low rate of
survival. The syndrome is characterised by multiple congenital
CLINICAL EFFECTS OF CHROMOSOMAL ABNORMALITY malformations of heart, kidneys, central nervous system (CNS),
The phenotype due to chromosomal abnormality depends on gastrointestinal tract (GIT), etc. besides low-set malformed
gain or loss, fusion, rearrangement, or altered parental inheritance ears, hypertelorism, cleft lip/palate, clenched hands,
of genes located on the chromosome. Most aneuploidies of underdeveloped thumbs, Rocker bottom feet and joint
autosomes, unbalanced structural abnormalities of autosomes, contractures.
triploidies, tetraploidies and other polyploidies are spontaneously
Trisomy 13 (Patau Syndrome)
aborted. Remaining aneuploidies and unbalanced structural
abnormalities of autosomes produce mental retardation and It affects approximately one in 10,000 live births. It is associated
varying degree of dysmorphism. Sex chromosome aneuploidies with severe growth retardation and major congenital
often produce hypogonadism. anomalies. The typical features are holoprosencephaly,
microcephaly, microphthalmia, spinal defect, omphalocoele,
Trisomy 21 Down's Syndrome (DS) cleft palate, polydactyly, overlapping of fingers and rocker-
Trisomy 21 is the commonest autosomal aneuploidy in live bottom feet. Trisomy 13 cases usually do not survive beyond a 181
births (1 in 800 to 1000). It is caused by presence of all or part few months of life.
 47, XXY Male (Klinefelter Syndrome) malformations. Robertsonian translocations also increase risk
It is seen in one out of every 1,000 males. The patient is usually of unbalanced gametes.
tall, and presents with small testicles, reduced fertility and Triploidy/Polyploidy Syndrome
gynaecomastia. About 50% cases of Klinefelter syndrome have
Triploidy accounts for 2% of all conceptions, but only one in
mosaicism, where 47, XXY cell line is present along with 46, XX;
50,000 are live births. Triploid newborns die immediately
46, XY; 48, XXYY or 48, XXXY cell lines.
after birth. They present with growth retardation, relative
Other Trisomy of Sex Chromosomes (47, XYY male and macrocephaly, cleft lip, low-set ears, agenesis of corpus callosum,
47, XXX Female) heart defects, dysgenetic kidney and omphalocoele. The
About 1 in 1,000 boys are born with a 47, XYY karyotype. 47, polyploidies generally lead to miscarriage, still birth or partial
XYY boys may have increased growth velocity, learning difficulty hydatidiform mole and are often associated with cancer.
and acne at puberty. Testosterone levels are normal with normal Chromosomal Breakage/Instability/Fragile Syndrome
sexual development and fertility. 47, XXX female (triple X Chromosomal breakages may occur either spontaneously, or
syndrome) occurs one in 1,000 girls. It does not cause any be induced by DNA damaging agents like radiation, ultraviolet
unusual features due to lyonisation of the extra X chromosome light or alkylating agents. The examples include Fanconi
(leaving only one X chromosome active). However, females with anaemia, Bloom syndrome, ataxia telangiectasia, xeroderma
this condition may have menstrual irregularities, including early pigmentosum, etc.These diseases are caused by the defects in DNA
onset of menarche and early menopause. repair genes, and have a high-risk of developing malignancies.
Monosomy X (Turner Syndrome; 45, X) Sometimes chromosomal fragility/stricture occurs at defined
Turner syndrome occurs once in 2,500 female births. sites known as fragile sites. One of the common abnormalities
Approximately 98% of Turner syndrome conceptuses end up is Fragile-X syndrome. These patients have characteristic facial
with miscarriage (Figure 3).Turner syndrome cases present with appearance, mental retardation, and may have large testes.
short stature, broad chest, low hairline, low-set ears, webbed
neck, increased carrying angle of the elbow and gonadal MICRODELETION/MICRODUPLICATION SYNDROMES
dysfunction. Major systemic problems are also frequently Microdeletion/microduplication syndromes are characterised
present, including congenital heart defect (bicuspid aortic valve, by small (< 5Mb) chromosomal deletions/duplications in which
coarctation of the aorta), kidney defect (horse shoe kidney), one or more genes are involved. They are frequently associated
hypothyroidism, diabetes mellitus, vision problems, hearing with multiple congenital anomalies or neuropsychiatric disease.
defect, etc. The phenotype is the result of haploinsufficiency/over-
expression of genes in the critical interval. The examples of
microdeletion syndromes are Velocardiofacial syndrome
(22q11.2), Prader-Willi syndrome/Angelman syndrome (15q11-
13), Williams syndrome (7q11.23), Smith-Magenis syndrome
(17p11.2), Cri-du-chat syndrome (5p15.2), Miller-Dicker
syndrome (17p13.3), WAGR syndrome (11p13), Hereditary
neuropathy with pressure palsy (17p12), Wolff Hirschhorn
syndrome (4p 16.3), Tricho-rhino-pharyngeal syndrome (8q
24.1) and ATR 16 (16 p 13.3). The examples of microduplication
syndromes are Charcot-Marie-tooth neuropathy 1A (17p 12),
Alzheimer disease (21q 21.3), Spinocerebellar ataxia type 20
(11q 12), Pelizaeus-Merzbacher disease (Xq 21-22), Parkinson
disease (4q 21), etc.
Velocardiofacial/DiGeorge Syndrome
It is the commonest microdeletion syndrome. It is seen with a
frequency of 1 in 4,000 births. Almost all cases have 22q11.2
microdeletion (involving COMT, TBX1, UFD1L, HIRA, etc. genes;
Figure 4A). Most deletions are the result of a de novo event,
though 5% to 10% cases are inherited. The major clinical
Figure 3: Turner syndrome abortus with cystic hygroma.
features are facial dysmorphism (long broad nose with
Translocations and Disease bulbous tip, hypertelorism, low-set ears, etc. Figure 4B), palatal
abnormalities (velopharyngeal incompetence, submucous cleft
Translocation is caused by rearrangement between parts of palate, etc.), hypocalcaemia, T-cell immunodeficiency, cono-
nonhomologous (usually) chromosomes. In the process, a fusion truncal heart defects (tetralogy of fallot, truncus arteriosus, etc.)
gene may be created by joining of two separated genes. and learning disabilities.
This is a common event in cancer, infertility and congenital
malformation. Reciprocal translocations are usually harmless. William Syndrome
However, if a gene is disrupted or disregulated at the breakpoint, Its prevalence is estimated to be one in 7,500-10,000 births.
it is likely to cause symptoms like autism, intellectual disability, Individuals with this syndrome have periorbital fullness,
congenital anomalies, etc. Besides, it can give rise to gametes long philtrum and prominent lips (Figure 5A). Cardiovascular
182 with unbalanced chromosomes leading to miscarriages or anomalies like supravalvular aortic stenosis and pulmonic
 Clinical and Molecular Cytogenetics
later show truncal ataxia and hypertonia of limbs. Episodes of
prolonged laughter, hyperactivity, sleep disorder and seizure
are also common. Both Prader-Willi and Angelman disorders
result from loss of 15q11-13 (SNRPN, MKRN3, MAGEL2, necdin,
UBE3A, etc. genes) – the difference being that Prader-Willi
syndrome is of paternal origin while Agelman syndrome AS is
of maternal origin in 70% to 75% cases.

Figures 4A and B: Velcardiofacial syndrome: hemizygous deletion of 22q11.2

(A) and facial profile (B).

valvular stenosis are common. Other symptoms include dental

malocclusion, hypercalcaemia, hyperacusis and a hoarse voice.
Over 90% cases of William syndrome are due to microdeletion
of 1.6 Mb size in 7q11.23 locus involving elastin gene.
Prader-Willi and Angelman Syndromes
These are seen with prevalence between 1 in 10,000 to 25,000
births. Prader-Willi syndrome is recognised by almond-shaped
eyes and inverted V-shaped upper lip (Figure 5B). Neonates
present with hypotonia, weak cry, poor sucking and
hypothermia. Children present with voracious appetite, obesity,
decreased pain, disturbed thermoregulation, psychomotor
retardation, and impulsivity. Adolescence cases present with
absence of pubertal growth spurt, hypogonadism, small hands Figures 5A to C: Facial profile of William syndrome (A); Prader-Willi syndrome
(B); and Angelman syndrome (C).
and feet, diabetes mellitus and hypercholesterolaemia. Many
symptoms of Prader-Willi syndrome are related to hypothalamic
dysfunction. The clinical features of Angelman syndrome are Charcot-Marie-Tooth Disease Type 1A (CMT 1A)
microcephaly, large mouth, mandibular prognathism, This is one of the most common inherited neurological disorder
hypopigmentation and mental retardation (Figure 5C). Patients that affects one in 3,000 individuals. It is associated with 183
 duplication (in 90%) of 17p11.2 (PMP22; Figure 6). Clinical (indirect FISH) or chromogenic dyes (chromogenic in situ
presentation comprises of toe walking, pes cavus, claw hand, hybridisation or CISH). The probe can be cloned DNA
slapping gait, foot drop, absent or decreased deep tendon sequence, or generated by polymerase chain reaction (PCR)
reflexes, nerve hypertrophy and loss of touch sensation from flow-sorted chromosomes, micro-dissected chromo-
predominantly in feet and legs. somes or even whole genome. Probes may be from alphoid
sequence of centromeres (150-250 bp repeats), telomeric/
subtelomeric sequence (5-6 bp repeats), or unique sequence
(100-500 Kb), etc. FISH is highly sensitive and can detect cell-
cell heterogeneity and mosaicism. Further, FISH has been
modified to spectral karyotyping, Rx FISH, or Multiplex FISH
to identify all 24 chromosomes in one experiment; fibre FISH
to characterise break points or Padlock probe FISH to improve
resolution to single nucleotide level.

Figure 6: Hemizygous duplication (arrow) of 17p11.2 locus in a case of Charcot-

Marie-Tooth disease Type 1A (Courtesy: Prof. Mariano Rocchi, Uniba Biologia, Italy).

GENOMIC DISORDERS
Genomic disorders are a group of diseases that result from
genomic rearrangements, such as insertions, deletions,
duplications, inversions, etc. Human genome is a highly dynamic
structure. Approximately 5% (~800 genes) of the human
genome is structurally variable in the normal population.
Genome architecture makes the genome susceptible to
rearrangements through recombination mechanisms. Non-
allelic recombination between low-copy repeats (LCRs) results
in loss or gain of genomic segments. LCR DNA spans 10-400 kb,
shares ~97% sequence homology and provides the substrate
for recombination, thus predisposing the region to
rearrangements. The mechanisms by which rearrangements
contribute to various phenotypes (such as diversity, traits,
susceptibility, behaviour or disease like microdeletion/
duplication syndromes, schizophrenia, autism, etc.) are diverse
and include gene dosage alterations, gene disruption, gene
fusion, position effects, mutations, etc. Rearrangements
introduce variation into our genome and serve as evolutionary
function.
FLUORESCENCE IN SITU HYBRIDISATION (FISH) Figure 7: Various steps of FISH procedure.
FISH is a molecular cytogenetic technique used to detect and
localise presence or absence of specific DNA sequence on The major application of FISH is in the field of cancer (Figures
chromosomal/nuclear DNA. It uses fluorescent probes (labelled 8A and B) followed by prenatal diagnosis (PND), preimplantation
nucleic acid sequence) that bind to DNA that have sequence diagnosis (PGD), microdeletion-microduplication syndrome
homology. There are two types of FISH techniques—direct and diagnosis, specific postnatal diagnosis and meiotic segregation
indirect. In the direct method (Figure 7), fluorescent molecules error study. Detection of cancer-specific chromosome
(FITC, Cy3, etc.) are directly attached (enzymatically or non- abnormality such as Philadelphia chromosome (bcr-abl fusion
enzymatically) to the probe so that probe-target hybrid can be gene) assists in diagnosis/sub-classification of disease and
visualised under fluorescent microscope immediately after selecting appropriate treatment besides monitoring of
hybridisation. In the indirect method, reporter molecules (biotin minimal residual disease, early relapse and engraftment of sex-
or digoxigenin) are attached to the probe and the probe is mismatched allogenic bone marrow transplant. Rapid prenatal
184 detected by either affinity cytochemistry with fluorescent dyes diagnosis can be made using FISH (Figures 9A and B) that
 Clinical and Molecular Cytogenetics
Figures 8A and B: Interphase FISH on tumour cells showing gene amplifications
C MYC and cells-to-cells heterogeneity (A); copy numbers 1 to 6 with
chromosome 1 FISH (B).

reduce parental anxiety and guide obstetric management

quickly. In PGD, typically one or two blastomeres are biopsied
from embryo and subjected to FISH for aneuploidy screening
or specific translocation identification. FISH is capable of doing
rapid sexing in a situation like ambiguous genitalia at birth
where immediate assignment of sex is required for not only
social reason but also for appropriate management. It has similar
value in an acutely sick baby with congenital malformation
syndrome suggestive of aneuploidy or microdeletion syndrome
requiring urgent intensive care. FISH is the main modality of
chromosome analysis for meiotic chromosome segregation and
microdeletion syndrome besides the study of chromosome
function and behaviour in interphase cells.

COMPARATIVE GENOMIC HYBRIDISATION (CGH)

CGH is a FISH technique that allows comprehensive analysis of
chromosomal imbalance (relative copy number) in entire
genome (molecular karyotyping at cytogenetic resolution; ~5 B
Mb) by single test without metaphase preparation and cell Figures 9A and B: Interphase FISH on amniotic fluid cells showing 3 copies
culture of the test samples. The strategy of CGH is based on co- of chromosome 18 (A); leading to termination of pregnancy with trisomy 18
foetus (B).
hybridisation of differentially labelled whole genomic test
and control DNA in equal ratio on normal metaphase spread, quantification of fluorescence intensities of each karyotyped
like dual FISH (Figures 10A to C). The slide is visualised using chromosome is done by computer software. Hybridisation
epifluorescence microscope. Image processing along with results into general staining of all chromosomes. If the test DNA 185
 Figures 10A to C: Showing principles of CGH and high resolution molecular karyotyping (aCGH) procedure (A); CGH binned view of chromosome 8 showing C
MYC amplification (B); and magnified view (C) of array showing DNA amplifications (green spots), deletion (red spots) and no change in copy numbers (yellow
spots).

186
 Clinical and Molecular Cytogenetics
contains additional copies of DNA material, hybridisation will HIGH RESOLUTION MOLECULAR KARYOTYPING (ARRAY
reveal higher signal intensity of test DNA (if labelled with green, CGH)
then more green) at the corresponding target region of the High resolution molecular karyotyping is an extension of CGH.
hybridised chromosome. Similarly, deletion/monosomy will give It is carried-out on the principle of CGH (Figures 10A to C),
rise to lower signal intensities (Figures 11A to C).The CGH cannot though with some modifications (co-hybridisation is
detect mosaicism of less than 40%, balanced translocation and carried out on DNA spots/arrays rather than metaphase
tetraploidy. CGH is labour intensive, difficult (karyotyping of DAPI chromosomes). Following hybridisation of differentially
banded chromosome) and time consuming. This technique is labelled test and reference genomic DNA to the target
getting replaced by high resolution molecular karyotyping. sequences on the microarray, the slide is scanned to measure

Figures 11A to C: Showing CGH metaphase (A) green as amplification, red as deletion, yellow as no change in copy numbers and blue as heterochromatin
karyotype (B); and profile/analysis (C) from tumour samples (green amplification and red deletion).
187
 fluorescence intensities at each target on the array. The syndrome), chromosome-specific, or other (sub-telomeric)
fluorescent ratio for the test and reference DNA is then plotted arrays are available for specific applications.
against the position of the sequence along with the
chromosomes. Gains or losses across the genome are shown RECOMMENDED READINGS
by values higher or lower than normal 1:1 ratio (as in CGH). 1. Beatty B, Mai S, Squire J, (eds). FISH: A Practical Approach. Oxford: Oxford
The resolution depends on the size, number of targets and University Press; 2002.
position of targets on the genome. It also depends on the 2. Gersen SL, Keagle MB, (eds). Principles of Clinical Cytogenetics; 2nd Edn. New
Jersey: Human Press Inc., Totowa; 2005.
platform used (BAC based arrays have lower resolution than
3. Halder A, Halder S, Fauzdar A et al. Molecular approaches of chromosome
SNP based arrays). The molecular karyotyping result is
analysis: an overview. Proc Indian Natl Sci Acad 2004; B70 (2): 153-221.
presented using the ISCN, along with a written description and
4. Halder A, Halder S, Fauzdar A. A preliminary investigation on molecular
interpretation of the result. Molecular karyotyping (aCGH) basis for clinical aggressiveness in cervical carcinoma by comparative
procedure is rapid (24-36 hours). It provides whole genome genomic hybridisation and conventional fluorescent in situ hybridisation.
view at a very high resolution (up to 100 Kb), and does not Indian J Med Res 2005; 122: 434-46.
depend on live cell, or cell culture. It detects majority of 5. Halder A, Fauzdar A. Potential use of blood, buccal and urine cells for rapid
microscopic as well as sub-microscopic chromosomal changes noninvasive diagnosis of suspected aneuploidy using FISH. J Clin Diag Res
2007; 1: 32-8.2.
from any DNA source in a single experiment without prior
6. Mark HFL, editor. Medical Cytogenetics. New York: Marcel Dekker Inc.; 2000.
knowledge of abnormalities. The only limitation is its inability
7. Nuber UA, (ed). DNA Microarrays. New York: Taylor and Francis Group;
to detect polyploidy or balanced chromosome abnormalities. 2005.
It has the potential of diagnostic application in the evaluation
8. Shaffer LG, Slovak ML, Campbell LJ, (eds). ISCN 2009 (An International
of multiple malformations, mental retardation, prenatal System for Human Cytogenetic Nomenclature 2009). Basel: Karger in
diagnosis and cancer. Now disease-specific (microdeletion collaboration with Cytogenetic and Genome Research Group; 2010.

188
 6.4 Genetic Tests

Ashwin Dalal

Advances in the field of genetics have made it possible to detect In these cases, however, knowledge of genetic mutations is a
genetic abnormalities in increasing number of genetic prerequisite for prenatal diagnosis. Presence of DNA from at least
disorders. This has brought the field of medical genetics to the one affected member in the family can be of great assistance in
forefront of clinical practice. identifying the mutation in the family for counselling and PND.
In contrast, there is another group of diseases where genetic
DEFINITION testing is the only way to conclusively diagnose the disease
Genetic testing is defined as ‘the analysis of human DNA, RNA, condition as there is no other diagnostic test available, e.g.
chromosomes, proteins, and metabolites to detect heritable Huntington disease, spinocerebellar ataxias, Friedreich’s ataxia,
disease-related genotypes, mutations, phenotypes, or etc. This also includes use of genetic tests for carrier testing and
karyotypes for clinical purposes’. It includes a broad range of preimplantation genetic diagnosis (PGD). Genetic tests can also
techniques that can be used for diverse applications, including be used for diagnosis and classification of tumours, prognostic
diagnosis of genetic disease in foetuses, newborns, children, and prediction and diagnosis of cancer predisposing conditions, e.g.
adults; identification of future health risks to the individual; and familial adenomatous polyposis (see chapter on Cancer Genetics).
prediction of drug responses, etc.
Predictive Testing
HISTORY Predictive testing is done where the person is not having any
Genetic testing before 1959 was limited to biochemical tests signs or symptoms of the disease but is likely to develop the
like G6PD test, sickle cell test, etc. since necessary tools for direct condition in future. This information can be used to prevent or
genetic analysis were not available. Lejeune for the first time delay onset of the disease, if appropriate medical or lifestyle
discovered the chromosomal cause of Down's Syndrome in interventions are available. Predictive testing includes pre-
1959 which led to application of genetic testing in humans. symptomatic and predisposition testing.
Since then the field of cytogenetics has blossomed to cover a In pre-symptomatic genetic testing, a healthy person is tested
wide range of disorders, particularly genetic syndromes, mental for diseases with delayed onset. A positive result indicates
retardation, congenital malformations and cancer (see chapter that the patient will develop the condition but does not indicate
on cytogenetics). Direct detection of genetic mutations in when this will occur. Evaluating a healthy person with a family
humans had to wait till the 1970s when discovery of restriction history of Huntington disease is an example of pre-symptomatic
endo-nucleases, cloning of human genes and blotting genetic testing. Although there is no cure for this disease,
techniques made it possible to amplify and probe human DNA. a positive result can be used for life planning, including
The completion of Human Genome Project in 2003 has reproductive planning, etc. However, it is essential to provide
heralded a new era of ‘molecular genetics’. The number of adequate and appropriate pre-test and post-test counselling
genetic tests for human diseases has increased to several to the patient in these cases.
thousand in the last 20 years.
Predisposition genetic testing informs individuals of increased
CLASSIFICATION OF GENETIC TESTS or decreased risk of developing a particular disease, however,
Genetic tests can be classified into the following categories the degree of certainty is unknown. This most often applies
based on the purpose for which these are conducted: to cancer predisposition testing (e.g. BRCA1, BRCA2 in breast-
ovarian cancer families, etc.) in which a positive result indicates
1. Diagnosis including prenatal diagnosis (PND) of human
need for increased surveillance, while a negative result implies
genetic diseases
risk similar to the general population. Eventually, this area is
2. Predictive testing for genetic markers associated with likely to include risk estimates for a wide range of common
polygenic disorders, and presymptomatic diagnosis; and disorders like hypertension, diabetes mellitus, coronary artery
3. Forensic testing for establishment of identity, paternity disease, etc. and response to drugs and other treatments
testing, and zygosity testing, etc. (pharmacogenetics).

Diagnosis and Prenatal Diagnosis of Human Genetic Disease TECHNIQUES IN GENETIC TESTING
Genetic tests are commonly employed for the diagnosis and Genetic testing by molecular genetic methods involves
prenatal diagnosis of human single gene disorders. Many of the various techniques designed to amplify and probe the DNA
single gene disorders can be diagnosed based on typical clinical so that meaningful information can be obtained. All molecular
features (tuberous sclerosis, neurofibromatosis), or investigations DNA tests need DNA to be extracted from a patient’s sample
like muscle biopsy and immunohistochemistry (Duchenne containing some nucleated cells. DNA is commonly extracted
muscular dystrophy), haemoglobin electrophoresis (beta from peripheral blood leukocytes or tissue samples in cases
thalassaemia), factor VIII level determination (haemophilia A), etc. of cancer. The DNA once extracted can be stored for long
189
 periods in a stable condition and subjected to various tests as 1. Denaturation: The template DNA which is double-stranded
required. is separated to single strands at a temperature of around
92-96°C;
Southern Blotting
2. Annealing: Primers bind to the specific target regions of the
Southern blotting is a method of detection of mutations in
single-stranded DNA at a temperature of around 50-65°C
which genomic DNA is isolated from peripheral blood
(exact temperature is specific for each primer pair); and
leucocytes or solid tissue samples and digested with a
restriction endonuclease. Restriction endonucleases are 3. Extension: The primers are extended at a temperature of
nucleolytic enzymes which cut the DNA at a specific sequence. around 68-78°C in the presence of DNA polymerase, dNTPs
This is followed by size separation by electrophoresis. The size- and Mg2+ ions. The concentration of Mg 2+ ions is critical for
fractionated DNA is transferred to a solid membrane support each PCR reaction. It is determined empirically.
by means of capillary action and target sequences are detected The newly synthesised DNA strand acts as a template for the
by hybridisation with sequence-specific probes labelled next cycle, which is repeated around 25 to 30 times, leading to
with radioisotopes. Although, Southern blotting remains a formation of millions of copies of the specific target DNA. In
useful technique for detecting large deletions or genomic order to retain the activity of DNA polymerase enzyme at such
rearrangements, it is seldom used in clinical laboratories due high denaturation temperature, Taq DNA polymerase, extracted
to its labour intensive and cumbersome nature. Southern from a micro-organism called Thermus aquaticus is used in the
blotting is rapidly being replaced by assays based on fluorescent PCR reaction. This particular enzyme has an optimum working
dyes which eliminate the risk of radiation. However, Southern temperature around 80°C.
blotting still remains the gold standard in testing for certain
diseases like triplet repeat disorders, e.g. fragile-X syndrome. Applications of PCR
PCR is the starting point in most of the molecular genetic tests.
Polymerase Chain Reaction and Its Applications
Some important clinical applications of PCR are as follows
Polymerase chain reaction (PCR) was discovered by Kary Mullis (Figures 2A to E):
in 1983. This technique allows selective amplification of specific
1. Mutation detection for genetic disorders: Genetic mutations
target nucleic acid sequences from total DNA using a pair of
can be detected by PCR alone (e.g. Huntington disease), PCR
15-25 nucleotide long forward and reverse primers specific for
followed by digestion with restriction endonucleases (for
the target region to be amplified. The main components of a
detection of restriction fragment length polymorphism)
PCR reaction include a heat stable DNA polymerase, four
(e.g. diagnosis of spinal muscular atrophy), PCR followed
nucleotide triphosphates (dATP, dGTP, dCTP and dTTP) and a
by dot-blot hybridisation (e.g. thalassaemia mutation
suitable buffer containing magnesium ions. The basic steps of
detection), PCR followed by capillary electrophoresis
a PCR cycle are shown in Figure 1. They include the following:
for genotyping (e.g. detection of triplet repeat disorders),
etc.
2. Sequencing: PCR is used as first step for DNA amplification
for all methods of DNA sequencing.
3. Detection of pathogens: PCR is used to detect small
quantities of pathogen DNA in human samples, e.g. PCR for
Mycobacterium tuberculosis. PCR can also be used to detect
viruses, including use of reverse transcriptase enzyme for
RNA viruses, and real-time PCR (RT-PCR) for quantification
of viral load in diseases like hepatitis B and C, human
immunodeficiency virus (HIV), etc.
4. Forensic genetics: PCR is used in forensic laboratories to
identify DNA sequences that are unique to each individual.

Real-time PCR and its applications

The RT-PCR is a type of PCR which allows quantification of the
PCR product in ‘real-time’. It is used to quantify the amount/
number of copies of input DNA/RNA. The method utilises
5’-exonuclease activity of Taq polymerase, and a dual-labelled
internal non-extendable probe with reporter dye at one end
and quencher dye at the other end. The probe emits
fluorescence signal on cleavage, based on the principle of
fluorescence resonance energy transfer (FRET). To start with,
the primer binds to the DNA and is extended by Taq polymerase.
As the extended end of the primer approaches the probe
already bound to specific region of the template DNA, the
5’-exonuclease activity of the polymerase enzyme cleaves the
reporter dye present at 5’ end of the probe resulting in increase
Figure 1: Principle of polymerase chain reaction.
190 of reporter fluorescence emission (e.g. FAM at 518 nm) in
 Genetic Tests
Forensic Genetic Testing
Forensic testing uses DNA sequences to identify an individual
for legal purposes. This type of testing can identify crime or
catastrophe victims, rule-out or implicate a crime suspect, or
establish biological relationships between people (for example,
paternity).
Association Studies in Complex Disorders
Complex disorders or multifactorial disorders are conditions
Figures 2A to E: Molecular diagnostic tools used in the molecular genetics resulting from interplay of genetic susceptibility and
laboratory. Agarose gel electrophoresis showing 100 bp ladder in lane 1 and environmental influences. Very little is known about the
PCR product (450 bp) in lanes 2, and 3 (A); Capillary electrophoresis for
genotyping showing 2 alleles (blue peaks) and sizing ladder (red peaks) (B);
genetics of these disorders. Traditional genetic methods like
Electropherogram showing sequence of nucleotides (C); Micro-array slide linkage analysis cannot be used for deciphering the genetic
showing dots corresponding to amplification (green dots), deletion (red dots) factors in these disorders. Hence, we have to resort to association
and normal (yellow dots) (D); Real-time PCR showing exponential increase in studies, similar to the ones conducted for deciphering the
PCR product (red line) followed by plateau formation (E).
environmental factors involved in these diseases, e.g. smoking
and lung cancer. Genetic association studies look at the
every cycle. The RT-PCR is used for a broad range of applications association of SNPs with occurrence of a particular disease, using
including quantitative gene expression analysis, single a set of cases and controls from specific ethnic populations.
nucleotide polymorphism (SNP) genotyping, point mutation When such a study is conducted by looking at thousands of
detection, copy number analysis, quantification of viral load, and SNPs throughout the genome, these studies are termed as
drug target validation, etc. Genome Wide Association Studies (GWAS). These types of
studies need high throughput methods which can detect
DNA Sequencing multiple SNPs in a single assay. This type of high throughput
DNA sequencing is a PCR-based technique in which sequence data can be generated using micro-arrays which can detect
of the DNA can be determined at single nucleotide level. Various millions of SNPs in a single assay.
methods employed in the past used radioactivity for detection
of sequences. More recent methods are based on fluorescent Microarrays
dyes. Some of these methods include: Microarray is a collection of small oligonucleotides spotted on
1. Chain termination method: It was developed by Sanger in to a glass slide or silicon chip. The micro-array technique is based
the 1970s. In this method, PCR is carried out in presence on complementary hybridisation of nucleic acids. In this
of small amounts of dideoxynucleotides (ddNTPs), in technique, sequence complementarity leads to the hybridisation
addition to usual constituents of the reaction mixture. between two single-stranded nucleic acid molecules, one of
Each ddNTP is labelled with a different fluorescent probe. which is immobilised on a matrix like glass slide or silicon chip.
Incorporation of ddNTP, which lacks the 32-hydroxyl group There are two types of the chips: cDNA micro-arrays and
on the ribose sugar, required for continuation of the oligonucleotide arrays. They differ in the size of the arrayed
polymerisation process, blocks further elongation of the nucleic acids. In cDNA micro-arrays, relatively long DNA molecules
DNA chain. For example incorporation of ddATP in place are immobilised on a solid surface such as membranes, glass or
of dATP at sites where thymine is present in the template silicon chips. These types of arrays are used for large-scale
DNA will lead to formation of DNA fragments of different screening and expression studies. The oligonucleotide arrays are
sizes ending with ddATP. Correspondingly, DNA fragments spotted with short nucleic acids (oligonucleotides up to 25
of different sizes ending with ddTTP, ddCTP and ddGTP nucleotides) and are useful for the detection of mutations and
are produced. All the different sized fragments are then expression monitoring, gene discovery and mapping.
resolved by capillary electrophoresis and resulting Applications of cDNA arrays: expression profiling
electropherogram is analysed by software, such as cDNA arrays are used for expression profiling by hybridising
Chromas 2.0, etc. which calls the sequence of individual cDNA obtained from specific samples/tissues to look for up-
bases in the DNA. regulation or down-regulation of genes in disease states so that
2. Micro-array: In this method small oligonucleotides with this knowledge can be used to develop new biomarkers and
varying combination of nucleotides are used and the treatment strategies. Expression profiling has been used
sequence is detected based on hybridisation of the extensively for various cancers and has resulted in development
template DNA with the immobilised oligonucleotides. of novel drugs for treatment of various cancers, e.g. monoclonal
3. Next generation sequencing: The present methods of antibody (trastuzumab) treatment in cases of breast cancers
sequencing using capillary electrophoresis can be used for with HER2/neu gene amplification.
sequencing of limited number of base pairs at a time. These
Applications of oligonucleotide microarrays
are being replaced by high throughput sequencing
methods called next generation sequencing methods Oligonucleotide microarrays are used for typing of alleles at
different loci throughout the genome. They can be used for:
which can sequence the entire human genome of 3 billion
base pairs for less than $5,000. It is hoped that the newer 1. Detection of mutations in human genetic disorders
technologies will bring down the cost to less than $1,000 2. Detection of microdeletions/microduplications and copy
in the near future. number changes throughout the genome. 191
 3. Genotyping of SNPs:The data obtained from typing of these Limited Information
polymorphisms can be used for genome-wide association The genetic basis of some disorders is not completely
studies in multifactorial disorders like hypertension, understood and hence genetic testing in these diseases will
diabetes mellitus, etc. and mapping of genes for single gene give limited information regarding genetic etiology, e.g. retinitis
disorders by linkage analysis. pigmentosa, deafness, etc.
SPECIAL CONSIDERATIONS IN HUMAN GENETIC TESTING DIRECT-TO-CONSUMER TESTING
Genetic test results not only apply to the individual across his/ Direct-to-consumer (DTC) genetic testing is advertised and
her entire lifespan, but have implications to other family offered directly to the consumer without having to go
members as well. Hence, special considerations need to be kept through a health care professional. In this case the test can
in mind while ordering a genetic test. be ordered by the patient, family member at risk, or anyone
1. Confidentiality: It is very important to maintain from the population on-line themselves. While on one hand
confidentiality regarding the results of genetic tests since it offers the advantage of privacy and confidentiality, on the
they have a bearing on various issues like insurance, job other it suffers from the danger of creating confusion due
security, etc. to misinterpretation of genetic information. A variety of DTC
2. Quality assurance: As newer and newer methods and tests are being offered by different companies, ranging from
assays are available for genetic testing, proper quality testing for breast cancer risk, macular degeneration risk,
control needs to be maintained by the testing adverse drug reaction risk, etc. to ancestry analysis. The DTC
laboratories. Accreditation of laboratories and practice testing is not under any regulation regarding marketing
of internationally recognised standards and guidelines claims, and quality of services provided. Advertising of DTC
needs to be ensured. has been criticised for conveying exaggerated and
inaccurate messages about connection of genetic test result
LIMITATIONS OF GENETIC TESTING and disease risk, utilising emotions as a selling factor. Truly
The patient needs to be counselled regarding limitations of speaking, we still do not have enough data to quantify the
genetic tests before conducting the test. Some limitations of risks conferred by the risk alleles towards occurrence of
genetic tests include: various disease phenotypes. It would be advisable to defer
the application of DTC tests until such data and knowledge
Multiple Mutations is available.
Different types of mutations can result in a single phenotype/
disease, e.g. Duchenne muscular dystrophy can be caused Properly designed educational programmes are urgently
due to deletion of any/some of the 79 exons in dystrophin needed to aid the medical fraternity and general public in
gene or due to point mutations in the same gene. Thus, we understanding implications of molecular diagnostic studies.
have to use different genetic methods to look for deletions Judicious application of molecular genetic testing can go a
long way in improving the health of populations in future.
and point mutations to establish the genetic basis of this disorder.
Errors in Genetic Testing RECOMMENDED READINGS
Various errors can occur during genetic testing either due to 1. Gene Tests. Available at www.ncbi.nlm.nih.gov/sites/GeneTests.
human errors, machine related errors, reagent related errors, etc. 2. Genetic Test – Geneclinics Website (http://www.geneclinics.org).
All precautions need to be taken to prevent errors during 3. Min YS, Choi JH, Lee SY, et al. Applications of DNA microarray in disease
genetic testing. It is recommended always to use a positive and diagnostics. J Microbiol Biotechnol. 2009; 19 (7): 635-46.
negative control during assays like PCR so that errors due to 4. Nussbaum RL, McInnes RR, Willard HF. Genetics in Medicine; 6th edition.
contamination of foreign DNA can be avoided. Thompson and Thompson: WB Saunders; 2001.

192
 6.5 Inborn Errors of Metabolism

Madhulika Kabra

Traditionally, management of patients with inborn errors of

metabolism (IEM) has been a concern of paediatricians. Most
of these disorders present exclusively in infancy and childhood,
and due to their severity patients may succumb early in life.
Paediatric forms of the disease are more severe, hence, more
easily recognisable. Newborn screening programmes for several
of these disorders exist in developed countries, and have helped
in early diagnosis and prompt management. Early diagnosis,
strict dietary management, biochemical interventions, and
careful medical care have led to increasing number of patients
with inherited biochemical defects surviving into adulthood.
In addition to increasing age of survival of children with early-
onset biochemical disorders, some milder variants first present
late as adult-onset disease. It is now clear that potentially every Figure 1: Consequences of enzyme deficiency in a metabolic pathway.
disorder has a milder form with a later onset and there is a
distinct possibility that diagnosis in adults may be missed due CLASSIFICATION
to lack of awareness among physicians. Examples include adults
IEM are classified in two major groups—small molecule diseases
with organic acidaemia and movement disorders, urea cycle
and large molecule diseases (Table 1).
disorders, late onset lysosomal storage disorders, etc. The age
of onset is determined by the presence of variable activity of Table 1: Clinical Classification of Inborn Errors of Metabolism
the defective enzyme that results from different genetic Acute (generally Intermittent Chronic (generally
mutations. Adult female carriers of the X-linked ornithine present in (Precipitated by present late in
transcarbamylase deficiency may have variable manifestations infancy) stress, infection, childhood/adults)
of hyperammonaemia after protein ingestion—confusion, starvation, diet)
ataxia, migraine headache, or even frank coma. Internists not Due to small molecule Caused due to Due to large molecule
only need to assume responsibility of taking care of surviving defect (amino acids, milder metabolic defect
patients, but should also be competent to diagnose and organic acids, simple derangement (storage disorders)
manage adult-onset IEM. sugars, etc) (energy deficiency)
Poor feeding, vomiting, Repeated episodes Progressive central
DEFINITION AND EPIDEMIOLOGY lethargy of Reduced level of nervous system
IEM are conditions caused due to a genetic defect related to Convulsion, hypotonia consciousness degeneration
synthesis, metabolism, transport or storage of various Cataract Acidosis or ketosis manifested as seizures,
biochemical compounds. The genetic defect usually causes Abnormal body odour or hypoglycaemia development delay or
Negative septic screen Weakness failure to thrive,mental
deficiency of one or more enzymes or transport proteins.
in a sick infant Ataxia/spasticity retardation
Worldwide incidence of IEM has been estimated to be about vomiting, Hypotonia/spasticity,
3-4 per 1,000 live births. More than 300 such defects are known. Reye syndrome muscular weakness
Most IEM are inherited in an autosomal recessive manner, some like episodes Associated
organomegaly,
are X-linked. Exact incidence of IEM in India is not known as no
abnormal fundus,
population based data is available. In one study, 5% of the cases of coarse facies
mental retardation due to genetic cause were due to IEM [Indian
Council of Medical Research (ICMR) multicentric study]. In other The major categories of IEM which can present as an acute
studies from India, 0.5% to 2.4% of mentally retarded children have emergency include—organic acidurias (OA), fatty acid oxidation
been reported to have an amino acid metabolism disorder. (FAO) defects, mitochondrial encephalomyelopathies,
aminoacid disorders [phenylketonuria (PKU), maple syrup
AETIOPATHOGENESIS urine disease (MSUD), non-ketotic hyperglycinemia (NKH),
IEM are disorders which are caused by deficiency of an enzyme tyrosinaemia], urea cycle defects (UCD) and disorders of
that leads to a block in the metabolic pathway. This leads to: carbohydrate metabolism (galactosaemia)].
(i) deficiency of the end product, (ii) accumulation of the substrate,
and (iii) generation of secondary metabolites through some CLINICAL PRESENTATION AND SUSPICION OF IEM
alternate pathway. Symptoms are caused both due to deficiency Infants and Children
of the product and accumulation of the substrate/alternate The classical presentation in newborns is of an initial period of
metabolite. Figure 1 illustrates the mechanism. normalcy, followed by symptoms, usually getting precipitated 193
 by feeding which resemble sepsis. In infants and older children, (b) Chronic encephalopathy: Psychomotor retardation/
symptoms may get precipitated by intercurrent illness or dietary developmental delay are the commonest manifestation
factors and may be intermittent. If untreated, patients may of IEM. The retardation tends to be global and
rapidly deteriorate and slip into encephalopathy. History of progressive. History of regression of milestones may be
consanguinity, family history of developmental delay or sudden present. Irritability, aggressiveness,hyperactivity and lack
infant death syndrome, onset of symptoms with institution of of night sleep are commonly associated. In addition,
feeds, unexplained growth disturbances, recurrent vomiting, retardation is often associated with objective
poor feeding, seizures, apnoea, breathlessness may be neurological signs, like tone changes, pyramidal or extra-
important clues. pyramidal deficits. Seizures, visual failure, extra-pyramidal
disturbances are signs of grey matter disease.
Physical findings
Involvement of non-neural organs like hepato-
Clinical findings are non-specific and include tachypnoea, splenomegaly gives important clues to diagnosis.
apnoea, lethargy, hypertonia, hypotonia, hepatosplenomegaly,
(c) Movement disorders: In patients with IEM can be seen
ambiguous genitalia, jaundice, dysmorphic or coarse facial
in a large variety of disorders and are usually associated
features, rashes or patchy hypopigmentation, ocular findings
with other neurologic signs. Movement abnormalities
(cataracts, lens dislocation or pigmentary retinopathy),
can be intermittent or progressive. These may occur in
intracranial haemorrhage, and unusual odours. Table 2 gives
the form of ataxias, dystonia, choreoathetosis and
some important clinical markers for IEM.
Parkinsonism. Common examples of IEM presenting as
Table 2 : Clinical Pointers to Specific Disorders movement disorder are organic acidurias, neuronal
ceroid lipofuscinosis (late onset forms), lysosomal
Cutaneous abnormality: Perioral eruption (multiple carboxylase
storage disorders and urea cycle disorders, etc.
deficiency), increased pigmentation (adrenoleukodystrophy),
decreased pigmentation (phenylketonuria) (d) Myopathy: IEM presenting with myopathy are usually
Abnormal urinary or body odour: Musty (phenylketonuria), maple due to defects in energy metabolism. The myopathy
syrup (maple syrup urine disease), sweaty feet (isovaleric acidaemia, can be progressive, e.g. glycogen storage disease,
glutaric acidaemia type II), cat urine (multiple carboxylase mitochondrial disorders.
deficiency), sulphurous (homocystinuria) 2. Hepatic syndromes: Liver involvement is seen in a number
Hair abnormalities: Alopecia (multiple carboxylase deficiency), of IEM. There are four possible presentations: (i) Jaundice
kinky hair (Menkes disease), arginosuccemic aciduria, multiple (unconjugated—G6PD deficiency, Gilbert, Crigler-Najjar,
carboxylase deficiency) and conjugated—galactosaemia, tyrosinemia, fructose
Dysmorphic features: Zellweger syndrome, glutaric acidaemia intolerance); (ii) Hepatomegaly (asymptomatic
type II hepatomegaly is common, e.g. GSD); (iii) Hypoglycaemia
Ocular abnormalities: Cataract (galactosaemia, Zellweger, galactosaemia, GSD); and (iv) Hepatocellular dysfunction
homocystinuria), iris heterochromia/retinitis pigmentosa (Zellweger galactosaemia, GSD (IV and III), Niemann-Pick type B,
syndrome), KF ring (Wilson’s disease) α1 antitrypsin deficiency, etc.
Hepatomegaly: Galactosaemia, glycogen storage disease,
3. Cardiac syndromes: Serious cardiac disease has been found
tyrosinaemia
to be associated particularly with fatty acid oxidation defects,
Hepatosplenomegaly: Storage disorders – Niemann-Pick, Gaucher
mitochondrial disorders, GSD II, Fabry’s disease and MPS.
disease, mucopolysaccharidosis
Renal enlargement: Zellweger, GSD I, tyrosinaemia Clinical Presentation in Adults
A history of intermittent attacks triggered by feeding or fasting
Laboratory findings or some stress may suggest milder intermittent forms of small
Laboratory findings which should raise a suspicion of IEM molecule diseases like disorders of urea cycle, amino acid
include metabolic acidosis with increased anion gap, primary metabolism, or fatty acid oxidation. A slow progressive course
respiratory alkalosis, hyperammonaemia, hypoglycaemia, may suggest a lysosomal storage disease or a peroxisomal
ketosis or ketonuria, lactic acidosis, non-glucose reducing disorder. Often detailed questioning may disclose evidence
substance in urine, abnormal liver functions, unexplained of problems in childhood or adolescence. A positive family
neutropaenia and thrombocytopaenia. In general, IEM can have history may also give a clue. A detailed enquiry for mild clinical
one of the following presentations: symptoms at an early age is warranted as those symptoms may
be passed off as non-specific and unrelated. These features
1. Neurologic syndromes: These can present as acute often remain unrecognised, as they may be mild and often
encephalopathy, chronic encephalopathy, movement intermittent in nature. Specific neurological findings such as
disorders, myopathy, and psychiatric problems. vertical supranuclear ophthalmoplegia or a cherry red spot may
(a) Acute encephalopathy: Encephalopathy in acutely suggest a lysosomal storage disorder. Alternatively, there may
presenting IEM has certain characteristics. It usually be abnormalities affecting other organ systems. The internist
occurs with little warning in a previously healthy may confront a group of disorders caused by mutations in
individual and early signs may be taken as a behavioural mitochondrial DNA that express themselves as disorders of
problem. The condition often progresses rapidly and cellular energy metabolism secondary to electron transport
consciousness may fluctuate. History of recurrent chain defects. The manifestations may involve single organ
similar episodes may be present. system or may be these disorders may mimic an idiopathic,
194
 Inborn Errors of Metabolism
organ-specific, degenerative disease. Affected persons may patient presenting with hypoglycaemia. For definitive diagnosis
present at any age with variable features of myopathy, a combination of investigations is required. These include
ophthalmoplegias, encephalopathy, strokes and cardiac tandem mass spectrometry (TMS), gas chromatography mass
manifestations. The cardinal biochemical feature is lactic spectroscopy (GCMS, primarily for organic acidurias) and high
acidaemia; lactic acid elevation in the cerebrospinal fluid performance liquid chromatography (HPLC for amino-
may be the sole abnormality. Table 3 gives brief information acidopathies). Enzyme assays are required for the diagnosis of
about inherited metabolic disorders with adult onset lysosomal storage disorders. DNA-based diagnosis for causative
forms. mutations is the most reliable diagnostic modality but is difficult

Table 3: IEM with Adult Onset

Disease Presentation
Lysosomal storage diseases
Pompe’s disease Muscle weakness, cardiomyopathy
Fabry’s disease Peripheral nerve pain, renal failure, angiokeratoma, cardiomyopathy, stroke-like episodes
Gaucher’s disease type III Horizontal supranuclear gaze defect, developmental delay, skeletal abnormalities,
psychosis, organomegaly
Gaucher’s disease type I Anaemia, splenomegaly, thrombocytopaenia
GM1 gangliosidosis Extrapyramidal signs, sometimes with psychosis
Krabbe’s leukodystrophy Pes-cavus, spastic tetraparesis, leukodystrophy, visual problems
Metachromatic leukodystrophy Loss of cognitive function or behavioural abnormalities, neuromuscular weakness with
impaired nerve conduction, leukodystrophy
Niemann-Pick’s disease type C Psychomotor retardation, ataxia, dystonia
Amino acid disorders
Arginase deficiency Disorientation, coma
Citrullinaemia Disorientation, coma, restlessness
Hartnup’s disease Dementia, ataxia ± skin lesions
Homocystinuria Occlusive cerebrovascular disease, dislocated lenses, osteoporosis, psychiatric
disturbances
Hyperornithinaemia Gyrate atrophy of the retina and choroid
Ornithine transcarbamylase deficiency Behavioural disturbances, coma episodes, sleep disorders
Fatty acid oxidation defects Muscle weakness, easy fatigability ± liver disease ± cardiomyopathy ± hypoglycaemia
Organic acid disorders
Glutaric aciduria type 1 Dystonia ± hypoglycaemia, may present with Reye-like syndrome
Propionic acidaemia Chorea, dementia, recurrent vomiting
Peroxisomal disorders – X-linked ALD Onset at 20-30 yrs in males, gait disturbance, spastic paraparesis, intellectual function
usually intact, impotence ± Addison’s disease, occasionally cerebral symptoms
Mitochondrial disorders Encephalopathy, stroke-like episodes, muscle weakness, multisystem disease (NARP,
MELAS, MERRF, Kearns-Sayre syndrome, LHON)
Glycogen storage diseases Muscle weakness, cardiomyopathy, hepatomegaly, hypoglycaemia, myopathy
Homocystinuria and methylmalonic aciduria Megaloblastic anaemia, dystonia, stroke
Juvenile Batten’s disease Seizures, visual loss, dementia
Porphyrias Limb, neck, and chest pain, muscle weakness, sensory loss, seizures,behavioural abnormalities
Refsum’s disease Retinitis pigmentosa, peripheral polyneuropathy, cerebellar ataxia, abdominal symptoms,
photosensitivity
Segawa disease Cyclical dystonia
Wilson’s disease Dystonia, pseudobulbar palsy, Parkinsonian features, liver disease
Lesch-Nyhan syndrome Choreiform movements, dysarthria ± renal problems

LABORATORY APPROACH TO SUSPECTED IEM due to limited availability and heterogeneity in different
populations.
Screening and Definitive Diagnosis Definitive diagnosis may not be available promptly; hence,
treatment has to be started empirically in most situations.
Based on history and suspicious clinical course, an investigational Table 4 gives details of workup which is required for acutely
plan for IEM should be followed. Initial screening investigations presenting IEM. Routine tests such as blood sugar, serum
will help in disease classification and instituting presumptive calcium, liver function tests, blood counts and urine tests (Table 5)
therapy. Figure 2 gives step-wise approach to a suspected IEM. may give some clues to diagnosis. Four laboratory tests are
Figures 3A and B give details of evaluating a child with metabolic particularly useful in broad classification of IEM and instituting
acidosis and Figures 4A and B give differential diagnosis of empirical therapy—arterial blood gas analysis, blood lactate,
hyperammonaemia. Figure 5 gives details of evaluation of a blood ammonia, and urine ketosis (Table 6). 195
 Figure 2: Approach to a case of suspected IEM.
*Phenylketonuria, # Non-ketotic hyperglycinaemia

Figure 4A and B: Approach to a patient with hyperammonaemia.

Figure 3A: Approach to a patient with metabolic acidosis.

196 Figure 3B: Approach to a patient with metabolic acidosis.

 Inborn Errors of Metabolism
Figure 5: Approach to a patient with hypoglycaemia.
* HFI = Hereditary fructose intolerance; AA = Amino acids; OA = Organic acids; FAOD = Fatty acid oxidation defects; FFA = Free fatty acids.

Table 4: Investigations for Acutely Presenting IEM

Investigations Sample storage for specific investigations
Urine Smell (special odour) Urine collection: Collect each fresh micturition
Look (special colour) separately and put it in the refrigerator
Acetone (acetest, ames) Freezing: Freeze at -20 °C, samples collected
Reducing substances (clinitest, ames) before treatment and, afterward, an aliquot
Keto acids (DNPH) of 24-hour collection on treatment
Blood Blood cell count Plasma, heparinised, 5 mL at -20 °C
Electrolytes (for anion gap) Blood on filter paper (as ‘Guthrie test’)
Glucose, calcium Whole blood 10 to 15 mL collected in EDTA vial
Blood gases (for molecular biology/enzyme studies)
Uric acid
Prothrombin time
Transaminases (and other liver tests)
Ammonia
Lactic and pyruvic acids Arterial blood sample
Miscellaneous Lumbar puncture Skin biopsy (fibroblast culture)
Chest radiograph Cerebrospinal fluid, 1 mL frozen
Echocardiography, EMG Post-mortem: Liver, muscle biopsies
Cerebral ultrasound (macroscopic fragment frozen at -70 °C)
CT, MRI, EEG
Specialised
investigations HPLC, GCMS, TMS
197
 Table 5: Urine Metabolic Screen
Disorder Ferric Chloride DNPH* Reducing Nitroprusside MPS Spot
Substances Test**
Phenylketonuria + + – – –
Galactosaemia – – + – –
Organic aciduria + + – – –
Amino aciduria – + – – –
Homocystinuria – – – + –
Mucopolysaccharidosis – – – – +
* DNPH = Dinitrophenyl hydrazine ** MPS spot test = Mucopolysaccharidoses spot test

Table 6: Four Basic Tests for Inherited Metabolic Disorders

Group Acidosis Ketosis Lactate Ammonia Diagnosis
I – + – – MSUD
II + + – – Organic aciduria
III + + + – Lactic acidosis
IV – – – + Urea cycle disorder
V – – – – NKH, sulfite oxidase,
Peroxisomal, PKU galactosaemia

Points to Remember when Collecting Samples TREATMENT

Samples should be collected before specific treatment is started Immediate Management of Acutely Presenting Disorders
or feeds are stopped, as tests may be falsely normal if the child Initial emergency treatment should be started empirically even
is off feeds. Samples like serum ammonia and lactate should be on suspicion of IEM, and even without knowledge of the specific
immediately tested. Lactate level should be arterial and metabolic diagnosis or disease category.
collected after 2 hours fast. For children ammonia sample is to
1. General measures:
be collected approximately after 4–6 hours while in adults it
should be collected after a longer period of fasting. Detailed (a) Airway, breathing and circulation should be
history including drug details should be provided to the established,
laboratory. (b) Treat precipitating/associated conditions like
septicaemia.
Investigation for a Dying Child (Biochemical Autopsy)/Post-
mortem Investigations (c) Seizures: These should be managed as per the
protocols. Pyridoxine should be given to neonates with
If a child (suddenly) dies of an unknown, possibly metabolic
disease, it is essential to collect representative post-mortem seizures unresponsive to conventional anticonvulsants.
samples and discuss the analysis with a metabolic specialist. Valproate and phenobarbitone are preferably avoided
Without diagnosis, genetic counselling of the parents and as they interfere with mitochondrial metabolism.
reliable risk assessment for future children is not possible. The 2. Correction of metabolic abnormalities
following should be collected for post-mortem analysis if a 3. All oral intake should be stopped to reduce levels
metabolic disorder is suspected but specific investigations have of potentially harmful proteins and sugars. Treat
not yet been performed: hypoglycaemia and prevent catabolism. Maintain fluid and
1. Serum and plasma (centrifuge several millilitres electrolyte balance. Treat acidosis. For intractable acidosis,
immediately, freeze in separate fractions). haemodialysis/peritoneal dialysis is required.
2. Guthrie-card (dried blood spot on filter paper). 4. Removal of toxic metabolites: Abnormal metabolites are
3. Urine (10-20 mL, freeze immediately, consider bladder wash removed by restricting intake of the offending substrate,
with NaCl). or by promoting renal excretion of toxic metabolites. In
4. DNA (3-10 mL EDTA blood, freeze without centrifuging), and severe cases, dialysis (preferably haemodialysis) is
5. Consider CSF (several 1 mL fractions, freeze immediately, if required. Although haemodialysis has advantages over
possible at -70°C). peritoneal dialysis (PD), vascular access remains the
Consider fibroblasts (skin biopsy may be stored 1 to 2 days at primary technical problem and PD is, therefore, usually
4°C in culture fluid). offered.

Biopsies SPECIFIC MANAGEMENT

The acquisition of organ biopsies depends on the clinical picture Hyperammonaemia
and should be discussed with the laboratory/metabolic specialist Kidneys clear ammonia poorly. Its removal is hastened by
(samples are usually frozen immediately in liquid nitrogen): formation of compounds other than urea, hence, decreasing load
198 muscle (skeletal, consider heart), liver, kidney and brain. on the urea cycle. Compounds used are sodium benzoate, phenyl
 Inborn Errors of Metabolism
acetate and arginine. Intravenous preparations of sodium medium chain triglycerides may be beneficial. Avoid valproate
benzoate and phenyl acetate are not available in India. as an antiepileptic drug if possible.
Oral sodium benzoate is available and can be used in the same
Mitochondrial Disorders
dose.
Most approaches used for the treatment of mitochondriopathies
Ammonia level more than 200 μ mol/L to 350 mg/dL have not been scientifically evaluated, and success is limited.
Protein intake is to be stopped, and catabolic state is interrupted General measures include avoidance of drugs that inhibit the
by high-calorie infusion (>120 kcal/kg/day). Arginine respiratory chain, e.g. valproate, barbiturates, tetracyclines,
hydrochloride 360 mg/kg, carnitine 50 mg/kg, Na-benzoate 350 chloramphenicol. L-Carnitine 50-100 (up to 200) mg/kg/day in
mg/kg and Na-phenylbutyrate or Na-phenylacetate 250 mg/ 4 doses; avoid lactic acidosis by limiting excessive physical
kg should be started. The patient should be transferred to a exercise, controlling fever, early and efficiently, and early
referral centre. Citrulline may be used in the dose of 170 mg/kg treatment of seizures.
per day in CPS and OTC deficiency. Anticonvulsants like sodium Treatment regimen in acute lactic acidosis and suspected
valproate should be avoided.
mitochondriopathy includes: coenzyme Q10 + riboflavin (in the
NH3 level more than 400 μ mol/L neonate: 100 mg/day), vitamin C, carnitine, biotin (20 mg/day),
In addition to the above measures, extracorporeal detoxification phylloquinone or menadione and thiamine.
should be started as soon as possible. Use haemodialysis, if Specific long-term treatment, though of uncertain efficacy,
possible; otherwise, peritoneal dialysis. includes: coenzyme Q10 4-5 mg/kg/day in 2 doses, riboflavin 3-
Long-term treatment of urea cycle defects 20 mg/kg/day in 4 doses, thiamine 25-100 mg/kg/day,
Start low-protein diet containing essential amino acids early. tocopherol (vitamin E) 100-300 (up to 1,000) mg/day and
Na-benzoate orally in a dose of 250-400 mg/kg/day and Na- Creatine 4-10 g/day (stop every 4th month), e.g. in mitochondrial
phenyl-butyrate orally in a dose of 250-500 mg/kg/day is also myopathy. Corticosteroids are not indicated.
to be administered. Supplement vitamins (e.g. folic acid 500 μg/ Vitamin/Cofactor Therapy
day) and trace elements. If carnitine is low, supplement carnitine
In certain IEM, enhancement of the activity of a mutant
in the dose of 30-50 mg/kg. Consider lactulose as it binds
enzyme can be achieved by giving mega-doses of a vitamin
intestinal ammonia due to acid pH. The target value of NH 3 is
cofactor required for enzyme’s action. One-third of the cases
less than 80. Essential amino acids should be in the normal
of homocystinuria due to cystathionine b-synthetase
range.
deficiency are pyridoxine responsive. Deficiency of multiple
Organic Acid Disorders biotin-dependent carboxylases responds to 10 mg of biotin
Emergency treatment in the hospital includes the following: given daily. Some cases of methylmalonic acidaemia respond
to pharmacological supplementation of intramuscular
(a) Interrupt catabolic state: High-dose energy substitution,
hydroxycobalamin in a dose of 1 mg per day. A diet low in fat
usually glucose intravenous (exceptionally via nasogastric
and protein together with a trial of oral riboflavin (200-300
tube), if necessary with intravenous insulin.
mg per day) and carnitine may be helpful in some patients
(b) Stop protein intake: In some disorders, the accumulation of with glutaric aciduria type I and II.
toxic metabolites can be reduced by intestinal antibiotic
treatment (metronidazole, colistin). Dietary Therapy and Enzyme Replacement
(c) Ensure adequate fluid and electrolyte intake: Aim for a sodium Specific therapy will depend on the final diagnosis. Dietary
concentration >140 mmol/L to reduce the risk of cerebral therapy is required for PKU, MSUD, galactosaemia, homocystinuria,
oedema. etc. Cost of the special diets is high and critical monitoring is
required for effective management. Enzyme replacement
(d) Carry-out detoxifying measures depending on the disease
therapy is available for many lysosomal storage (e.g. Gaucher’s,
and laboratory findings: Increased diuresis, dialysis,
MPSI, MPSII, GSDII, Fabry’s, MPSVII) disorders with excellent
haemofiltration.
results. Bone marrow/stem cell transplantation is another
(e) Consider specific drug treatment (vitamins, carnitine, etc.) option for lysosomal storage disorders.
depending on the disease and laboratory findings.
Newborn Screening
Long-term treatment includes the following: (a) Diet: protein
restriction, (b) If indicated give specific vitamins or co-factors, Newborn screening is a well-tested strategy for secondary
(c) Carnitine (50-100 mg/kg/day), and (d) Regular laboratory prevention of IEM. Most developed countries test for IEM using
monitoring (depending on the disease). TMS in addition to screening for congenital hypothyroidism and
congenital adrenal hyperplasia. Samples are collected by heal
Disorders of Fatty Acid Oxidation prick 48 to 72 hours after birth. Early diagnosis and timely
The main therapy is prevention of fasting and catabolic states. In management prevents neurological sequelae and mortality.
acute situations, intravenous glucose infusion (8-10 mg/kg/min) India does not have a national newborn screening programme
should be started without delay. In contrast, in patients with presently. The ICMR has initiated a multicentric pilot project
defects in LCAD metabolism, low fat diet supplemented with for newborn screening of 100,000 babies for congenital

199
 hypothyroidism and congenital adrenal hyperplasia to study RECOMMENDED READINGS
the incidence of these disorders and also the feasibility of 1. Bruton BK. Inborn errors of metabolism in infancy: a guide to diagnosis.
introducing such a programme in India. The Governments of Pediatrics 1998. 102: E 69.
Chandigarh and Goa, India have also initiated newborn 2. Clarke JTR. The management of inherited metabolic diseases: a review. J
screening programmes recently. Pediatr Obster Gyn. 2005; 31: 186-96.
3. Graya RGF, Preecea MA, Greenb SH et al. Inborn errors of metabolism as a
Genetic Counselling and Prenatal Diagnosis cause of neurological disease in adults: an approach to investigation. J
As most IEM are autosomal recessive, the risk of recurrence Neuro Neurosurg Psychiatry. 2000; 69: 5-12.
in subsequent pregnancies is 25%. For X-linked disorders 4. Marburg JZ, Marburg GH. Vademecum metabolium. Manual of metabolic
recurrence risk is 50% for male offspring. Prenatal diagnosis is Pediatrics. Milupa, Schattaner 1999.
possible by enzyme assay in chorionic villous biopsy or 5. Scriver CR, Beaudet AL, Sly WS Valle D. The Metabolic and Molecular Bases of
amniotic fluid cells. Mutation analysis on DNA extracted from Inherited Disease. Vol 1; 8th Ed. McGraw Hill; 2001.
chorionic villous sample or amniotic fluid cells is a more robust 6. Stanton Segal, Karl S Roth. Inborn errors of metabolism: a new purview of
and preferred modality if causative mutations are known. internal medicine. J Neuro Neurosurg Psychiatry. 2000; 69: 5-12.

200
 6.6 Molecular Genetics, Human Genome
Project and Genomic Medicine
Girisha KM

The understanding of the structure, function, regulation and

variations in DNA is the key to the understanding of human
health and disease. This chapter discusses the molecular basis
of life, gives insight into genetic variation between individuals
and its clinical implications.

STRUCTURE OF DNA
Deoxyribonucleic acid (DNA) is a long polymer of nucleotides.
Each nucleotide is made up of a nitrogenous base [purines:
adenine (A) and guanine (G); and pyrimidines: cytosine (C) and
thymine (T)], a deoxyribose sugar, and a phosphate group.
Ribonucleic acid (RNA) differs from DNA in having a ribose
sugar in place of deoxyribose, and pyrimidine uracil (U) in
place of thymine. Watson and Crick (1953) demonstrated how
deoxynucleotides are assembled to form the double stranded
helical structure of DNA, where sugar and phosphate molecules
form two sides of the ladder that are held by strong
phosphodiester bonds, and rungs of the ladder are formed by
nitrogenous bases facing inside, being held together by
hydrogen bonds that are weaker and separate during
replication and transcription. The two strands run anti-parellel Figure 1: Helical structure of the DNA showing the sugar-phosphate backbone
and the nitrogenous bases. The DNA resembles a ladder with the sides formed
to each other with one strand having the orientation of 5’ to 3’ by the phosphodiester bond between phosphoric acid and deoxyribose sugar
direction and the other of 3’ to 5’ direction (Figure 1). and the rings formed by hydrogen bonds in-between the nitrogenous bases.
Two hydrogen bonds are formed between adenine (A) and thymine (T) and
In human nucleated cells, approximately 2 metres of DNA is three hydrogen bonds between guanine (G) and cytosine (C).
condensed about 10,000 times and packaged into
chromosomes. The DNA is first wound around a histone protein
TRANSCRIPTION AND RNA PROCESSING
core to form a nucleosome, which in turn forms a helical
solenoid. The solenoids are organised into chromatin loops, Transcription is the process whereby genetic information
which are attached to a protein scaffold and further packaged stored in DNA is utilised for gene function. It leads to
into chromosomes. formation of RNA which migrates to cytoplasm for synthesis
of proteins. The transcript of the coding DNA is known
DNA REPLICATION as messenger RNA. The mRNA is single stranded. It is
Replication of DNA is the key event for transmission of genetic synthesised by the enzyme RNA polymerase that adds
information from parent cell to its progeny. The process leads complementary ribonucleotides to the RNA chain (uracil
to formation of two identical copies of the original DNA that replaces thymine in mRNA). The particular strand of DNA that
get segregated into two daughter cells during cell division. acts as a template for synthesis of mRNA is called ‘antisense
The replication begins with uncoiling and separation of two strand’ so that the new molecule of mRNA is the copy of the
strands of the DNA molecule by the enzyme helicase. Each other ‘sense strand’.
strand of the DNA directs synthesis of its complementary copy The mRNA leaves the nucleus to cytoplasm after several
through complementary base pairing (adenine pairs with processing events. The RNA processing includes removal of
thymine and cytosine pairs with guanine) resulting in introns at specific splice sites in mRNA (splicing), addition of a
formation of two DNA molecules (semi-conservative methylated guanine nucleotide to the 5’ end of the molecule
synthesis) identical to the original parent molecule. This (5’ capping) and addition of about 200 adenylate residues at
process conserves the genetic information, and transmits it the 3’ end (polyadenylation). Now the mRNA molecule is ready
unchanged to each daughter cell. The key enzyme that carries to be translated.
out DNA synthesis is DNA polymerase. The process initiates at
several sites simultaneously during the S (synthetic) phase of THE GENETIC CODE
cell cycle. The synthesis of a new DNA strand proceeds in 5’ to The 20 different amino acids in proteins are coded by the four
3’ direction. This leads to formation of one continuous strand different nucleotides (bases) in DNA (Figure 2). The sequence
(leading strand) which is the copy of the 3’ to 5’ strand; and of triplet nucleotide bases in the DNA molecule that specifies
the other strand is synthesised in parts (Okazaki fragments) the sequence of amino acids in the protein molecule is called
that are later joined together by the enzyme DNA ligase. the genetic code. The genetic code from DNA is transmitted to 201
 Figure 3: The genetic code: Triplet nucleotides in the mRNA form codons and
code for specific amino acids. An amino acid may be coded by more than one
codon and three codons stop the elongation of polypeptide chain.

Figure 2: Central dogma of molecular biology.

turn act as templates for synthesis of DNA. This DNA may get
codons of the mRNA during transcription which is then integrated into nuclear DNA of other cells.
decoded into specific amino acids during translation.
GENE: THE FUNCTIONAL UNIT OF DNA
The codons on mRNA are non-overlapping, and are read as
A ‘gene’ may be conceptualised as the sequence of DNA that
per translational reading frame. Among 64 possible triplet
contains the information required for a functional product
codons from 4 nucleotides, some code for same amino acid
(Figure 4). The product encoded may be a polypeptide or RNA
(degeneracy, since there are only 20 amino acids). Three codons
molecule. Previously, it was thought that the coding sequence
code for termination of the polypeptide synthesis (stop codons).
of a gene lies in continuity, which is now known to be a rarity.
The process of transfer of genetic information from DNA to RNA
Now, the ‘gene’ has been shown to consist of amino acid coding
to protein is sometimes referred to as ‘central dogma’ or ‘holy
exons, intervening non-coding introns, promoter sequences at
trinity’ of molecular biology (Figure 3).
5’ region that initiate transcription and other regulatory
TRANSLATION elements like enhancers, silencers, and locus control regions.
Genes may overlap, may be found within another gene, or even
The genetic code in the DNA (of a gene) is transmitted on to
the same sequence may be transcribed in reverse direction to
the codons of mRNA and these direct the synthesis of
produce another product.
polypeptide chain by incorporating specific amino acids during
the process of translation. In the ribosomes, the site of protein REGULATION OF GENE EXPRESSION
synthesis, the mRNA molecules with the help of specific transfer
The estimated 23,000 genes in each human cell control all the
RNAs (tRNA) carrying the ‘anticodons’ for individual amino
cellular processes in the living being. Their expression varies at
acids synthesise the polypeptide chain, originally directed by
different stages of development, and depending on the type
the genetic code in the gene. The polypeptide chains, thus
of the cell/tissue. Several complex pathways are involved in
synthesised, undergo several post-translational modifications
controlling temporal and spatial expression of genes.
(hydroxylation, methylation, glycosylation, proteolytic cleavage,
etc.) to become functional proteins that are transported to their Signalling molecules called transcription factors bind to regulatory
specific cellular locations. sequences of DNA, nuclear receptors (hormones) or even specific
ligands located at the cell surface for signal transduction. The
REVERSE TRANSCRIPTION transcription factors may bind to promoter elements (TATA, GC
In most situations, the genetic information flows from DNA to and CAAT boxes) of the specific genes located adjacent to the
RNA. However, in certain types of viruses (retroviruses) genetic coding region (cis-acting) to regulate the pace of protein synthesis,
information can flow in reverse direction from RNA to DNA. This or to enhancer or silencer elements located at a distance and act
is termed reverse transcription or RNA-directed DNA synthesis on both copies of the gene (transacting) to enhance or suppress
and involves the enzyme reverse transcriptase. Some regions the transcription. Transcription factors themselves are coded by
202 of the DNA serve as templates for synthesis of RNA, which in genes and bind to DNA to regulate gene expression.
 Molecular Genetics, Human Genome Project and Genomic Medicine
Figure 4: Structure of a gene: A typical gene is made up of a promoter, a transcriptional start site, exons, introns, translational stop site and a Poly A signal.The promoter
facilitates the binding of RNA polymerase to the gene during transcription; the transcriptional start site contains the initiation codon ATG, which marks the start of
transcription. Exons encode the information for a functional protein. The 5’ and 3’ untranslated sequences play a role in gene regulation.

Gene activity may also be related to patterns of chromatin resemble known structural genes but do not express. They
condensation. Heterochromatin is usually highly condensed are thought to have arisen either by duplication of genes
and is characterised by histone modification that makes it that have lost function due to mutations or by insertion of
inaccessible to transcription factors, whereas euchromatin is complementary DNA sequences lacking promoter sequences.
decondensed and transcriptionally more active.
Extragenic DNA
Though regulation of expression of most of the genes is The sequences that represent all the genes of the human body
mediated by transcription factors, regulation can also occur at constitute around 1.5% of the genome. The rest of the human
various stages of protein synthesis, viz. RNA processing, transport, genome is made up of repetitive DNA sequences that are
and translation. Alternative splicing is a mechanism where a gene predominantly inactive. These have also been referred to as junk
can code for more than one protein or at varying rates. DNA, but have some uncertain regulatory role.
STRUCTURE AND ORGANISATION OF THE HUMAN GENOME Tandem repeats
The ‘human genome’ refers to the total genetic information The non-coding DNA may occur in tandem repeats or may be
in human cells. In simple terms, genome refers to the entire interspersed in the genome. Satellite DNA is clustered around
DNA content of the cell. It consists of the larger nuclear the centromeres of certain chromosomes and contains very
genome (3x109 bp) and the very small mitochondrial genome large series of tandemly repeated sequences that are
(16.6 kb). The nuclear genome encodes bulk of genetic transcriptionally inactive. Mini-satellites consist of repetitive
information, most of which specifies synthesis of proteins of sequences found at the telomeres of chromosomes. Highly
the body. Mitochondrial genome encodes its own transfer polymorphic short tandem repeats of core units made up of
RNA, ribosomal RNA and few of its own polypeptides. 10-100 base pairs are used in DNA fingerprinting. Micro-satellite
Nuclear Genes DNA consists of tandem repeats of 1-4 base pair sequences
located throughout the genome.
It is estimated that there are about 23,000 genes in the entire
nuclear genome. The size of the genes varies greatly, with small Highly repeated interspersed repetitive DNA
genes comprising of one to three exons (e.g. beta globin gene) Approximately one-third of the human genome is made up of two
and large genes with up to 79 exons (dystrophin gene, ~2.5 Mb). main classes of short and long repetitive DNA sequences that are
Unique single-copy genes are present in single copy (in the interspersed throughout the human genome. These include
haploid set of chromosomes). These encode the polypeptides several lakhs of copies of short interspersed nuclear elements
that are involved in a wide variety of cellular functions: enzymes, (SINEs) and the long interspersed nuclear elements (LINEs).
receptors, regulators, etc. Some others are members of Mitochondrial DNA
multigene families. These arise through gene duplication events
during evolution.These may be found in physically close clusters Mitochondria contain their own 16.6 kb circular DNA (mtDNA).
like alpha and beta globin genes on chromosome 16 and 11, It encodes for 37 genes including 2 for ribosomal RNA, 22 for
respectively or dispersed throughout the genome like the transfer RNA and 13 for polypeptide sequences. It may be noted
HOX gene family, which are important developmental genes. that most of the protein component of mitochondria are
The genes which encode the ribosomal RNAs are clustered product of nuclear genes.
as tandem arrays at the short arms of the acrocentric
DNA CLONING
chromosomes and those encoding the transfer RNAs occur in
numerous clusters throughout the genome. These constitute Cloning refers to selective amplification of a specific DNA
classic gene families. Genes encoding the human leukocyte fragment of interest to produce it in a large quantity for further
antigens (HLA) and the T-cell receptor genes belong to the analysis. This can be done by either one cell based in vivo
immunoglobulin gene superfamily. Pseuodogenes closely amplification, or via polymerase chain reaction in vitro. 203
 To clone a segment of DNA, the first step is to generate DNA generation to generation, whereas a somatic mutation (that can
fragments. This can be done by various methods, the most lead to cancer) is confined to somatic cells.
popular being digestion with restriction enzymes that cleave
Mutations in individual genes are classified on basis of sequence
the DNA into fragments at recognition sites specific to the
change and its consequence on protein product and its function.
enzyme. Enzymes that produce staggered (sticky) ends are used
Substitution refers to replacement of a single nucleotide by
for DNA cloning. Next, a suitable vector (plasmid, bacteriophage,
another, and is the most common type of mutation. Transition
cosmid, bacterial or yeast artificial chromosome) is also digested
refers to substitution of the same type of nucleotide (i.e. purine
with the same restriction enzyme. The sticky ends of the DNA
by purine, or pyrimidine by pyrimidine nucleotide). The reverse
fragment and the DNA of the vector are attached by the enzyme
is transversion. Substitutions can result in a synonymous change
DNA ligase to generate a recombinant DNA molecule. The
(silent, with same amino acid retained in the protein product), or
recombinant vector is then introduced into especially modified
a non-synonymous change of amino acid. Non-synonymous
bacterial or yeast host cell that gets transformed. When the
mutations are missense when the altered amino acid affects
host cell multiplies, large quantities of DNA of interest or clones
protein function or stability, and nonsense when it leads to
are also synthesised. The transfected cells are then screened creation of a stop codon. A substitution may also affect the splice
for antibiotic resistance or sensitivity genes incorporated in the site leading to aberrant splicing of mRNA, or the promoter that
transforming vector or for the product of gene of interest. leads to altered gene expression.
Specific clones containing the desired DNA inserts are then
selected and cultured separately. This clone serves as the source Deletions involve the loss of one or more nucleotides. If it occurs
of amplified DNA fragment of interest for further analysis. in the coding sequence, it may disrupt the reading frame (frame
shift mutation), unless the deletion affects nucleotides that are
DNA Libraries a multiple of three (in frame). Larger deletions involving a part
DNA libraries contain a large number of clones representing or whole of the gene also occur.
entire repertoire of DNA/RNA derived from a given source. When
whole DNA from nucleated cell is used as the source, the Insertion refers to addition of one or more nucleotides into a gene.
resultant product is called genomic DNA library. It may also be Depending on the number of nucleotides inserted, the mutation
chromosome specific library if clones are prepared from sorted may cause a shift in the reading frame. Expansion of triplet repeats
is a form of insertion. It is described elsewhere in this section.
chromosomes. When mRNA is used to synthesise the DNA
(complementary DNA (cDNAJ) and library is created from it, it Substitution, insertion and deletion may affect the splice site,
is termed cDNA library. The cDNA library contains DNA either by activating a cryptic splice site or by abolition of a
sequences that are copies of transcribed mRNA. Specific clones regular splice site. This may result in exon skipping, retention of
from the library may be used for different purposes. intronic sequences and frame shift.
VARIATIONS IN HUMAN GENOME Functionally, a mutation can lead to loss of function of a protein
Humans display a remarkable degree of genetic variation. The [deletion of dystrophin gene (some exons) in Duchenne muscular
dystrophy], haploinsufficiency (50% of the protein product
most obvious traits include height, blood pressure and skin
is insufficient for normal cellular function as in familial
colour. This also encompasses variation in disease traits and
hypercholesterolaemia) or gain of function (as in achondroplasia),
susceptibility to diseases, etc. Even though the sequence of
or rarely a dominant-negative effect where product of mutant
human nuclear DNA is 99.9% similar between any 2 individuals;
gene in heterozygous state results in loss of activity of normal
only 0.1% is sufficient for no. 2 individual to be alike.
gene product of the corresponding allele as well.
Mutations and Polymorphism
Single Nucleotide Polymorphisms
Genetic variations originate from ‘mutation’ that is defined as
a change in DNA sequence that is heritable. As a result of Single nucleotide polymorphisms (SNPs, also pronounced as
mutations, DNA sequences and genes may vary from person- SNIPS) refer to single base differences in the DNA sequence,
to-person. Different sequences on a particular location (locus) found throughout the human genome with a frequency of
of the chromosome are referred to as alleles. A homozygote about 1 per 1000 bp, in more than 1% of the population. These
are mostly biallelic and occur in both coding and non-coding
has the same allele on both members of a chromosome pair,
regions of the genome. It is easy, fast and inexpensive to assay
but alleles differ in a heterozygote. The genotype refers to the
SNPs, and many sites can be assayed simultaneously and
alleles present at a given locus.
automated. They are almost always found near the genes
If a locus has 2 or more alleles where the frequency of minor allele of interest. Combination of SNPs can be used to construct
exceeds 1% in population, the locus is said to be polymorphic. haplotypes, or SNP profiles which serve as powerful tools to
Usually such alleles do not produce significant phenotypic effect study linkage, genetic predisposition to multifactorial diseases,
(i.e. these are neutral in effect), but are presumed to be selected/ detection of submicroscopic chromosomal imbalances,
maintained in the population.These can serve as a useful genetic pharmacogenetics, etc. More recently SNP microarrays have
marker. been extensively used for genome wide association studies.
Types of Mutations Copy Number Variations
The variations in the human genome may be at the genomic Being diploid, humans have two copies for any particular
level as in aneuploidy, chromosomal level as in translocations, segment of DNA. However, in some areas, the number of copies
or at the gene level as in point mutations. A germline mutation of the particular segment varies between two human genomes
204 affects cells that produce gametes and is transmitted from (of two individuals). This phenomenon has now been termed
 Molecular Genetics, Human Genome Project and Genomic Medicine
copy number variation (CNV) and more and more such copy to methods suitable for study of functions of different genes
number variants are being uncovered by the use of array identified in the genome. Functional genomics aims to study
comparative genomic hybridisation technique that is being functions of a gene at biochemical, cellular and organismal level,
used widely. A CNV may vary in size from 1 kb to several mega including gene-gene interactions and gene-environmental
bases and can occur anywhere in the genome. Usually they interactions. The approach also takes into consideration the
result from deletion-duplication events and are heritable. It is role of conserved genes in model organisms and human
estimated that approximately 0.4% of the genome of unrelated homologues. Transgenic (those which carry the gene of interest)
people typically differs with respect to copy number. Like any and knock-out (where the gene of interest is absent or mutated)
other genetic variation, CNVs have been found to be associated models provide invaluable insight into function of genes.
with disease susceptibility and resistance. CNVs encompass Transcriptomics (study of total mRNA transcript of the cell)
more DNA than SNPs. CNVs can be limited to a single gene or provides more scope for linking genes and their products into
include contiguous set of genes. CNVs can result in having either functional pathways and networks. Expression pattern also
too many or too few of the dosage sensitive genes, which may reveals how changes in gene expression coordinate the
be responsible for substantial amount of human phenotypic biochemical activities of the cell in health and disease.
variability, complex behavioural traits, and disease susceptibility. Development of microarray technology has provided useful
It is often difficult to determine whether a particular CNV that means to study expression of thousands of genes at a time. The
is uncovered in a chromosomal array is pathogenic or not. field of proteomics encompasses the analysis of protein
A CNV that arose de novo in an individual with abnormal expression, protein structure and protein interactions to
phenotype is likely to be pathogenic whereas a CNV that is understand the functions and interactions of genes.
inherited from an asymptomatic parent or a CNV that is found Metabolomics refers to the study of metabolites and metabolic
in other unaffected individual is likely to be a polymorphism. networks (pathways).

HUMAN GENOME PROJECT GENOMIC MEDICINE

It has been one of the most ambitious undertakings in the Each person has a unique genome, except for monozygotic
history of biomedical research. The Human Genome Project twins, and hence different phenotype (physical traits). Its needs
(HGP) began in 1991 and produced the first draft sequence of and responses with respect to nutrition, disease susceptibility,
the human genome by 2001, well ahead of its scheduled date preventive care, disease phenotype, complications, treatment,
of completion. A completed, highly accurate sequence was response to drugs, are likely to be unique. All physicians will
unveiled in 2003. The entire data is now available in the public soon need to understand the concept of genetic variability, its
interactions with the environment, and its implications for
domain. In addition to sequencing of the entire human genome,
patient care. With sequence of the human genome now
the project had set several other objectives and areas of work
available and technology making it possible to sequence the
as well: human gene maps and mapping of human inherited
whole genome of any individual, the practice of medicine will
diseases, maps of model organisms, development of new DNA
enter into a new era in which an individual patient’s genome
technologies, development of bioinformatics, comparative
will help determine the optimal approach to care, be it
genomics and functional genomics. The project also had an
preventive, diagnostic, or therapeutic.
ethical component to look into various issues arising out of
genome research. The project has provided a map of genetic With rapid progress in technologies to unravel the genome,
markers using many thousands of polymorphisms (variations) proteome and even metabolome, there is a paradigm shift in the
distributed throughout the genome. Additionally, more than 4 research focus from disease causing genes to modifier genes,
million SNPs have been identified in the human genome. structure to function, aetiology to pathogenesis, and disease
In addition to the human genome, genomes of several other diagnosis to susceptibility recognition. Though stem cell therapy
organisms like Escherichia coli, Haemophilus influenzae, and gene therapy still remain a dream despite over two decades
Saccharomyces cerevisiae (yeast), Caenorhabditis elegans, of research, we are likely to see major discoveries demystifying
Drosophila melanogaster (fruit fly), mouse, rat, and zebra fish human health and disease at an astonishing pace in the coming
have also been sequenced. The genes in these organisms show years. All the monogenic disorders and the underlying defects
significant homology to genes in humans and provide an will be characterised enabling molecular diagnosis of all and
prenatal diagnosis whenever indicated. This will open up new
opportunity to study candidate genes for human diseases
treatment options based on innovative strategies. Predictive
(comparative genomics). These model organisms are also
testing is already possible for some disorders and the number is
invaluable tools to study expression of genes and function of
likely to increase in case of multifactorial diseases. The ultimate
their protein products in normal development as well as their
aim of understanding the human genome is to offer genomic
dysfunction in inherited disorders. Developments in molecular
medicine where the genetic make-up of an individual paves the
techniques and computational abilities have made gene
way for a healthy lifestyle, prevention of disease, and optimal
mapping easier and faster. But it has also thrown many ethical,
treatment of medical conditions. Simultaneously, progress in the
legal and social challenges. Completion of HGP project
medical field, in all likelihood will increase the debate on social
represents the beginning of an era of scientifically exciting, but
and ethical issues involved.
socially complex, biomedical research and molecular medicine.
RECOMMENDED READINGS
POST-GENOMIC ERA OF ‘OMICS’
1. Collins FS, McKusick VA. Implications of the human genome project for
The major goal of HGP was to provide entire structure of human medical science. JAMA. 2001; 285: 540-4.
genome (structural genomics). But this is of limited use without 2. Guttmacher AE, Collins FS. Genomic medicine—a primer. N Engl J Med. 2002;
205
knowing function of the genome. The emphasis has now shifted 347: 1512-20.
 6.7 Gene Therapy

Rita Mulherkar

INTRODUCTION therapeutic gene is selected, the sequences which regulate

There are more than 3000 genetic disorders caused by single expression of the gene, i.e. the promoter sequences also need
gene defects. In addition, there are many other multifactorial to be selected. A tissue-specific promoter would regulate
disorders where genetic variation plays a significant role in expression of the therapeutic gene in that particular tissue.
the aetiology of the disease. The strategies of conventional A ubiquitous promoter, on the other hand, would express
treatment for genetic disorders often require life-long the gene in most tissues, e.g. a viral promoter such as
treatment and are expensive. Besides, for many disorders there cytomegalovirus (CMV) promoter. The choice of vector is
is nothing to offer. The possibility of curing the genetic disorder equally important. Most efficient vectors are viral vectors which
by replacing the defective gene or repairing the mutation in- are modified in the lab to become non-pathogenic. Viruses have
situ appears to be much more logical. Recent advances in evolved over a period of time to efficiently utilise the cellular
molecular biology have made gene therapy an achievable goal. machinery for its own advantage and make numerous copies
of itself in the cell. Thus a gene cloned in a viral vector also
Gene therapy, as yet, is an experimental modality of treatment replicates itself along with the virus and either gets integrated
where a functional gene is introduced into a cell to take over in the host genome or remains in the nucleus as an episomal
the function of the defective gene. The first gene therapy trial body. Adenoviral and adeno-associated virus vectors have been
in humans was approved in 1989. Since then more than 1500 the most widely used vectors in clinical trials so far.
trials in various conditions have been carried out. These studies
have provided the ‘proof of principle’ but safe and effective gene IN VIVO AND EX VIVO DELIVERY OF A THERAPEUTIC GENE
therapy for genetic disorders is still a long way to go. In addition The therapeutic gene along with its regulatory sequences can
to monogenic disorders, clinical trials using gene therapy are be introduced into the patient either directly as naked
also being carried out for disorders like cardiovascular disease, deoxyribonucleic acid (DNA) or through a vector, which is
diabetes mellitus, cancer and infectious diseases like human injected intramuscularly or systemically. This is known as in vivo
immunodeficiency virus (HIV). gene delivery. On the other hand, the therapeutic gene can be
Gene therapy can be carried out to correct the genetic defect introduced into cells removed from patient’s body and
in a fertilised egg (Germline Gene Therapy), or in somatic cells manipulated in vitro before injecting them back into the
(Somatic Gene Therapy). Due to fear of possible adverse effect humans. This is called as ex vivo gene delivery. In ex vivo gene
on future generations and other social, ethical and legal issues, delivery, there is scope for selectively expanding the cells
germline gene therapy is not permitted in any country at carrying the transgene, and carry-out quality assurance
present. For somatic gene therapy, special guidelines for clinical procedures before administering it to the patient. Stem cells,
trial protocols and permission of ethics committee and other because of their capacity to survive indefinitely, are good
regulatory bodies of the country may be essential. candidates for ex vivo gene therapy.
Methods of Gene Delivery
REQUIREMENTS FOR GENE THERAPY
Techniques for gene (DNA) delivery into cells in culture have
The prerequisites of successful human gene therapy (HGT),
been the crux of success of recombinant (DNA) technology.
include selecting a therapeutically suitable gene (with a proven
Various chemical and physical methods have been used to
role in the pathophysiology of the disease), appropriate gene
introduce DNA into cells in vitro, the process being called
delivery system (e.g. viral and non-viral vectors to transfer the
transfection of cells. The cheapest and most widely used
gene into the cells), efficacy and safety studies in appropriate
method in the laboratory is transfection via calcium phosphate
animal models, and suitable manufacturing and analytical
precipitation where DNA is trapped in a fine precipitate and
processes to produce well-defined HGT products for clinical
layered onto cells in culture. The DNA enters the cell via
investigations. It is only after successful pre-clinical trials for
endocytosis. Other chemical methods include the use of
gene therapy in cell culture and animal models, that the
cationic (positively charged) molecules, such as liposomes,
therapeutic gene be tested in clinical trials.
which bind both to the negatively charged DNA on one hand
In monogenic disorders, addition of the wild type gene has and the negatively charged cell membrane on the other,
shown some promise in several clinical trials. The first successful thereby, facilitating DNA entry into the cell. Physical method,
gene therapy trial for severe combined immunodeficiency such as electroporation, is another commonly used method for
syndrome (SCID) due to adenosine deaminase (ADA) deficiency introducing DNA into cells in culture. It is a technique where
was carried out in 1990. In this disorder, the wild type ADA gene cells are mixed with the DNA construct and then briefly exposed
was introduced in T-cells of the patient and the transduced cells to pulses of high electrical voltage. This creates transient,
were transferred back to the patient. This resulted in dramatic reversible pores on the cell surface allowing foreign DNA to
improvement in immune competence of the patient, so enter the host cell. However, the most efficient method for DNA
206 much so that she could attend the normal school. Once the delivery is the use of viral vectors. These include retroviruses,
 Gene Therapy
such as Moloney murine leukaemia virus and adenoviruses short hairpin RNA, (shRNA) which is made synthetically and
which are the common cold viruses. Some important properties introduced into cells, like DNA, for gene therapy. The sequence
desired of an ideal vector are as follows: (a) should protect and of the dsRNA molecule is the same as the sequence of the
deliver DNA into the cell without any alteration, (b) transit easily RNA that is targeted to be destroyed. This approach could be
through cell membrane and from cytoplasm to nucleus, (c) of great benefit in diseases such as cancer, where proteins
persist in host cell nucleus, (d) be non-toxic (non-pathogenic, if known to play a role in cell proliferation and anti-apoptosis
viral) and non-immunogenic, and (e) be easy to produce in large can be manipulated by this technique. Also, knocking down
quantities. of the genes which confer resistance to chemotherapy/
radiotherapy could sensitise tumour cells to treatment.
Depending on tropism, selected retroviruses can infect all
Numerous trials blocking gene expression at RNA level are in
dividing mammalian cells. They carry ribonucleic acid (RNA) as
progress and have shown promise.
their genome which is converted to cDNA by the enzyme
reverse transcriptase inside the infected cell. The cDNA of the Gene Therapy for SCID
virus along with the therapeutic gene, under appropriate In 1990, the first genetic disorder to be treated by gene therapy
regulatory sequences, gets incorporated in the host genome. was ADA-SCID. The ADA mini gene was transferred by retroviral
Thereafter, the virus uses the host cellular machinery to make vector ex-vivo into peripheral blood lymphocytes from
the therapeutic gene product. Adenoviruses, on the other hand, 2 patients undergoing enzyme replacement therapy. Long-
are DNA viruses; they enter the cell via membrane receptors term survival of transfected T- and B-lymphocytes, marrow cells,
and remain episomal (unintegrated in the host DNA) in the and granulocytes expressing the transferred ADA gene was
nucleus.The transduction efficiency (infectivity) of adenoviruses demonstrated and resulted in restoration of cellular and
is much greater than that of retroviruses in human tissues. They humoral immunity. Although the haemopoietic stem cell would
also have the advantage of transfecting non-dividing cells. But have been the ideal target cell for somatic cell gene therapy of
they are immunogenic and do not last for long. Recently, vectors the haematopoietic system, the use of T-lymphocytes as gene
based on HIV lentivirus are being tested as they are the most therapy vehicle was chosen since they represent the affected
efficient vectors. Viruses are made non-pathogenic by removing cells and known to be long survivors. Subsequently, 8 out of 10
some structural genes from its genome. children with ADA deficiency have been successfully treated
following infusion of autologous CD34+ cells transduced with
STRATEGIES FOR GENE THERAPY the ADA gene.
Gene therapy strategy for different diseases varies depending
More recently children with X-linked SCID have shown almost
on the genetic information available for a particular disease.
complete reconstitution of their immune system after receiving
Various strategies employed for gene therapy are described
retrovirally transduced autologous CD34+ haematopoietic stem
below.
cells carrying a functional gamma chain of multiple cytokine
Gene Augmentation Therapy receptor genes. These children are able to lead a normal life, have
For a disease caused by a mutation leading to loss of function, responded to several childhood immunisations and have shown
introduction of a functional copy of the gene into the patient’s good antibody response to infections. However, five of the 20
cells will restore normal function of the cell. However, sustained, treated children subsequently developed a leukaemia-like
long-term expression of the therapeutic gene in an adequate disease after 3.5 years, probably due to the undesired activation
and regulated amount is a major problem. For diseases like of an oncogene by retroviral integration in the host genome.
severe combined immunodeficiency syndrome (SCID) due to Gene Therapy for Lysosomal Storage Disorders
adenosine deaminase deficiency, and haemophilias, expression Gene therapy is an attractive alternative in many lysosomal
of even a small amount of protein is sufficient to ameliorate storage disorder patients who have responded poorly to bone
the symptoms. Such diseases are good candidates for gene marrow transplantation or enzyme replacement therapy. The
therapy. primary goal is to introduce a normal copy of the gene for the
Targeted Mutation Correction lysosomal enzyme into a depot organ such as liver or muscle,
If a mutated gene produces a defective protein which by itself so that there is sustained production and reconstitution of
has the harmful effect, i.e. dominant negative effect, then the therapeutic levels of the enzyme in the affected tissues. A
mutation has to be repaired. In this situation, introduction of a mouse model of Gaucher disease has been developed. In this
normal copy of the gene will not be effective. For this purpose, model, chemically induced deficiency of glucocerebrosidase
a normal copy of the gene is required to be targeted to the (GC) is created which results in accumulation of elevated levels
same location as the defective gene by homologous of glucosylceramide (GL-1) in lysosomes of Kupffer cells. When
recombination. This approach has not yet been possible, these animals were administered mannose-terminated GC
although much research is continuing in this area. (cerezyme) there was reduction of GL-1 levels in liver. Gene
transduction of hepatocytes with a plasmid DNA vector
RNA Interference (RNAi) for Inhibiting Gene Expression encoding human GC (pGZB-GC) achieved similar results. Based
RNA interference is the technology by which expression of on pre-clinical studies, clinical trials are being carried-out where
the gene can be inhibited, so that the protein it codes for is gene coding for GC is transferred to the haematopoietic cells.
not made. The system depends on introduction of double- In one of the clinical trials, the GC gene was targeted via
stranded RNA (dsRNA) inside the cell which activates a cascade retroviral vector to CD34+ progenitor cells. Preliminary results
of events leading to destruction of the specific RNA molecule. indicate engraftment of genetically corrected cells in the
The dsRNA may be in the form of silencing RNA (siRNA) or patient. Further results are awaited. 207
 GENE THERAPY IN CANCER the bench.This has also served as an impetus to improve vectors
The largest number of gene therapy trials have been done in and lay greater emphasis on in situ gene correction. Successes
patients with cancer (about 65%). It may be not only because continue to be achieved in experimental models. Recently, it
cancer is a genetic disease at somatic cell level, but more so out has been possible to cure sickle-cell disease in an experimental
of desperation. Several approaches have been tried for this animal using transduced induced pleuripotent stem cells. The
purpose, viz. (a) introduction of a gene to convert a prodrug to unbridled enthusiasm of the nineties has given way to more
active cytocidal drug in tumour cells causing selective tumour sober and more realistic expectations. So far the promise
cell destruction, (b) introduction of a multidrug resistant (MDR) continues and the efforts are on. The success in treating SCID,
gene in normal bone marrow cells to protect them from and understanding the molecular basis of leukaemogenesis
toxic effects of chemotherapy, (c) introduction of genes for indicates that the dream may still come true.
enhancing antitumour immune responses, and (d) introduction
of tumour suppressor gene, such as p53, mutation of which is RECOMMENDED READINGS
related to several cancers. The latter therapy has even been 1. Agarwal SS. Gene therapy: how close to clinical reality? Natl Med J India.
2009; 22: 1-4.
approved in China for the treatment of head and neck cancer.
2. China offers alternative gateway for experimental drugs. Nature Biotech.
2006; 24: 117-8.
FUTURE OF GENE THERAPY
3. http://www.wiley.co.uk/genmed/clinical/ This site gives the current status
So far four patients have died related to gene therapy. In of ongoing gene therapy clinical trials.
addition, the occurrence of leukaemia in successfully treated 4. Mulherkar R. Gene therapy for cancer. Curr Sci. 2001; 81: 101-5.
children with X-SCID has been a big dampner. Generally, 5. Ratko TA, Cummings JP, Blebea J; et al. Clinical gene therapy for non-
reaction of the scientific community has been to go back to malignant disease. Am J Med. 2003; 115: 560-9.

208
 6.8 Genetic Counselling and Prenatal Diagnosis

Shubha R Phadke

For most of the genetic disorders there is no curative INDICATIONS FOR GENETIC COUNSELLING
treatment at present, or the treatment is cumbersome, costly The following clinical presentations indicate the need for
and associated with risks. Also, many genetic disorders are referral to a clinical geneticist and genetic counselling:
associated with decreased life expectancy, and mental or
1. Congenital malformation: Lethal or non-lethal, isolated or
physical handicap. Due to these reasons, families with a genetic
multiple, prenatal or postnatal.
disorder or those at risk of having an offspring with a genetic
disorder, need information about the disease to help them 2. Still births/perinatal deaths with or without malformation.
cope with the problem and ways to prevent the occurrence or 3. Developmental delay or mental retardation with or without
recurrence of the disorder. The process of communication of malformations, facial dysmorphism and/or neurological
this information is genetic counselling. It is aimed to answer deficit.
the questions of the family, viz. ‘Why did this happen to me?”, 4. Neurodegenerative diseases presenting as focal neuro-
and “Will it recur in my family?’ As genetic disorders can involve logical deficit, ataxia, spasticity, hypotonia, seizures or
any system of the body, it is important that clinicians in psychomotor regression.
all specialities are able to identify clinical presentations 5. Mypopathies and muscular dystrophies.
which are due to, or can possibly be due to, genetic disorders, 6. A neonate or an infant with acute sickness, or failure to
counsel them and refer them to a geneticist for appropriate thrive or has recurrent episodes of vomiting, acidosis and/
investigations and advice where available. In this chapter the or convulsions.
importance of genetic counselling in the management of
genetic disorders is stressed and basic principles of genetic 7. Ambiguous genitalia or abnormalities of sexual
counselling are discussed. development like primary amenorrhoea and delayed
puberty.
DEFINITION OF GENETIC COUNSELLING 8. Infertility and poor obstetric history like recurrent
spontaneous abortions and foetal losses.
The American Society of Human Genetics defined genetic
9. Proportionate or disproportionate short stature.
counselling as ‘a communicative process which deals with
human problems associated with the occurrence and/or 10. Childhood deafness.
recurrence of a genetic disorder in a family’. This process 11. Known monogenic disorders like thalassaemia, Wilson
involves an attempt by one or more appropriately trained disease, haemophilia A, mucopolysaccharidosis, etc.
persons to help an individual or a family to: (i) comprehend 12. Down's Syndrome and other chromosomal disorders.
the medical facts, including the diagnosis, probable course of 13. Familial cancers or cancer prone disorders.
the disorder and available management; (ii) understand the 14. Relatives of an individual having a structural abnormality
manner in which heredity contributes to the disorder, and the of a chromosome or chromosomes.
risk of recurrence in the family; (iii) understand the alternatives
15. Any unusual disease of the skin, eyes, bones or unusual
for dealing with the risk of occurrence or recurrence; (iv)
facial features.
choose a course of action which seems to them appropriate
in view of this risk, their family goals, ethical and religious 16. Any disease which is familial.
standards and to act in accordance with the decision; and (v) 17. Exposure to a known or possible teratogen during
make the best possible adjustment to the disorder in an pregnancy.
affected family member and/or to the risk of recurrence of 18. Consanguineous marriage.
that disorder. 19. Advanced maternal age.
It is clear from the above definition that the primary goal of the 20. Carrier of a genetic disorder.
genetic counselling is to educate the concerned persons about 21. Positive screening test for a genetic disorder.
the medical aspects of the genetic disorder in their family. The
family can use the information in a meaningful way to cope STEPS IN GENETIC COUNSELLING
with the disorder and the risk of recurrence in accordance with The process of genetic counselling is quite complex. It requires
their psychosocial and religious background. correct diagnosis and latest information about medical and
A person who seeks genetic counselling is called consultand genetic aspects of the disorder. The steps of genetic counselling
or ‘counsellee’, and the person who gives the advice is called are as follows:
the counsellor. In association with a medical specialist, persons 1. Accurate diagnosis of the proband
with various backgrounds such as nursing, sociology, (a) History taking
psychology or genetics can be trained as genetic counsellor. (b) Pedigree drawing
209
 (c) Clinical examination such a child is 1%. Four per cent of Down's Syndrome cases are
(d) Biochemical, haematological, imaging and other because of translocation of chromosome 21 to 14, 15, 21 or 22
necessary investigations. (Figure 2). Karyotypes of both parents of such a case are essential.
2. Chromosomal or DNA tests, as needed. The risk of recurrence varies depending on the chromosome
involved and sex of the carrier parent (Table 1). The karyotyping
3. Latest information about pathophysiology of the disease,
of parents of a child with free trisomy 21 is not indicated.
available treatment, risk of recurrence, and availability of
prenatal diagnostic test.
4. Communicating the information in simple, layman’s
language to the consultand and family members concerned.
5. Giving the consult and a written or typed case summary
which includes the case details, diagnosis and details of
genetic counselling.
6. Follow-up sessions may be needed to support the family,
communicate new information, and observe any
progression of the disease in the proband.
In addition to accurate diagnosis, consideration of many other
issues like psychosocial, religious, educational and ethical are of
paramount importance for effective genetic counselling. Success
of genetic counselling depends on whether the consultand feels
Figure 2: Partial karyotypes showing balanced translocation between
benefited by genetic counselling or not. Hence, it is important
chromosomes 14 and 21.
to assess the expectations of the consultand and to tailor the
counselling accordingly, keeping in mind the psychosocial,
Table 1: Risk of Recurrence of Down’s Syndrome in the Offspring
religious and educational backgrounds of the consultand.
of a Parent with a Balanced Translocation
Genetic counselling for some common genetic disorders is Translocation Carrier Father Carrier Mother
discussed below. This is to illustrate the principles of genetic
counselling and various issues involved in the process. t(14; 21) 1% to 5% 15%
t(21; 22) 1% to 5% 15%
CASE-I t(21; 21) 100% 100%

Down’s Syndrome: A Common Chromosomal Syndrome and Genetic counselling

the Commonest Genetic Cause of Mental Retardation
The challenge in this case is to break the news of the
A 3-month-old infant was brought to the clinic with rapid breathing, diagnosis of Down’s syndrome to the parents. Further, the
feeding difficulty and excessive crying. The child had a pansystolic parents are to be advised regarding the need for surgical
murmur in the left parasternal region and typical facial features treatment of the cardiac defect, and associated problem of
like flat face, hypertelorism, upslant of eyes and Simian crease on mental sub-normality and developmental delay which would
both hands. The diagnosis was Down’s syndrome with ventricular become more pronounced as the child grows. Realistic
septal defect with congestive cardiac failure. information about mental abilities is essential. Though the
In addition to echocardiography and treatment of cardiac failure, intelligent quotient (IQ) of Down’s syndrome cases varies
the karyotype from blood was recommended. Karyotype is from 40 to 70 or more, most of the cases with Down’s
needed not only to confirm the diagnosis of Down’s syndrome syndrome are moderately retarded. Though late, they learn
but also to know the type of chromosomal abnormality. Ninety- to walk, talk, carry-out self-care activities, and can also be
five per cent of Down’s syndrome cases are due to free trisomy taught to do simple repetitive tasks. They can work in a
21 (47,+21) (Figure 1), and the risk of recurrence in siblings of supervised and sheltered workplace. They can lead a loving,
useful and happy life but need lifelong super vision.
Importance of regular surveillance for hypothyroidism and
hearing and ophthalmological problems needs to be
stressed, but increased risk of leukaemia and atlanto-axial
dislocation need not be told in the first visit as the risk of
these conditions is very small. Risk of recurrence of Down’s
syndrome in any subsequent pregnancy should be discussed
after the karyotype report is available. Prenatal diagnosis in
the next pregnancy can prevent recurrence and the family
should be provided the information before planning the next
pregnancy.
Messages
1. The diagnosis of Down’s syndrome is obvious at birth and
should be communicated to the family soon after birth.This
Figure 1: Karyotype showing free trisomy 21.
210 helps in screening for major malformations immediately
 Genetic Counselling and Prenatal Diagnosis
after birth and timely treatment. Of course giving the bad of isolated neural tube defect in the next pregnancy after the
news of the birth of a child with mental sub-normality to birth of one affected child is 5% and can be reduced by intake
the family, happy with the childbirth and an apparently of folic acid by the mother during periconceptional period. If
normal looking neonate is a challenge to the paediatrician the meningocoele/meningomyelocoele is a part of a multiple
and obstetrician. malformation syndrome like spondylothoracic dysplasia or
2. Chromosomal analysis of all children with Down’s Meckel-Gruber syndrome then the risk of recurrence is 25%.
syndrome is important to provide the risk of recurrence and Accurate diagnosis is also important to provide prenatal
prenatal diagnosis. diagnosis during the next pregnancy which can be done
ultrasonographically, as early as at 14 weeks. One USG at 16 to
3. Prenatal diagnosis of Down’s syndrome is possible by doing
18 weeks by an ultrasonographer with specialisation in prenatal
karyotype analysis from chorionic villi or an amniotic fluid
diagnosis will be able to detect open neural tube defect with
sample.
almost 100% sensitivity.
4. The primary care physician or a paediatrician can take up
the responsibility of providing regular follow-up needed Messages
for children with Down’s syndrome. This includes clinical 1. One routine USG examination should be offered at 16 to 18
examination for associated abnormalities, investigations weeks of gestation for prenatal diagnosis of malformations.
for iron deficiency anaemia, hypothyroidism and
ophthalmologic and ear examinations. 2. Accurate diagnosis of associated malformations and foetal
chromosomal analysis is important for giving information
CASE-II about prognosis of malformation.
Prenatally Detected Mild Ventriculomegaly at 20 Weeks of 3. The information about possible outcomes of the
Gestation on Routine Ultrasound Examination malformation, especially if the malformation is treatable,
A 32-year-old lady married for 8 years, who conceived after will help the family in deciding about continuation or
treatment for infertility, came for routine ultrasonography (USG) termination of pregnancy.
at 20 weeks of gestation. In the first year of her marriage, she 4. The uncertainties in providing exact outcome in each case
had two spontaneous abortions at 10 weeks of gestation. The should be truthfully shared with the family.
USG showed mild ventriculomegaly. Hence, she was referred
5. The genetic counselling should be non-directive.
for genetic counselling.
Possibilities of good and bad outcomes should be told
The first step of genetic counselling was to get a targeted with their likelihood. Many other factors like presence of
ultrasonographic examination done to look for associated previous normal or similarly affected children, age of
malformations. It showed mild dilatation of the lateral ventricles mother, history of infertility may affect the family’s
of the brain with open spinal defect and a large sac in the decision. In this case, due to long period of infertility and
thoracolumbar region. There was no talipes equinovarus two spontaneous abortions, the family may not take up
deformity or any major malformation of the heart, kidneys, the option of amniocentesis for karyotyping as it is an
abdominal wall, face, etc. invasive procedure and associated with a small risk of
abortion.
Genetic counselling
6. Autopsy of foetuses terminated after prenatal diagnosis
Meningomyelocoele is a major malformation which is often
of malformations is important not only for confirmation
associated with Arnold-Chiari malformation and obstructive
of prenatal diagnosis but also to look for associated
hydrocephalus. These defects are surgically treatable. But in
malformations which may have been missed on USG, or
spite of surgery after birth, many (50% or more) of the operated
may not be detectable on USG. Autopsy may change the
cases may have residual neurological defects including
diagnosis in about 30 to 50% foetuses, hence, essential
paraplegia, bladder-bowel incontinence and cognitive defects
for genetic counselling.
due to ventriculomegaly. In some cases hydrocephalus
progresses rapidly, which may need destructive surgery for large CASE-III
head causing obstructed labour or may lead to stillbirth. The
Pre-pregnancy Counselling for Family History of
mother should be asked about the history of taking teratogenic
Huntington Chorea
drugs like anticonvulsants, and investigated for diabetes
mellitus, as these are common risk factors for neural tube A couple married for 2 years and planning to raise a family came
defect. Though the chance of chromosomal abnormality with for genetic counselling. The husband was 32-year-old and the
isolated neural tube defect is low, prenatal chromosomal wife was 27-year-old. The husband’s brother who is 40-year-
analysis by amniocentesis is recommended for proper old had developed abnormal movements since the last 4 years
counselling. If the family opts to continue the pregnancy regular and was diagnosed to have Huntington chorea. His father died
follow-up USG examination, delivery at a good centre with good at the age of 65 years, who suffered from similar problems for
neonatal facilities, consultation with a paediatric surgeon or a 10 years and had become bed-ridden. The couple wanted to
neurosurgeon needs to be arranged. know whether their child could have the same disease and
whether it could be avoided.
If the family opts for termination of pregnancy, foetal autopsy,
or after delivery detailed clinical and radiological examination Genetic counselling
of the baby is essential for counselling regarding risk of The first step of genetic counselling is to draw a pedigree chart
recurrence in a subsequent pregnancy. The risk of recurrence and confirm the diagnosis. A 3-generation pedigree chart was 211
 drawn which showed that two of the uncles of the consultand 2. The confirmation of diagnosis in the proband or affected
(husband in this case) were similarly affected and one of them member of the family is an important first step before
was seen as an out-patient at the Department of Genetics. The providing genetic counselling.
family was asked to get the medical records of the affected uncle 3. Mutation detection is essential for prenatal diagnosis based
with his permission. The records confirmed the diagnosis of on DNA analysis.
Huntington chorea by a neurologist as well as by DNA-based
mutation analysis. The DNA test showed that the uncle with 4. The counselling should be non-directive and the family
Huntington disease had 44 CAG repeats in HD gene and the should make their own reproductive decisions.
other copy was normal (20 CAG repeats). This confirmed the 5. The genetic counselling involves providing a lot of scientific
presence of mutated HD gene in the family. information and probabilities, which may be a difficult task,
for which very good communication skills are needed to
Now, the question: What is the risk of Huntington disease
be a good genetic counsellor.
mutation in the offspring of the couple? This will depend on
whether the consultand himself is carrying the mutation or 6. The information provided during genetic counselling may
not. As Huntington disease usually manifests after 40 years of be psychologically disturbing and adequate pre-test and
age, many individuals who carry the mutation will be clinically post-test counselling is necessary.
normal at 32 years of age. Hence, it is essential to test the 7. Pre-symptomatic and prenatal diagnosis of late onset
husband’s DNA for HD mutation. If he is not the carrier of the genetic disorders pose a lot of ethical, legal and social
mutation, he will not develop the disease in future and also dilemmas and need to be dealt with sensitivity.
there is no risk of Huntington disease in the offspring of the 8. Pre-pregnancy counselling plays an important role in
couple and prenatal diagnosis is not indicated. But if he is a genetic disorders and is the most appropriate time for
carrier of mutation, then there is 50% chance that the offspring genetic counselling, as it provides time for organising
may inherit the mutated copy of the gene from him and develop investigations, understanding the situation and making
the disease in future. The age of onset of symptoms depends appropriate decisions.
on the number of CAG repeats and the number of repeats may
increase when the mutation is transmitted from one generation CASE-IV
to the next.The individuals with repeats around 80 may develop
Counselling for Familial Breast Cancer
the disease in childhood. The birth of a child with HD mutation
can be avoided by prenatally testing the mutation in chorionic A 28-year-old married woman comes for genetic counselling
villi at 10 to 12 weeks of gestation providing the couple an as her 35-year-old sister is diagnosed to have carcinoma breast
option for reproductive planning. All DNA-based tests have and her mother died of carcinoma breast at the age of 50 years.
some error rate, usually around 1%. Pedigree chart showed that one sister of her mother had
carcinoma of ovary. Her maternal uncle’s wife also had
This opens a lot of issues for the family. First, pre-symptomatic carcinoma breast.
diagnosis in the husband may cause major psychological
problems as there is no treatment for the disease. Also, if this Genetic counselling
information if not kept private and confidential it may cause Presence of three blood relatives with carcinoma breast and
problems at the job, and for medical insurance, etc. Hence, the ovarian carcinoma suggests familial breast cancer. Note that the
couple should be given time before opting for DNA testing. If wife of her maternal uncle is not her blood relative and medical
after adequate counselling and careful deliberation the ailments in her do not influence the risk of genetic disorders
consultand wants to go for a DNA test, then it should be ordered. in the consultand. Such an individual needs to be offered
After the results are available, the couple should be explained surveillance for carcinoma breast and ovaries as early detection
the results, and post-test counselling should be provided. may help in better treatment and improve outcome. This is the
Continued psychological support may be needed. If the case where mutation detection in carcinoma breast related
husband is the carrier of mutation, there is 50% risk of genes, namely, BRCA1 and BRCA2 is indicated. The BRCA1 and
transmitting the mutation to the offspring. Many laboratories BRCA2 account for 50% and 30% of familial breast cancers,
and also families are not comfortable with the idea of respectively. First the mutation has to be tested in one of the
termination of a affected pregnancy as the foetus will not individuals with carcinoma breast (it can be done on the
manifest the disease until 3 to 4 decades. This is ethically operated breast cancer tissue), and if the mutation is detected
debatable, especially with the present pace of developments then DNA testing of the consultand and other probable carriers
in the field of genetics, where new treatments for many genetic in the family (who are more than 18 years of age) needs to be
diseases are expected in the future. After discussing all these discussed. The individuals who have the mutation need to
issues in a non-directive manner, the family may take their be kept under close surveillance for carcinoma breast and
reproductive decision. The whole process may take many ovaries as per accepted guidelines. The confirmed carriers of
sessions to understand difficult scientific information and BRCA gene mutations can be offered even radical measures like
various complexities of the situation. prophylactic mastectomy or oophorectomy.
Messages Messages
1. DNA-based diagnosis is available for many single gene 1. Three or more family members with one type of cancer or
disorders and is useful for diagnosis of patient and prenatal related cancers should alert the clinician for the possibility
diagnosis. of familial cancers and refer the family for genetic counselling.
212
 Genetic Counselling and Prenatal Diagnosis
2. The pointers towards the possibility of familial cancer fertilisation and single cell genetic test which in addition to
include cancer at young age, co-occurrence of multiple being costly is also not easily available.
primary cancers and bilateral cancers in paired organs,
The other treatable causes of recurrent abortion should also
associated clinical features like hyperpigmentation of lips
be simultaneously investigated as more than one cause
(Peutz-Jeghers syndrome), adenomatous polyposis colon,
may coexist. Investigations for toxoplasmosis, rubella and
neurofibromatosis, etc.
cytomegalovirus infections are not indicated as they do not
3. Mutation detection in the individual with the cancer is cause recurrent abortions.
important before the mutation-based screening can be
offered to the unaffected family members. Messages
1. About 5% of the couples with recurrent spontaneous
4. Mutation testing for carcinoma breast and other familial
abortions have one spouse with balanced chromosomal
cancers is technically demanding, costly and not easily
rearrangement.
available. Even if mutation detections not done, continued
surveillance for early diagnosis can be offered to individuals 2. If the karyotype is abnormal, there is no treatment but
with familial cancer. counselling, and prenatal diagnosis is needed.
3. One in 500 normal people have a balanced chromosomal
CASE-V
translocation, and such carriers are usually phenotypically
A Couple with Three Recurrent Spontaneous Abortions normal.
in the First Trimester
4. The individual with balanced translocation is not at any risk
A non-consanguineous couple with three spontaneous of medical ailment due to chromosomal abnormality.
abortions was referred for genetic testing. The chromosomal
analysis from peripheral blood was done for both the spouses. 5. All attempts should be made while counselling such a
The karyotype of the wife showed a balanced translocation couple to protect from blame or guilt in the family.
between chromosomes 7 and 11 (Figure 3). 6. Chromosomal variants, such as long ‘Y’ chromosome,
Genetic counselling pericentric inversion of chromosome 9, etc. are not known
to be associated with recurrent spontaneous abortions.
The balanced translocation in this case is likely to be the cause
of recurrent spontaneous abortions in this case. The gametes CASE-VI
of an individual with a balanced rearrangement may have
A Family with a Two-year-old Child with Metachromatic
unbalanced karyotype and the conceptus with a major
Leukodystrophy
chromosomal imbalance may not be compatible with life and
abort spontaneously. As such individuals also have gametes A couple came with a 2-year-old son who was diagnosed as a
with normal chromosomal complement, or balanced case of cerebral palsy. The mother of the child was 6 weeks
chromosomal complement, so they can have normal offspring pregnant. The family wanted to know the risk of recurrence of
as well. The risk of repeated abortions is about 30% but may a similar problem in the next child.
vary depending on the chromosomes involved and their
The pedigree chart showed that the parents were cousins and
breakpoints. There is no treatment to prevent formation of
their first child had a similar problem and had died at two- and-
unbalanced gametes or to prevent abortion. Some of the
a-half years of age. The proband (the affected child) was
chromosomal imbalances may be small and such foetuses
normally developing till about one year of age and was able to
may not be aborted but may have malformations or a mental
stand without support. Then he lost the milestones, and
handicap. Hence, this couple should be offered prenatal
developed scissoring of lower limbs (Figure 4). There was
karyotyping by amniocentesis if the pregnancy continues
hypertonia of limbs with exaggerated knee reflexes and absent
beyond the first trimester.
ankle reflex. The deterioration continued. Magnetic resonance
The other options are use of donor ova (or sperms, if husband imaging (MRI) brain showed changes indicative of white
is the carrier of a balanced chromosomal rearrangement), matter involvement. The enzyme assay for metachromatic
or preimplantation diagnosis. The latter involves in vitro leukodystrophy showed deficiency of aryl sulphatase A which
confirmed the diagnosis of metachromatic leukodystrophy.

Genetic counselling
Metachromatic leukodystrophy is an autosomal recessive
disorder and the risk of recurrence to a subsequent child of these
parents is 25%, i.e. 1 in 4. The prenatal diagnosis can be carried out
by assaying the enzyme in chorionic villi at 11 weeks of gestation.
If the foetus is found to be deficient in the enzyme, the family can
take an appropriate decision according to their convictions.
If by DNA sequencing of the aryl sulphatase A gene (ARSA)
mutations can be identified in the proband or his parents
then prenatal diagnosis by mutation detection can be done.
Figure 3: A karyotype showing a balanced translocation between chromosomes DNA-based prenatal diagnosis is more accurate than that by
7 and 11. biochemical test (enzyme assay). 213
 variety of tissues can be collected from the foetus for
chromosomal, DNA and biochemical analysis. These include
chorionic villi (11-12 weeks of gestation) and amniotic fluid
(16-20 weeks). Rarely, foetal skin, muscle, liver biopsy or blood
sample may be collected for biochemical or tissue analysis.
Analysis of foetal cells and foetal DNA from mother’s blood has
become technically possible and can be used for foetal Rh typing.
Prenatal diagnosis based on free foetal DNA in mother’s plasma
is used not only for single gene disorders but also for aneuploidy
detection.Preimplantation diagnosis is a good option for families
who do not approve of termination of pregnancy.
High resolution ultrasonography can detect a number of
structural malformations of the central nervous system, gut,
kidneys, limbs, spine and heart. Detection of associated
malformations and chromosomal analysis is useful for providing
counselling in a case with prenatally detected malformation.
But for counselling regarding next pregnancy, examination
of baby or foetus after delivery or termination (foetal autopsy)
is important, because in 30% to 40% cases associated
malformations may be missed or may not be detectable on
ultrasonography.

CONCLUSION
Figure 4: A child with metachromatic leukodystrophy. Note the scissoring of All cases in which a genetic disorder is diagnosed or suspected,
lower limbs.
a complete evaluation of the affected individual and genetic
investigations are important. Genetic counselling is an integral
Messages part of management of a case with genetic disorder. It is the
1. All children with developmental neurological problems responsibility of the primary care physician to suspect cases
should not be labelled as cerebral palsy without evaluation, with a probable genetic disorder and refer them to a clinical
as many genetic disorders may manifest as developmental genetics centre. As the clinical geneticists are few in number,
delay or mental retardation which superficially mimics paediatricians, obstetricians and physicians may have to take
cerebral palsy. up the responsibility of providing diagnosis and counselling
for common genetic disorders.
2. Presence of normal development followed by regression
of milestones is characteristic of metabolic disorders. RECOMMENDED READINGS
3. Presence of consanguinity, or similarly affected 2 or more 1. Burke W. Taking family history seriously. Ann Intern Med. 2005; 143: 388-9.
siblings, suggests the possibility of an autosomal recessive 2. Ensenauer RE, Michels VV, Reinke SS. Genetic testing: practical, ethical, and
disorder. counselling considerations. Mayo Clin Proc. 2005; 80: 63-73.

4. Confirmation of genetic metabolic disorder by enzyme 3. Martin JR, Wilikofsky AS. Integrating genetic counselling into family
medicine. Am Fam Physician. 2005; 72: 2444.
assay of involved metabolic pathway is essential for
4. Mujezinovic F, Alfirevic Z. Procedure-related complications of
diagnosis, genetic counselling and prenatal diagnosis. amniocentesis and chorionic villous sampling: a systematic review. Obstet
Gynecol. 2007; 110: 687-94.
PRENATAL DIAGNOSIS
5. Skotko BG, Capone GT, Kishnani PS. Postnatal diagnosis of Down's
The availability of prenatal diagnosis for a number of genetic Syndrome: synthesis of the evidence on how best to deliver the news.
disorders has made counselling and decision-making easier. A Down's Syndrome Diagnosis Study Group. Pediatrics. 2009; 124: e751-8.

214
 6.9 Pharmacogenomics and
Personalised Medicine
C Adithan

Optimal therapy for major illnesses is still elusive. The drug Further, its activity depends on the enzyme epoxide reductase
therapy of psychiatric illnesses, cancer, hypertension and many complex 1 encoded by the gene VKORC1. Variations in the
other common diseases is associated with unsatisfactory nucleotide sequences of the coding region of these enzymes
response and undesirable adverse effects. Many approaches result in altered metabolism and activity of warfarin. Patients
have been adopted to improve this condition. Among them the with the variant genotypes, such as CYP2C9 *1/*3 and VKORC1
role of genetic factors in drug response is very important. AA have six-times lower dose requirement compared to the
common genotypes of CYP2C9 *1/*1 and VKORC1 GG. The
PHARMACOGENETICS AND PHARMACOGENOMICS United States Food and Drug Administration (US-FDA) has
The action of a drug is regulated by several factors, namely made label changes in warfarin and recommended genetic
drug metabolising enzymes, transporter proteins, receptors testing for these two genes before initiation of warfarin
and several other mediators. These enzymes and proteins are therapy. Based on the genotype of the patient, the dose has
encoded by genes in the deoxyribonucleic acid (DNA). A to be adjusted to an optimum level of international normalised
number of variations have been identified in the structure of ratio (INR).
genes encoding these factors. This can result in varying drug
Anticancer Drugs
responses in each individual depending upon their genetic
make-up. A genetic variation occurring in more than 1% of the Irinotecan, an inhibitor of the enzyme topoisomerase 1 is used
population is termed as genetic polymorphism. The study of as an anticancer agent. It is a pro-drug and gets converted to
the effect of a single gene or genetic polymorphism on drug an active form SN 38 which inactivates topoisomerase 1, and
response is called pharmacogenetics. Study of the effect of thus, inhibits DNA replication. The SN 38 gets inactivate by
variations in multiple genes, including whole genome approach, the process of glucuronidation by the enzyme UGT1A1. This
on drug response is called pharmacogenomics. It is predicted enzyme is encoded by the gene UGT1A1. It was found that
that application of pharmacogenomics in clinical practice may the variant genotype UGT1A1 *28/*28 was associated with
lead to individualised drug therapy (personalised medicine), impaired conjugation, and hence, results in higher plasma
thus, paving the way for improved effectiveness and reduced levels of SN38. This genotype was associated with greater
adverse drug reactions. haematological toxicity. This led to changes in the label of
irinotecan by the US-FDA which also recommended genetic
PERSONALISED MEDICINE testing for patients who are to be started on treatment with
Personalised medicine is the science concerned with providing irinotecan.
medical care tailored to the genomic and molecular profile of Anticancer agents such, as azathioprine and 6-mercaptopurine
an individual patient. The physician selects the drug and its are metabolised by the enzyme thiopurine methyl transferase
dosage using detailed information about the patient including enzyme (TPMT) encoded by the gene TPMT. Individuals with
clinical data, genotype or level of gene expression, drug profile, variant genotype of TPMT have reduced or absent enzyme
as well as genetic details of the causative organism, if any. The resulting in high drug levels and greater myelo-toxicity. It is
important pre-requisites for success of personalised medicine recommended to do a genotype or phenotype test for TPMT
are valid biomarkers and availability of reliable, simple and before starting thiopurine therapy.
affordable genetic tests.
Other drugs where genetic testing is preferred, include
CLINICAL APPLICATIONS trastuzumab, rituximab, imatinib and maraviroc. Trastuzumab,
The clinical practice of personalised medicine has started to a monoclonal antibody targeting the HER2 protein is used in
receive attention with more drugs being discovered using breast cancer patients who are over-expressing HER2/neu
methods of pharmacogenetics. For a drug to be used clinically protein. It is more effective in the treatment of early stage HER2
based on pharmacogenetic data, identification and establish- positive breast cancer patients. Rituximab, a monoclonal
ment of a valid pharmacogenetic biomarker is necessary. Some antibody directed against the CD-20 protein in B-cell
of the drugs for which a valid pharmacogenetic biomarker has lymphocytes is approved for use in B-cell non-Hodgkin
been identified are warfarin, irinotecan, carbamazepine, lymphoma and rheumatoid arthritis. The patients may be tested
abacavir, azathioprine, trastuzumab, imatinib, maraviroc, for expression of CD-20 protein by the B-cells for initiation of
rituximab, omeprazole, and clopidogrel. therapy with rituximab. Imatinib mesylate is used for treatment
of chronic myeloid leukaemia which is associated with
Oral Anticoagulant Drugs the chromosomal abnormality termed as ‘Philadelphia
Warfarin, an oral anticoagulant is used in patients with chromosome’ which produces mutant protein responsible for
cardiovascular disorders. The most common complication of cell proliferation. Imatinib inactivates this overactive protein
warfarin includes bleeding manifestations. It is metabolised BCR-ABL-tyrosine kinase. Thus, testing for this genetic
by the enzyme CYP2C9 encoded by the gene CYP2C9. abnormality is necessary for treatment with imatinib mesylate. 215
 Antiretroviral Drugs yet to be incorporated in clinical practice to a large extent. This
Abacavir, the antiretroviral drug was found to have higher can be attributed to factors, such as increase in cost of therapy
incidence of hypersensitivity reactions associated with patients due to inclusion of pharmacogenetic testing as part of drug
having human leucocyte antigen (HLA)*5701.The development therapy and difficulty in imparting the pharmacogenetic
of high resolution HLA typing enabled identification of patients knowledge to clinicians on a wider scale. Further, availability of
at risk for abacavir hypersensitivity and avoided adverse drug laboratory facilities to do pharmacogenetic tests is necessary
reactions. After the publication of PREDICT1 and SHAPE studies, for the widespread use of pharmacogenetics in clinical practice.
there has been an increased demand for HLA typing tests for Most clinicians prefer to rely on clinical and biochemical
patients with human immunodeficiency virus (HIV) infection. parameters for dose selection and empiric dose titration rather
than testing for genetic make-up of the individual.
Maraviroc, an antiretroviral drug, prevents entry of HIV into the
host cell by binding the CCR5 protein on cell surface. The virus The cost of genotyping could be a major limiting factor in
requires binding to CCR5 protein for cell membrane fusion application of pharmacogenetics on a larger scale in clinical
and entry into host cell. Thus, the entry of CCR5 tropic viruses is practice. One alternative is to do bulk testing. The cost of
inhibited. However, the viruses which are CXCR4 tropic do not genotyping 1000 DNA samples is approximately 0.3 to 0.5 USD
respond to maraviroc and result in dominance of CXCR4 tropic (US Dollors) per genotype compared to 130 USD for testing of
strains. It is recommended to test for tropism of the virus strain a single sample. This difference is due to the fixed price of the
in a patient before initiation of therapy with maraviroc. set-up of assay marker. Hence, patient samples can be analysed
only when collected in large numbers.
Omeprazole and Clopidogrel
Several ethical issues arise with the application of
The proton pump inhibitor omeprazole is metabolised by
pharmacogenetic methods. Categorisation of populations
CYP2C19 enzyme. Patients with variant genotype CYP2C19 *2/*2
based on genotypes may result in exclusion of smaller groups
have markedly reduced metabolism of omeprazole. This has
of people from usage of drugs which are brought into the
been found to result in higher cure rates with anti-Helicobacter
market based on pharmacogenetic tests. Further, revelation of
pylori regimen in such patients. For a patient with similar variant
genetic risk factors for late onset diseases and variation in drug
genotype CYP2C19 *2/*2, the anti-platelet drug clopidogrel can
response for such diseases may have profound psychological
have reduced therapeutic effect due to reduced conversion to
impact on the patient and affect the quality of life. This
its active metabolite by the enzyme CYP2C19. In such patients,
information can also lead to denial or increased cost of
genotyping for CYP2C19 polymorphism would enable selection
insurance policy coverage for such people.
of a suitable alternative anti-platelet drug.
Pharmacogenomics and personalised medicine have many
Stevens-Johnson Syndrome
promising features but there are issues in their application on
Stevens-Johnson syndrome (SJS), a severe form of a larger scale for clinical practice. They can be solved only by
dermatological manifestation of hypersensitivity reaction to further refining of the process involved in it and policy decision
drugs, was found to occur with the anti-epileptic drugs, making by the government.
carbamazepine. Studies have shown a strong association
between the HLA-B*1502 and occurrence of SJS in patients RECOMMENDED READINGS
receiving this drug. This variant gene was found to occur at 1. Avigan MI. Pharmacogenomic biomarkers of susceptibility to adverse
higher frequency in Hans Chinese, Malays and Thais. Based on drug reactions: just around the corner or pie in the sky? Per Med. 2009; 6:
strong association demonstrated, the US-FDA made label 67-78.
changes in carbamazepine and recommended testing for 2. Ingelman-Sundberg M, Sim SC. Pharmacogenetic biomarkers as tools for
HLA-B*1502 in Asian populations before starting therapy with improved drug therapy; emphasis on the cytochrome P450 system.
Biochem Biophys Res Commun. 2010; 396: 90-4.
carbamazepine. This would help in identifying patients who are
3. Miller MP, Grant DM. The art and science of personalized medicine. Clin
at risk of developing SJS with carbamazepine, and thus, avoid Pharmacol Ther. 2007; 81: 311-5.
drug-induced morbidity.
4. Ramasamy K, Narayan SK, Chanolean S. et al Severe phenytoin toxicity in a
CYP2C9*3*3 homozygous mutant: first case report from India. Neurology
BARRIERS FOR PHARMACOGENETIC TESTING India. 2007; 55: 408-9.
Although extensive studies are being done in the field of 5. Surendiran A, Pradhan SC, Adithan C. Role of pharmacogenomics in drug
pharmacogenomics, the concept of personalised medicine is discovery and development. Indian J Pharmacol. 2008; 40: 137-43.

216
 6.10 Cancer Genetics

Rajiv Sarin

CANCER IS A GENETIC DISEASE establishment of an autonomous, malignant clone with

Cancer is a ‘genetic disease’, as gene mutation/s and chromo- selective growth advantage which leads to formation of a
somal alterations are the hallmark of all cancer cells. The term tumour mass. During their long natural history, most cancers
‘genetic’ in this context refers to molecular pathology of the develop molecular heterogeneity due to development of sub-
disease and not to transmission from generation to generation, clones, ultimately leading to development of the ‘metastatic
as is often the case for hereditary diseases. It shall be noted that clone’ which eventually kills the individual.
while all cancers are characterised by genetic alterations, only
GENOMIC INSTABILITY
2% to 5% of human cancers are hereditary. It is because the
genetic alterations in cancers are acquired, and remain Genomic instability is a cardinal feature of cancer. In certain
restricted to the somatic cell. The origin of hereditary cancers is hereditary cancer syndromes, the underlying defect mismatch
discussed separately. repair pathway, as seen in hereditary non-polyposis colon
cancer (HNPCC), or neucleotide excision repair pathway (NERP)
The genes associated with causation of cancer are broadly as seen in xeroderma pigmentosa (XP), which results in
classified into two types, viz.‘tumour suppressor genes’ (TSGs) genomic instability and cancer. In sporadic cancers, the
and ‘proto-oncogenes’, based on their normal cellular genomic instability is often the result of accumulation of
function and mechanism of causation of cancer. Knowledge several mutational events during malignant transformation
of specific genetic alteration/s which gives rise to a particular and progression.
cancer has been of immense use in improving prognostic
classification, and development of targeted therapy for ONCOGENES AND TUMOUR SUPPRESSOR GENES
several cancers. In case of hereditary cancers it can be used Oncogene, the activated form of proto-oncogene, is the
for detection of carrier status, genetic counselling and cancer ‘accelerator switch’ of cell division while tumour suppressor
prevention. gene (TSG) is the ‘natural brake’ of cell division (Table 1).
MULTI-STEP CARCINOGENESIS AND CLONAL ORIGIN OF Mutations in specific domains of proto-oncogenes, their
CANCER amplification or translocation, sometimes leading to formation
of fusion genes, result in gain of function and constitutive
The process of carcinogenesis is characterised by three steps - activation of mechanisms controlling cell proliferation. Germline
initiation, promotion and progression. Accumulation of 5-10 point mutation in the cysteine rich extracellular domain or
mutations in specific genes is invariably required for a normal intracellular tyrosine kinase domain of RET proto-oncogene
cell to transform into a malignant phenotype as shown for resulting in multiple endocrine neoplasia (MEN-2) syndrome is
the colon cancer model by Vogelstein (Figure 1). According a classical example of oncogene driven hereditary cancer. A
to the clonal theory of cancer, cancer initiates from a single somatic mutation, or over-expression of oncogenes, is a
cell. It progresses through a series of mutations at successive common mechanism of sustained growth stimulus in sporadic
cell divisions, with selection at each step, resulting in the cancers. Some clinically relevant examples include point
mutations in phosphate binding loop of K-RAS in pancreatic,
colon and lung cancer; catalytic kinase domain of epidermal
growth factor receptor (EGFR) in head, neck, lung and pancreatic
cancers; over-expression of C-ERBB2 in breast cancer and the
BCR-ABL fusion gene in chronic mylogenous leukaemia (CML).
In contrast to gain-in-function mutations of oncogenes, TSGs
undergo loss-of-function when certain mutations or
chromosomal alterations lead to diminution in normal activity
of proteins controlling apoptosis (p53 protein); cell cycle
regulation (RB protein), or DNA damage repair (BRCA1 or XP
proteins), etc. Somatic mutation in p53 gene is one of the most
frequently occurring genetic alterations in human cancers.
TSGs are broadly classified as Gatekeeper or Caretaker genes
based on their normal cellular function. As the names imply,
the gatekeeper genes control critical events and check points
in the cell cycle (RB, TP53, APC, etc.), while the caretaker genes
maintain genomic integrity through their critical role in DNA
repair (mismatch repair genes, nucleotide excision repair genes,
Figure 1: Multi-step carcinogenesis (Vogelstein’s colon cancer model).
BRCA1, etc). 217
 Table 1: Comparison Between Oncogenes and Tumour Suppressor Genes
Oncogene (Activated Proto-oncogene) Tumour Suppressor Gene
Encode components of a signalling pathway that regulate cell Regulate cell cycle progression (e.g. RB), apoptosis (e.g. p53)
proliferation and control the machinery of cell cycle (e.g. MYC, RAS or and DNA damage repair (e.g. BRCA1/2)
EGFR, etc).
Mutation or over-expression of a single allele results in gain of function Mutation or deletion of both alleles results in loss of tumour
which drives cell proliferation and malignant transformation suppressor function thereby allowing malignant transformation

Examples Examples
Point mutations (missense) Point mutations (missense, nonsense, frameshift)
KRAS in pancreatic and colon cancers TP53 in Li-Fraumeni syndrome
RET in multiple endocrine neoplasia (MEN-2) syndrome RB1 gene in retinoblastoma
BRCA1 and 2 in HBOC syndrome
Gene amplification/over-expression
APC genes in familial adenomatous polyposis
NMYC in neuroblastomas
Mismatch repair genes in HNPCC
C-ERBB2/HER2neu in breast cancer
Large genomic rearrangements
Chromosomal translocation
BRCA1 and 2 in HBOC
ABL (9q34) to BCR (22q11) in CML
Mismatch repair genes in HNPCC
MYC (8q24) to IgH (14q32) in Burkitt’s lymphoma
FLI1 (11q24) to EWS (22q12) in Ewing’s sarcoma Deletion
WT1 in Wilm’s tumour
Aneuploidy
SMAD4 in pancreatic and colon cancers
Loss of chromosome 10 (PTEN) in glioblastomas

KNUDSON’S TWO HIT HYPOTHESIS FOR TUMOUR be inactivated for development of cancer and why most
SUPPRESSOR GENE (RETINOBLASTOMA PARADIGM) forms of hereditary cancer occur at a younger age, are
Knudson proposed the “two hit hypothesis” to explain genesis frequently bilateral, and multiple as compared to their
of retinoblastoma, a childhood malignant tumour of the eye, sporadic counterparts. It is important to note that while the
and clinical features distinguishing hereditary from sporadic mutation is recessive at cellular level (requiring both alleles
retinoblastoma. Hereditary form of retinoblastoma occurs at to be inactivated), the inheritance pattern for cancer risk is
a younger age, generally in the first year of life and sometimes autosomal dominant. Progeny of germline mutation carriers
at birth; frequently arises in both eyes; and could be multifocal have 50% probability of inheriting the germline mutation (one
within each eye. In this form, first hit is the inherited germline mutated allele in each cell of the body). Subsequently a very
mutation in one of the two alleles of RB genes present in all high proportion of these carriers acquire the second
cells of the body and second-hit is the somatic mutation in inactivating mutation in one of the target organ cells (somatic
second of RB gene in one of the retinal cells, resulting in mutation) resulting in 70% to 100% penetrance for cancer
development of retinoblastoma (Figure 2). This hypothesis development in mutation carriers.
explains why both alleles of a tumour suppressor gene are to EPIGENETIC REGULATION IN CANCER
Epigenetic alteration refers to the change in genome (or gene
expression), which is inherited by the daughter cells without
any alteration in the DNA sequence. Common epigenetic
modifications include DNA methylation of CpG islands
(cytosine precedes Guanine) in the promoter region of a
gene, thereby controlling gene expression, and acetylation
of histones that could silence TSGs. Global genomic
hypomethylation in the CpG islands of TSGs and specific
histone modifications are commonly seen in many human
cancers. Being reversible, these epigenetic changes are
attractive drug targets with various drugs like histone
deacetylase inhibitors undergoing evaluation in clinical
trials. Analysis of epigenetic silencing of the MGMT gene by
promoter methylation is now in clinical use to predict
response to temozolamide chemotherapy for glioblastoma.

HEREDITARY CANCER SYNDROMES AND GENETIC TESTING

It is estimated that 2% to 5% of all cancers are hereditary,
occurring as a result of germline mutation in one of the several
TSGs (BRCA1, BRCA2, TP53, NF1, etc), or proto-oncogene. Vast
majority of hereditary cancer syndromes are autosomal
dominant (Table 2) with few rare syndromes associated with
Figure 2: Kundson’s two hit hypothesis in retinoblastoma.
218 DNA repair defects being autosomal recessive (Table 3).
 Cancer Genetics
Table 2: Autosomal Dominant Hereditary Cancer Syndromes and Their Phenotypic Features
Genetic Syndrome Malignancy (Lifetime Risk of a Cancer) Phenotypic/Tumour Features
Hereditary breast ovarian Breast cancer (70% to 80%), Cancer presents at young age, frequently bilateral and
cancer (HBOC) syndrome Ovarian cancer (40% to 60%) same person may develop breast and ovarian primaries
Incidence: 1 in 1000 Male breast cancer, prostate, pancreas, BRCA1 associated breast tumours are generally ER,
Genes: BRCA1 (17q); colon, etc. (especially in BRCA2 carriers) PR and C-ERBB2 negative (Triple –ve) and poorly
BRCA2 (13q) differentiated
Hereditary non-polyposis All cancers (70% to 90%) Colon polyps in 30% cases but unlike FAP polyps in
colon cancer (HNPCC) Colorectal cancer (30% to 75%) HNPCC rarely exceed few dozen
syndrome
Incidence: 1 in 400 Endometrial cancer (20% to 40%) Compared to sporadic cases, HNPCC associated colon
Genes: One of the mismatch Other cancers: Gastric, brain, small bowel, cancer is generally right-sided (ascending or transverse
repair genes MSH2 (2p) pelvi-ureteric, hepatobilliary colon) and at younger age
Amsterdam -II Criteria for HNPCC
MLH1 (3p) Lynch-I syndrome: HNPCC with only colorectal – At least 3 first degree relatives with colon, endometrial,
cancers in the family small bowel or pelvi-ureteric carcinoma
MSH6 (2p) Lynch-II syndrome: Extracolonic cancers of – At least 2 generations affected
HNPCC in the family – At least one affected person <50 years age
PMS2 (7p) Turcot’s syndrome: Person with colon cancer – FAP should be excluded
PMS1 (2q) and brain tumour
Familial adenomatous Colorectal carcinoma (100%) Hundreds to thousands of polyps by 2nd decade leading
polyposis (FAP) Upper gastrointestinal (duodenum) cancer to cancer by 4th decade
Incidence: 1 in 1,000 Periampullary cancer Attenuated FAP: Fewer polyps (10-100)
Gene: APC (5q) Papillary thyroid cancer Gardners syndrome: FAP variant with extracolonic
Brain tumours lesions like desmoid tumours, osteoma, epidermoid
Hepatoblastoma cysts, dental abnormalities, fibroma, and congenital
Desmoid tumour hypertrophy of retinal pigment epithelium
Peutz-Jeghers syndrome All cancers (50%) May present with intussuseption in childhood due to
Incidence: 1 in 250,000 Common cancers are colorectal, pancreatic, hamartomatous jejunal/gastrointestinal polyps
Gene: STK11 (19p) breast, ovarian, testicular, endometrial and Mucocutaneous melanocytic macules in lips and buccal
melanomas mucosa (95%)
Multiple and sometimes atypical naevi
Hereditary retinoblastoma Bilateral retinoblastoma (90%) Childhood tumour which presents at an average age of
Incidence: 1 in 25,000 Rarely trilateral retinoblastoma 1 year for bilateral and 1.5 years for unilateral cases and
Gene: RB1 (13q) Osteosarcoma in adolescence 90% cases by 3 years age
Li-Fraumeni syndrome (LFS) All cancers (90%) LFS: Sarcoma before 45 years of age in proband with
Incidence: 1 in 50,000 Breast cancer, soft tissue sarcoma or bone one 1st degree relative with cancer before 45 years of
Gene: TP53 (17p) sarcoma, brain tumours, leukaemia, age and one 1st or 2nd degree relative with cancer
adrenocortical tumours before 45 years of age or sarcoma at any age.
Multiple endocrine Medullary carcinoma thyroid (MTC) develops MEN2A: MTC, phaeochromocytoma and
neoplasia 2A and 2B in (70% to 100%) parathyroid adenoma MEN2B: MTC, phaeochromocytoma, mucosal neuromas
(MEN2A and MEN2B) RET mutation carriers and penetrance depends over tongue and lips (Blubbery lips), corneal nerve
Incidence:1 in 30,000 on location of mutation thickening, skeletal anomalies, gastrointestinal (GI)
Gene: RET (10q) Bilateral phaeochromocytoma (50%) gangloneuromatosis but parathyroid is normal
Neurofibromatosis Cutaneous neurofibroma (100%) Cutaneous stigmata (widespread neurofibromas,
Type 1 (NF1) Café-au-lait spots, axillary freckling) and Lisch nodules
Incidence: 1 in 2500 Plexiform neurofibroma (20%) (hamartomas) in iris are diagnostic.
Gene: NF1 (17q) Childhood optic glioma (15% to 20%) Learning disabilities in 50%
Malignant peripheral nerve sheath Hypertension is common
Tumour – MPNST (5% to 15%) Scoliosis and pseudoarthrosis in 10%
Neurofibromatosis Bilateral acoustic neuroma (85%) Cutaneous stigmata of NF1 generally absent but few
Type 2 (NF2) (< 6) Café-Au-lait spots in some
Incidence: 1 in 25,000 Spinal schwannoma (65%) Acoustic neuromas present with unilateral or bilateral
Gene: NF2 (22q) Skin schwannoma (65%) deafness
Meningiomas (45% to 50%) Posterior subcapsular cataract and retinal hamartomas
Other gliomas in 1/3rd cases
Cowden syndrome Early onset breast cancer (30% to 50%) Mucocutaneous stigmata by 3rd decade
Incidence: 1 in 200,000 Bowel cancer (20%) Diagnostic criteria: Cobblestone-like papules of the
Gene: PTEN (10q) Follicular thyroid cancer (3% to 10%) gingiva and buccal mucosa. Facial trichilemmomas, acral
keratosis
Other features in 40% cases (GI polyps and macrocephaly)
Contd... 219
 Contd...
von Hippel-lindau All tumours (80% to 90% penetrance) Retinal angioma are the earliest lesions detected at a
syndrome (VHL) Cerebellar and spinal haemangioblastoma mean age of 25 years in 40% to 70% cases. Renal, liver
Incidence: 1 in 36,000 (35% to 85%) and pancreatic cysts are common
Gene: VHL (3p) Renal cell cancer (25% to 48%),
phaeochromocytoma (15%)
Tuberous sclerosis (TS) Sub-ependymal giant cell astrocytomas Characteristic facial angiofibroma (adenoma sebaceum),
(Type 1 and 2) (SEGA) is a characteristic hypopigmented ash leaf spots and leathery Shagreen
Incidence: 1 in 10,000 benign tumour of TS, patches over neck or back
Gene: TSC1 (9q) Ependymoma Renal angiomyolipoma is very common which may
TSC2 (16p) Renal cell carcinoma bleed or cause renal failure by compression
Cardiac rhabdomyoma are common
Characteristic CNS hamartomas (sub-ependymal
nodules and cortical tubers) which causes epilepsy,
autism and common learning difficulties

Table 3: Autosomal Recessive Hereditary Cancer Syndromes and Their Phenotypic Features
Genetic Syndrome Malignancy (Percentage Lifetime Risk) Other Phenotypic Features
Bloom syndrome All cancer (penetrance 80%) Low birth weight, physical and mental growth
Incidence: Very rare Prone for all cancers (except prostate cancer) at retardation. Characteristic facial appearance (narrow
Gene: BLM (15q26) unusually young age (mean 25 years) skull, malar hypoplasia, small mandible); characteristic
Multiple primary cancers are common voice, photosensitive skin, telangiectasia and hypo/
Particularly prone for AML hyperpigmented patches
Immunodeficiency and infertility are common
Ataxia telangiectasia Breast cancer Cerebellar ataxia, telangiectases, immune defects,
Incidence: 1 in 100,000 Lymphoma (B-CLL) gonadal dysfunction, thymic hypoplasia
Gene: ATM (11q22) Leukaemia (T-CLL) Increased sensitivity to X-rays
Serum AFP is elevated in 95%
Xeroderma pigmentosum Skin cancer (basal cell carcinoma commonest All forms of XP have extreme UV sensitivity which
Incidence: 1 in 250,000 followed by squamous carcinoma and results in actinic keratosis, freckling and finally skin
Gene: XPA-G and V melanoma) in tropical countries most patients and conjunctival/corneal cancers
(9q,2q,3p,19q,11p, 6p, develop skin cancer by adulthood Neurologic abnormalities and mental retardation are
13q and 6p) commonly seen in XP-B, XP-D, XP-A
Fanconi anaemia Almost all patients develop bone marrow failure Commonly present with progressive bone marrow
Incidence:1 in 350,000 or haematological malignancy (commonly AML) failure starting from childhood
14 Genes in 16p if they live long enough Pigmentary changes in skin, malformations of the
FANC ‘A’ to FANC ‘G’ If cured of the haematological condition, heart, kidney and limbs
FANC ‘I’-‘J’ and FANC ‘L’ to most patients will develop (aplasia of the radius, thumb deformity)
FANC ‘O’ solid tumours Endocrinopathy and growth retardation
Recessive hereditary Adenomatous colon polyps seen in most cases which
colon cancer Colon cancer could vary from as few as 5 polyps to frank polyposis
Gene: Mut YH (1p34) Extracolonic features of FAP/ Gardener’s syndrome
not seen and extra-colonic cancers not seen

While many hereditary cancer syndromes such as hereditary associated phenotypic features or cancers. Mutation analysis
breast ovarian cancer (HBOC) syndrome or Li-Fraumeni of the gene(s) likely to be implicated in the suspected syndrome
syndrome do not have any specific phenotypic feature before helps in confirmation of the syndromic diagnosis, risk estimation
the occurrence of cancer, some cancer predisposition and genetic counselling of the family.
syndromes have characteristic phenotypic features that pre-
date cancer diagnosis by many years or decades. These The gold standard for mutation analysis is automated DNA
phenotypic features include cutaneous signs in NF1, XP, sequencing but it is expensive, may detect sequence changes
tuberous sclerosis, Peutz-Jegher’s syndrome or characteristic of unknown clinical significance and may fail to detect large
benign hamartomatous lesions or cysts in internal organs or genomic rearrangements. In addition to these technical and
eye as seen in FAP, NF1, tuberous sclerosis, VHL, etc. In syndromes interpretive issues, genetic testing has several other ethical, legal
without characteristic external or internal phenotypic features, and social implications (ELSI) and is, therefore, advisable only
the diagnosis of a hereditary cancer syndrome is based on when inherited cancer predisposition is suspected and genetic
detailed family history of types of cancers, age at cancer testing is likely to modify or aid clinical management for patients
diagnosis, or bilateral, multifocal or multiple primary cancers in or high risk cases in that family. Genetic testing is generally done
an individual. Based on detailed family history and clinical first for the cancer affected member of the family on a gene
examination of the proband if a cancer predisposition which is most likely to be involved (e.g. BRCA1 and BRCA2 for
syndrome is evident or suspected, further radiological or HBOC). With the small likelihood of a false negative or false
220 laboratory investigations are performed to look for other positive result due to technical errors, the four possible results
 Cancer Genetics
of mutation analysis are: (1) Known deleterious mutation drives oncogenesis is targeted through tyrosine kinase
identified; (2) Known polymorphism identified; (3) Sequence inhibitors (imatinib) as shown in Figure 3. Imatinib is now the
variation of unknown clinical significance identified; and (4) No standard of care in patients of CML who test positive for this
mutation or sequence variation identified. A counsellor has to translocation.
be well versed with the interpretation of all the alternatives to
provide effective counselling. MOLECULAR DIAGNOSTIC TECHNIQUES IN CANCER
CANCER SCREENING AND PREVENTION IN HIGH RISK A greater variety of high throughput tests are becoming
INDIVIDUALS/MUTATION CARRIERS available which also have greater sensitivity and specificity
to study chromosomal alterations, gene over-expression,
Healthy members of families with specific hereditary cancer gene mutation and global gene expression profile. These
syndromes would be considered to be at a high-risk for
technologies which were instrumental in making major
developing cancer based on their relationship with the affected
discoveries of molecular and genetic basis of cancer are now
members and in families where a specific mutation is known
being routinely used in molecular diagnosis of cancer. Some
all those who are found to be mutation carriers are considered
of the key diagnostic methods are outlined below.
at high-risk. There are well established guidelines for screening
of such high-risk individuals from families with common Fluorescent In Situ Hybridisation (FISH)
hereditary cancer syndromes with organ specificity (HBOC,
Characterises chromosomal aberration using DNA probes,
HNPCC, FAP, MEN-2). High-risk women from HBOC families are
specific for a gene, chromosome segment or whole
recommended to have monthly breast self examination, six-
chromosome. FISH has the advantage of directly obtaining the
monthly clinical breast examinations by a trained oncologist,
position of the probes in relation to chromosome bands or to
surgeon or a gynaecologist. Annual breast imaging is
other previously mapped reference probes and visualise
recommended using mammography and/or breast MRI in
cytogenetic aberration on interphase nuclei without the need
young women with dense breasts. Breast screening should start
for having metaphase preparation. FISH is particularly useful
between 25 to 30 years of age or five years before the age of
for translocations in paediatric tumours and haematolymphoid
earliest cancer in the family. The sensitivity of ovarian cancer
malignancies and more quantitative study of over-expression
screening in detecting early stage ovarian cancer in such high-
risk women is not well established but annual transvaginal of Her2Neu in breast cancer.
ultrasound and CA-125 tumour marker starting at 35 years of Microsatellite Instability Test
age may be considered. Microsatellites are small repetitive DNA sequences that undergo
Preventive strategies in high-risk women from HBOC families expansion or contraction of the repeat sequences during DNA
vary from non-invasive chemoprevention with antiestrogens replication. The mismatch repair (MMR) genes survey the newly
to prophylactic bilateral mastectomy with breast reconstruction replicated DNA for possible errors and repair the mismatched
or prophylactic oopherectomy. Prophylactic oopherectomy bases. Defect in MMR genes as seen in HNPCC would result in
reduces the risk of ovarian cancer by almost 100% (rare microsatellite instability (MSI) which is characterised by change
occurrence of primary peritoneal carcinoma still exists) and of length of the microsatellite (insertion or deletion of repeats)
reduce the risk of breast cancer by 50%. While bilateral within the colonic tumour as compared to the DNA from normal
prophylactic nipple sparing mastectomy with reconstruction tissue. For HNPCC, a panel of five microsatellite markers
can reduce breast cancer risk by almost 100%, the psychosexual recommended by National Cancer Institute (Bethesda Panel) is
issues of such surgery in healthy young women have to be used for detection of MSI. If two or more microsatellite markers
discussed in detail during counselling. are unstable, it suggests HNPCC which can be confirmed
through germline mutation analysis using automated DNA
MOLECULAR SIGNATURES OF CANCER FOR DIAGNOSIS, sequencing of hMLH1, hMSH2 and hMSH6 genes.
PROGNOSIS AND GUIDING TARGETED THERAPY
Classification of various tumours has evolved from Gene Expression Profiling
conventional morphology based histopathology to immuno- In addition to a large number of genetic pathways involved
histochemistry and finally to molecular pathology in which in the multi-step carcinogenesis, there is underlying genetic
tumour specific gene mutations, over-expression, chromo- instability and epigenetic modifications of gene expression.
somal rearrangements and global gene expression profile is Newer techniques such as RNA microarrays are now used to
characterised and used in clinical management of certain study the differential expression profile of thousands of
cancers. Molecular sub-classification of tumours helps in genes in the neoplastic cells as compared to the normal cells
refining diagnosis, prognostification and predicting response of the same tissue origin. Such studies have led to molecular
to specific targeted therapies based on the molecular classification of breast cancers, lymphomas and few other
pathology. The common examples include accurate diagnosis tumours and allowed better understanding of the pathways
of Ewing’s sarcoma (EWS-FLI1 translocation) and lymphomas relevant to development of particular cancer type and in
(CD markers); prognostication of neuroblastoma (N-MYC identifying molecular targets for cancer diagnosis and therapy.
amplification) and breast cancer (gene expression profile) and
guiding targeted therapy for breast cancer with HER2/Neu Automated DNA Sequencing
over-expression (Herceptin) and CD-20 positive lymphoma DNA sequencing using automated capillary sequencer is the
(rituximab). The classical t(9;22) (q34.1;q11.2) translocation gold standard for gene mutation analysis. In the commonly used
of CML which results in BCR-ABL fusion gene which Sangers method which is frequently done by dideoxy- chain
221
 Figure 3: Chromosomal translocation: BCR-ABL fusion gene in CML has increased tyrosine kinase activity is down-regulated by imatinib.

termination, the DNA template which is to be sequenced is laid on developing specific diagnostic tests and novel therapies
prepared as a PCR amplicon product. Sequencing is achieved targeting the molecular signatures resulting in a shift in the way
by utilising fluorescent labelled nucleotides incorporated we practice medicine, from generalised therapy to a more tailor-
into the DNA copy. The DNA sequence can then be derived by made individualised therapy. For hereditary cancers, genetic
the positions of the fluorescent labelled nucleotides. Laser testing has helped in precise risk estimation, counselling, with
stimulated fluorescent emissions are read directly by an optical appropriate surveillance and cancer prevention strategies.
detector as the DNA fragment passes past it. The sequencing
data are stored, analysed and converted to complete DNA RECOMMENDED READINGS
sequence by special software and compared with normal 1. Croce CM. Oncogenes and cancer. N Engl J Med 2008; 358: 502-11.
reference DNA sequence. A major advantage of the automated 2. Eeles RA, Easton DF, Ponder BAJ, Eng C. Genetic Predisposition to Cancer;
2nd edition. London: Arnold; 2004.
sequencing is the speed of detection and the information
3. Esteller M. Epigenetics in cancer. New Engl J Med 2008; 358: 1148-59.
it gives about the nature of the change found. Capillary
4. Golub TR, Slonim DK, Tamayo P et al. Molecular classification of cancer:
sequencers are also used for estimating the fragment length
Class discovery and class prediction by gene expression monitoring.
polymorphisms for microsatellite analysis, haplotype analysis Science 1999; 286: 531-7.
and DNA fingerprinting. The possible results of DNA sequencing 5. Kowtal P, Vyas S, Joshi N et al. Hereditary breast ovarian cancers: genetic
of a gene and certain caveats are described earlier in the Genetic testing and its implications. J Obstet Gynecol India 2007; 57: 298-306.
testing section. 6. Mulero-Navarro S, Esteller M. Epigenetic biomarkers for human cancer: the
time is now. Crit Rev Oncol Hematol 2008; 68: 1-11.
CONCLUSION 7. OMIM data base-Online Mendelian Inheritance in man. http://
www.ncbi.nlm.nih.gov/omim.
Cancer genetics has undergone a revolutionary change in the
8. Squire J, Ozcelik H, Andrulis IL. Investigating the genetics of cancer.
past two decades. This knowledge of molecular mechanisms Oxford Textbook of Oncology; 2nd edition. London: Oxford University
underlying cancer initiation, promotion and progression has Press; 2002; 3-13.
brought about a major change in the way we diagnose and 9. Vogelstein B, Kinzler KW. The Genetics Basis of Human Cancer; 2nd edition.
manage certain cancers. Presently, a greater emphasis is being New York: McGraw Hill; 2002.

222
Section 7
Critical Care Medicine
Section Editor: Surendra K. Sharma
7.1 Basic Considerations in Critical Care 224
R.K. Mani
7.2 Monitoring of Critically Ill Patients 227
M. Hanumantha Rao
7.3 Fluid and Electrolyte Balance in Health and Disease 232
Sanjay Jain
7.4 Acid-Base Disorders 239
Alladi Mohan, Surendra K. Sharma
7.5 Enteral and Parenteral Nutrition in Critically Ill Patients 246
Shilpa S. Joshi
7.6 Acute Respiratory Failure 251
Ashit M. Bhagwati
7.7 Sepsis and Acute Respiratory Distress Syndrome 256
Alladi Mohan, Surendra K. Sharma
7.8 Mechanical Ventilation 263
Surender Kashyap, Surinder Singh
7.9 Non-Invasive Ventilation 271
Dhruva Chaudhry, Inderpaul Singh
7.10 Hypotension and Shock 277
Anil Dhall, Sanjat S. Chiwane
7.11 Cardiopulmonary Resuscitation 282
Ashit M. Bhagwati
7.12 Brain Death and Support of the Brain-Dead Organ Donor 289
Rajesh Chawla, Guneet Singh
 7.1 Basic Considerations in Critical Care

RK Mani

CRITICAL VERSUS NON-CRITICAL CARE Inherent to critical care is the early recognition of organ system
Critical care is not merely an extension of patient care to an dysfunction and prompt institution of appropriate support. At
acute setting. The urgency of acute illness in critical care has any point in such evaluation, one may need to return to the initial
led to a departure from traditional approaches. The usual linear steps to ensure that physiological targets are being achieved.
method of history, physical examination, investigations,
diagnosis and treatment has given way to an iterative approach TIMELINESS OF INTERVENTIONS
in critical care (Figure 1). Owing to the emergent nature of The concept of the ‘golden hour’ that mandates timely and
presentations the correction of life-threatening physiological appropriately aggressive intervention is of essence in critical
derangements receives first priority that translates as the CAB care. Therapeutic efficacy that translates to favourable outcome
(circulation, airway and breathing) after eliciting brief historical has been proven to be a function of how early the therapy was
information and conducting rapid physical examination. instituted from the time of presentation. Notable examples of
This is followed by close monitoring to stabilise the patient this principle are the early goal-directed therapy for septic
(electrocardiogram, mean arterial pressure, oxymetry, central shock, timing of the 1st dose of antibiotic and antifungal therapy,
venous pressure, urine output, sensorium, intracranial pressure, thrombolysis and revascularisation procedures for acute
etc.) that is the hallmark of critical care. The next step involves myocardial infarction, surgical source control, thrombolytic
detailed history-taking and physical examination towards therapy for acute ischaemic stroke and adjuvant therapies such
formulation of a working diagnosis and management strategy. as activated protein C for severe sepsis and septic shock, to

Figure 1: General approach to the management of the critically ill patient.

* The curved arrow represents the iterative approach in the management of the critically ill patient.
ACLS = Advanced cardiac life support; ATLS = Advanced trauma life support.
224
 Basic Considerations in Critical Care
name a few. Thus, it is also crucial to institute early support to use of immunosuppressive medications and implanted devices
organ systems in the form of oxygen supplementation, non- and organ transplantation all have added to the challenges of
invasive (NIV) and invasive mechanical ventilatory support, critical care. However, when critical care fails, it greatly escalates
circulatory support through fluids and vasopressors, the emotional, social and financial burdens of the family. Most
haemodialysis and renal replacement therapy, and nutritional interventions also carry significant risks and costs requiring an
support. A sense of urgency is vital to minimise the eventual informed consent from the patient or his/her family. Therefore
mortality and morbidity as well as the cost of treatment. ethical considerations weigh heavily on clinical decision-
making. The physician must integrate the ethical principles of
MINIMISING RISKS OF ORGAN SUPPORT respect to patient’s autonomy, beneficence, non-malefiscence
Mechanical ventilation (MV) is one of the primary interventions and social justice in his practice.
that saves lives. However, safe ventilatory strategies that
As a corollary to ethical decision-making, it behoves the
minimise mechanical complications (barotrauma) as well
physician to disclose early and honestly poor prognosis, and
as microstructural trauma called ventilator-associated lung
offer palliative end-of-life care options to the family. Since death
injury (VALI) is an essential tenet of critical care. Non-invasive
is a common occurrence in the intensive care unit (ICU),
ventilation has obviated the need for more potentially injurious
appropriate care of the dying is an important tenet of critical
MV in a sizeable number of patients especially in the setting of
care. Ethical, social, humanitarian and legal factors impact on
exacerbation of chronic obstructive pulmonary disease (COPD).
issues relating to voluntary foregoing of life-supporting
The concept of ‘protective ventilation’ is a widely accepted
therapies. A pathway to end-of-life care decisions has been
concept that finds practical application in the form of low tidal
suggested by the Indian Society of Critical Care Medicine
volume and positive end expiratory pressure (PEEP) in acute
(ISCCM) (Figure 2). Palliative care aimed at ensuring patient
respiratory distress syndrome (ARDS), permissive hypercarbia
comfort starts from the time of initial care and gradually
for ARDS, bronchial asthma and COPD, and recruitment
assumes centre stage as therapeutic strategies shift from the
manoeuvres, such as prone positioning. The need to protect
‘cure’ to the ‘care’ mode when attempts at cure are deemed to
the lungs has also led to the search for supports such as extra-
have failed.
corporeal membrane oxygenation (ECMO) and other extra-
corporeal lung-assist devices. FAMILY NEEDS
The risks of aggressive fluid resuscitation are minimised by As opposed to non-critical conditions where care is said to be
improved monitoring of haemodynamic variables and the patient-centric, critical care is patient- and family-centric. This
emerging awareness of the need to monitor intra-abdominal is because more than 95% of critically ill patients lose the
pressure. capacity to decide for themselves. It is of utmost importance
that the intensivist communicates daily with the family for
The adverse effects of sedation and neuromuscular blocking
prognostication, emotional support, decision-making and
agents have been reduced by setting specific therapeutic
informed consent, cost estimations and where appropriate,
targets and by the practice of daily sedation interruption.
end-of-life decision-making. This is best done by the senior
INFECTION CONTROL staff of the unit along with primary physicians and senior
The critical care unit is well recognised as the epicentre for the nurses.
development of multiple drug-resistant flora. One of the key CRITICAL CARE ORGANISATION
responsibilities of the intensivist is to adopt practices that
The ICU constitutes a team of doctors, nurses, technicians,
minimise the incidence of nosocomial infections, prevent
therapists and other support staff. Most of the staff needs to
horizontal transmission and limit the emergence of resistant
work in shifts to provide uninterrupted round-the-clock cover.
pathogens. This includes attention to hand hygiene and
Adequacy of staffing is vital to ensure efficiency, infection
handling of intravenous (IV) cannulae and airways, aseptic
control, patient and family satisfaction and avoidance of
measures for bedside procedures and imaging, head-up
caregiver fatigue and attrition. Ongoing education, training and
positioning and general housekeeping. Refining antibiotic
clinical research activities are integral to constant upgradation
prescribing practices are vitally important for optimising
and search for excellence.
therapy, reducing the incidence of bacterial resistance and
minimising costs. Protocols and policies are essential to regulate ‘OPEN’ VERSUS ‘CLOSED’ INTENSIVE CARE UNITS
these processes.
In the ‘open model’ of critical care units consultant physicians
PREVENTION OF COMPLICATIONS AND GENERAL CARE direct the care of their individual patients with the assistance
of house staff that provides round-the-clock on-the-spot patient
Careful attention to detail includes pharmacological and/or
care. An intensivist, if available, is not involved directly in the
mechanical measures to prevent deep venous thrombosis, eye
care of most of the patients. Because the primary physician
care to protect against exposure keratitis, mouth care to reduce
often does not have the time or the skills required to provide
bacterial colonisation, skin care to prevent pressure sores and
comprehensive care to the patient, he often apportions
bowel care to prevent constipation.
management to several single organ specialists.
ETHICS, END-OF-LIFE CARE AND PALLIATION A ‘closed’ system implies that patient care is either directed or
The increasing efficacy of modern critical care has raised its co-managed by an intensivist. In this model, the intensivist
expectations often to unrealistic levels. The aging population, assumes full responsibility for treatment planning and
the increasing complexity of surgical interventions, the frequent integrates the inputs from several sub specialists. He provides 225
 Figure 2: Pathway to end-of-life decision.

leadership in the management of individual patients, foreseeable future he will be called upon to identify the
organises ‘on call’ cover, puts in place infection and quality potential organ donor early and notify the nearest organ
control practices, staff training and clinical research. In an open procurement organisation.
structure, an ‘open-door’ policy may exist for admission and
discharges. QUALITY AND SAFETY
Patient safety requires that systems are in place to evaluate the
Several retrospective and prospective studies showed improved
quality and safety issues of the ICU. This includes data collection
outcomes in terms of mortality, morbidity and cost especially
and monitoring to audit parameters such as mortality, length
in seriously sick patients, when ICUs adopted the closed
of stay, ventilator-associated pneumonia and blood stream
model. This model also facilitates early end-of-life decisions
infection rates, critical incidents and sentinel events, medication
and appropriate reduction of futile care that minimise the
errors, etc. With training and experience, the complications of
escalation of costly interventions in terminally ill patients. The
ICU procedures can be minimised. A culture that promotes
limitation of this model is the scarcity of trained and
safety, a team spirit that believes in constructive self-criticisms,
experienced intensivists. Currently ‘open’ and ‘semi closed’
setting protocols and standard operating procedures are
models pre-dominate in India and true ‘closed’ units are a
essential for reducing errors and adverse events.
miniscule minority.
RECOMMENDED READING
ORGAN RETRIEVAL
1. Mani RK, Amin P, Chawla R, et al. Limiting life prolonging interventions
With expanding scope and expertise of organ transplantation and providing palliative care towards the end-of-life in Indian Intensive
the critical care specialist has a new role to play. In the Care Units. Indian J Crit Care Med 2006; 9: 96-107.
226
 7.2 Monitoring of Critically lll Patients

M Hanumantha Rao

Monitoring is one of the primary duties of an intensivist or Table 1: Physiologic Variables that are Frequently Monitored
critical care specialist. Effective vigilance is helpful in assessing in Critically ill Patients
the severity of organ dysfunction and suitably assist the organs
Electrocardiogram
by different methods. In order to ensure optimal care of these
Heart rate
patients, it is vital to understand the technology of advanced
Systemic arterial blood pressure
and sophisticated monitoring equipment including the cost- Temperature
benefit issues. Vigilance and anticipation of complications are Haemoglobin
the important issues in the intensive care unit (ICU). All critically Haematocrit
ill patients need different types of monitoring, because they Pulmonary capillary wedge pressure
are likely to develop dysfunction of different organ systems Urine output
during their stay in critical care unit. By proper monitoring one Arterial blood gas analysis
can assess the severity of dysfunction of each of these organs Blood volume
and then choose suitable therapeutic interventions and Plasma volume
artificial support for the failing organs like heart, kidney and Central venous pressure
lung. Many physiological measurements are necessary to Intracranial pressure
convey the patient’s condition. To assess all the aspects of Cardiac output
patient’s condition many physiologic measurements or group Oxygen saturation
End-tidal carbon dioxide
of measurements are required. This chapter briefly reviews the
Coagulation profile
indications, contraindications, techniques and complications of
Central venous oxygen saturation
frequently used monitors in critical care units. Airway pressures
Many monitoring techniques are available in clinical practice Scalars and loops
(Table 1) and specific monitoring is required for different Blood urea nitrogen
systemic diseases. However, many patients need monitoring Serum creatinine
of all systems. Some variables are monitored continuously Liver function tests
Serum electrolytes
and some intermittently. The variables that are monitored
Blood glucose
continuously include heart rate, arterial blood pressure, pulse
Intake and output chart
oximetry (Figure 1). Arterial blood gases and some laboratory
tests are monitored intermittently. CARDIOVASCULAR MONITORING
VITAL SIGNS Heart rate per minute is routinely monitored in all critically ill
patients. It is clinically counted by manual palpation of the radial
Simple, basic, economical and the most frequently used non- artery just above the wrist joint for one full minute. It can be
invasive method of monitoring the patient includes heart rate, automatically calculated by either electrocardiogram (ECG)
blood pressure, respiratory rate, and temperature. wave or arterial pulse wave. It is a non-specific, haemodynamic
variable. A slow heart rate less than 50 beats per minute is
defined as bradycardia and heart rate more than 100 beats per
minute is defined as tachycardia.
Electrocardiogram
It has become a routine to monitor ECG in all the critically ill
patients. Most of the patients have cardiac activity monitored
by a 3-lead system or a 5-lead system. Monitoring heart rate
and rhythm is a standard practice. It detects dysrhythmias,
myocardial ischaemia and function of pace-maker. To receive
the maximum signal of ECG, electrodes need to be placed
properly after de-greasing and cleaning the area with spirit.
Lead II is routinely used to monitor the rhythm and lead V5 for
ischaemia. ST segment analysis is crucial in suspecting
ischaemia. It is a routine practice to monitor two leads
Figure 1: A 4-channel monitor connected to a critically ill patient showing ECG simultaneously to assess both rhythm and ischaemia.
(green), SaO2 (blue), IBP (red), ETCO2 (yellow) and NIBP (white).
Alternatively, one can use modified chest leads CM5 or CS5 which
ECG = Electrocardiography; SaO2 = Oxygen saturation; IBP = Invasive blood pressure; detect both ischaemia and dysrhythmia. The factors that may
ETCO2 = end-tidal CO2; NIBP = Non-invasive blood pressure.
interfere with the signal is skin movement, muscle artifact, 227
 respiration and shivering. The leads used for ECG monitoring Rhythm should be documented on admission and the change
are disposable and for single use only. Signals are usually sent of each shift of the intensive care unit (ICU). Rhythm is better
to central monitoring station by a small radio transmitter. monitored in lead II or MCL1 which is a modified chest lead.
Haemodynamic Monitoring Pulmonary Capillary Wedge Pressure
Arterial blood pressure Pulmonary capillary wedge pressure (PCWP) is frequently used
Systemic arterial blood pressure is proportional to cardiac to assess the pre-load of the left ventricle and cardiac output by
output, when peripheral vascular resistance is constant. It is thermodilution technique.The pulmonary artery catheter, named
maintained by physiological compensation when there are after Swan and Ganz , is a balloon tipped, flow directed triple-
changes in cardiac output and blood volume. It is affected by lumen catheter introduced through right internal jugular vein
cardiac output, vasomotor tone and volume status of a patient. or subclavian vein and then the balloon is inflated and passed till
wedging occurs in the pulmonary capillary. After proper wedging
Blood pressure may be normal despite grossly impaired cardiac one can record PCWP tracing and digital values of pressures.
function and so is a crude indicator of the state of the circulation.
But if blood pressure is inadequate, tissue perfusion suffers. In Cardiac Output
critically ill patients auto-regulatory mechanisms in vascular Fick’s principle is usually used to monitor cardiac output (CO)
beds of vital organs, like brain, kidney and liver become impaired using thermodilution technique. The Swan-Ganz catheter has
and perfusion to these organs will be pressure dependent. a temperature measuring device (thermistor). Bolus of cold
Blood flow to tissues and perfusion is dependent on mean saline is injected into right atrium through the proximal lumen.
blood pressure. Mean pressure is not an arithmetic average of As the bolus reaches the thermistor, the change in temperature
systolic and diastolic pressures. It is one-third the sum of systolic is used to calculate the cardiac output. The injection of cold
plus twice the diastolic pressure. saline can be done intermittently to calculate the cardiac output.
The latest methods of monitoring the cardiac output are lithium
Non-invasive blood pressure dilution technique (LIDCO), pulse contour counter pulsation
Systemic blood pressure can be monitored non-invasively (PICCO) and ECG.
(NIBP) or invasively (IBP). The use of conventional sphygmom-
anometer can be simple and reliable. Other indirect methods Oxygen Delivery
of measuring blood pressure include palpation, auscultation Tissue perfusion and delivery of oxygen is important for the
and oscillotonometry. The NIBP monitors have a pneumatic survival of organs. It is deranged in different types of shocks.
cuff which is programmed to inflate and deflate periodically The delivery addresses three main issues in the supply of
depending on the programme. During this the phasic oxygen to the tissues, namely (i) cardiac output (CO), (ii)
oscillations in the pneumatic cuff pressure produced by arterial haemoglobin (Hb), and (iii) oxygen saturation (SaO2). It can be
pulsation are sensed and detects the systolic and diastolic calculated by using the formula.
pressures. The mean pressure is calculated by the pre- Delivery of oxygen = Hb (g/dL) × SaO2% × CO (L/min)
programmed computer device. This is a simple, basic and (ml/minute) × 1.34 x 10/100
reliable monitor when the pressure is normal or high. But in
hypotensive patients these are often inaccurate. Mixed Venous Oxygen Saturation
The blood from superior vena cava and inferior vena cava mixes
Invasive blood pressure in the right atrium and passes to pulmonary artery through the
The most accurate and beat to beat variation of blood pressure right ventricle. This sample is called mixed venous blood and it
is recorded by introducing a catheter into an artery and can be obtained from the distal port of pulmonary artery
measuring the invasive blood pressure (IBP). This is an invasive catheter (PAC) and some catheters have fibreoptic sensors
procedure and should be used only for selected patients embedded in them which directly measure SVO2. When there
where it is indicated. Most frequently, radial artery of the non- is inadequate delivery of oxygen to tissues, they compensate
dominant hand is used. Alternatively, femoral, dorsalis pedis, by extracting more oxygen from arterial blood leading onto
ulnar arteries can be used. The catheter introduced into artery decrease in SVO2.
is connected to a pressure monitoring line filled with
heparinised saline which is connected to an electronic pressure RESPIRATORY SYSTEM
transducer. The transducer needs to be zeroed to atmospheric The monitoring of the respiratory system is very important and
pressure now and then. The fluid in the pressure monitoring crucial in the management of patients who are critically ill. It is
line transmits pressure from the artery to pressure sensitive less advanced technologically compared to cardiovascular
diaphragm of the transducer, which is connected to a monitor. monitoring. Respiratory rate, tidal volume and minute volume
The arterial pressure wave-form is displayed on the monitor and can be assessed by bed-side portable hand-held spirometers.
the digital values of systolic, diastolic and mean pressures. The All the parameters are displayed on the monitoring screen of
readings are reliable and highly accurate if the transducer is any latest ICU ventilator, if the patient is intubated and ventilated
zeroed and calibrated correctly. There is risk of infection and (Figure 2). Tachycardia, excessive sweating, use of accessory
many complications are reported because of its invasive nature. muscles of respiration can be monitored clinically to indicate
impending respiratory failure.
Dysrhythmia
Different types of dysrhythmias are not uncommon in critically Oxygen Saturation
ill patients. Therefore, it is important to monitor and record the A simple and non-invasive way of monitoring SaO2 is by pulse
228 initiation and termination of dysrhythmia in the ECG monitoring. oximeter (Figure 3). Oxyhaemoglobin and reduced haemoglobin
 Monitoring of Critically Ill Patients
analysis can be done intermittently. However, continuous
monitoring can be done using a arterial catheter with fibreoptic
electrode. From the analysis of ABG sample, PaO2, partial pressure
of carbon dioxide (PaCO2), pH, HCO3, absolute and standard base
excess can be assessed. Proper anticoagulation of arterial blood
with heparin and quick transport in ice slush to the nearest ABG
analyser (Figure 4) is very important to get accurate values. PaO2
should always be interpreted in relation the fraction of inspired
oxygen (FiO2). The ratio of PaO2 to FiO2 of inspired air (PaO2/FiO2)
gives adequacy of gas exchange. In acute respiratory distress
syndrome (ARDS) the ratio is less than 200. Serum electrolytes,
lactate, blood glucose can also be measured in an ABG sample.
Serial ABG analysis gives very useful information during
mechanical ventilation and weaning process as well.

Figure 2: An intensive care unit ventilator showing the trace of airway pressure
scaler (yellow), flow scaler (green) and volume scaler (blue).

Figure 4: Arterial blood gas analyser.

NEUROMUSCULAR MONITORING
Figure 3: A pulse oximeter showing saturation wave and digital values of SaO2 Central Nervous System
(green) and heart rate (red). Clinical examination of the central nervous system is simple and
non-invasive way of evaluating the brain. However, the
absorb light in the visible and near infrared regions at different
requirement of opioids, sedation, propofol and muscle relaxants
wavelengths. In majority of patients measurement of SpO2 by
make the clinical exam extremely difficult in critically ill patients.
pulse oximeter reflects arterial saturation and partial pressure
Glasgow Coma scale score (Table 2) is an another simple way
of oxygen (PaO 2 ) can be estimated by oxyhaemoglobin
to assess the neurological status in the management of these
dissociation curve. However, in critically ill patients, peripheral
patients.
perfusion is often reduced where saturation measurements are
not reliable. The sensor probe can be applied to the tip of finger, Table 2: Glasgow Coma Scale Score
toes, or lobule of ear. Oxygen saturation and heart rate can
Eyes (E) Open Spontaneously 4
be continuously monitored. In hypothermia the SpO2 is not
To command 3
accurately recorded. It is advisable to cover the probe from the
To pain 2
ambient light, which affects the signal. No response 1
Capnography Best verbal response (V) – Oriented 5
Capnography is the technique of displaying carbon dioxide Disoriented 4
concentration changes during the respiratory cycle. Capno- Inappropriate words 3
Incomprehensible 2
graphy provides a non-invasive means of rapidly identifying the
No response 1
problems, such as oesophageal intubation, inadvertent
Best motor response (M) To command Obeys 6
bronchial intubation and apnoea. Overall it provides a means
To pain Localises to pain 5
to evaluate the integrity of the airway and the quality of patient’s
Flexion—withdrawal 4
cardio-pulmonary functions. Decorticate rigidity 3
Arterial Blood Gas Analysis Decerebrate rigidity 2
No response 1
The analysis of arterial blood gases (ABG) helps to differentiate
Total 15
type I and type II respiratory failure and the severity as well. ABG
229
 Intracranial Pressure HEPATIC SYSTEM
Sterile catheter can be placed in the ventricle of a patient in Even though the damage to liver may not affect its activity
supine posture and by connecting it to a transducer system because of its tremendous functional reserve, it is routine to
can give us the intracranial pressure (ICP) and trace. The normal monitor the function because it performs important functions
ICP is 10 to 15 cm H2O. The indications of ICP monitoring are of synthesis, storage, metabolism and excretion of toxic
head injury, subarachnoid haemorrhage and post-operative products. The tests of liver function alone are poor indicators
neurosurgical patients. Continuous measurement of ICP can of the degree of liver disease, and therefore, indicators of cell
be done by a number of devices placed within the cranium damage are frequently used instead, for instance hepatic
through a small burr hole made in parietal or frontal bone on enzymes. Albumin, because of long half-life is not a sensitive
non-dominant side. Subdural catheter, extradural or subdural indicator of liver function. Disorders of clotting factors and
bolt and intra-ventricular catheter can be connected to fluid prothrombin time are useful indicators of monitoring liver
filled system, which are connected to conventional pressure function.
transducer and recording systems. Catheter block and infection
are important and serious complications of these systems. HAEMATOLOGICAL MONITORING
Fibreoptic system can introduce a miniature pressure Acquired coagulopathies and haemostasis abnormalities
transducer into parenchyma to record the ICP. The transcranial are not uncommon in critically ill patients. Clotting function
Doppler is a non-invasive technique which calculates blood flow assessment is monitored by platelet count, prothrombin time,
in the arteries and detects cerebral ischaemia. activated partial thromboplastin time, fibrinogen concentration
and fibrin degradation products (FDP) or D-dimer.
Cerebral Function Monitor (CFM)
This is a compact form of electroencephalogram, where Oxygen delivery to the tissues is important and haemoglobin
unwanted frequencies are filtered and summated. It uses only plays a crucial role and should be monitored frequently.
3 electrodes and monitors electrical activity continuously. It is Monitoring total leukocyte count and differential count is
used in patients who develop seizures in ICU. important to differentiate infective or non-infective causes and
may give a clue of acute or chronic type of infection.
Jugular Venous Oxygen Saturation
Jugular venous oxygen saturation measurement and difference GASTROINTESTINAL SYSTEM
of cerebral arterio-venous oxygen content have been used Bleeding from gastrointestinal system can occur in critically ill
in neuro ICU to indicate global cerebral ischaemia and to patients and simple periodic naso-gastric tube suction confirms
investigate hypotension. Indwelling catheters enable to record the diagnosis. Paralytic ileus needs to be diagnosed promptly
the jugular bulb oxygen saturation continuously and they and treated. The important function of gastrointestinal system
reflect global changes in cerebral functions. is nutrition. Naso-gastric tube feeding or enteral feeding should
be considered, if there are no contraindications.
Peripheral Nervous System and Peripheral Neuropathy
The damage of the peripheral nerves may result in peripheral Gastric Tonometry
neuropathy. It is caused by diabetes mellitus, uremia, human In critically ill patients development of acidosis in gastric
immunodeficiency virus or nutritional deficiency. Other causes mucosa may be a significant factor contributing to stress
include mechanical pressure, such as compression or ulceration and consequent gastrointestinal bleeding. The
entrapment, direct trauma, injuries and contusion. Diagnosis of acidosis is possibly due to mucosal ischaemia. Gastric
neuropathy is based on symptoms and physical examination. tonometry detects ischaemia. The mucosal pH may be
Examination of muscle strength, reflexes and sensitivity to measured indirectly as tissues are highly permeable to CO2,
position, vibration, temperature and light touch are to be and hence, the PCO2 of fluid within the lumen of the gut is
assessed. Vibration perception is more sensitive than touch and equilibrated with that of the cells in the superficial layers of
pressure. gut wall. The measurement of intra-luminal PCO2 is made
using a silicone balloon of approximately 3 ml capacity which
RENAL FUNCTION is permeable to CO2 and is positioned at the distal end of the
A very useful guide indicating adequacy of cardiac output, nasogastric tube.
splanchnic perfusion and renal function is hourly urine output
monitoring. Specific gravity and osmolality of the urine are NUTRITION
useful monitoring tools to differentiate pre-renal and renal Critically ill patients offer an exceptional challenge with regard
failure. to metabolism and nutrition and it is often neglected. So
metabolic status needs to be monitored repeatedly. The intake
Blood Urea and Serum Creatinine
of calories, lipids, proteins, fluids, electrolytes and minerals
Blood urea, serum creatinine and electrolyte trends are useful administered by enteral and parenteral routes are documented
in evaluation of the progress of renal function. A rise in blood and monitored at regular intervals.
urea can occur in the absence of renal dysfunction in
gastrointestinal bleeding, high protein intake and increase Electrolytes
catabolism. Estimation of the concentration ability of the Measurement of serum electrolytes is particularly important in
kidneys can be derived by comparing the blood and urine critically ill patients. ECG helps in monitoring hypokalaemia and
sodium, potassium and urea. Urine/plasma osmolality ratio hyperkalaemia. Tall peaked ‘T’ waves are seen in hyperkalaemia.
of <1.2, urea ratio of <10 and a urinary sodium of >40 mmol/L Decreased T wave amplitude and ‘U’ waves are seen in
230 indicates acute renal failure. hypokalaemia. Syndrome of inappropriate antidiuretic
 Monitoring of Critically Ill Patients
hormone (SIADH) results from inappropriate secretion of infections. Neutropaenia is seen in viral infections, brucellosis.
antidiuretic hormone (ADH) and result in retention of ingested Lymphocytosis is seen in brucellosis and tuberculosis.
or infused water. Monitoring of serum osmolarity, serum sodium, Monitoring of acute phase reactants like C-reactive protein is
and urine sodium and urine osmolarity are to be done. also raised in acute infections. Microbiological culture profiles
of blood, sputum, urine, central venous pressure catheter tip
Endocrine and Metabolic Monitoring
and urinary catheter are important monitors of the infection
Different endocrine abnoramalities can occur in critically ill and for institution of appropriate antibiotic.
patients. Serial blood glucose and ABG analysis are important
monitoring tools for hyperglycaemia, diabetic ketoacidosis and SUMMARY
volume depletion. An elevated ACTH levels and decreased Critically ill patients have different physiological reserves and
cortisol levels occur in primary adrenal insufficiency. respond to insults in different ways. Monitoring is focused to
Deep Venous Thrombosis examine the components of different systems including cardiac
Deep venous thrombosis (DVT) is mostly asymptomatic except output, oxygenation of blood, etc. It may be difficult to monitor
for mild discomfort and swelling. The incidence of venous all the variables in all the patients. Different modalities of
thrombosis is high in patients with cancer, varicose veins, obesity monitoring needs different monitors which are expensive.
and long period of lying down. DVT produces severe swelling Cost benefit ratio should always be kept in mind. Invasive
of the extremity and without treatment can lead to long-term monitoring is used only in patients when indicated and analyse
complications, like pulmonary embolism. Soleal veins of the whether information obtained can modify the treatment. No
lower leg are the most frequent sites of DVT. They are mostly amount of monitoring can cure a patient. However, successful
asymptomatic, but may have mild calf tenderness (Homans management of critically ill patients requires the use of monitors
sign). This condition is diagnosed by venography, Doppler to allow formulation of appropriate management. Monitoring
ultrasound and impedance plethysmography. is not only expensive but can also produce complications, which
outweigh the benefits some times. One should strike a balance
Monitoring of Infection in managing the monitoring modalities of a patient who is
Clinical and laboratory evaluation is required for monitoring of critically ill.
infections in critically ill patients. Patients may have the clinical
signs like raised body temperature (>38°C) or hypothermia RECOMMENDED READINGS
(<36°C), heart rate more than 90 beats per minute, increased 1. Rao MH, Ganesan C. Nutrition in the intensive care unit, In: Sharma SK,
Behera D, Mohan A, editors. Recent Advances in Respiratory Medicine;
respiratory rate (>20 breaths per minute). Laboratory
vol 2. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2005: pp
investigations show raised total leucocyte count (>12000 cells/ 235-59.
mm3 or presence of 10% immature forms) or leucopaenia 2. Shoemaker WC, Ayres SM, Grenvik A. Textbook of Critical Care; 5th edition.
(<4000 cells/mm 3). Neutrophilia is seen in acute bacterial Philadelphia: Elsevier Saunders; 2005: pp 735-9.

231
 7.3 Fluid and Electrolyte Balance in
Health and Disease
Sanjay Jain

INTRODUCTION artifact due to accumulation of other plasma constituents, viz.

A thorough understanding of the homeostatic mechanisms, triglycerides or plasma proteins.
that controls fluid and electrolyte balance, is essential for the Causes of Hyponatraemia
accurate assessment and treatment of the wide variety of
Causes of hyponatraemia are discussed in Table 1. In hyper-
disorders. These homeostatic mechanisms function via
glycaemia, relative insulin deficiency causes myocytes to
carefully regulated mechanisms in the kidneys, lungs and
become impermeable to glucose which in turn acts as an osmole
the skin to maintain specific tonicity, volume and ionic
drawing water into the cell. For every 100 mg/dL rise in plasma
composition of the body fluids.
glucose concentration, there is a 1.4 mEq/L fall in sodium.
DISTRIBUTION OF TOTAL BODY WATER
Table 1: Causes of Hyponatraemia
Water is the most abundant fluid in the body comprising 60%
of total body weight in males and 50% in females. Two-third of Isotonic hyponatraemia
this is distributed intra-cellularly and one-third is present extra- Following transuretheral resection of prostate: Isosmotic (mannitol)
or hyposmotic (glycine/sorbitol) irrigation of the bladder
cellularly. Out of the extra-cellular compartment, three-fourth
is present in the interstitium and the remaining one-fourth is Hyperlipidaemia
distributed intra-vascularly. Another small compartment of fluid, Hyperproteinaemia
the transcellular compartment, includes fluid in the synovial, Hypertonic hyponatraemia
peritoneal, pericardial and intraocular spaces, as well as the Hyperglycaemia
cerebrospinal fluid. The ionic composition of the extra-cellular Intravenous administration of mannitol
and the intra-cellular fluids is different. The plasma and Hypotonic hyponatraemia
interstitial fluid are similar in composition being separated Hypovolemic hyponatraemia, i.e. primary Na+ loss (secondary water
by only a thin, highly permeable capillary membrane. The gain)
only significant difference lies in the much higher protein Renal loss, e.g. diuretics (almost always thiazides), post-
concentration of the plasma due to the lower permeability of obstructive diuresis, osmotic diuresis
the capillaries to the plasma proteins. Due to a net negative Extrarenal loss, e.g. gastrointestinal loss (diarrhoea, vomiting),
charge of the proteins, they tend to hold a slightly higher integumentary loss (sweating), third space loss (burns,
concentration of sodium in the plasma. For the same reason, pancreatitis, muscle trauma)
the concentration of anions is higher in the interstitium. Euvolemic hyponatraemia, i.e. primary water gain (secondary Na+
loss)
Radioactive water (tritium, 3H2O) and heavy water (deuterium, Primary polydipsia
2H2O) mix well with total body water and can be used to SIADH
measure the same using the dilution principle. Extra-cellular Hypothyroidism
fluid (ECF) volume can be measured using radioactive sodium, Adrenal insufficiency
chloride, iothalamate and inulin. The presence of higher Chronic kidney disease
concentration of albumin in the plasma can be used to
Abnormal arginine vasopressin secretion
determine plasma volume (I125 tagged albumin). Interstitial
Malignancy: Pulmonary and mediastinal tumours
fluid volume and intra-cellular fluid volume are indirect
CNS: Acute psychosis, stroke, haemorrhage
measurements and cannot be measured directly.
Miscellaneous: Beer potomania, severe nausea, HIV infection
Plasma osmolality is determined by the following formula: and post-operative state
Hypervolemic hyponatraemia: Primary Na+ gain (secondary excess
(Na+ × 2) + (glucose/18) + (BUN/2.8)
water gain)
The Na+ concentration is expressed in mEq/L while glucose and Congestive heart failure
blood urea nitrogen (BUN) in mg/dL. The normal osmolality is Nephrotic syndrome
290 to 310 mosm/L. All fluids, with sodium and potassium Cirrhosis
concentration equal to 150 mEq/L, are considered to be isotonic. Acute and chronic kidney disease
Pregnancy
HYPONATRAEMIA
SIADH = Syndrome of inappropriate antidiuretic hormone;
Hyponatraemia is defined as a serum sodium less than 136
CNS = Central nervous system; HIV = Human immunodeficiency virus
mmol/L and is the most frequent electrolyte abnormality in
clinical medicine. Clinical Features
Pseudohyponatraemia is a rare situation in which serum Na + The signs and symptoms depend on the degree of
232 is low but the ECF osmolality and tonicity are normal. It is an hyponatraemia and the rate of decline of sodium. Nausea and
 Fluid and Electrolyte Balance in Health and Disease
malaise are the earliest findings, and may be seen when the 1. Restricting water intake
plasma sodium concentration falls below 125 to 130 mEq/L Water restriction to below the level of output is the primary
acutely. This may be followed by headache, lethargy, muscle therapy for hyponatraemia in oedematous states (such as heart
cramps, confusion, disorientation and obtundation, and failure and cirrhosis), SIADH, primary polydipsia and advanced
eventually seizures, coma and respiratory arrest, if the plasma renal failure.
sodium concentration falls below 115 to 120 mEq/L.
2. Giving oral or intravenous sodium chloride
The cerebral adaptation permits patients with chronic hypo-
Sodium chloride, usually as isotonic saline or increased dietary
natraemia to appear to be asymptomatic despite a plasma
salt, is given to patients with true volume depletion and adrenal
sodium concentration that is persistently as low as 115 to
insufficiency, and to some patients with SIADH. Administration
120 mEq/L. Symptomatic chronic hyponatraemia is rarely, if
of hypertonic saline is limited to patients with symptomatic or
ever, associated with cerebral oedema severe enough to
severe hyponatraemia or, occasionally to patients with SIADH
cause herniation of the brain. During hyponatraemia, brain
and highly concentrated urine.
cells that have been exposed to hypotonic plasma swell,
because of intracellular fluid shift. The early adaptive 3. Giving vasopressin antagonist
response of the brain cells to hyponatraemia is by loss of Conivaptan is an intra-venous formulation that blocks V2 and
water into the cerebrospinal fluid (CSF) followed by extrusion V1a receptors while lixivaptan, tolvaptan and satavaptan are oral
of sodium and potassium from the brain cells. The late adaptive formulations that are exclusively V2 receptor antagonists.
response occurs with the extrusion of organic osmolytes such
as myoinositol, glycerophosphatylcholine, glutamate, Osmotic demyelination syndrome (ODS) is associated with rapid
glutamine, creatinine and taurine. If adaptation of the brain is correction of hyponatraemia. A rapid increase in the plasma
incomplete, raised intracranial tension develops which may sodium concentration can lead to ODS, previously known as
eventually lead to death. central pontine myelinolysis. This rapid cellular dehydration
originally was identified in the pons, but has now been
Diagnosis identified in other areas of the brain.
The diagnostic approach to the patient with hyponatraemia
consists of a directed history and physical examination, HYPERNATRAEMIA
appropriate laboratory tests, and in selected patients, assessing Hypernatraemia is defined as elevation of serum sodium
the response to volume expansion with isotonic saline. concentration to a value exceeding 145 mEq/L.
Laboratory work-up includes serum osmolality, urine osmolality Causes of Hypernatraemia
and urine Na+.The plasma osmolality, which normally ranges from It can be caused by either a net water loss or rarely by a gain of
275 mOsm/kg to 290 mOsm/kg, is reduced in most hyponatraemic hypertonic sodium solution. Net water loss can occur in the
patients, because it is primarily determined by the plasma sodium absence of a sodium deficit (free water deficit) or in its presence
concentration and accompanying anions. In patients with (hypotonic fluid loss). Various causes of hypernatraemia are
hyponatraemia and a low plasma osmolality, the urine osmolality described in Table 2. Thirst is the most important protective
can be used to distinguish between impaired water excretion mechanism against sustained hypernatraemia, thus the highest
(which is present in almost all cases) and primary polydipsia, in risk exists in those with altered mentation, intubated patients,
which water excretion is normal but intake is so high that it exceeds infants and elderly patients. The other protective mechanism is
excretory capacity.The normal response to hyponatraemia (which
ADH secretion stimulated by hyperosmolality caused by
is maintained in primary polydipsia) is to completely suppress
hypernatraemia.
antidiuretic hormone (ADH) secretion, resulting in the excretion
of maximally dilute urine with an osmolality below 100 mOsm/kg Clinical Manifestations
and a specific gravity ≤ 1.003. Values above this level indicate an The primary manifestation of hypernatraemia reflects central
inability to normally excrete free water, most commonly because nervous system dysfunction, which in turn, is a consequence of
of continued secretion of ADH. cellular dehydration in the brain. Signs and symptoms vary with
In patients with hyponatraemia, hypo-osmolality and the degree, rapidity of onset of hypernatraemia and the age of
inappropriately concentrated urine, the urine sodium the patient. Elderly patients generally have few symptoms until
concentration can be used to distinguish between hyponatraemia the serum sodium concentration exceeds 160 mmol/L. Intense
caused by a decreased effective arterial blood volume and thirst may be present initially, but it dissipates as the disorder
euvolaemic hyponatraemia. The urine sodium concentration progresses and is absent in patients with hypodipsia.
is usually below 25 mEq/L in hypovolaemia, unless there is Convulsions are rare except during inadvertent sodium loading,
renal salt wasting while it is more than 40 mEq/L in syndrome of rehydration or in the presence of intracranial bleed. Values
inappropriate antidiuretic hormone hyper-secretion (SIADH). above 180 mEq/L are associated with a high mortality rate,
Later is also associated with increased uric acid excretion. particularly in adults.
Management Diagnosis
The two primary goals of therapy are: to initiate treatment of The history should include a review of recent and current
the underlying condition and to restore the normal serum medication use and questions regarding exercise, heat
osmolality without causing an iatrogenic complication. exposure, sweating, vomiting, diarrhoea, urine output, recent
The following methods of increasing the serum sodium fluid intake and the presence of thirst. Physical examination
concentration and to restore serum osmolality can be used: should include an assessment of ECF volume and a complete 233
 Table 2: Causes of Hypernatraemia Management
For treating acute hypernatraemia, normal saline solutions are
Net water loss
initially given intravenously. In the highly volume-contracted
Pure water loss: Euvolaemic hypernatraemia
patient with severe hypernatraemia, administering isotonic
Insensible water losses
saline solutions has two advantages. It provides fluid
Hypothalamic lesions impairing thirst or osmoreceptor function
resuscitation in impending cardiovascular collapse. Moreover,
Central diabetes insipidus
the isotonic salt solution, which is hypotonic with respect to
Congenital nephrogenic diabetes insipidus
the hypertonic patient, avoids an unnecessary rapid fall in the
Acquired diabetes insipidus
serum sodium level.
Hypotonic fluid: Hypovolaemic hypernatraemia
Renal causes Amount of the water deficit and ideal rate of correction
Loop diuretics must be considered while correcting the water deficit in the
Osmotic diuretics hypernatraemic patient. The maximum safe rate at which the
Post-obstructive diuresis plasma sodium concentration should be lowered, is by ≤ 0.5
ATN-diuretic phase mEq/L per hour and no more than by 12 mEq/L per day. The
Intrinsic renal disease preferred route for administering fluids is the oral route or a
Gastrointestinal causes feeding tube. If neither is feasible, fluids should be given
Vomiting intravenously. Only hypotonic fluids are appropriate including
Nasogastric drainage pure water, 5% dextrose, 0.2% sodium chloride (referred to as
Enterocutaneous fistula one-quarter isotonic saline) and 0.45% sodium chloride (one-
Diarrhoea
half isotonic saline).
Cutaneous causes
HYPOKALAEMIA
Burns
Excessive sweating
It is one of the most common electrolyte abnormalities in
Pemphigus
clinical practice. Hypokalaemia is defined as serum potassium
(K+) less than 3.6 mEq/L.
Hypertonic sodium gain: Hypervolaemic hypernatraemia
Hypertonic sodium bicarbonate infusion Spurious hypokalaemia is an entity when serum K+ levels
Ingestion of sodium chloride are low but total body K+ stores are normal. It may be seen
Hypertonic saline enemas in marked leucocytosis (TLC >1,00,000) where white blood
Hypertonic dialysis cells take-up K + , if the serum sample is stored at room
Cushing’s syndrome temperature. It may be seen in the setting of an insulin dose being
Primary hyperaldosteronism given just prior to taking a serum sample due to intracellular shift
of K+.
neurologic evaluation. Urine volume should be monitored,
urine osmolality should be measured in several spot urine Causes of Hypokalaemia
samples and 24-hour urine osmolar excretion should also be The causes of hypokalaemia may be classified into reduced
measured if polyuria is present. In the less common situation of K+ intake and increased K+ losses (Table 3). Decreased intake of
hypervolemic hypernatraemia, there is often an antecedent K+ rarely causes hypokalaemia. The daily requirement is 40 to
history of medical intervention that includes the administration 120 mEq/L; however, the normal kidney is able to decrease the
of sodium-containing solutions. The findings on physical daily excretion of K+ in the presence of low intake.
examination are consistent with ECF volume expansion,
Clinical Manifestations
whereas the cause of hypernatraemia is usually apparent (e.g.
diarrhoea), the urine osmolality may be useful in clarifying the The clinical manifestations tend to be proportionate to the
cause in patients without obvious gastrointestinal or insensible degree of hypokalaemia. Patients are asymptomatic above
water losses. During hypernatraemia caused by extrarenal water the K+ level of 3.0 mEq/L. However, rapidly falling K+ levels or
losses, the renal response should be to generate hypertonic other conditions predisposing to arrhythmias can give rise to
urine with an osmolality of 700 to 800 mOsm/kg. symptoms at a much higher level. The usual manifestations are
described below:
If the urine osmolality (Uosm) is less than 300 mOsm/kg, then water 1. Muscle weakness
loss is occurring via the kidneys, secondary to decreased
hypothalamic release of ADH (central diabetes insipidus) or Hypokalaemia is one of the causes of acute flaccid paralysis
impaired sensation in the cortical collecting tubule (nephrogenic starting in the lower limbs and progressing upwards. It can also
diabetes insipidus). In central diabetes insipidus, provision of ADH lead to respiratory muscle involvement to cause respiratory
results in an increase in Uosm, whereas in nephrogenic diabetes failure or affect gastrointestinal muscles resulting in ileus. Other
insipidus, it results in little to no increase in Uosm. muscular manifestations include cramps, paresthesias and
tetany.
If Uosm is between 300 mOsm/kg and 800 mOsm/kg, patients
might have partial forms of nephrogenic or central diabetes 2. Cardiac arrhythmias
insipidus or an osmotic diuresis from urea or glucose. In patients Various types of cardiac arrhythmias can be induced by
believed to have diabetes insipidus, a water deprivation test hypokalaemia including atrial pre-mature complexes,
can be performed to assess the integrity of pituitary release ventricular pre-mature complexes, sinus bradycardia,
234 and renal response to ADH. paroxysmal atrial tachycardia, atrioventricular block and
 Fluid and Electrolyte Balance in Health and Disease
ventricular tachycardia (VT)/ventricular fibrillation (VF). Presence does not have any contraindication to oral supplementation.
of concomitant coronary ischaemia, digitalis, increased beta Intravenous K+ supplementation is used for profound, life-
adrenergic activity and hypomagnesemia increases the risk of threatening hypokalaemia and in patients who do not
arrhythmias. tolerate oral solution. Electrocardiogram (ECG) monitoring
should be done with supplementation rates >20 mEq/hr. The
3. Renal abnormalities
concentration of administered potassium should be no more
Hypokalaemia can induce impaired urinary concentrating than 40 mEq/L in a peripheral vein or 60 mEq/L in a central vein.
ability, increased ammonia production, increased renal Infusion rates should be limited to <20 mEq/hr with peripheral
bicarbonate production and hypokalaemic nephropathy. cannula and >40 mEq/hr via central line. In all cases, serum K+
4. Rhabdomyolysis should be checked after 2 to 4 hours of ongoing replacement.
Serum Mg2+ levels should be checked if hypokalaemia is
Severe hypokalaemia (< 2.5 mEq/L) may induce rhabdomyolysis
refractory to correction.
and myoglobinuria.
HYPERKALAEMIA
Table 3: Causes of Hypokalaemia
Hyperkalaemia is a common and life-threatening electrolyte
Decreased potassium intake
imbalance. Early recognition of this condition can allow for the
Increased transcellular shift initiation of corrective measures. Hyperkalaemia is defined as a
Metabolic alkalosis serum K+ concentration of larger than 5.0 mEq/L. The normal
Insulin administration concentration of K+ depends on the K+ intake, its excretion by
Beta-2 adrenergic agonists the kidney, and by the balance between extra-cellular and intra-
Increased potassium loss cellular spaces.
Renal
Diuretics, especially loop diuretics Causes of Hyperkalaemia
Primary mineralocorticoid excess The causes of hyperkalaemia may be divided into two major
Metabolic acidosis groups as described in Table 4.
Hypomagnesemia In normal individuals, a phenomenon referred to as K +
Amphotericin B adaptation ensures a proportionate rise in K+ secretion by the
Salt wasting nephropathy kidney in response to an increase in ingested K+. Hence, in the
Polyuria presence of normal renal function, hyperkalaemia due to excess
Non-reabsorbable ions intake is rare. Of these metabolic acidosis is a frequently seen
Extra-renal loss cause. In response to every 0.1 unit reduction in extra-cellular
Excessive sweating: Generally insignificant, may be seen after pH, the plasma K+ concentration will rise by 0.6 mEq/L (range
heavy exercise when sweating is > 10 L per day 0.2-1.7 mEq/L).
Gastrointestinal losses, e.g. diarrhoea, nasogastric aspiration,
vomiting Table 4: Classification of Causes of Hyperkalaemia
Dialysis or plasmapheresis Hyperkalaemia due to excess release of intracellular potassium
Diagnosis Metabolic acidosis
Insulin deficiency and hypertonicity
Total body K+ depletion may result from renal or extrarenal
causes. Most of the times, a good history and examination Tissue catabolism
reveals the source of K+ loss (renal versus extrarenal). If the source Exercise
is unclear, a 24-hour urinary K+ excretion may be of benefit. A Beta-adrenergic blockade
24-hour urinary K+ >20 mEq/L implies that renal potassium loss Drugs, e.g. succinylcholine, digitalis overdose
is the cause of hypokalaemia. The presence of metabolic Hyperkalaemic periodic paralysis
acidosis is most often due to diabetic ketoacidosis or renal Pseudohyperkalaemia
tubular acidosis type 1 or type 2. The transtubular potassium Hyperkalaemia due to reduced renal clearance
concentration gradient (TTKG) is used to evaluate the force for
Renal failure
K+ secretion in the cortical collecting duct in the kidney.
Decreased effective circulating volume
The electrocardiographic changes of hypokalaemia include Impaired sodium reabsorption, e.g. primary hypoaldosteronism,
flattening or inversion of T waves (early), prominent U waves, ST- adrenal insufficiency, secondary hypoaldosteronism, renal tubular
segment depression, prolonged PR interval and widening of QRS acidosis, drugs (angiotensin converting enzyme inhibitors, non-
complex.These changes do not correlate well with plasma K+ levels. steroidal anti-inflammatory drugs, potassium sparing diuretics)
Increased chloride reabsorption, e.g. Gordon’s syndrome,
Treatment cyclosporine
In the absence of an independent factor, causing transcellular Ureterojejunostomy
K+ shifts, the magnitude of the deficit in body stores of K+
correlates with the degree of hypokalaemia. On an average, Clinical Manifestations
serum K+ decreases by 0.3 mmol/L for each 100 mmol reduction Hyperkalaemia is associated with very few overt symptoms and
in total body stores, but the response is extremely variable. signs, and these manifests only at very high levels or when the
Oral correction is recommended in all non-urgent settings rise is rapid. Severe muscle weakness and paralysis may be seen
where patient does not have any arrhythmias or paralysis and in some cases. The primary cause of mortality in hyperkalaemia 235
 is cardiac rhythm disturbances. As a result, hyperkalaemia can 25 to 50 g mixed in 20% sorbitol to prevent constipation.
be recognised by some typical ECG abnormalities. It lowers plasma K+ concentration by 0.5 to 1.5 mEq/L. A
retention enema may also be used.
A tall and symmetrical T-wave is the first sign of hyperkalaemia.
T-waves are usually taller than half of the preceding QRS 6. The most effective way of lowering K+ is by haemodialysis.
complexes when considered significant and may appear tented Severe hyperkalaemia, not responding to conservative
in severe cases. Due to slowing of cardiac conduction, other management, is an indication for haemodialysis. Peritoneal
subsequent changes ensue, including progressive lengthening dialysis may be done in hypotensive patients but is only
of the PR interval and QRS duration, atrioventricular conduction 15% to 20% effective.
delay and loss of P-waves, progressive widening of the QRS
complex and merging of the T- and U-waves resulting in a ‘sine CALCIUM METABOLISM
wave’ pattern. The terminal event is ventricular fibrillation or Calcium plays a vital role in body homeostasis. Diverse physiologic
asystole. The level of K+ does not correlate with the degree and processes in body like muscle contraction, neuromuscular
progression of ECG changes. signaling, blood coagulation and hormone secretion take place
Diagnosis because of calcium. Total body calcium is around 1 to 2 kg of
which 99% is in the bones. The normal total levels of calcium in
The most common causes of hyperkalaemia, such as renal failure,
body are 8.5 to 10.5 mg/dL of which 50% is ionised.The remainder
drugs and transcellular K+ shift, are relatively simple to identify.
is ionically bound to negatively charged proteins (albumin and
Chronic hyperkalaemia not related to these aetiologies is usually
immunoglobulins) or loosely complexed with phosphate, citrate,
due to impaired secretion of K+. Assessment of the TTKG is helpful
sulphate or other anions. Intra-cellular calcium concentrations
to differentiate between decreased effective circulating volume
are 10,000 folds lower than extra-cellular levels. The levels are
(TTKG >10) and other causes (TTKG <5). In cases where TTKG is <
maintained by feedback mechanism involving parathyroid
5, the presence of kaliuresis in response to administration of
hormone and active vitamin D. Liver, kidneys, intestines and bones
mineralocorticoid indicates hypo-aldosteronism.
are the principle sites of metabolism.
Management
Causes of Hypocalcaemia
Hyperkalaemia requires emergent treatment. Severe arrhythmias
can occur at K+ levels >7.5 mEq/L but may also occur at lower The causes of hypocalcaemia can be classified according to the
levels. The goals of therapy are to decrease membrane activity of parathyroid hormone (PTH) (Table 5).
excitability; thereby preventing arrhythmias, shifting K+ to the Table 5: Causes of Hypocalcaemia
intra-cellular space and promoting K + loss and removal of
exogenous source of K+. Low or absent parathyroid hormone (PTH)
Parathyroid agenesis: Isolated/DiGeorge syndrome
1. Membrane excitability is controlled by the infusion of 1000 Parathyroid destruction: Radiation/surgical/infiltration by
mg (10 ml of a 10% solution) of calcium gluconate over metastases/autoimmune process
2 to 3 minutes. The effect begins within minutes but is short Decreased PTH release: Hypomagnesemia, activating
lived (only 30 to 60 minutes). The dose can be repeated if calcium sensing receptor (CaSR)
no change in ECG is noted within the next 5 to 10 minutes. mutations
This does not affect the levels of K+. High or ineffective PTH
2. Insulin causes a shift of extra-cellular K+ into the cells by Chronic renal failure
enhancing the effect of the Na +-K + ATPase pump. An Vitamin D deficiency/resistance
infusion of 10 to 20 units of regular insulin in 20 to 50 g Pseudohypoparathyroidism
of dextrose can result in the fall of K+ by 0.5 to 1.5 mEq/L in Drugs: Calcium chelators, bisphosphonates, phenytoin,
15 to 30 minutes. This effect peaks at 30 minutes and lasts ketoconazole
several hours. Diabetic patients with hyperglycaemia may Severe acute hyperphosphataemia: Tumour lysis, rhabdomyolysis
be given insulin alone. Miscellaneous
Acute pancreatitis
3. Sodium bicarbonate is effective in shifting K+ into the intra- Hungry bone disease (after parathyroidectomy)
cellular space when given in hyperkalaemia associated with
Severe burns, sepsis, acute renal failure, extensive transfusions with
metabolic acidosis. The action begins within 30 to 60 citrated blood (transient)
minutes and persists for several hours.
Clinical Manifestations
4. Beta-2-adrenergic agonists promote the cellular uptake
Hypocalcaemia may be asymptomatic if the decrease in serum
of K+. The onset of action is within 30 minutes and lasts for
calcium are relatively mild and chronic. Moderate-to-severe
2 to 4 hours. These drugs can be effectively used in the
hypocalcaemia is associated with paresthesias, usually of the
treatment of acute hyperkalaemia, lowering the plasma K+
fingers and toes, and circumoral region. Tapping the inferior
concentration by 0.5 to 1.5 mEq/L.
portion of zygoma produces twitching of perioral muscles
5. Removal of potassium can be achieved using loop or (Chvostek’s sign). Carpal spasm can be induced by inflation of
thiazide diuretics if renal function is adequate. Potassium blood pressure cuff to 20 mmHg above the patient’s systolic
binding resins, like sodium polystyrene sulfonates, are blood pressure for 3 minutes (Trousseau’s sign). Life-threatening
useful in binding dietary potassium in the gut and complications, like cardiac arrhythmias, bronchospasm,
preventing its absorption. One gram of resin binds 1 mEq laryngospasm and seizures, may occur due to severe hypo-
236 of K+ and releases 2 to 3 mEq of sodium. The usual dose is calcaemia.
 Fluid and Electrolyte Balance in Health and Disease
Diagnosis Clinical Manifestations
Besides measuring serum calcium, it is useful to determine Hypercalcaemia is largely asymptomatic in half of the patients.
albumin, phosphorus and magnesium levels. Each 1 g/dL Mild hypercalcaemia (upto 11 to 11.5 mg/dL) may present with
reduction in the serum albumin concentration lowers the total vague symptoms like difficulty in concentration, personality
calcium concentration by approximately 0.8 mg/dL (0.2 mmol/L) changes or depression. Groans (constipation), moans (psychotic
without affecting the ionised calcium concentration. Serum noise), bones (bone pain, especially if PTH is elevated), stones
intact PTH measurements provide critical information in (kidney stones) and psychiatric overtones (including depression
patients with hypocalcaemia, but can be interpreted correctly and confusion) are a common mnemonic for hypercalcaemic
only when serum calcium is measured simultaneously. symptoms. Symptoms are common at calcium levels of 12 to
Suppressed PTH levels along with hypocalcaemia suggests 13 mg/dL, especially if they develop acutely and may include
absent or reduced PTH secretion as the cause of hypocalcaemia. lethargy, stupor or coma, as well as gastrointestinal tract
Elevated PTH levels should direct to search for secondary symptoms like anorexia, nausea, constipation or pancreatitis.
hyperparathyroidism. Levels of 25-hydroxy vitamin D should be Bone pains, pathologic fractures, polyuria or polydipsia may also
done if nutritional cause of hypocalcaemia is suspected. 1, 25 occur. ECG changes in the form of short QT interval, widened T-
dihydroxy vitamin D levels are useful in patients with renal waves and atrioventricular conduction disturbances may also
dysfunction and hypocalcaemia. occur. Severe hypercalcaemia (> 15 mg/dL) is life-threatening
and coma or cardiac arrest could occur. Immediate measures
Management
should be taken to decrease the levels.
The treatment depends on the severity of hypocalcaemia, the
rapidity with which it develops and accompanying complications. Management
Acute symptomatic hypocalcaemia is treated with intravenous The treatment of hypercalcaemia depends on the serum
calcium gluconate 10 ml 10% wt/vol (90 mg) diluted in 50 ml of calcium levels, symptom presentation or rapidity with which
5% dextrose or 0.9%; normal saline is given over 5 minutes. It it develops. Mild asymptomatic hypercalcaemia does not
may be followed by a continuous infusion of 5 ampules of calcium require immediate treatment. The steps in the treatment include
gluconate (450 mg) in dextrose 5% or normal saline 500 ml over hydration, diuretics like furosemide, bisphosphonates, calcitonin
12 hours. Intra-muscular or subcutaneous route should be and glucocorticoids. Use of oral or parenteral phosphate is not
avoided due to chances of necrosis. Associated magnesium recommended due to systemic toxicity of calcium-phosphate
deficiency should also be corrected. complex. Dialysis can be used as a useful therapy in emergency
Asymptomatic chronic hypocalcaemia can be treated with oral conditions where severe hypercalcaemia is associated with
formulations containing calcium (1 to 2 g/day) and vitamin D2 renal failure and is difficult to manage medically.
or D3 (25,000 to 1,00,000 U daily) or calcitriol (1,25 dihydroxy
MAGNESIUM
vitamin D) 0.25 to 2 µg/day. Vitamin D deficiency is treated with
oral supplementation of vitamin D (50,000 U 2 to 3 times per Magnesium is a critical co-factor in more than 300 enzymatic
week for several months). reactions in the human body and is essential to the normal
functioning of the human body. The average daily intake of
HYPERCALCAEMIA magnesium is 360 mg, out of which approximately one-third
It is a very common problem in day-to-day practice. It could be is absorbed through the small bowel. It is mainly excreted
an incidental finding on laboratory testing or reflection of some through the kidneys; with 15% to 25% ultrafiltrate magnesium
serious underlying disease. reabsorption through the proximal tubule and 5% to 10% in the
distal tubule. Approximately 1% of total body magnesium is
Causes of Hypercalcaemia
present in the serum and interstitial space with the normal plasma
Broadly, the aetiology can be classified on the basis of either magnesium concentration of 1.4 to 2.2 mEq/L. Magnesium is
related to or unrelated to PTH (Table 6). found in various dietary sources, best being green leafy vegetables.
It is also found in nuts, soybean and whole grain foods.
Table 6: Classification of Aetiology of Hypercalcaemia
Parathyroid hormone (PTH) related
Hypermagnesemia
Primary hyperparathyroidism: Solitary adenomas/multiple Under normal physiological conditions, magnesium is excreted
endocrine neoplasia (MEN) in the urine. Hypermagnesemia is seen when either the renal
Tertiary hyperparathyroidism (CKD with long-term stimulation of function is impaired or there is excess of magnesium load.
PTH)
Lithium therapy Causes of hypermagnesemia
Familial hypercalciuric hypercalcaemia Causes of hypermagnesemia are listed in Table 7.
PTH unrelated
Malignancy associated: Solid tumours (breast, lung, kidney), blood
Clinical manifestations
disorders (myeloma) Depends on the serum magnesium concentration, symptoms
Vitamin D associated: Vitamin D intoxication, granulomatous disease can range from asymptomatic (<3 mEq/L) to life-threatening
like sarcoidosis, lymphomas cardiac and neuromuscular effects (>4 mEq/L). Magnesium
High bone turnover: Hyperthyroidism, immobilisation, thiazides, concentration of 4 to 6 mEq/L leads to nausea, headache,
vitamin A intoxication lethargy and sluggish deep tendon reflexes. Concentration
Excessive calcium intake: Milk alkali syndrome, total parenteral of 6 to 10 mEq/L leads to somnolence, hypocalcaemia,
nutrition
hypotension and absent reflexes. Levels more than 10 mEq/L 237
 Table 7: Causes of Hypermagnesemia Table 8: Causes of Hypomagnesemia
Renal failure: Hypermagnesemia up to 2 to 3 mEq/L is seen in end- Gastrointestinal losses: Chronic diarrhoea especially if associated
stage kidney disease. Severe hypermagnesemia is seen only if excess with dietary deficiency, malabsorption, steatorrhoea and small
exogeneous magnesium load is given. bowel resection
Magnesium infusion: Parenteral infusion like treatment for pre- Acute pancreatitis, alcoholic patients
eclampsia, eclampsia Renal losses: Loop and thiazide type diuretics, primary defect in renal
Magnesium enemas and oral ingestion which exceeds the renal tubular magnesium handling, Bartter’s and Gitelman’s syndrome
excretory capacity
Hormonal: Primary aldosteronism
Hormonal: Primary hyperparathyroidism, diabetic ketoacidosis,
adrenal insufficiency Hypercalcaemia: Resulting from increased reabsorption of calcium
in the loop of Henle leading to hypomagnesemia
Tumour lysis syndrome
Milk alkali syndrome Drugs: Aminoglycosides, amphotericin B, cisplatin, cyclosporine,
pentamidine, proton pump inhibitors
causes muscle paralysis, complete heart block, respiratory and Hungry bone syndrome following parathyroidectomy
cardiac arrest.
Management Clinical manifestations
Prevention is by avoiding magnesium loading in patients with The clinical features of hypomagnesemia include tetany,
impaired renal functions. Cessation of magnesium supplements positive Chvostek’s and Trousseau’s signs and generalised
in patients with normal renal function will allow restoration to convulsion. ECG changes include widening of QRS complex,
normal levels. Intravenous calcium gluconate can be given as peaking of the T-waves, prolongation of PR interval and
a magnesium antagonist. Haemodialysis may be required in diminution of T-wave and ventricular arrhythmias, especially
patients with renal failure or with severe life-threatening during myocardial ischaemia. hypomagnesemia can also
hypermagnesemia. present along with hypocalcaemia. Mild hypomagnesemia can
lower the plasma concentration of calcium. Vitamin D
Hypomagnesemia deficiency is also noted in hypocalcaemic and hypo-
Hypomagnesemia is especially common in intensive care magnesemic patients.
unit settings with nutrition, diuretics, etc. In the presence of
Management
hypomagnesemia, kidney can decrease the renal excretion.
Hypomagnesemia can occur in the setting of gastrointestinal It is important to correct the underlying cause of hypo-
or renal losses. However, it is often associated with other magnesemia, e.g. stopping the offending drug. Magnesium
metabolic abnormalities like hypokalaemia, hypocalcaemia and is replaced by oral route in asymptomatic patients or
metabolic acidosis. those with mild deficiency by sustained release formulations,
dose being 2 to 4 tablets per day. Intravenous magnesium
Causes of hypomagnesemia replacement is required in conditions like ventricular
Causes of hypomagnesemia are listed in Table 8. arrhythmias and tetany.

238
 7.4 Acid Base Disorders

Alladi Mohan, Surendra K Sharma

INTRODUCTION Table 1: Relationship between pH and [H+]

In critical care practice, a wide range of disorders affecting the
pH [H+] (nmol/L)
acid-base balance are encountered. In addition to diseases that
cause primary acid-base disorders, a number of disease states 6.8 158
either predispose patients to develop these conditions or 6.9 125
require the use of medications that alter renal, gastrointestinal, 7.0 100
or pulmonary function and secondarily alter acid-base balance. 7.1 79
The history and physical examination and measurement of 7.2 63
blood and urinary indices allow identification of the underlying 7.3 50
cause of these disorders in most cases. Arterial blood gas (ABG) 7.4 40
analysis, considered to be one of the most precise measure- 7.5 31
ments in medicine, is a crucial investigation that is frequently 7.6 25
employed in the critical care setting. It provides valuable 7.7 20
precise information regarding the acid-base, ventilation and 7.8 15
oxygenation status of the patient.
Dissolved carbon dioxide (CO2) is in equilibrium with carbonic acid
BASIC PHYSIOLOGICAL AND CHEMICAL CONCEPTS
Carbonic anhydrase
Interpretation of the ABG report requires a clear under- CO2 + H2O ⎯⎯⎯⎯ → H2CO3–
standing of the basic concepts and physiological principles →
⎯ ⎯ ⎯⎯
underlying the disorders of acid-base homeostasis, Carbonic acid ionizes according to the equation
oxygenation and ventilation. A brief overview regarding the Carbonic anhydrase
essential fundamental physiological concepts is provided and H2CO3 ⎯⎯⎯⎯ → H+ + HCO3–
a practical approach for the bed-side interpretation of ABG By the law of mass action
results is described.
[H+] [HCO3–]
Acid-Base Chemistry = K’
pH [H2CO3 ]
The concept of pH was put forward by the Danish chemist, Soren Taking logarithm on both sides, we have
Peter Sorensen in 1909 to refer to the negative logarithm of [H+] [HCO3–]
hydrogen ion (H+) concentration. log = log K’
+
pH = – log [H ] [H2CO3]
Therefore,
The pH is a ‘dimensionless representation’ of the H +
concentration, it has no units and is just a number. There are [HCO3–]
several advantages of the expression pH compared to H+. log [H+] + log = log K’
[H2CO3]
Measured by the pH electrode, pH is related to the logarithm of
H+ ‘activity’ rather than ‘concentration’ of H+ and this seems and
physiologically more appropriate. The relationship between pH [HCO3–]
and H+ is shown in Table 1. For each 0.1 pH unit increment, H+ +
log [H ] = log K’ – log
falls by 20%; by remembering this relationship, the intermediate [H2CO3]
values can be derived accurately.
By changing signs on both sides of the equation, we have
Overview of Acid-Base Balance in the Human Body
[H2CO3–]
The normal extracellular fluid (ECF) H+ concentration is 40 – log [H+] = – log K’ + log
nmol/L. Under normal physiological conditions, the H + [H2CO3]
concentration varies little from its normal value due to the +
Since – log [H ] is called pH and – log K’ is called pK, the equation
processes of acid-base regulation as maintenance of H + can be re-written as
concentration at this level is considered to be essential for
normal cellular processes. In order to achieve this, close [HCO3–]
pH = pK + log
interaction between three physiological systems of the body,
[H2CO3 ]
namely, the chemical buffers of the body namely kidneys and
the lungs is considered essential. This has been called the ‘Henderson-Hasselbalch’ equation.
239
 The pK represents the pH at which maximum buffering capacity in Table 3. The typical alterations in the ABG results and the
can be achieved for that reaction. Since the carbonic acid expected compensatory mechanisms in simple acid-base
concentration is dependent on the amount of dissolved CO2 disorders are listed in Tables 4A and B.
which in turn is dependent on its solubility and the partial
pressure of carbon dioxide (PaCO 2) in the arterial blood. Table 2: Nomenclature for Clinical Interpretation of ABG
Therefore, in this equation, H2CO3 can be substituted by s x Measurements: Acid-Base Status
PaCO2, where, s = solubility coefficient. In the clinical setting, Acidosis is an abnormal process or condition which would lower
pK = 6.1; s = 0.0301. arterial pH if there were no secondary changes in response to the
primary aetiological factor
Therefore,
Alkalosis is an abnormal process or condition which would raise
[HCO3–] arterial pH if there were no secondary changes in response to the
pH = 6.1 + log primary aetiological factor
0.0301 × PaCO2
Acidaemia = Arterial pH < 7.36
The body responds to the perturbations in the acid-base Alkalaemia = Arterial pH > 7.44
balance by buffering, which is the immediate response followed
Simple acid-base disorders are those in which there is a single
by respiratory (alteration in ventilation) and renal (alteration in primary aetiological acid-base disorder
bicarbonate excretion) responses.
Mixed acid-base disorders are those in which two or more primary
The major buffer system in the ECF is the CO2-bicarbonate buffer aetiological disorders are present simultaneously
system. Other buffer systems that play a role in buffering are Respiratory disorders are caused by abnormal processes which
protein and phosphate buffer systems. In the blood, tend to alter pH because of a primary change in PaCO2 levels
concentration of phosphate is very low and it is quantitatively Metabolic disorders are caused by abnormal processes which tend
unimportant. Protein buffers in blood include haemoglobin and to alter pH because of a primary change in HCO3–
plasma proteins. Haemoglobin is an important blood buffer
ABG = Arterial blood gas; PaCO2 = Partial pressure of carbon dioxide;
particularly for buffering CO 2. According to the ‘isohydric HCO3– = Bicarbonate
principle’, at a given moment, all buffer systems which
participate in defense of acid-base changes are in equilibrium Table 3: Normal Laboratory Values and Acceptable Therapeutic
with each other. It is important to remember that the carbonate Ranges for pH and PaCO2
and phosphate salts in bone act as a long-term supply of buffer,
Variable Mean 1SD 2SD Acceptable
especially during prolonged metabolic acidosis.
Therapeutic
NOMENCLATURE FOR CLINICAL INTERPRETATION OF Range
ARTERIAL BLOOD GAS MEASUREMENTS pH 7.40 7.38-7.42 7.35-7.45 7.30-7.50
The nomenclature for clinical interpretation of ABG PaCO2 (mmHg) 40 38-42 35-45 30-50
measurements are listed in Table 2. Normal laboratory values SD = Standard deviation; PaCO2 = Partial pressure of carbon dioxide
and acceptable therapeutic ranges for pH and PaCO2 are shown

Table 4A: Expected Compensatory Mechanisms in Respiratory Acid-Base Disorders

Acid-base Initial Compensatory Equations for Expected Range of Compensation
Disorder Change Response

Respiratory acidosis ↑PaCO2 ↑HCO3–

Acute For every 10 mmHg↑ in PaCO2, pH decreases by 0.08 units
Expected pH = 7.4 – [0.008 × (PaCO2 – 40)]
Chronic For every 10 mmHg↑ in PaCO2, pH decreases by 0.03 units
Expected pH = 7.4 – [0.003 × (PaCO2 – 40)]
Respiratory alkalosis ↓PaCO2 ↓HCO3–
Acute For every 10 mmHg↓ in PaCO2, pH increases by 0.08 units
Expected pH = 7.4 + [0.008 × (40 – PaCO2)]
Chronic For every 10 mmHg↓ in PaCO2, pH increases by 0.03 units
Expected pH = 7.4 + [0.003 × (40 – PaCO2)]

Table 4B: Expected Compensatory Mechanisms in Metabolic Acid-Base Disorders

Acid-base Initial Compensatory Equations for Expected Range of Compensation
Disorder Change Response

Metabolic acidosis ↓HCO3– ↓PaCO2 ↓PaCO2 = 1.2 ×  (HCO3–)

Expected PaCO2 = [1.5 × (HCO3–) + 8] ± 2 (Winter’s formula)
Metabolic alkalosis ↑HCO3– ↑PaCO2 ↑PaCO2 = 0.7 ×  (HCO3–)
Expected PaCO2 = [0.7 × (HCO3–) + 21] ± 2
240
 Acid Base Disorders
Indices for Acid-Base Balance Examples:
Indices for acid-base balance include PaCO2, actual bicarbonate, 1. pH 7.06, PaCO2 = 74, predicted pH = 7.23
standard bicarbonate and buffer base. Standard bicarbonate is Difference between predicted and measured
the measurement made in the clinical laboratory after the blood pH = 7.23 – 7.06 = 0.17
has been equilibrated at 37oC with a PaCO2 of 40 mmHg. Actual
Applying 2/3 rule, 0.17 × 2/3 = 0.11
bicarbonate is calculated from PaCO2 and pH using Henderson-
Hasselbalch equation. Base excess is defined as the number Base deficit = 11 mEq/L
of mEq of acid or base needed to titrate 1 L of blood to a pH of 2. pH 7.48, PaCO2 = 20, predicted pH = 7.60
7.40 at 37oC while PaCO2 is held constant. For quick bed-side Difference between predicted and measured
calculation, it can be assumed that at PaCO2 held constant at 40 pH = 7.6 – 7.48 = 0.12
mmHg, 7 mEq of acid or base are required to change pH by
Applying 2/3 rule, 0.12 × 2/3 = 0.08
1 unit (0.10). Base excess (or deficit), which is a true reflection of
non-respiratory component of acid-base balance, is an estimate Base deficit = 8 mEq/L
and not an actual measurement. Therefore, it will be reliable 3. pH 7.20, PaCO2 = 90
only if the measurements used to derive it, the pH and PaCO2 90 – 40 = 50
are estimated accurately. Base excess is determined as follows:
PaCO2 variance = 0.50
Calculating PaCO2 Variance 0.50 × ½ = 0.25
First, the PaCO2 variance is determined by calculating the Predicted respiratory pH = 7.40 – 0.25 = 7.15
difference between the measured PaCO2 and 40; then, the Difference between predicted and measured
decimal point is shifted two places to the left. pH = 7.20 – 7.15 = 0.05
Example: Applying 2/3 rule, 0.05 × 2/3 = 0.033
pH 7.06, PaCO2 = 74 Base excess = 3 mEq/L
74 – 40 = 34 Base excess/deficit calculation serves as a useful guide for
PaCO2 variance = 0.34 bicarbonate administration.
pH 7.48, PaCO2 = 20 Anion Gap
40 – 20 = 20 Anion gap (AG) represents the concentration of all the
PaCO2 variance = 0.20 unmeasured anions in the plasma (Table 5) and is calculated
Calculating Predicted pH by the following formula:
Predicted respiratory pH is calculated as follows. If the PaCO2 is AG = [Na+] – [Cl–] + [HCO3–]
greater than 40, half the PaCO2 variance is subtracted from 7.40. Normal AG is 12 ± 4 mEq/L. Conditions resulting in metabolic
If PaCO2 is less than 40, the PaCO2 variance is added to 7.40. acidosis other than hydrochloric acidosis usually lead to a
Examples: decrease in the serum bicarbonate concentration without a
concomitant rise in serum chloride thereby increasing the AG.
1. pH 7.06, PaCO2 = 74
74 – 40 = 34 Table 5: Unmeasured Anions and Cations Contributing to the
PaCO2 variance = 0.34 Anion Gap
0.34 × ½ = 0.17 Unmeasured Anions Unmeasured Cations
Predicted respiratory pH = 7.40 – 0.17 = 7.23 Serum proteins, mostly serum Calcium (5 mEq/L)
2. pH 7.48, PaCO2 = 20 albumin (15 mEq/L)
40 – 20 = 20 Organic acids (5 mEq/L) Potassium (4.5 mEq/L)
Phosphates (2 mEq/L) Magnesium (1.5 mEq/L)
PaCO2 variance = 0.20
Sulphates (1 mEq/L)
Predicted respiratory pH = 7.40 + 0.20 = 7.60
Total = 23 mEq/L Total = 11 mEq/L
Estimate of Base Excess/Deficit
Delta Ratio
The difference between the predicted respiratory pH and the
measured pH reflects the metabolic pH change. Normally, a Delta ratio is related to the AG and buffering, and is defined as:
10 mEq/L variance from normal buffer baseline represents a Delta ratio = increase in AG/decrease in bicarbonate
pH change of 0.15. If the pH decimal point is moved two places
A high delta ratio can occur when the bicarbonate levels are
to the right, a 10 (10 mEq/L) to 15 (0.15) relationship will be
already elevated at the onset of the metabolic acidosis either
evident and this has been expressed as “ 2/3 relationship”. due to a pre-existing metabolic alkalosis, or as a compensation
By determining the difference between the measured pH and for pre-existing respiratory acidosis. A low delta ratio occurs with
the predicted respiratory pH, moving the decimal point two hyperchloraemic normal AG acidosis (Table 6).
places to the right and multiplying by 2/3, base excess/deficit
can be calculated. DIAGNOSIS OF ACID-BASE DISORDERS
When the measured pH is greater than the predicted pH, it is Clinical Assessment
termed as base excess. When the measured pH is less than the Patients with acid-base disturbances (Tables 7A and B) may
predicted pH, it is termed as base deficit. present with symptoms due to the aetiological causes that 241
 Table 6: Utility of Delta Ratio when Assessing Metabolic Acid- Step 1: Validity of the ABG report
Base Disorders First, whether pH, PaCO2 and HCO3– are compatible should be
Delta Ratio Interpretation confirmed using the Henderson-Hasselbach equation which
can also be expressed as:
<0.4 Hyperchloraemic normal AG acidosis
<1 High AG and normal AG acidosis PaCO2
1 to 2 Usual for uncomplicated high AG acidosis H+ = 24 ×
Lactic acidosis: average value 1.6 [HCO3–]
DKA more likely to have a ratio closer to 1 due
to urine ketone loss Step 2: Acidosis or alkalosis?
>2 High AG acidosis and a concurrent metabolic Net deviation in the arterial pH will indicate whether an acidosis
alkalosis or a pre-existing compensated or an alkalosis is present (Table 2). If pH is normal, either no acid-
respiratory acidosis base disorder is present or compensating disorders are present.
AG = Anion gap; DKA = Diabetic ketoacidosis
Step 3: Identifying the primary disturbance: respiratory or
resulted in the disturbance. They may also present with metabolic?
manifestations that develop as a consequence of the Simple acid-base disorders result in a predictable change in
disturbance as well as with symptoms that have nothing to do the PaCO2 and HCO3– (Tables 4A and B). Low PaCO2 and HCO3–
with the acid-base disturbance. Therefore, a carefully obtained indicate respiratory alkalosis or metabolic acidosis; but a mixed
history and a thorough physical examination are essential for disorder cannot be excluded. Elevated PaCO2 and HCO3– indicate
the interpretation of ABG report. The following sequence may respiratory acidosis or metabolic alkalosis; but a mixed disorder
be followed to interpret the ABG report to diagnose acid-base cannot be excluded. If PaCO2 and HCO3– show a change in
disturbances (Figure 1). opposite directions, it is indicative of a mixed disorder.
Table 7A: Causes of Metabolic Acid-Base Disorders
Metabolic Acidosis Metabolic Alkalosis
Elevated AG Alkali load
Endogenous Milk-alkali syndrome
Ketoacidosis Bicarbonate administration
Diabetes mellitus Excess bicarbonate-precursor administration
Starvation Contraction alkalosis
Alcohol-induced Gastric causes
L-Lactic acidosis Vomiting
Hypoxic (e.g., shock, hypoxaemia, severe anaemia, cyanide Gastric aspiration
poisoning,carbon monoxide poisoning) Renal alkalosis
Non-hypoxic (e.g., diabetes mellitus, liver failure, kidney failure, sepsis, Diuretics
drugs [ethanol, ethylene glycol, methanol, salicylates, phenformin], Post-hypercapnoeic metabolic alkalosis
neoplasms) Diarrhoea states
D-Lactic acid acidosis (associated with jejuno-ileal bypass, short bowel Villous adenoma
syndrome or intestinal obstruction; due to formation of D-lactate by Hereditary chloride-losing diarrhoea of infancy
gut bacteria) Uraemic acidosis Metabolic alkalosis without volume contraction
Exogeneous Steroid excess (primary)
Methanol Primary mineralocorticoid excess [e.g. adrenal adenoma
Ethylene glycol (Conn’s syndrome); bilateral adrenal hyperplasia
Salicylates (pseudo-Conn’s syndrome); adrenal carcinoma]
Paraldehyde Cushing’s syndrome
Normal AG Indeterminate hyperaldosteronism
Non-renal Dexamethasone-suppressible hyperaldosteronism
Diarrhoea Secondary aldosterone excess
Pancreatic fistula Renovascular disease
Urinary diversion Renin-secreting tumours
Acid ingestion Errors of steroid metabolism
Renal 11-hydroxylase deficiency
Uraemia 11- dehydrogenase deficiency
Proximal RTA 17- hydroxylase deficiency
Hypokalaemic distal RTA (e.g. classic, amphotericin-induced) Terminal steroid metabolism defect
Hyperkalaemic distal RTA (e.g. short-circuit distal RTA, such as, Liddle’s syndrome
urinary tract obstruction; sickle cell disease; drug-induced) Bartter’s syndrome (loss of function mutations in TALH)
Mineralocorticoid deficiency (e.g. Addison’s disease; selective Gittleman’s syndrome (loss of function mutation in Na+-Cl-
aldosterone deficiency; hyporeninemic hypoaldosteronism) cotransporter in DCT)
Iatrogenic hypermineralocorticoidism
Others Exogenous corticosteroids
Pyroglutamic acidaemia Glycyrrhizic acid
(acetaminophen induced) Carbenoxolone fludrocortisone
242 AG = Anion gap; RTA = Renal tubular acidosis; TALH = Thick ascending limb of Henle’s loop; DCT = Distal convoluted tubule.
 Acid Base Disorders
Table 7B: Causes of Respiratory Acid-Base Disorders
Respiratory Acidosis Respiratory Alkalosis
Neurological causes Pregnancy
Poliomyelitis Pulmonary receptor
Excessive sedative, hypnotic drug use stimulation
Spinal cord injury with quadriparesis Pneumonia
Phrenic nerve palsy Pulmonary embolism
Guillain-Barré syndrome Bronchial asthma
Myasthenia gravis Hypoxia
Eaton-Lambert syndrome High altitude
Paralytic agents Left to right shunts
Botulism Congestive heart failure
Myopathies, muscular dystrophies, Pulmonary oedema
myositis Psychogenic Drugs
Motor neuron disease Theophylline
Electrolyte abnormalities Catecholamines
Hypokalaemia Salicylates
Hypocalcaemia, Progesterone
Hypophosphataemia Doxapram
Chest-wall disease Central nervous system
Scoliosis Subarachnoid
Flail chest haemorrhage
Pleural disease Respiratory centre disease
Pneumothorax Cheyne-Stokes respiration
Massive pleural effusion Cirrhosis of liver
Obstructive airway disease Fever
Acute tracheal, laryngeal, bronchial Sepsis
obstruction Errors of ventilator
Obstructive sleep apnoea management
Diffuse (small-airway) obstruction Excessive tidal volume
Errors of ventilator management Excessive ventilation rate
Excessive dead space
Insufficient tidal volume
Insufficient ventilation rate
Others
Myxoedema (idiopathic alveolar hypoventilation)
Oxygen therapy in chronic hypoxia

Figure 1: Stepwise approach for interpretation of an arterial blood gas (ABG)

Step 4: For respiratory disturbance: acute or chronic?
analysis report and assessment of acid-base status.
In acute respiratory disturbances, a PaCO2 variation from normal
AG = Anion gap; PaCO2 (mmHg); HCO3– (mEq/L)
by 10 mmHg is accompanied by a pH shift of approximately
0.08 units. In chronic respiratory disturbances, renal
compensation and bicarbonate shift requires several hours to accounts for a significant proportion of the unmeasured
develop and is likely to be maximal after 4 days. Thus, during anions (Table 5). A 50% reduction in the serum albumin
chronic respiratory disturbances, a PaCO 2 variation from concentration will result in a 75% reduction in the AG. In
normal by 10 mmHg is accompanied by a pH shift of only 0.03 patients with severe hypoalbuminaemia, eventhough
(Table 4A). If the expected values and the actual values match, elevated AG metabolic acidosis is actually present, the
a mixed disorder is unlikely. If the expected values and the actual measured AG may be less than or equal to 12. So, in a patient
values differ, a mixed disorder is present. with severe hypoalbuminaemia if the AG increases and
approaches 12, an additional metabolic cause for the
Step 5: For metabolic acidosis, calculating the anion gap increased AG must be suspected and looked for.
The AG should be measure in all patients with metabolic
acidosis. For the purposes of routine clinical use, AG greater than Two methods are used to correct the AG for the influence of
12 is considered to be elevated AG. Causes of elevated AG albumin in patients with hypoalbuminaemia. The expected AG
metabolic acidosis can be remembered with the mnemonic is calculated using the serum albumin and phosphate
MULEPAKIR [M = methanol poisoning; U = uraemia; L = lactic concentrations, as follows:
acidosis; E = ethylene glycol poisoning; P = paraldehyde Expected AG (mEq/L) = (2 × albumin [g/dL]) +
ingestion; A = aspirin overdosage; K = ketoacidosis (diabetic (0.5 × PO4 [mg/dL])
keotacidosis; alcoholic ketoacidosis and starvation); I = isoniazid
The expected AG is then compared with the AG calculated using
overdosage; and R = rhabdomyolysis].
the formula (Na+ - [Cl– + HCO3–]). If the calculated AG is found to
Serum albumin level has important bearing while calculating be more than the expected AG, the difference is attributed to
the AG. Albumin has a negative charge on its surface and unmeasured anions from non-volatile acids. 243
 Alternatively, adjusted AG can be calculated using the formula: concurrent respiratory disturbance is also concurrently present,
it would be defined by the direction the PaCO2 varies beyond
Adjusted AG = Calculated AG + 2.5 × [4.5 – measured
the range predicted by Winter’s formula rather than the PaCO2
albumin (g/dL)]
variation from the normal value of 40.
Conditions causing normal AG acidosis (≤12) can be
In metabolic alkalosis, the magnitude of respiratory
remembered by the acronym ACCRUED (A = acid infusion;
compensatory response is not easily predictable because
C = compensation for respiratory alkalosis; C = carbonic
degree of PaCO2 increase does not exhibit an exactly linear
anhydrase inhibitors; R = renal tubular acidosis; U = ureteral
relationship with the HCO3-. However, for practical purposes,
diversion; E = extra-alimentation or hyper-alimentation; D =
the following equation has been found to be useful to
diarrhoea). Normal AG metabolic acidosis can also be grouped
as per the serum potassium levels. Causes of normal AG acidosis calculate the expected:
with a normal to high potassium include hyperaldosteronism, PaCO2 = [0.7 × (HCO3–) + 21] ± 2
type IV renal tubular acidosis (RTA), moderate degree of renal
In compensated metabolic alkalosis, the measured PaCO2 is
failure, administration of hydrochloric acid and post-
hypocapnia. Normal AG acidosis with a low potassium level can equivalent to the expected PaCO2. If the measured PaCO2 is
be seen in proximal type II RTA and distal type I RTA. higher than the expected PaCO2, the respiratory compensation
is not adequate, and the condition is termed as a primary
When urine electrolytes are available, assuming a urine pH of metabolic alkalosis with a superimposed respiratory acidosis.
less than 6.1 and euvolaemia, urinary AG, [calculated as urinary In primary metabolic alkalosis with a superimposed respiratory
(Na+ + K+) – Cl–] can help in distinguishing renal from non-renal alkalosis, the PaCO2 is lower than the expected.
causes. A negative urinary anion gap indicates a non-renal cause
of acidosis (e.g. diarrhoea). TREATMENT
Others The aetiological causes responsible for acid-base disturbances
Delta ratio is also useful in the assessment of elevated anion largely determine the status and prognosis in patients with acid-
gap metabolic acidosis to determine if a mixed acid-base base disorders. Therefore, it is essential to recognise the
disorder is present. Osmolar gap is also useful in differentiating underlying cause responsible for the disturbance so that
the causes of elevated AG metabolic acidosis. Osmolar gap is specific treatment can be instituted.
calculated by subtracting the calculated serum osmolality from Metabolic Acidosis
measured osmolality using the formula shown below: Metabolic acidosis may induce a wide range of adverse
Glucose (mg/dL) clinical effects, some of which may be life-threatening. In life-
Calculated osmolality = 2[Na+ (mEq/L)] + threatening metabolic acidosis, exogeneous alkali therapy
18 aims to prevent or reverse the detrimental consequences
Blood urea nitrogen (mg/dL) of severe acidaemia affecting the cerebral, respiratory,
+
2.8 metabolic and cardiovascular systems. Intravenous sodium
bicarbonate is the mainstay of alkali therapy and should be
given judiciously in amounts that will return blood pH to a
Osmolar gap = Measured osmolality – Calculated osmolality safer level of about 7.20. The distribution of HCO3– being 40%
Osmolar gap > 10 mOsm/L is considered abnormal when of the body weight, the amount of HCO3– required to return
calculated using this formula. Conditions causing increased the serum concentration to normal can be calculated as
osmolar gap metabolic acidosis include ethanol, ethylene glycol, follows:
methanol, acetone and propylene glycol poisoning. While a high HCO3– deficit = Body weight (kg) × 0.4 ×
AG, high osmolar gap metabolic acidosis is seen in methanol (desired HCO3– – measured HCO3–)
and ethylene glycol poisoning, normal AG, high osmolar gap
metabolic acidosis is seen in isopropyl alcohol poisoning. Except in situations of extreme acidaemia, sodium bicarbonate
should be administered as an infusion rather than a bolus; about
Step 6: Determining whether other metabolic disturbances 30 minutes must elapse following the completion of the
co-exist with an elevated anion gap acidosis infusion before its clinical effect can be judged. One-half of the
A normal AG acidosis or a metabolic alkalosis may exist calculated deficit can be replaced in 3 to 4 hours, if severe heart
concurrently with an elevated AG acidosis. In this situation, failure is not present. Subsequently, monitoring of the patient’s
corrected bicarbonate should be calculated as follows: acid-base status will determine additional alkali requirements.
Corrected HCO3– = measured HCO3– + (AG – 12) Alterations in respiratory function, dyselectrolytaemia
(especially hypokalaemia) and hypo-tension must be
where, AG = anion gap recognised and treated. Specific therapy is required in the
If the corrected HCO3– is greater than 24, a metabolic alkalosis setting of poisoning and overdosage. Chronic metabolic
co-exists; if it is less than 24, then a normal AG metabolic acidosis acidosis (e.g. chronic kidney disease) is treated with oral sodium
co-exists. bicarbonate.
Step 7: Assessing the normal compensation by the respiratory Metabolic Alkalosis
system for a metabolic disturbance Metabolic alkalosis is usually mild; when severe (pH >7.6) or
In simple metabolic acidosis, the measured PaCO2 will fall rapidly developing it may be life-threatening. The chloride-
244 within the range predicted by Winter’s formula (Table 4B). If a responsive metabolic alkalosis can be treated with intravenous
 Acid Base Disorders
saline administration. When alkalosis is severe, or there is a risk 2. Adrogué HJ, Madias NE. Management of life-threatening acid-base
of volume overload, 1N hydrochloric acid administration may disorders. Second of two parts. N Engl J Med 1998; 338: 107-11.
be required. Chloride-unresponsive alkaloses are more difficult 3. Driscoll P, Brown T, Gwinnutt C,Wardle T. A Simple Guide to Blood Gas Analysis.
to treat and treatment is directed at the underlying cause. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2002.
4. Fall PJ. A stepwise approach to acid-base disorders. Practical patient
Respiratory Acidosis evaluation for metabolic acidosis and other conditions. Postgrad Med 2000;
Treatment of respiratory acidosis is directed at improving 107: 249-50, 253-4, 257-8 passim.
ventilation using non-invasive or invasive ventilatory strategies; 5. Laski ME, Kurtzman NA. Acid-base disorders in medicine. Dis Mon 1996; 42:
administration of bicarbonate can be harmful and should be 51-125.
avoided. 6. Mohan A, Sharma SK. An approach to interpret arterial blood gases. In
Agarwal AK, editor Clinical Medicine Update 2006; Vol. IX. A publication of
Respiratory Alkalosis Indian Association of Clinical Medicine. New Delhi: Jaypee Brothers Medical
Treatment of respiratory alkalosis should be directed towards Publishers (P) Ltd; 2006; pp 73-81.
the underlying cause, identification and correction of 7. Mohan A, Sharma SK. How to interpret blood gas data. In: Singal RK, editor
electrolyte abnormalities that usually co-exist. Usually, re- Medicine Update. Mumbai: Association of Physicians of India; 2007:pp (17):
assurance, re-breathing from a bag or treating the underlying 145-51.
psychological stress is enough to alleviate respiratory alkalosis. 8. Morganroth ML. An analytic approach to diagnosing acid-base disorders.
J Crit Ill 1990; 5: 138-50.
Controlling fever, seizure activity and sepsis will also help.
9. Morganroth ML. Six steps to acid-base analysis: clinical applications. J Crit
RECOMMENDED READINGS Ill 1990; 5: 460-9.
1. Adrogué HJ, Madias NE. Management of life-threatening acid-base 10. Narins RG, Emmett M. Simple and mixed acid-base disorders: a practical
disorders. First of two parts. N Engl J Med 1998; 338: 26-34. approach. Medicine (Baltimore) 1980; 59: 161-87.

245
 7.5 Enteral and Parenteral Nutrition in
Critically Ill Patients
Shilpa S Joshi

Feeding is not considered medical therapy under ordinary Advantages of Enteral Feeding
circumstances. But when patients are critically ill and cannot Various advantages of enteral feeding are: (i) it is a preferred
eat themselves food takes the form of medical therapy. route of nutrition support as it is more physiologic, (ii) cost-
The incidence of hospitalised malnutrition is well documented, effective, (iii) safe, (iv) fewer side-effects as compared to
especially in critically ill patients. Despite the advances in parenteral nutrition, (v) maintenance of GI immune barrier, (vi)
medicine, definitive indications for the use of nutritional support avoidance of central catheter related complications. The
are unclear. Use of enteral and parenteral therapies should be indications for enteral feeding are listed in Table 1.
widespread for various reasons:
Table 1: Indications of Enteral Feeding
1. Protein calorie malnutrition is common in a variety of
hospitalised patients. Oral intake inadequate or Mechanical: stroke, central nervous
system
2. Documented association between malnutrition and contraindicated Disorders, coma, oropharyngeal and
increased morbidity and mortality. oesophageal disorders, partial or
3. It seems intuitive that well-nourished patients would complete oesophageal or gastric
respond more favourably to therapeutic interventions than obstruction
malnourished patients. Poor appetite: chemotherapy,
radiation therapy, drug effect, nausea
4. Nutritional support can be provided safely to a wide variety Transitional feeding: advance from
of patients. parenteral to oral intake
5. Several randomised prospective clinical trials showed that Psychological: anorexia nervosa,
nutritional support benefits the patients. depression, Alzheimer’s disease
Increased nutritional Burns, trauma, sepsis, surgical or
Therefore, there is a clear-cut evidence base for the role of requirements medical stress
enteral and parenteral therapies in hospitalised as well as Digestive and absorptive Inflammatory bowel disease, short
critically ill patients. disorders bowel syndrome, pancreatitis,
irradiated bowel, proximal and distal
Nutritional support is a delivery of formulated enteral or intestinal fistulae, immunocompro-
parenteral nutrients to appropriate patients for the purpose of mised syndromes
maintaining/restoring nutritional status. Metabolic and excretory Glycogen storage disease, hepatic
disorders encephalopathy, renal disease
ENTERAL NUTRITION
By definition, enteral nutrition means ‘within or by the way Contraindications of Enteral Feeding
of gastrointestinal (GI) tract’. In practice, enteral nutrition is Enteral feeding is contraindicated in patients with peritonitis, distal
generally considered tube feeding. The consensus of nutritional intestinal obstruction, intractable vomiting or severe diarrhoea.
experts is that the GI tract is more physiologically and
metabolically effective than the intravenous route for nutrient ASSESSMENT OF NUTRITIONAL NEEDS OF A PATIENT
utilisation. Any disease process that adversely affects oral intake Before initiation of feedings, assessment of nutritional status
may ultimately lead to significant nutritional deprivation and of every patient is fundamental and includes some key
depletion. Patients who cannot eat, will not eat, or should not components: nutritional history, anthropometric procedure,
eat, yet who have adequate function of the GI tract, are clinical examination, biochemical data, evaluation of weight loss
candidates for enteral tube feeding. and previous nutrient intake before admission, level of disease
Once the patient has been assessed and found to be a good severity, co-morbid conditions, and function of the GI tract.
candidate for enteral nutrition, the clinician selects the Assessment of these parameters will help to document
appropriate tube and route of access for tube placement. presence of malnutrition and will help clinician to select best
Enteral access selection depends on several factors as given method for providing nutrients and allows objective
below: monitoring of nutritional efforts. These assessment are also
1. Anticipated length of time for which enteral feeding will needed to estimate caloric protein, micronutrient requirement
be required and also help to select/make right kind of formula.
2. Degree of risk for aspiration or tube displacement
FORMULA COMPOSITION
3. Presence or absence of normal digestion and absorption
4. Whether or not there is a planned surgical intervention Energy
5. Administration issues such as formula viscosity and The target goal of enteral nutrition (defined by energy
246 volume. requirements) should be determined and clearly identified at
 Enteral and Parenteral Nutrition in Critically Ill Patients
the time of initiation of nutritional support therapy. Energy function of lymphocytes to preserve muscle glutamine pool
requirements may be calculated by Harris Benedict equation, and to improve overall nitrogen balance.
which is as follows:
Arginine
Males (kJ/day): REE = 278 + 58 (Wt) + 21 (H) -28.5 (Af) x SF Arginine is a conditionally essential amino acid, i.e. it can be
Females (kJ/day): REE = 2734 + 40 (Wt) + 7.7 (H) -19.7 (Af) x SF conditionally essential after injury. Human and animal studies
have shown that increased intake of arginine after trauma
where, kJ = Kilo Joules; REE = Required energy requirement;
decreases nitrogen losses and accelerate wound healing.
Wt = Weight in kilograms; H = Height in meters, Af = Activity
factor, and SF = Stress factor Standard formulas contain arginine in the amount of 1 g and
2 g/L. Arginine enriched formulas contain 14 to 15 g/L.
Values for activity factor and stress factor for various diseases
to be considered as standard are given below: Nucleotides
Activity factor (AF) Stress factor (SF) Nucleotides are added to some formulas as immunity enhancers.
Bed rest = 1.0 Post-operative with In animals, dietary supplementation of nucleotides has shown
complication = 1.24 to facilitate growth and maturation of developing gut.
Ambulatory = 1.1 Skeletal trauma = 1.1-1.3
Agents such as ribonucleic acid (RNA) nucleotides increase total
Active = 1.2-1.3 Sepsis = 1.3-1.6
lymphocyte count, lymphocyte proliferation and thymus function.
Cancer = 1.2
where, 1 calorie is about 4.185 kJ. Taurine
Taurine is conditionally essential nutrient since it can be
Efforts to provide more than 50% to 65% of goal calories should
synthesised by dietary cysteine or methionine.
be made to achieve the clinical benefit of enteral nutrition
over the first week of hospitalisation. Studies suggest that more EPA-DHA
than 50% to 65% of goal calories may be required to prevent Omega-3 fatty acids eicosapentaenoic acid and docoso-
increases in intestinal permeability in burn and bone-marrow hexaenoic acid displace omega-6 fatty acids from the cell
transplant patients, to promote faster return of cognitive membranes of immune cells. This effect reduces systemic
function in head injury patients and to improve outcome from inflammation through the production of alternative biologically
immune modulating enteral formulations in critically ill patients. less active prostaglandins and leukotrienes.
If unable to meet energy requirements (100% of target Patients with acute respiratory distress syndrome and severe
goal calories) after 7 to 10 days by the enteral route alone, acute lung injury should be placed on an enteral formulation
consider initiating supplemental parenteral nutrition. Initiating characterised by an anti-inflammatory lipid profile (i.e. omega-
supplemental parenteral nutrition before this 7 to 10 days 3 fish oils, borage oil) and antioxidants.
period in the patients already on enteral nutrition does not
improve outcome and may be detrimental to the patient. High Nitrogen Products
These have increased proportions of branched chain amino
Proteins
acids. These products are used for patients with catabolic stress.
Proteins in the diet serve as a source of amino acids that body
cannot make (essential amino acids) and provide nitrogen for Most of formulas contain a non-protein kcal: nitrogen ratio of
the synthesis of other amino acid (non-essential amino acids). 150:1 (with ranges between 100:1–200:1) which is thought to
Insufficient protein intake can potentially affect all aspects of a be optimal for patients.
patient’s care, for example, it can lead to muscle atrophy and Most of the enteral formulations offer high nitrogen products.
can make it difficult to wean off the patient from ventilator. In Patients who do not need high nitrogen formulas are likely to
addition to the importance of adequate amounts of protein is use amino acids for energy and increase urea production. As a
the quality of protein. result this formula should be given carefully to renal patients.
Proteins can be modified in various ways in enteral formulation, Carbohydrates
for example intact protein, hydrolysed protein, amino acids. Intact
Carbohydrates (CHO) provide 30% to 90% of total calories of
proteins and protein isolates requires normal pancreatic enzymes
enteral formulas and in most of the formulas these are the
to catabolise them into small polypeptides and free amino acids.
principle source of energy. The main difference among the
Hydrolysed protein formulas can be directly absorbed into the formulas is the form and composition of CHO. In general, the
blood stream. These feeds can be administered when the feeds longer carbohydrate molecule are less osmotic, taste less sweet
are administered via jejunum and where only absorption of are require more digestion than the shorter ones.
proteins takes place.
Lactase deficiency is most prevalent disaccharide deficiency
IMMUNOMODULATORY AGENTS and hence, most of the enteral formulas are lactose free.
Glutamine and Branched Chain Amino Acids Fibre
Glutamine and branched chain amino acids are amino acids Enteral formulas containing fibre may have potentially clinical
found in skeletal muscles. These have been identified as key applications including ameliorating constipation and tube
amino acids in preserving nitrogen balance during stress and feeding-associated diarrhoea, improving mucosal healing in
injury. Numerous studies have indicated that glutamine is inflammatory bowel disease, supporting gut barrier of critical
necessary to maintain integrity of intestinal mucosa, immune ill patient and increasing intestinal adaptation in short bowel 247
 syndrome. Predominant source of fibre of enteral formula is soya solution in water. These particles include electrolytes, minerals,
derived polysaccharides. carbohydrates, proteins or amino acids and are expressed in
milli osmoles per kilogram of water. All nutrients and dietary
Soluble fibre may be beneficial for the fully resuscitated,
components except water contribute to osmolality solution. It
haemodynamically stable critically ill patient receiving enteral
has been widely thought that isotonic formulas (osmolality
nutrition who develops diarrhoea. Insoluble fibre should be
ranging from 280 to 320 milli osmoles/kg) are tolerated well
avoided in all critically ill patients. Both soluble and insoluble
than hyper or hypotonic formulas.
fibre should be avoided in patients at high-risk for bowel
ischaemia or severe dysmotility. Renal Solute Load
Lipids Renal solute load refers to the constituents in the formula that
must be excreted by the kidneys. Protein, sodium, potassium,
Fat is a dense source of energy and also serves as a vehicle for
and chloride are the major constituents of enteral formulas that
fat soluble vitamins and essential fatty acids. Most of the enteral
contribute to the renal solute load. It is important, as there is
formulas contain vegetable oil as primary source of fat.
obligatory water loss with each unit of solute.
Vegetable oil is also a good source of essential fatty acids. Fat
does not contribute to osmolality of enteral formula. Nutritional Formulations
Long Chain Triglycerides A wide variety of commercially prepared formulas with variable
Vegetable oils are predominant source of fat in enteral formulas. sources and concentrations of protein, carbohydrate and fat are
Long chain triglycerides are slowly cleared from blood stream currently available.
and require carnitine for its absorption. Polymeric Formulas
Medium Chain Triglycerides (MCTs) Polymeric formulas are composed of intact proteins,
MCTs are 6 to 12 carbon long and are usually prepared disaccharides and polysaccharides and variable amount of fat.
from palm kernel or coconut oil. They offer many advantages The osmolality of polymeric formula is usually lower than that
over long chain triglycerides, as they are absorbed intact of elemental formulas. These formulas require a functioning GI
without appreciable pancreatic or biliary function and are tract for digestion and absorption of nutrients. Polymeric
subjected to more rapid clearance from blood stream. They formulas can be further subdivided into hypercaloric formulas,
are transported to the liver principally via portal venous normocaloric formulas, etc.
system where they cross mitochondrial membrane and can Pre-Digested Formulas
be oxidised independent of carnitine. These should not be Pre-digested formulas are composed of low molecular nutrients,
used in patients who are prone to high ketone levels as they have minimal residue and are thought to lead less stimulations
produce ketone. of pancreatic and GI secretion and are less allergic than other
Vitamins, Minerals and Trace Elements formulas. These formulas have greater osmolalities than the
A combination of antioxidant vitamins and trace minerals polymeric formulas because of the small molecule weight of
should be provided to all critically ill patients receiving nutrients.
specialised nutritional therapy. Modular Products
Supplemental vitamins and minerals should be given when Individual macro-nutrients modules, such as glucose polymers,
quantity of formula does not fulfil the requirement. proteins, and lipids, are available as additives to foods and
enteral formulas to change overall fuel composition.
Water
Fluid balance in patients receiving enteral nutrition should be Disease Specific Formulas
monitored. The daily water requirement for a healthy adult is These products are designed for patients who have specific
1 mL/kcal taken for approximately 30 to 32 mL/kg. Minimum medical conditions that may require nutrient modifications.
of 30 mL of water every 6 hours is recommended as a flush for Formula Selections
tube patency alone.
Selection of appropriate formulas is based on patient’s medical
Probiotics and nutritional status, digestive and absorptive capabilities
Administration of probiotic agents has been shown to improve indicate whether pre-digested or polymeric formulas can be
outcome (most consistently by decreasing infection) in specific used.
critically ill patient populations involving transplantation, major
Administration of Tube Feeding
abdominal surgery, and severe trauma. No recommendations
can currently be made for use of probiotics in the general Proper administration of enteral formulas ensures safe delivery
intensive care unit population because of a lack of consistent of desired nutrients, enhanced patient tolerance and optimal
outcome effect. nutritional support. There are various methods of feeding the
patients. Choice of technique depends upon GI function,
PHYSICAL CHARACTERISTICS OF A FORMULA feeding site, and ultimately patient’s response.
Osmolality 1. Bolus feeding
Osmolality is a physical phenomenon of net permeability Bolus feeding is rapid administration of large volumes of
resulting in equilibrium across the cell membrane. It is a measure formula over a short period of time usually by syringe. This
248 of concentration of free particles, molecule or ions in a given form of feeding is least cumbersome but is associated with
 Enteral and Parenteral Nutrition in Critically Ill Patients
increased possibility of aspiration, regurgitation and GI side- RATIONAL OF PARENTERAL NUTRITION
effect. A rate of 30 mL/min or a volume of 500 to 750 mL 1. The patient is well nourished before admission but after 7
per feed appears to mark physical tolerance limit. days of hospitalisation enteral nutrition has not been
2. Continuous feeding feasible or target goal calories have not been met
consistently by enteral alone.
Continuous infusion is controlled delivery of prescribed
volume of formula at a constant rate over a continuous 2. On admission, the patient is malnourished and enteral
period of time using infusion pumps or gravity assisted sets. nutrition is not feasible.
This method is considered advantageous since gastric A major surgical procedure is planned, the pre-operative
cooling is minimised and few GI tract side effects are assessment indicates that enteral nutrition is not feasible
experienced. Continuous infusion into jejunum is more through the peri-operative period and the patient is
analogous to normal gastric emptying. malnourished.
3. Intermediate infusions 3. Indications: The basic indications for the use of parenteral
In intermediate feeding, total quantity of formula needed nutrition are required for nutrition when the GI tract is
for 24 hours is divided into equal portions and required either not working or not available or not appropriate
fractions are administered in 3 to 6 feedings. Each feeding (Table 3).
is administered over 30 to 90 minutes period.
Table 3: Indications for Parenteral Nutrition
Techniques of Feeding
Non functioning gut, e.g. paralytic ileus
1. Selection of appropriate formulas.
Malnourished patients after major abdominal surgery
2. Elevate the head of the patient’s bed to at least 30 degree
Severe mucositis systemic chemotherapy, upper gastrointestinal
to horizontal levels before feeding begins. strictures or fistulae and acute pancreatitis
3. Aspirate through nasogastric or gastrostomy tube before Patients with major resections of the small intestine (short bowel
initiating feeding to determine whether retained gastric syndrome) before compensatory adaptation occurs
secretions are present. Patients in the intensive care unit with systemic inflammatory
4. Begin feeding schedule of 100 to 150 mL of isotonic or response syndrome or multiple organ dysfunction syndromes.
slightly hypertonic formulas every 4 hours.
5. Increase formula amount by 50 mL every 1 or 2 feeding up PARENTERAL MACRONUTRIENTS
to 450 mL every 4 hours. Proteins/Amino Acids
6. Flush the tube at least with 30 mL of water after feeding The primary function of protein in parenteral nutrition is to
and every 4 hours to maintain patency. maintain nitrogen balance, thus, preventing skeletal muscle
Complications of enteral feeding are shown in Table 2. from being degraded from gluconeogenesis. Protein
requirement can be very high during intensely catabolic state.
Table 2: Complications of Enteral Feeding A positive nitrogen balance may not be feasible during the first
few days of the catabolic stress. A positive caloric balance is
Mechanical complications Blockage of tube
Dislocation of tube necessary to establish a positive nitrogen balance. For delivered
Aspiration pneumonia amino acids to be incorporated into new protein rather than
Gastrointestinal complications Delayed gastric emptying
catabolise the ratio of non-protein calories to gram of nitrogen
Constipation should approach 150:1. This ratio is based on the fact that 10%
Malabsorption to 15% or more of required calories during catabolism are
derived from protein breakdown.
PARENTERAL NUTRITION Commercial amino acids are available. Dilute solutions are
Parenteral nutrition is a form of intravenous therapy that most often used for peripheral administration. Amino acid
provides opportunity to replenish or maintain nutritional status. profiles of parenteral solutions are based on Food and
Parenteral nutritional was originally developed to nourish those Agriculture Organisation – World Health Organisation (FAO-WHO)
whose GI tract was not capable of digesting and absorbing recommendations for optimal proportion of essential amino acids.
nutrients.
Carbohydrates
Central parenteral nutrition is delivery of nutrients through the Primary function of parenteral carbohydrate is to serve as
large diameter vein usually subclavian or superior vena cava. energy source. Optimum carbohydrate is an amount adequate
Peripheral parenteral nutrition is usually delivered through to spare protein without exacerbating hyperglycaemia.
small veins usually in the forearm. Central parenteral nutrition Commercial carbohydrates consist of N-hydrate, dextrose
is indicated when volume and concentration of solution monohydrate in sterile water.
preclude peripheral administration and when anticipated
duration of therapy is greater than 7 days to 2 weeks and when Fats
substantial depletion of body fat and protein has occurred. Parenteral lipids provide as a source of essential fatty acids and
Peripheral parenteral nutrition is preferred when solution calories. These can be substituted for dextrose calories for
concentration is less than 1000 mOsm/L and duration of therapy patients with glucose intolerance or used as concentrated
is less than 10 days. caloric source for patients who require volume restriction. Fats 249
 have lower respiratory quotient than carbohydrates, which is a Body maintains serum osmolality between 280-300 mOsm/kL.
rational for use of lipids to provide large proportion of non- To avoid the irritation to veins, solutions with osmolarity greater
protein calories in patients with respiratory failure. Because than 900 mOsm/L are not usually administered peripherally.
fat emulsions are isotonic, these can be administered through
Initiation of Parenteral Nutrition
peripheral vein. Alternatively these may be directly added to
parenteral nutritional solution. Prior to initiation of parenteral nutrition, a baseline biochemistry
profile should be checked and fluid and electrolyte abnormalities
Electrolytes should be corrected.
Electrolytes requirement for patients receiving total parenteral
Monitoring
nutrition may vary depending on body weight, presence of
malnutrition or catabolism, the degree of electrolyte depletion, During the first week of parenteral nutrition (and subsequently
change in organ function, ongoing electrolyte losses and if patient is unstable with respect to fluid and electrolyte or
disease process. metabolic issues) the patient should be monitored intensively.
Vitamins Reintroduction of Diet
Vitamin requirements during parenteral nutrition therapy are Diet should be reintroduced in a graded fashion.
uncertain because these are not based on balanced studies.
COMPLICATIONS
Recommendations for parenteral nutritional therapy have been
made by American Medical Association—Nutrition Advisory The complications of parenteral therapy can be divided into
Group. three categories: (i) technical—pneumothorax, malposition,
subclavian artery puncture, air embolism etc; (ii) septic—
Water catheter related sepsis, septic thrombosis; and (iii) metabolic –
Water requirements vary depending on the capacity of patient hyperglycaemia, hypoglycaemia, hyperkalaemia, hypo-
to excrete an osmotic load. Usually requirements are 30 ml/kg phosphataemia, etc. With proper patient monitoring, most of
in normal adult or approximately 1 ml/kcal delivered. An these complications can be minimised.
additional 360 ml per day is recommended for each centigrade
of temperature elevation. Also 300 to 400 ml of water per day RECOMMENDED READINGS
may be necessary for new intra-celluloid fluid, if anabolism is 1. Barr J, Hecht M, Flavin KE et al. Outcomes in critically ill patients before and
being induced. after the implementation of an evidence-based nutritional management
protocol. Chest 2004; 125: 1446-57.
Restriction of water is necessary during volume overload and 2. Calo L, Bianconi L, Colivicchi F, et al. N-3 fatty acids for the prevention of
presence of hyponatraemia. Patients who become hyperosmotic atrial fibrillation after coronary artery bypass surgery: A randomised,
may need additional free water on daily basis. controlled trial. J Am Coll Cardiol 2005; 45: 1723-8.
3. Martindale RG, McClave SA, Vanek VW, et al. Guidelines for the provision
Trace Elements and assessment of nutrition support therapy in the adult critically ill patient:
Trace elements are those nutrients that make-up less than 4 g Society of Critical Care Medicine and American Society for Parenteral and
Enteral Nutrition. Crit Care Med 2009; 37: 1-30.
or 0.01% of total body content. Individual trace elements may
4. Pontes-Arruda A, Aragao AM, Albuquerque JD. Effects of enteral feeding
be supplemented in appropriate dose as specific patients
with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in
deficiency dictates. mechanically ventilated patients with severe sepsis and septic shock. Crit
Care Med 2006; 34: 2325-33.
Osmolality and Osmolarity
5. Singer P, Theilla M, Fisher H, et al. Benefit of an enteral diet enriched with
While osmolality is most often used in reference to enteral eicosapentaenoic acid and gamma-linolenic acid in ventilated patients
feeding, osmolarity is preferred term for parenteral solutions. with acute lung injury. Crit Care Med 2006; 34: 1033-8.

250
 7.6 Acute Respiratory Failure

Ashit M Bhagwati

INTRODUCTION Table 1: Aetiology of Type 1 Respiratory Failure

Respiratory system is responsible for gas exchange in the human Respiratory System
body. Inability to maintain a normal state of gas exchange leads Airway disease: Asthma, COPD
to respiratory failure. Disorders involving the respiratory centre Parenchymal:
in the brain, peripheral nerves, respiratory muscles, airways, Airspace: Pneumonia (bacterial, viral, mycoplasmal, fungal),
pleura, lung parenchyma and the chest wall can lead to atelectasis, bronchiectasis, and tumours
compromise of gas exchange; thereby leading to a clinical Vascular: Pulmonary embolism, fat embolism, pulmonary arterial
scenario of acute respiratory failure (ARF). ARF is one of the most hypertension
common life-threatening disorders encountered in the intensive Pleura: Pneumothorax
care unit (ICU) and is associated with poor prognosis. Chest Wall: Flail chest
DEFINITION Cardiovascular System
Pulmonary oedema (cardiac failure), cyanotic congenital heart
Clinically, respiratory failure occurs when hypoxaemia (PaO2 is disease
less than 60 mmHg), i.e. inadequate oxygenation of the blood Miscellaneous: Obesity
or hypercarbia (arterial PCO2 is >50 mmHg), i.e. excess content
of circulating carbon dioxide; or frequently, a combination of Physiology
both types of gas exchange abnormalities occur.
The process of gas exchange has two components: the flow of
CLASSIFICATION gas between the atmosphere and the terminal airways; and the
diffusion of gases between the terminal lung regions and the
ARF is classified as hypoxaemic respiratory failure (type 1), hyper-
pulmonary capillary blood. The efficiency of gas exchange
capnic respiratory failure (type 2), post-operative/peri-operative
can be evaluated clinically by measuring the PAO2, PaCO2 and
respiratory failure (type 3) and shock-related respiratory failure
the alveolar-arterial (A-a) PO 2 gradient. Thus, patients with
(type 4).
hypoxaemia may be divided into those with a normal gradient
Respiratory failure is also classified as per its onset; acute or and those with an increased gradient (Table 2). The alveolar
chronic respiratory failure. ARF refers to disorders of recent PO2 can be calculated from the alveolar air equation:
onset (hours to days). It suggests that respiratory failure has
PAO2 = (PB – PH2O) FiO2 – (PaCO2 /R)
developed too rapidly for physiologic compensation to occur;
therefore, pH is less than 7.3. Chronic respiratory failure develops here, PAO2 is alveolar PO2; FiO2 is fraction of inspired oxygen;
overmonths to years, allowing compensatory mechanisms to PB is barometric pressure (760 mmHg at sea level), PH2O is water
improve oxygen transport and to buffer respiratory acidaemia; vapour pressure (47 mmHg at sea level), and R is respiratory
therefore the pH is slightly decreased. Sometimes, ARF may be exchange ratio (assumed to be 0.8).
superimposed on chronic respiratory failure.
Ventilation-perfusion mismatch and intrapulmonary shunting
HYPOXAEMIC (TYPE 1) RESPIRATORY FAILURE are the clinically important causes of hypoxaemia in ARF.
Hypoxaemic respiratory failure (type 1) is defined as a Ventilation-Perfusion Mismatch
condition in which the respiratory system exhibits a failure in
In the presence of disease, the V/Q units vary. The low V/Q units
its gas exchange function of oxygenation, PaO2/FiO2 <200,
contribute to hypoxaemia and hypercapnia as compared to high
respiratory rate >35 breaths/min and with active use of
units where wastage of ventilation may occur without affecting
accessory muscles of respiration. It is also associated with a
the blood gases unless quite severe. If the patient is given 100%
normal or low PaCO2. The underlying physiologic aberration
oxygen to breathe, there is a dramatic increase in the PaO2 as it
results from a disease process that involves the lung itself
eliminates low V/Q units, thereby correcting the hypoxaemia.
such as a ventilation-perfusion (V/Q) mismatch, shunting or
diffusion impairment. The classic example of acute hypoxaemic Intrapulmonary Shunts
respiratory failure is acute lung injury (ALI) or acute respiratory Normally in health some degree of intrapulmonary shunting
distress syndrome (ARDS). does occur, i.e. referred to as anatomical shunt accounting for
Aetiology 2% of the shunt. In addition, cyanotic congenital heart diseases
or A-V malformations in the lungs cause right-to-left shunt.
Type 1 ARF is usually seen in diseases of the lung parenchyma,
cardiovascular system and lower airways. The causes are due to When the deoxygenated blood bypasses the ventilated alveoli
low inspired concentration of oxygen (alveolar hypoventilation), and mixes with the oxygenated blood that has perfused the
impairment of diffusion, VA/Q mismatch, intrapulmonary ventilated alveoli, reduction in the arterial content of oxygen
shunting and low mixed venous oxygen content (Table 1). occurs, i.e. hypoxaemia (PaO2 level decreases). Such situation 251
 occurs in conditions such as pneumonia, atelectasis and severe Chest radiograph may be normal initially but later on (in
pulmonary oedema of either cardiac or non-cardiac origin. established cases) may show bilateral infiltration (interstitial,
Hypercapnia occurs when the shunt exceeds > 60%. airspace or both). Arterial blood gas analysis is central to
diagnosis and reveals hypoxaemia with normal, but usually a
In low V/Q mismatch and intrapulmonary shunting, the
low PCO2.
decreased PaO2 is always associated with an elevated P (A-a)
oxygen gradient. In patients with low V/Q mismatch, the PaO2 Criteria for Diagnosis of Acute Respiratory Distress
has a dramatic rise in response to 100% oxygen, whereas in Syndrome (ARDS)
patients with intrapulmonary shunting, it shows a much smaller 1. Predisposing factors for ARDS, viz. sepsis, burns, pancreatitis,
response. Differentiating between these causes of hypoxaemia aspiration, malaria, leptospira, etc.
is important clinically (Table 2).
2. Tachypnoea, breathlessness, tachycardia, crackles on
Table 2: Physiological Conditions Causing Type 1 Respiratory auscultation.
Failure 3. Progressive infiltrates in both the lung fields.
Pathophysiology of P (A-a) O2 PaCO2 4. Normal pulmonary capillary wedge pressure.
Hypoxaemia Gradient
Low partial pressure of Normal Normal or decreased
5. Refractory hypoxaemia with PAO2/FiO2 ≤200.
inspired oxygen 6. Decreased lung compliance ≤40 mL/cm water.
Low ventilation-perfusion Increased Normal or decreased
mismatch HYPERCAPNIC (TYPE 2) RESPIRATORY FAILURE
Right-to-left shunt Increased Normal or decreased Aetiology
Diffusion impairment Increased Normal or decreased Type 2 respiratory failure can result from abnormalities in any
ARDS is the classic example of severe hypoxaemic respiratory one component of the respiratory system including the brain,
failure. The European American Consensus Conference on spinal cord, neuromuscular system, thorax, pleura and upper
ARDS defined ALI and ARDS. ALI is a syndrome of inflammation airways. Diseases of the lower airways (alveoli) or circulatory
and increased permeability that is associated with a system are rare causes of type 2 respiratory failure (Table 3).
constellation of clinical, radiologic and physiologic abnor- Table 3: Aetiology of Type 2 Respiratory Failure
malities that cannot be explained by, but may co-exist with,
left atrial or pulmonary capillary hypertension. The clinical Brain
criteria for ALI include: (i) acute onset of pulmonary failure, Drugs: narcotics, barbiturates, sedatives, poisons, general
(ii) hypoxia with a PaO2/FiO2 ratio ≤300 mmHg, (iii) bilateral chest anaesthetics
infiltrates visible on chest radiograph, and (iv) a pulmonary Metabolic: hyponatraemia, hypocalcaemia, hypercapnia, severe
alkalosis, myxoedema
artery occlusion pressure ≤18 mmHg or no clinical evidence of
increased left atrial pressure on the basis of chest radiograph Infections: meningitis, encephalitis, bulbar polio, cerebral abscess
and other clinical data. Neoplasms
Trauma
On the other hand, ARDS is defined as a more severe form of Central alveolar hypoventilation, obstructive sleep apnoea
ALI with a PaO2/FiO2 ≤200, regardless of the level of positive Occult status epilepticus
end-expiratory pressure (PEEP) used on the ventilator.
Spinal Cord
Clinical Manifestations Traumatic transection, compressive tumours, poliomyelitis
Manifestations of hypoxaemic respiratory failure are due to a Neuromuscular
combination of features of arterial hypoxaemia and tissue Drugs: neuromuscular blockers, aminoglycosides
hypoxia. Arterial hypoxaemia causes hyperventilation due to Metabolic: hypokalaemia, hypophosphataemia, hypomagnesemia
stimulation of carotid body chemoreceptors, leading to Infections: tetanus, Guillain-Barré syndrome, sepsis
dyspnoea, tachypnoea and hyperpnoea. There may be Trauma
cyanosis; degree of cyanosis depends on the concentration Neoplasm
of the haemoglobin and the patient’s perfusion. Other features Myasthenia gravis
include generation of lactic acid due to anaerobic metabolism. Others: critical illness neuropathy, muscular dystrophies, respiratory
Increased blood lactate levels may further stimulate muscle fatigue
ventilation. Mild hypoxia may also lead to impaired mental
Upper Airways
performance. With the progression of hypoxia alteration in the
sensorium, somnolence, coma, seizures can occur leading to Upper airway mass: adenoid hyperplasia, goiter, polyps, malignant
tumours
permanent brain damage.
Infections: epiglottitis, laryngotracheitis
Patient develops tachycardia, diaphoresis, and systemic Trauma
vasoconstriction leading to hypertension. Severe hypoxia can Others: bilateral vocal cord palsy, tracheomalacia, laryngeal oedema
lead to bradycardia, vasodilation, hypotension, myocardial
Chest Wall
ischaemia, infarction, arrhythmias and cardiac failure. The
Trauma: Flail chest
manifestations of hypoxia are further amplified in the presence
Others: kyphoscoliosis, scleroderma and massive pneumothorax or
of tissue hypoxia. Symptoms and signs also reflect not just acute
pleural effusion
252 hypoxaemia, but also the underlying cause of respiratory failure.
 Acute Respiratory Failure
Physiology arterial blood gas study, not only to determine the presence
The hallmark of acute hypercapnic respiratory failure is an and severity of respiratory failure but also to differentiate
elevated PaCO2. Three processes, alone or in combination, can between type 1 and type 2 respiratory failure.
produce acute hypercapnic respiratory failure: a reduction in
POST-OPERATIVE/PERI-OPERATIVE (TYPE 3)
minute ventilation, an increase in CO2 production and alveolar
RESPIRATORY FAILURE
hypoventilation.
Post-operative/peri-operative respiratory failure can be defined
Reduction in minute ventilation can be affected by processes as the need for intubation and mechanical ventilation (MV)
affecting the central nervous system, peripheral nervous system, within the 48 hours after surgery. In the post-operative/peri-
neuromuscular junction, respiratory muscles, chest wall operative period, surgical patients following general
abnormalities, metabolic and electrolyte abnormalities, and anaesthesia often develop reduction in functional residual
upper airway obstruction. In these disorders alveolar-arterial capacity leading to atelectasis in the dependent lung units. This
oxygen pressure difference (A-aDO2) is usually normal unless leads to respiratory failure referred to as post-operative/peri-
lung disease is present. operative respiratory failure (Table 4). To avoid this situation, a
Excessive CO2 production is usually due to fever, burns, sepsis, proper pre-operative assessment is mandatory to identify the
high carbohydrate diet, burns and hyperthyroidism. Agitation, patients who are at increased risk after non-thoracic and
myoclonus, or other causes of muscle activity can increase VCO2 thoracic surgery. These subgroup of patients are best managed
and contribute to type 2 respiratory failure. Increase in the with frequent change of posture, chest physiotherapy, adequate
respiratory quotient, which is normally 0.8-2.0 doubles VCO2. analgesia for post-operative pain relief. Non-invasive ventilation
Reduced CO2 elimination also occurs due to decreased alveolar (NIV) also may be used to tide over the crises. However,
ventilation. evidence-based studies on the usefulness of respiratory
physiotherapy, incentive spirometry and NIV to prevent
Alveolar hypoventilation may result from VA/Q mismatch (high respiratory complications are lacking.
VA/Q, increased physiological dead-space and wasted
ventilation) as in pulmonary embolic diseases, intrinsic lung Table 4: Aetiology of Type 3 Respiratory Failure
diseases (e.g. emphysema, asthma, cystic fibrosis or pulmonary
Intra-pulmonary Causes
fibrosis) and in chest wall disorders (e.g., scoliosis).
Atelectasis, aspiration, pneumonia
Hypoventilation is characterised by hypercapnia and
Acute lung injury/acute respiratory distress syndrome
hypoxaemia. As minute ventilation reduces to less than 4 L/min,
Volume overload/congestive heart failure
the PaCO2 rises dramatically. Usually these patients have normal
A-aDO2 gradients. Pulmonary embolism
Asthma/Chronic obstructive pulmonary disease
Patients at risk of hypercapnic respiratory failure may also Pneumothorax
be divided into two major categories: those with normal Extra-pulmonary Causes
lungs (e.g., sedative overdose, neuromuscular disorders or
Upper airway obstruction
chest wall abnormalities) and those with intrinsic lung disease
Obstructive sleep apnoea syndrome
(e.g., emphysema, chronic bronchitis or asthma) where
Diaphragmatic dysfunction/phrenic nerve injury
maldistribution of ventilation and perfusion results in an
increase in dead space. The final result is inadequate CO 2
SHOCK-RELATED (TYPE 4) RESPIRATORY FAILURE
clearance despite normal or increased minute ventilation.
Respiratory muscles consume less than 5% of the total cardiac
Clinical Manifestations output and oxygen delivery. Shock leads to increase in dead-
Patients with acute hypercapnic respiratory failure largely space ventilation and pulmonary inflammation. The increase
present with central nervous system (CNS) disturbances. in dead-space ventilation is an early accompaniment of shock.
Hypercapnia is a CNS depressant leading to lethargy, It leads to hypoperfusion of the respiratory muscles, leading to
somnolence, coma, asterixis, restlessness, tremors, slurred respiratory muscle fatigue, causing a combined metabolic (lactic
speech, headache and papilloedema. acidosis) and respiratory acidosis. Under this situation, more
than 40% of the cardiac output is distributed to the respiratory
Symptoms of hypercapnia may overlap those of hypoxaemia.
muscles.
Basically, hypercapnic patients may have either decreased or
increased minute ventilation depending on the primary Intubation and MV help redistribution of the cardiac output to
disorder. As a result these patients have dyspnoea, tachypnoea, the vital organs while shock is being treated.
hyperpnoea with tachycardia and uncompensated respiratory
MANAGEMENT
acidosis.
The general principles of support are similar regardless of the
Diagnosis type of respiratory failure. The priorities in the management of
History is most important in diagnosis of ARF. It should aim at ARF vary according to the aetiology. However, the primary aim
eliciting relevant information about possible predisposing in all the cases are the same: (i) to maintain a patent airway and
factors, co-morbid conditions and identifying processes that ensure adequate ventilation and oxygenation; and (ii) to treat,
affect prognosis. The clinical signs and symptoms of ARF reflect if possible, the primary condition. This includes removal of
the underlying disease process and the associated hypoxaemia excessive secretions to maintain clear airway, use of aerosolised
and hypercapnia. Diagnosis of respiratory failure requires bronchodilators, antibiotics, viz. aminoglycoside (tobramycin),
253
 colistin according to sensitivity pattern and effective systemic Hypercapnic Respiratory Failure (Type 2)
antimicrobials for the treatment of infections. Oxygen therapy
Hypoxaemic Respiratory Failure (Type 1) Hypoxaemia secondary to hypoventilation can be easily treated
Patients with acute hypoxaemic respiratory failure are best with by supplemental oxygen (increasing FiO2). Failure of PaO2
managed in the ICU. The management of these patients to improve should alert to the possibility of an unsuspected
involves both supportive and specific strategies that are concomitant lung disease producing a shunt effect (e.g.
generally performed simultaneously. Supportive therapy is pneumonia, atelectasis). In many patients with chronic
aimed at stabilising the clinical condition of the patient by ventilatory failure, especially chronic obstructive pulmonary
improving gas exchange and includes airway management and disease (COPD), oxygen therapy can cause acute worsening of
correction of hypoxaemia. Hypoxaemia is corrected by oxygen hypercapnia. Three mechanisms have been proposed to
administration and use of ventilatory support (non-invasive and explain this phenomenon. These patients may have a ‘blunted’
invasive mechanical ventilatory support). Measures are also CO2 drive to breathe and the hypoxaemic drive is suppressed
directed towards specific therapy for identifying and reversing by supplemental oxygen. Oxygen may increase V/Q inequality
the underlying pathophysiologic mechanisms. Specific therapy by inhibition of hypoxic pulmonary vasoconstriction or by
varies depending on the underlying disease (e.g. use of changing bronchomotor tone. Finally, haemoglobin affinity for
antibiotics to treat patients with pneumonia and diuretics for CO2 decreases with increasing oxygen saturation (Haldane
pulmonary oedema). effect), which may further contribute to hypercapnia. Therefore,
supplemental oxygen therapy for ventilatory failure aims at
Oxygen therapy maintenance of PaO2 in a ‘safe’ range that does not compromise
Oxygen supplementation is the most important therapy for systemic oxygen delivery but minimises the possibility of
hypoxaemic respiratory failure. After the airway is secured, worsening hypercapnia (SaO2 of 90% to 92%).
attention is directed to the management of hypoxaemia. The
Air entrainment oxygen masks (venturi masks) can be used to
treatment goal is to provide adequate oxygen delivery to the
deliver precise doses of oxygen. If venturi masks are unavailable
tissues (SaO2 >90% and PaO 2 ≥60 mmHg). Oxygen can be
or are not feasible, a nasal cannula at flow rates of 0.5-2.0 L/min
delivered by different means (nasal cannula for flow rates
may be used to treat hypoxaemia (low-flow oxygen therapy).
≤ 5 L/min, face mask for flow rates ≥6 L/min or use of air
However, despite therapy, progressive hypercapnia and acidosis
entrainment devices, (i.e. venturi masks for higher flow rates).
may develop in some patients and lead to confusion, stupor or
If the patient’s condition does not improve with high-flow
coma, even when the FiO2 is increased only moderately. Such
oxygen: MV, either invasive or non-invasive, should be
patients may require tracheal intubation and MV.
considered.
Therapy in patients with asthma or COPD consists of oxygenation,
Non-invasive ventilation
hydration and aggressive treatment of the underlying
In last few years, substantial data has emerged on the use of aggravating factor with bronchodilators (theophyllin,
NIV in patients with acute hypoxaemic respiratory failure to anticholinergics and beta-agonists) and corticosteroids. Infection
avoid endotracheal intubation and ventilator-associated needs to be treated with appropriate antibiotics and any
pneumonia, thereby reducing mortality. However, despite electrolyte abnormality must be corrected. In patients who
emerging studies regarding NIV as an adjunct in the progress to respiratory muscle fatigue, elective intubation and
management of hypoxaemic respiratory failure, its safety and MV may be necessary to prevent respiratory arrest.
efficiency remains unanswered. This is mainly due to varied
aetiologies in subgroups of patients causing respiratory failure. Non-invasive ventilation (NIV)
Recently, a few studies have focused on some of the individual NIV is most commonly applied in acute hypercapnic respiratory
diagnoses within the large category. It has been found to be failure commonly associated with COPD, where the ventilatory
very effective in cardiogenic pulmonary oedema. NIV may response to raised PaCO2 is decreased.
also be useful when some components or degree of cardiac
Administration of NIV in patients with COPD with respiratory
decompensation participates in the clinical feature, even if it is
failure helps to increase the neural output to the diaphragm
not the main or only cause of episode of respiratory failure.
and other respiratory muscles, and thus, resets the respiratory
It should be noted that patients with hypoxaemic respiratory control centre making it more responsive to an increased PaCO2.
failure should preferably be ventilated with a full face mask These patients are then able to maintain a normal PaCO2
during acute phase and may be shifted to nasal mask, once the throughout the daylight hours without the need for MV.
condition stabilises.
The use of NIV in patients with acute exacerbations of COPD is
Mechanical ventilation considered the ventilatory mode of choice. It helps by reducing
The two major goals of therapy are to maintain alveolar the rate of endotracheal intubation. It also improves the vital
ventilation and correct hypoxaemia. In cases where NIV fails to signs, gas exchange, thereby reducing dyspnoea.
correct hypoxaemia, invasive MV is used. Patients with severe
There is also reduction in the in-hospital mortality, with
ARF and a large intrapulmonary shunting may require high FiO2
reduction in the complications like nosocomial pneumonia.
while on the ventilator. MV increases alveolar ventilation,
eliminates CO2 and corrects acidaemia. Due to the danger of NIV may also be used in patients with acute exacerbations of
oxygen toxicity, patients should be treated with the lowest bronchial asthma. Uncontrolled studies have reported
concentration of oxygen that provides adequate oxygenation. improvements in gas exchange and low rates of intubation after
254
 Acute Respiratory Failure
the initiation of NIV in patients with severe asthma. In another which leads to a compensatory reduction in bicarbonate. On
randomised trial, no benefit of NIV in asthma was demonstrated. resumption of spontaneous breathing, patients who are
chronically hypercapnic will retain CO2 rapidly (to their previous
Although the use of NIV in asthma is inconclusive, a trial of NIV
pre-morbid level). As the kidneys require more time (24 to 48
in selected patients is justified, particularly in patients who fail
hours) to compensate, an acute respiratory acidosis may ensue
to respond promptly to medical treatment and have no
and impede liberation from MV. Accordingly, the ventilatory
contraindications.
goal in patients with acute on chronic respiratory failure is not
It has also been suggested that aerosolised medicines a normal PaCO2 but rather a PaCO2 approximating their baseline
may be delivered more effectively by NIV. However, NIV is value when they are not acutely decompensated, at which the
not recommended for routine use in patient with asthma pH is normal range.
exacerbation.
RECOMMENDED READINGS
Mechanical ventilation
1. Burns KE, Sinuff T, Adhikari NK, et al. Bilevel non-invasive positive pressure
Some patients with ventilatory failure may respond to early and ventilation for acute respiratory failure: survey of Ontario practice. Crit Care
aggressive management of the primary disorder. Others, with Medicine 2005; 33: 1477-83.
progressive pathology or whose loads are not rapidly reduced 2. Ferreyra G, Ranieri MV. Non-invasive ventilation in hypoxaemic respiratory
may require MV. Although no PaCO2 absolutely mandates MV, if insufficiency controversies in intensive care medicine. ESICM Year book
the pH is < 7.20 and if rapid reversal with therapy is not expected, 2008; pp 3-7.
or failure of NIV occurs or NIV is contraindicated, then prompt 3. Hemmila MR, Napolitano LM. Severe respiratory failure: advance
treatment options. Crit Care Med 2006; 34 (9 Suppl): S278-90.
MV is initiated. Delayed MV in these patients increases the risk
of circulatory collapse and other complications. 4. Lichtenstein DA, Meziere GA. Relevance of lung ultrasound in the diagnosis
of acute respiratory failure. Chest 2008;134:117-25.
A common error in MV of a patient with acute on chronic 5. Martin Tobin. Principles and Practice of Mechanical Ventilation; 2nd Ed. New
respiratory failure is to reduce the PaCO2 to normal (40 mmHg), York: McGraw-Hill Professional Publishers;2006: pp 129-54.

255
 7.7 Sepsis and Acute Respiratory
Distress Syndrome
Alladi Mohan, Surendra K Sharma

SEPSIS caused by Gram-positive bacteria and fungi also. Polymicrobial

Sepsis (derived from the Greek word sepo meaning “decay aetiology of sepsis has also been described. In India, septic shock
or putrefaction”), severe sepsis (acute organ dysfunction can occur due to falciparum malaria, enteric fever, dengue fever
secondary to infection) and septic shock (derived from the and other infections.
French word choquer meaning ‘to collide with’), are major health Pathogenesis
care problems world over. The incidence of sepsis and related
The pathophysiological hallmark of sepsis and related
syndromes is increasing and the conditions affect millions of
syndromes is the mismatch of the host response to the intensity
individuals around each year.
of the pathogenic stimuli, ultimately leading to organ injury or
DEFINITION OF SEPSIS AND RELATED SYNDROMES
Table 1: Diagnostic Criteria for Sepsis in Patients with
Though the existence of sepsis and related disorders were Documented or Suspected Infection
known since time immemorial, formal definitions for the same
were laid by the American College of Chest Physicians (ACCP) General variables
and Society of Critical Care Medicine (SCCM) Consensus Fever (core temperature >38.3°C)
Conference in 1991. With advances in the understanding of Hypothermia (core temperature <36°C)
the pathophysiological aspects of septic shock and the Heart rate >90/min or >2 SD above the normal value for age
dissatisfaction in several quarters regarding these definitions, Tachypnoea
a Consensus Sepsis Definitions Conference was convened in Altered mental status
2001 under the auspices of ACCP, SCCM, the European Society Significant oedema or positive fluid balance (>20 mL/kg over
of Intensive Care Medicine, and the Surgical Infection Societies 24 hours)
to re-visit the definitions of sepsis and related conditions. The Hyperglycaemia (plasma glucose >120 mg/dL) in the absence
key change was regarding the definition of systemic of diabetes
inflammatory response syndrome (SIRS) [manifested by (but not Inflammatory variables
limited to) 2 or more of the following conditions: temperature Leukocytosis (WBC count >12,000 /mL)
> 38 °C or, < 36 °C; heart rate > 90 beats/min; respiratory rate > Leukopaenia (WBC count <4000/mL)
20/min or (PaCO2) < 32 mmHg; white blood cell count >12.0 × Normal WBC count with >10% immature forms
109/L, < 4:0 × 109/L, or > 10% immature (band) forms] which
Plasma C-reactive protein >2 SD above the normal value
was expanded to include longer list of possible signs of sepsis
Plasma procalcitonin >2 SD above the normal value
(Table 1).
Haemodynamic variables
As per the new guidelines, sepsis is defined as infection plus Arterial hypotension (SBP <90 mmHg, MAP <70, or an SBP
systemic manifestations of infection (Table 1). Severe sepsis is decrease >40 mmHg) or <2 SD below normal for age)
defined as sepsis plus sepsis-induced organ dysfunction or SvO2 >70%
tissue hypoperfusion (Table 1). Septic shock is defined as sepsis- Cardiac index >3.5 L/min/m2
induced hypotension persisting despite adequate fluid
Organ dysfunction variables
resuscitation.
Arterial hypoxaemia (PaO2/FiO2 <300)
Staging System for Sepsis Acute oliguria (urine output <0.5 mL/kg/h for at least 2 hours)
Since the definitions of sepsis and related syndromes does not Creatinine increase >0.5 mg/dL
allow for precise characterisation and staging of patients with Coagulation abnormalities (INR >1.5 or aPTT >60 sec)
this condition, staging systems have been proposed to stratify Ileus (absent bowel sounds)
these patients by both their baseline risk of an adverse outcome Thrombocytopaenia (platelet count <100,000/μL)
and their potential to respond to therapy. In line with the Hyperbilirubinaemia (plasma total bilirubin >4 mg/dL)
tumour, node, metastasis in vogue for cancer, a classification
Tissue perfusion variables
scheme for sepsis that will stratify patients basing on their
predisposing conditions, the nature and extent of the infection, Hyperlactatemia (>1 mmol/L)
the nature and magnitude of the host response, and the degree Decreased capillary refill or mottling
of concomitant organ dysfunction, termed PIRO staging system SD = Standard deviation; WBC = White blood cell; SvO2 = Central venous
has been described (Table 2). Several attempts are underway oxygen saturation; INR = International normalisation ratio; MAP = Mean
to apply the PIRO system clinically with promising results. arterial pressure; SBP = Systolic blood pressure; PaO2 = Partial pressure
Aetiology of arterial oxygen; FiO2 = Fraction of inspired oxygen; aPTT = Activated
partial thromboplastin time
Gram-negative bacterial infection is the most common cause Adapted from: Crit Care Med 2003; 31: 1250-6.
256 of sepsis and related syndromes. However, septic shock can be
 Sepsis and Acute Respiratory Distress Syndrome
Table 2: Some Clinical and Laboratory Variables Being Evaluated for the PIRO Staging System for Sepsis in Adults
Variable Clinical Parameters Laboratory Parameters
Predisposing conditions Age, co-morbid conditions (e.g. alcoholism, diabetes, Genetic polymorphisms in components of
cirrhosis of liver), gender, corticosteroid use, inflammatory response (e.g. TLR, TNF, IL-1, CD14)
immunosuppressive state, religious and cultural beliefs
Infection Site of infection (e.g. pneumonia, peritonitis, catheter), Virulence of the infecting organism, antimicrobial
Type of infection (hospital acquired versus community sensitivity, assay of microbial products
acquired) (e.g. LPS, bacterial DNA), gene transcript profiles
Response SIRS, other signs of sepsis, shock, CRP White blood cell count, prothrombin time, APTT,
blood lactate levels, biomarkers (e.g. CRP, PCT)
Organ dysfunction Blood pressure, urine output, Glasgow coma scale, PaO2/FiO2, serum creatinine, serum bilirubin,
organ dysfunction as number of failing organs or platelet count
composite score (e.g. MODS, SOFA, LODS)
TLR = Toll-like receptor; TNF = Tumour necrosis factor; IL-1 = Interleukin-1; LPS = Lipopolysaccharide; DNA = Deoxyribonucleic acid; SIRS = Systemic inflammatory
response syndrome; APTT = Augmented partial thormboplastin time; CRP = C-reactive protein; PCT = Procalcitonin; PaO2 = Partial pressure of arterial oxygen; FiO2 = Fraction
of inspired oxygen; MODS = Multiple organ dysfunction syndrome; SOFA = Sepsis-related organ failure assessment; LODS = Logistic organ dysfunction system.
Adapted from: Crit Care Med 2003; 31: 1250-6.

dysfunction with or without hypotension. This results in a

predominantly proinflammatory (SIRS), mixed [mixed
antagonistic response syndrome (MARS)], or predominantly
anti-inflammatory compensatory anti-inflammatory syndrome.
The current concepts underlying the molecular pathogenesis
of sepsis are shown in Figure 1. The major complications of
septic shock are listed in Table 3.

Table 3: Major Complications of Sepsis

Cardiopulmonary
Acute lung injury, acute respiratory distress syndrome
Depression of myocardial function
Renal
Acute kidney injury
Drug-induced renal damage
Disseminated intravascular coagulation
Neurological
Critical illness polyneuropathy
Multiorgan dysfunction syndrome

Clinical Manifestations
The clinical manifestations of sepsis result as a consequence of
the complex interplay among the immune, coagulation, and
neuroendocrine systems in response to severe infection.
These manifestations overlap the signs and symptoms
due to the underlying medical conditions and primary site of
infection. Septic shock should be suspected whenever,
a patient with fever or hypothermia, tachycardia and
tachypnoea and evidence of decreased organ perfusion
develops hypotension. It is not strictly necessary that
tachycardia, tachypnoea or fever be present to make the
diagnosis. Generally, there is predisposition to infections such
as a patient on cytotoxic or immuno-suppressive drugs,
chronic debilitating disease such as diabetes mellitus, cirrhosis
of liver, etc. Haemtogenous seeding of the skin or underlying
soft tissue can manifest as cellulitis, pustules, bullae, or
haemorrhagic lesions. Other features that help in pointing
towards a diagnosis of septic shock include evidence of
impaired organ perfusion, altered mental status, jaundice,
gastrointestinal bleed due to stress ulceration, disseminated
intravascular coagulation (DIC) and acute respiratory distress
Figure 1: Overview of the molecular pathogenesis of sepsis.
syndrome (ARDS). Acrocyanosis and ischaemic necrosis of 257
 peripheral tissues, usually digits, may be evident due to
hypotension and DIC.
Principles of Management
The basic principles of initial resuscitation (fluid therapy,
vasopressors, inotropic support, infection issues (source
identification and control, appropriate antibiotic therapy), blood
product administration and haemodynamic support described
in the updated Surviving Sepsis Campaign guidelines for the
management of severe sepsis and septic shock 2008 must be
followed meticulously (Figure 2).
Broad-spectrum, site-specific appropriate intravenous
antibiotics (monotherapy or combination therapy as
appropriate) should be started as early as possible, and always
within the first hour of recognising severe sepsis and septic
shock. The antimicrobial regimen must be assessed daily to
optimise efficacy, prevent resistance, avoid toxicity and
minimise costs. The antibiotic therapy must be administered
for 7 to 10 days. The duration may be longer if the response
is slow, the foci of infection are undrainable, or if
immunodeficiency is present. Low doses of corticosteroids
and recombinant human activated protein C may be considered
as useful adjunctive therapies in selected sub-groups of
patients. The optimal timing for initiating these modalities of
treatments appears to be 6 to 24 hours from onset of shock.
Patients receiving these treatments should systematically
be monitored for superinfection and serious bleeding
complications. Principles of mechanical ventilation (MV) are
described under ARDS. Factors indicating poor prognosis in
septic shock are shown in Table 4.

Table 4: Factors Indicating Poor Prognosis in Septic Shock

Pre-existing factors
Old age
Nature of co-existing illness (e.g. leukaemia)
Number of failed organs
Cardiovascular
Lack of ventricular dilatation
Persistence of tachycardia and raised cardiac output
Others
Delay in institution of treatment
Acute respiratory distress syndrome
Disseminated intravascular coagulation
Hypothermia
Leucopaenia
Hyperglycaemia
Metabolic acidosis Figure 2: Initial resuscitation with goal-directed therapy in severe sepsis and
septic shock.
Renal failure
Polymicrobial infection CVP = Central venous pressure; MAP = Mean arterial pressure; SvO2 = Central venous
oxygen saturation; SBP = Systolic blood pressure; CI = Cardiac index.

ACUTE RESPIRATORY DISTRESS SYNDROME

Definition
ARDS is defined as an acute lung injury (ALI) resulting in
extensive bilateral pulmonary infiltrates, severe refractory The American-European Consensus Conference definitions of
arterial hypoxaemia and stiff lungs. It is a common cause of ICU ALI and ARDS are simple to apply in the clinical setting and
admission world over. also recognise that the severity of clinical lung injury varies
according to the severity of arterial hypoxaemia. Recently,
Aetiology pulse oximetric saturation (SpO2) to fraction of inspired oxygen
Bacterial sepsis is the single most important cause of ARDS in (FiO 2) ratio (S/F ratio) has been found to correspond to the
hospitalised patients. Other common causes of ARDS are listed arterial oxygen tension (PaO2) to FiO2 ratio (P/F) (Table 6).
258 in Table 5. These non-invasive substitutes for assessing oxygenation can
 Sepsis and Acute Respiratory Distress Syndrome
Table 5: Causes of Acute Respiratory Distress Syndrome phase. Tachypnoea, tachycardia, cyanosis, crepitations and
rhonchi may also be present. Arterial hypoxaemia that is
Common Causes refractory to treatment with supplemental oxygen which may
Infections eventually warrant tracheal intubation and assisted MV is a
Gram-negative and Gram-positive bacterial sepsis characteristic feature of ARDS.
Pneumonia (bacterial, viral, mycoplasma, pneumocystis)
Pancreatitis Diagnostic Work-up
Burns The patient should be carefully evaluated for an underlying
Gastric aspiration cause keeping in mind the possibility of treatable infections,
Bilateral lung contusion such as sepsis, pneumonia, tuberculosis (TB), malaria among
Cardiopulmonary bypass others. Other useful investigations include:
Uncommon Causes Arterial blood gas analysis
Multiple blood transfusions
The ABG analysis usually reveals severe refractory hypoxaemia,
Inhalational injuries (ammonia, chlorine, nitrogen dioxide,
hypocapnia and alkalosis if the patient is breathing
phosgene, smoke, sulphur dioxide)
spontaneously. Hypercapnia usually does not occur unless
Fat embolism
chronic lung disease co-exists.
Raised intracranial pressure
Infections (pulmonary and miliary tuberculosis, falciparum Chest radiograph
malaria, enteric fever, leptospirosis) In patients with ARDS, the radiographic changes become
Drugs (e.g. thiazides, methadone, barbiturates, narcotics, evident by about 12 hours after the clinical onset of respiratory
lidocaine, cytosine arabinoside, phenytoin, salicylates) failure. Initially, patchy, ill-defined opacities may become
Heat stroke apparent through out the lungs. They rapidly coalesce and
High altitude pulmonary oedema diffuse massive air-space consolidation becomes evident. In
contrast to cardiogenic pulmonary oedema of cardiogenic
origin, air-bronchogram is frequently visible. After about a week,
Table 6: Definitions of Acute Lung Injury and Acute Respiratory
Distress Syndrome the lungs remain diffusely abnormal, but the pattern gradually
becomes ‘reticular’ or ‘bubbly’ suggestive of a diffuse interstitial
Acute lung injury Acute respiratory distress and air-space fibrosis.
syndrome
Acute onset Acute onset Computed tomography
PaO2/FiO2 ≤300* PaO2/FiO2 ≤200* Computed tomography (CT) of the chest also facilitates the
SpO2/FiO2 ≤315*† SpO2/FiO2 ≤235‡ identification of some causes of ARDS, such as, pneumonia
Bilateral infiltrates on the Bilateral infiltrates on the and lung abscess. The CT of the chest reveals diffusely
frontal frontal distributed, non-uniform, ground-glass opacification or
chest radiograph chest radiograph consolidation which may not conform to the gravity
PCWP ≤18 mmHg, or no PCWP ≤18 mmHg, or no distribution early in the exudative phase. Susbequently in
clinical clinical the exudative phase, the consolidation becomes more
evidence of left atrial evidence of left atrial
homogeneous and gravity dependent. As the proliferative
hypertension hypertension
and fibrotic stages evolve, there is a decrease in the overall
* Irrespective of level of positive end-expiratory pressure; lung density and the appearance of an interstitial reticular
† The sensitivity of 91% and specificity of 56% for identifying acute lung injury;
pattern. Complications of ARDS, such as pneumothorax,
‡ The sensitivity of 85% and specificity of 85% for identifying acute respiratory
distress syndrome. pneumomediastinum and interstitial emphysema may also
Adapted from: Am J Respir Crit Care Med 1994; 149: 818-24; Chest 2007; 132: 410-7. be evident on CT of the chest.
Echocardiography
be useful in the settings where arterial blood gas (ABG) Echocardiography is useful in differentiating ARDS from
analysis is not available and facilitate the monitoring of the cardiogenic pulmonary oedema.
course of the disease.
Swan-Ganz catheterisation
Clinicopathological Stages of ARDS Swan-Ganz catheterisation facilitates measurement of pulmonary
Irrespective of the precipitating factors ARDS usually evolves capillary wedge pressure (PCWP). A PCWP less than 18 mmHg
along a stereotypic common pathway with characteristic and cardiac index more than 2.1 L/min/m2 is altered in ARDS.
clinical, pathological and radiological changes as exudative
Fibreoptic bronchoscopy and bronchoalveolar lavage
phase, proliferative phase, fibrotic phase and phase of healing
and repair. These changes are usually described by the term Fibreoptic bronchoscopy and bronchoalveolar lavage (BAL)
diffuse alveolar damage. are employed to exclude infectious causes of ARDS. Most
prominent finding on BAL in patients with ARDS (though non-
Clinical Features specific) include increased number of polymorphonuclear
ARDS is acute and rapid onset of respiratory failure, dyspnoea, leukocytes (making up to nearly 80% of the total cell population;
dry cough, disorientation and agitation that usually develops 24 normal value <5%). Eosinophilia in the BAL fluid, when it occurs,
to 72 hours after the precipitating event marking the exudative has therapeutic implications. 259
 Differential Diagnosis patients. Aim of MV is to maintain gas exchange with minimal
Several conditions mimic ARDS clinically, but, alveolar complications. Initially, spontaneous ventilation using a face
inflammatory changes are characteristic of ARDS. These mask with a high flow gas delivery system can be used to deliver
conditions include: a FiO2 of up to 0.5 to 0.6. Continuous positive airway pressure
(CPAP) may be added to improve PaO2 without increasing FiO2.
Haemodynamic pulmonary oedema If a FiO2 of more than 0.6 and CPAP of more than 10 cm H2O are
In haemodynamic pulmonary oedema, PCWP is elevated (> 18 needed to achieve a PaO2 of more than 60 mmHg, tracheal
mmHg), and echocardiographic abnormalities may be evident. intubation and MV must be considered. The maximal clinical
Once PCWP is brought to normal, infiltrates on the chest benefit is likely to occur if MV is initiated early, i.e. within 96 hours
radiograph may clear. of the onset of ARDS, a time when alveolar recruitment potential
is the greatest.
Diffuse alveolar haemorrhage
The initial clinical presentation of diffuse alveolar haemorrhage Recent evidence suggests that, whatever mode of ventilation
may resemble ARDS and is accompanied by a dramatic is used, tidal volume should be set in the region of 6 mL/kg
fall in the haematocrit, occurrence of haemoptysis, and the (‘lung protective ventilation’) and the peak pressure should
presence of frothy red fluid on bronchoscopy. Haemosiderin- be limited to 30 to 35 cm H2O to prevent lung overdistension.
laden macrophages may be demonstrable in the BAL Presently, in the absence of routine static pressure-volume
fluid. curve measurement, positive end expiratory pressure (PEEP)
is set at a relatively high level such as 15 cm H2O in patients
Idiopathic acute eosinophilic pneumonia with ARDS. It is also a common practice to increase the I:E ratio
Patients with idiopathic acute eosinophilic pneumoia may to 1:1 or 2:1 (inverse ratio ventilation) with close monitoring
be previously healthy and present with cough, dyspnoea, of intrinsic PEEP and haemodynamics during pressure control
fever, and occasionally chest pain. Peripheral blood and BAL ventilation (Table 7). The usefulness of recruitment
fluid eosinophilia is present. This condition rapidly responds to manoeuvres such as the high function where intermittent
corticosteroid treatment, usually within 48 hours. breaths of larger tidal volume are administered either via the
Metastatic malignancy mechanical ventilators or by hand, sustained inflation or CPAP
aimed at increasing alveolar recruitment are also being
When malignancy presents as ARDS it is uniformly fatal.
studied.
Cytologic examination of blood drawn from pulmonary
circulation through the Swan-Ganz catheter keeping the Other ventilatory strategies
balloon inflated, or BAL fluid is usually helpful in confirming the Other alternative approaches to conventional MV include prone
diagnosis. More invasive procedures such as transbronchial lung positioning of the patient, high frequency ventilation (HFV, rate
biopsy, open lung biopsy may have to be undertaken at times
to ascertain the diagnosis. These procedures are, however, Table 7: Protective Lung Ventilation Protocol from the ‘ARDSNet
associated with increased risk of complications. Study’
Management Variable Setting
In the appropriate clinical setting, a high index of clinical Ventilator mode Volume assist-control
suspicion is necessary to diagnose ARDS early. Efforts directed Tidal volume (initial) 6 mL/kg of predicted body
at establishing the cause of ARDS must be actively pursued to weight* initially
facilitate institution of specific treatment. Plateau pressure < 30 cm H2O
Rate of respiration 6 – 35 breaths/min
General therapeutic measures
Ratio of the duration of
Patients with ARDS should be admitted in an ICU equipped with inspiration to
facilities for invasive monitoring and providing assisted MV. the duration of expiration 1:1 – 1:3
Ideally, pulmonary and systemic arterial lines should be inserted Oxygenation target
for haemodynamic monitoring and rational fluid replacement PaO2 7.3 – 10.7 kPa (55 – 80 mmHg)
therapy. SpO2 monitoring by pulse oximetry, periodic ABG SaO2 88 – 95 (%)
analysis must also be done. Adequate nutrition should be FiO2 and PEEP† FiO2 PEEP
ensured; enteral route is preferred to the parenteral route as it 0.3 5
does not cause the serious risk of catheter induced sepsis. If 0.4 5–8
sepsis is presumed to be the cause of ARDS, empirical antibiotic 0.5 8 – 10
treatment may be started in the early phase of the disease as 0.6 10
detailed above. 0.7 10 – 14
0.8 14
Haemodynamic stabilisation
0.9 14 – 18
The fundamental principles remain same as in Figure 2. 1.0 18 – 24
Ventilatory support * Predicted body weight of male patients = 50 + 0.91 [height (cm) – 152.4];
While some patients with ARDS can be managed with predicted body weight of female patients = 45.5 + 0.91 [height (cm) – 152.4]
† Set according to pre-determined combinations (PEEP range 5 – 24 cm H2O)
conservative measures and non-invasive ventilation, tracheal
PEEP = Positive end-expiratory pressure; FiO2 = Fraction of inspired oxygen
intubation and assisted MV are required in a majority of the
260
 Sepsis and Acute Respiratory Distress Syndrome
> 60/min) techniques such as high frequency jet ventilation
(HFJV) and high frequency oscillatory ventilation (HFOV), and
liquid ventilation, among others. The relative merits of these
alternative methods of MV must be critically weighed against
the potential side-effects in every setting.
Extracorporeal respiratory support
In extracorporeal membrane oxygenation (ECMO), venous
blood is removed via a cannula in the inferior vena cava or
right atrium, passed through a heart/lung machine, and is
returned to either the right atrium (veno-venous bypass) or
aorta (veno-arterial bypass). Extracorporeal carbon dioxide
(CO2) removal (ECCOR) involves use of an extracorporeal veno-
venous circuit with lower blood flow and oxygenation still
occurring via the patient’s lungs. These modalities may be
useful in selected patients and, studies with a large sample
size are required to clarify their role in the management of
ARDS.
Pharmacological therapies
Though various pharmacological therapies are directed at
the pathophysiologic mechanisms of ARDS. These include
neuromuscular blockade, inhaled nitric oxide, vasoactive agents
(intravenous phenylephrine, inhaled prostacyclins, almitrine,
among others. The therapeutic potential of these strategies
needs further study.
Corticosteroids
The role of corticosteroid treatment in the management of
ARDS is controversial. The studies published in the 1980s had
employed high-dose corticosteroids (1 to 8 doses of 30 mg/kg
methylprednisolone) for short durations (< 48 hours). Compared
with placebo, corticosteroid treatment resulted in either
no difference or increased the incidence of ARDS. In more
recent studies, low-to-moderate doses of corticosteroids Figure 3: Treatment algorithm for the management of ARDS.
(methylprednisolone 1 to 2 mg/kg per day to start) for longer FiO2 = Fraction of inspired oxygen; SaO2 = Arterial oxygen saturation
duration (mean 25 to 32 days), with gradual tapering has been
evaluated. Presently, corticosteroid therapy is not considered
to be beneficial before the onset of ARDS or early in its course. establishing this diagnosis must be pursued to facilitate early
A difference of opinion exists among experts regarding the institution of specific therapy.
efficacy of corticosteroids for late-stage ARDS. Even though low- Outcome
dose corticosteroid therapy improves lung function and
shortens the duration of MV in persistent ARDS, the impact on Interestingly, initial indices of oxygenation and ventilation
long-term mortality is unclear. More data are required from have not been found to be useful in predicting the outcome in
clinical trials before they can be recommended for routine use ARDS. Majority of deaths in patients with ARDS are attributable
in patients with unresolved ARDS. to sepsis or multi-organ dysfunction rather than primary
respiratory disease. Certain prognostic factors have been
Nutritional supplementation identified to predict risk of death at the time of diagnosis of
Enteral feeding with omega-3 fatty acids, such as, ARDS (Table 8).
eicosapentanoic acid, γ-linolenic acid, and antioxidants was
shown to facilitate improvement in oxygenation and reduction Table 8: Predictors of Mortality in Patients with ARDS
in mortality in earlier trials. However, this benefit has not been Advanced age
replicated in more recent clinical trials. Chronic liver disease
Figure 3 outline algorithm for the management of ARDS. Non-pulmonary organ dysfunction
Sepsis
ARDS in the Tropics
Organ transplantation
Infectious causes such as pulmonary and miliary tuberculosis Human immunodeficiency virus infection
TB, falciparum malaria, enteric fever, and leptospirosis are rare Active malignancy
but treatable causes of ARDS. When the cause of ARDS is not
Failure of pulmonary function to improve during the first week of
clear, especially in endemic areas, these aetiological causes
treatment
should be kept in mind and active efforts directed at
261
 Prevention 2. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign:
International guidelines for management of severe sepsis and septic shock.
No form of therapy is known to prevent the occurrence of ARDS. Int Care Med 2008; 34:17-60.
Corticosteroid therapy, routine administration of antibiotics in 3. Esan A, Hess DR, Raoof S, et al. Severe hypoxemic respiratory failure. Part 1:
the absence of evidence of infection, and use of prophylactic Ventilatory strategies. Chest 2010; 137: 1203-16.
PEEP have not been shown to prevent ARDS in patients at risk. 4. Levy MM, Fink MP, Marshall JC, et al. SCCM/ESICM/ACCP/ATS/SIS. 2001
SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.
RECOMMENDED READINGS Crit Care Med 2003; 31:1250-6.
1. Cinel I, Opal SM. Molecular biology of inflammation and sepsis: a primer. 5. Raoof S, Goulet K, Esan A, et al. Severe hypoxemic respiratory failure. Part
Crit Care Med 2009; 37: 291-304. 2: Nonventilatory strategies. Chest 2010;137:1437-48.

262
 7.8 Mechanical Ventilation

Surender Kashyap, Surinder Singh

Mechanical ventilation (MV) of the lungs is defined as assisting components are re-usable, expensive and include corrugated
or substituting spontaneous respiration of the patient with tubings, humidifier or (HME), flow sensor, Y-piece, water traps
artificial respiration with a lung ventilator or manual resuscitator and exhalation valve.
bag. Application of positive airway pressure overcomes the
Gas Flow
increased airway resistance (asthma, chronic obstructive
pulmonary disease [COPD]) and inflates less compliant alveoli Flow of the air (enriched with oxygen) in the breathing circuit
(acute respiratory distress syndrome [ARDS], pneumonias), is called gas flow. A number of ventilators use a continuous
improves functional residual capacity (FRC) and improves basal flow of 5 to 10 L which is used for sensing patient’s effort
oxygenation by recruitment of atelactic lung units. Positive and is called basal flow or bias flow.
pressure counteracts the hydrostatic pressure in capillaries and Diagnostic Functions
redistributes (decreases) extracellular lung water. However, MV
Newer ventilators can measure changes in compliance, resistance,
is associated with a number of complications which are
positive end-expiratory pressure (PEEP) and air trapping, etc.
discussed briefly in the following sections.
Auto-PEEP is measured by ‘end-exipratory hold’ or occlusion for
COMMONLY USED TERMS 5 to 10 seconds whereas similar manoeuvre after end-inspiration
‘inspiratory hold’ depicts plateau/alveolar pressure (PPLAT/ALV).
It is important to know the jargon of terms used in context to
These diagnostic functions are helpful in making rational
ventilation for better understanding of this subject. The
ventilator adjustments.
commonly used terms are as under:
Nebulisation
Cycling
Some of the ventilators have programmable nebulisers to allow
The mechanism used to terminate inspiration and switch
aerosol therapy without interruption, or modification of ventilation.
over to exhalation is called cycling. It is also used to classify
ventilators. MODES OF VENTILATION
Pressure Cycling Mode of ventilation specifies the method and type of
Inspiration is terminated after desired airway pressure (PAW) is ventilatory assistance being provided by the ventilator.
achieved. The tidal volume (VT) is directly proportional to PAW Commonly used modes for ventilating the lungs are as under:
and inversely proportional to airway resistance, e.g. in Manual Ventilation
bronchospasm.
It refers to the hand delivered ventilation using ambu bag-mask
Volume Cycling or bag-tracheal tube technique with or without oxygen
Inspiration stops after delivering the set VT. Airway pressure supplementation. Manual ventilation is quite effective, and
increases with airway resistance (bronchospasm) or low controlled or assisted ventilation can be given until a ventilator
compliance (pulmonary oedema). becomes available.
Flow Cycling Spontaneous Mode
Inspiration is terminated after the flow rate falls to a particular Ventilator does not give breaths, but delivers the set fraction
level e.g. 25% of peak flow rate. of inspired oxygen (FIO2), continous positive airway pressure
(CPAP) and pressure support.
Time Cycling
Controlled Mechanical Ventilation (CMV)
Inspiration is terminated after the set inspiratory time. Modern
ventilators use a combination of these cycling mechanisms. The ventilator is set to deliver fixed breath rate and VT (CMV-V)
or inspiratory pressure (CMV-P). Spontaneous respiration is
Trigger abolished with deep sedation or neuromuscular blocking drugs.
Trigger is the signal used to start ventilator breaths. Ventilator CMV is used in initial phase of ventilation.
itself triggers breaths at a set respiratory rate (RR). Alternatively,
ventilator senses patient’s inspiratory pressure (pressure trigger) Assist-Control
or inspiratory flow (Flow trigger) for triggering breaths. Recently, Respiratory rate, VT and trigger sensitivity level are set in this
electrophysiological activity of diaphragm is being used as mode and the patient triggered breaths are assisted by the
trigger (see NAVA). ventilator, otherwise it works CMV mode. Common assisted
modes are as follows:
Breathing Circuit
The arrangement of corrugated tubings designed to deliver gas Synchronised Intermittent Mandatory Ventilation (SIMV)
to the patient is called breathing circuit. It requires periodical Ventilator delivers the set breath rate and V T (SIMV-V) or
and between-patients cleaning and sterilisation. Most inspiratory pressure (SIMV-P) using patient trigger. SIMV 263
 improves patient comfort and allows spontaneous breathing Airway Pressure Release Ventilation (APRV)
between synchronised ventilator breaths. APRV has been tried in place of IRV with mixed results. The
Pressure Support Ventilation (PSV) lungs are kept continuously inflated with brief periods of relief
for exhalation without formal breath cycles. Spontaneous
Inspiratory efforts of the patient trigger the ventilator to breathing is possible with considerable effort. Airway pressures
augment gas flow to achieve the desired airway pressure. PSV and circulatory effects are less pronounced than IRV.
helps the patient to overcome increased airway resistance
and decreased compliance and thus it “off loads” the inspiratory Apnoea Back-up Ventilation
muscles. It is a safeguard CMV mode and starts automatically in case
patient stops breathing or triggering breaths. Parameters for
Proportionate Assisted Ventilation (PAV)
back-up ventilation should be adjusted for individual patient
Proportion of assisted ventilation is directly proportional to while starting the ventilation.
the effort of the patient. The proportion to be assisted is set as
percentage, but the assistance decreases with decreasing TYPES OF VENTILATORS
patient’s effort (exhaustion) and hypoventilation can occur. Different types of mechanical ventilators are available for use
Adaptive Support Ventilation (ASV) in the hospitals (ICU ventilators), for transport of the patient
(transport ventilators), for use at home (domiciliary ventilators)
The clinician determines minute ventilation and ventilator and (anaesthesia ventilators) for anaesthetic applications. A
algorithm manages the RR/VT relationship with changing lung simple but effective form of multi-purpose ventilator is manual
dynamics. If the patient fails to trigger, controlled breaths are resuscitator bag (Ambu bag).
delivered automatically to avoid hypoventilation.
INDICATIONS FOR MECHANICAL VENTILATION
Neurally Adjusted Ventilatory Assistance (NAVA)
Main indications for MV include respiratory failure associated
This under-investigation mode senses the electrical activity
with hypoxia, hypercapnoea or both, compromised circulatory
of diaphragm (through oesophageal electrode) to trigger
status and pulmonary oedema.
ventilator-assisted breaths and aims at enhanced patient
comfort by neuro-ventilatory coupling. The mode is not yet Clinical Indications
available in most of the available ventilators. Clinical indications include ARDS, acute severe asthma, COPD
Positive End-Expiratory Pressure (PEEP) with acute exacerbation, Landre Guillain Barré syndrome,
poliomyelitis, head injury with diffuse brain oedema, pulmonary
PEEP is achieved by adding resistance to the exhalation. It oedema and after major surgical operations. Severe tetanus
prevents complete emptying of alveoli, airway closure and (opisthotonus) and recently bird flu and swine flu have become
increases the duration for gas exchange. Application of indications for mechanical ventilation. Only those patients who
PEEP in ARDS protects the alveoli from shearing stress due to are likely to recover completely from underlying disease are
repeated collapse and expansion. However, inap-propriately selected for ventilation. Brain dead patients may require
high PEEP increases the risk of barotrauma and hypotension. ventilation until organ harvesting. Objective indications for
Continuous Positive Airway Pressure mechanical ventilation are given in Table 1.
PEEP during spontaneous respiration is called CPAP. In addition Table 1: Objective Indications for Mechanical Ventilation
to the effects of PEEP, it decreases the inspiratory work required
for opening up of closed airways. Blood gas values PaO2 <60 mmHg despite FiO2 0.6
PaCO2 >50 mmHg
Biphasic Positive Airway Pressure (BiPAP) HCO3 is also raised and pH <7.3
Two distinct phases of positive pressure are applied during Alveolar-arterial O2 gradient >400
inspiration and expiration. Inspiratory PAP (iPAP) resembles mmHg on 100% oxygen
PSV whereas expiratory PAP (ePAP) resembles CPAP. Apart Bedside measurements Respiration rate >35 breaths/min;
from intensive care unit (ICU) ventilators, separate BiPAP Rapid shallow breathing index, i.e.
machines are also available. S-PAP and DuoPAP are equivalents RR/ VT (L) >100
of BiPAP. Spirometric values Tidal volume <5 mL/kg
Minute ventilation >10 L/min
Volume Assured Pressure Support; Volume Support;
Vital capacity <15 mL/kg
Variable Pressure Support; and Pressure Augmentation
Peak inspiratory pressure (> –25 cm H2O
In addition to ventilator support, e.g. PSV, these modes ensure or 0 to 24 cm H2O
delivery of the desired VT in spontaneously breathing patient.
PaO2 = Arterial oxygen tension; PaCO2 = Arterial CO2 tension; HCO3 = Plasma
Ventilator monitors the inspiratory flow and if the patient is bicarbonate
unlikely to inhale desired VT, the ventilator augments the gas Note: All these parameters may not be available in every patient; hence, clinical
flow and delivers the set VT. judgement is important.
Inverse Ratio Ventilation (IRV)
PROCESS OF MECHANICAL VENTILATION
IRV is sometimes used in severe cases of ARDS by setting
an inspiration longer than exhalation during CMV. It can Initiation of Mechanical Ventilation
improve oxygenation with increased risk of cardiopulmonary Initiating MV has inherent risks and requires meticulous
264
complications. preparation, which should be based on ABCDE. A = Airway:
 Mechanical Ventilation
Maintenance of patient airway and tracheal intubation is gradually as the patient recovers and weaning from the ventilator
necessary. B = Breathing: Patient requires ventilation with is started. The sedatives may be with held in the morning to
oxygen and bag mask technique during tracheal intubation. allow the patients to wake up (daily sedation vacation).
C = Cardiovascular instability or even cardiac arrest may occur
Nutrition
in sick patients. An intravenous line must be secured with 18G
or 16G cannula and normal saline or Ringers’ lactate should be Maintenance of proper nutrition with sufficient calorie content
running unless contraindicated. D = A number of drugs are is mandatory in patients on MV. ESPEN 2004 guidelines state
needed; midazolam, or anaesthetic like thiopentone, muscle that enternal nutrition should be started within 24 hours in
relaxants usually succinylcholine are used to calm and relax the hemodynamically stable patient’s. Enteral feeding is preferred
patient for tracheal intubation. Adrenaline and atropine should because it is natural, emotionally satisfying and prevents sepsis
be ready for immediate use. E = Equipment must be checked by maintaining integrity of gut mucosa. Diet should be
in advance and includes laryngoscopes, oropharyngeal airways, adequate in calorific value which should be maintained at 25-
tracheal tubes, manual resuscitator (Ambu bag), ventilator and 30k cal/kg body weight per day for the patients. These calories
a patient monitor. are distributed as 50% carbohydrate, protein at 1g/kg per day
and rest comprises of fat. Excessive carbohydrates increase
Management of Ventilation carbon dioxide production and respiratory workload which
Airway is secured with oral or nasal tracheal tube and ventilation may be harmful in COPD patients. Dietary composition in
of both the lungs is ensured with careful auscultation. Orotracheal diabetics and hepatorenal disease requires additional
tubes require deeper levels of sedation and cause excessive considerations. Patients on ventilator start tolerating Ryle’s
salivation whereas nasotracheal tubes are tolerated better, nasogastric tube (RT) feed after 24 to 48 hours and require
require less sedation, but there is increased risk of epistaxis, insertion of RT. RT feed is started at 3 to 4 hourly intervals
bacteraemia and sinusitis. The VT, RR and airway pressure should with volumes of 4-5 ml/kg. RT feeds are not available in a
be appropriate for the size of the patient and lung pathology. It number of hospitals in our country (especially, after H1N 1
is safe to use 100% oxygen during first few minutes followed by epidemic, ventilators have been installed in district hospitals),
gradual reduction to a level necessary to maintain pulse oximetric and therefore, relatives may have to be trained to prepare RT
saturation (SpO2) more than 90%. Humidification of inhaled gases feed using common ingredients.
is essential for optimal mucociliary function and is achieved with Communication with Patient
a heated humidifier (e.g. Fischer Paykel humidifier) or a disposable Most patients undergoing MV are conscious, they should be
heat and moisture exchanger (HME). Blood gas analysis should re-assured and informed about their progress, explained about
be done 1 to 2 hours after starting ventilation make further the procedures to be done on them and taught to co-operate,
adjustments in ventilation. Lung physiotherapy with chest wall especially during weaning. Intubated patients cannot speak and
percussion, postural drainage of lungs and tracheobronchial often use tapping of bed rails or may sometimes write. Their
suctioning is done through tracheal tube intermittently. calls should always be attended with sympathetic and re-
assuring attitude.
CARE OF THE PATIENTS ON MECHANICAL VENTILATION
General Care Monitoring of Vital Signs
The patients on ventilator are totally dependant on nursing Continuous monitoring of vital signs like, electrocardiogram
staff and meticulous maintenance of hygiene is essential for (ECG), SpO2, and non-invasive blood pressure is required. Arterial
control of infection and optimal outcome of the patients. blood gas analysis and electrolyte status is needed in metabolic
General measures include dressing of hair, cleaning of eyes disorders, like diabetes. Unstable patients require monitoring
and use of lubricant eye ointment, oral hygiene with brush or of intra-arterial pressure, central venous pressure and cardiac
small pea-nut gauge soaked in chlorhexidine 2% and oral output. Non-invasive technology has largely replaced
suctioning, catheterisation of bladder, and diapers for pulmonary artery catheterisation. Neurological patients may
prevention of soiling with faecal matter. Skin is kept clean with require monitoring of electroencephalogram or intracranial
daily sponge bath, change of wet clothing or linen, talcum pressure. Urine output is recorded at hourly intervals in case of
renal dysfunction otherwise at 3 to 4 hourly intervals.
powder and wrinkle free sheets. Use of pneumatic mattresses
combined with change of posture every 2 hours reduces the Monitoring of Ventilation
risk of bedsores. These patients are susceptible to stress Most of the modern ventilators monitor and display parameters
induced gastrointestinal bleeding and an H2 blocker, proton like exhaled VT, minute volume, waveforms breath rate and peak
pump inhibitor or mucosal barrier like sucralfate should be airway pressure and display simple pressure/time or volume/
administered regularly. time waveforms on screen (Figure 1). Small variations (± 10%;
Sedation and Analgesia read user manual of ventilator) from set values are acceptable
and, therefore, alarms limits should be set accordingly.
In the initial phase of ventilation, sedation with narcotics,
midazolam or propofol, etc. is required to suppress respiratory Sophisticated ventilators display real time pressure, volume and
efforts of the patient and fighting with ventilator. In post- flow graphics in the form of waveforms or as loops, which are
operative, traumatised and other painful conditions, adequate utilised for diagnosing changes in resistance (resistive load, e.g.
analgesia is required. Muscle relaxants may cause myopathy, in asthma), compliance (elastance load, e.g. ARDS, pulmonary
complicate weaning and are avoided, except in neurosurgical oedema), air trapping and auto-PEEP (e.g. COPD). Basic
patients. Sedatives and muscle relaxants interfere with waveforms (open and loop) illustrating important findings are
neurological assessment of the patient. Sedation is reduced shown in Figures 2A and B. 265
 Figure 1: Airway pressure waveforms with different modes of ventilation left panel, right panel shows waveforms with 5 cm PEEP/CPAP.
VA = Assisted breath; S = Spontaneous breath

Hysteresis Lower inflection point (LIP)

The pressure and volume curves are not linear due to variable Pressure volume curve deviates towards pressure axis due
resistive and elastic properties of the lungs and chest wall. As a to resistance of closed airways and after opening up of
result inspiratory curve assumes sigmoid shape and the lung airways the curve becomes steep owing to the compliance
volume is always higher during expiratory phase at any given of alveoli. This shift creates a distinct point on the axis of
pressure. airway pressure called LIP or initial point of inflection (iPI). It
Upper inflection point (UIP) denotes excessive airway closure and requires application
Over filling of alveoli leads to abrupt rise in pressure and the of external PEEP (ePEEP). It has been recommended earlier
upper part of inspiratory pressure curve deviates the curve to that ePEEP value should be 2 to 3 cm more than the airway
the right (pressure axis). The upper part of pressure volume pressure corresponding to LIP, but recognition of air trapping
curve assumes a ‘duck-bill’ shape. UIP is an abnormal finding has led to recommendation of lower value of ePEEP based
and VT needs to be decreased so that the shape of the curve/ on detection of airway closure or autoPEEP on expiratory
266 loop becomes normal. curve.
 Mechanical Ventilation
Figures 2A and B: (A) Typical flow and pressure waveforms. (B) Loops showing points of inflection.
Insp = Inspiration; PIP = Peak inspiratory pressure; LIP = Lower inflection point; PEEP = Positive end-expiratory pressure

Titration of applied PEEP or ePEEP radiography, etc. should be followed. Appearance of new
There is no fixed method to determine the value of ‘best PEEP or signs and invasive procedures should be appropriately
optimal PEEP’ which would provide maximum gas exchange investigated.
without side effects, like air trapping and haemodynamic WEANING FROM MECHANICAL VENTILATION
compromise. Airway closure and iPEEP, both occur during
The process of discontinuation of lung ventilation is called
expiration and the fact, that lung volume (at corresponding point
‘weaning from ventilation’ and can take several hours to
on expiratory curve) at any given value of pressure on inspiratory
days. The patient should have substantially recovered from
curve is much higher. Application of PEEP/ CPAP the basis of LIP
respiratory distress, underlying disease and haemodynamically
may lead to the worsening of air-trapping (iPEEP) particularly in
stable with minimal cardio-respiratory support. Objective
COPD patients. The recent trend is to set ePEEP value up to 70-
assessment of readiness for weaning a patient from
85% of iPEEP. A number of methods like monitoring of oesophageal
ventilator is based on a number of criteria given in Table 2.
pressure,monitoring airway pressure and expiratory flow/ volumes,
Common methods used for weaning from ventilation are as
haemodyanamic status, computed tomography and trans-
under:
thoracic-electric impedance and values of PaO2, FiO2/PaO2 ratio
etc are being used with reasonable success. Transthoracic Table 2: Criteria to Assess Readiness for Weaning a Patient from
impedance is directly proportional to the lung volume and its Mechanical Ventilation
monitoring is somewhat similar to ECG monitoring. This non-
invasive method may become a useful tool for monitoring and Clinical parameters RR: ≤35 per minute with RSBI: <100
real time display of resting lung volume in future. Stable haemodynamic state
Spirometric values Tidal volume: ≥5 mL/kg
Pressure and flow volume loops Vital capacity: ≥10 mL/kg
Advanced ventilators display these curves in the form of Minute ventilation ≤10 L/min
pressure/volume or flow/volume loops, which are very useful Inspiratory pressure: < –25 cm H2O
in diagnosing various problems. (e.g. –26 to –50 cm H2O)
Schedule for Investigations or Tests Blood gas values SpO2: ≥ 90% with FiO2: ≤0.5
Alveolar-arterial O2 gradient: <400 mmHg
A bi-weekly or as per protocols of the hospital, schedule for on 100% oxygen
clinical tests like haemogram, cell counts, cultures and
267
 T-Piece Trial VENTILATOR SETTINGS FOR COMMON CLINICAL CONDITIONS
After short duration of ventilation, the ventilator is stopped Acute Respiratory Distress Syndrome
abruptly and oxygen (4 to 5 L/min) is administered through a Initial ventilator settings for these patients should be high FiO2,
T-piece attached to tracheal tube and after a successful trial of VT 6 to 8 mL/kg, RR 12 to 15 per minute and a PEEP of 5 to 7 cm
90 min to 2 hours, trachea is extubated. H2O. Further ventilator adjustments should be done on the basis
Spontaneous Mode of blood gas analysis after about one hour of ventilation. PaO2
≥60 mmHg, permissive hypercapnoea with PaCO2 ≥50 mmHg
Instead of attaching a T-piece, the ventilator is switched over
and a pH ≥7.2 should be the objective. Acute rise in PaCO2 can
to spontaneous mode, PSV value is reduced to 5-6 cm H2O
cause ventricular arrhythmias, therefore, careful monitoring of
(to overcome the resistance of breathing circuit) and FiO2 30%
ECG is essential. Since ARDS is one of the most complex lung
to 40% and extubation can be done after 90 min to 2 hours
conditions, all modes, e.g. APRV, IRV and non-conventional
trial.
modes have been used with variable success. Neuromuscular
Gradual Weaning blockers should be considered for first 48 hours.
Patients after prolonged ventilation are weaned by gradually Acute Severe Asthma
decreasing ventilatory support. Sustained tolerance of SIMV rate
These patients have hyper-reactive airways and tracheal intubation
≤4, PSV or iPAP level <8 and PEEP ≤5 alongwith FiO2 of less than
further worsens the bronchospasm. Intravenous ketamine
50%, is followed by spontaneous mode or T-piece trial and
(2 mg/kg) is the drug of choice due to its sympathomimetic and
extubation of trachea. Weaning is not always straight forward
bronchodilator properties. Intravenous lignocaine 1.5 to 2 mg/kg,
and on several occasions it becomes difficult to wean. Risk factors
administered 90 to 120 seconds before intubation may also be
include advancing age, COPD, malnutrition, sepsis, electrolyte
effective (evidence weak) in controlling the bronchospasm. Initial
imbalance and neuro-muscular diseases. Strategies like more
ventilator settings include VT 6 to 8 mL/kg, RR 8-10 per minute,
gradual weaning, optimisation of nutrition and electrolyte
higher flow rate (80-100 L/min), plateau pressure of 25-30 cm
balance, intermittent nocturnal ventilation, non-invasive CPAP
H2O and peak inspiratory pressure 30-35 cm H2O. Although higher
or BiPAP may be helpful. Ventilator dependence is both physical
flow rate decreases inspiratory time, it might increase peak
and psychological and should be treated accordingly.
inspiratory pressure. Alternatively, pressure control mode with
Post-Ventilation Care cycling pressure up to 40 cm H2O may be used. Permissive
After termination of ventilation, the patient should be hypercapnoea (PaCO2 ≤50 mmHg and a pH >7.2 may also be
monitored in ICU or in high dependency unit for next 24 to 48 allowed. Since these patients are likely to receive high doses of
hours to rule-out recurrence of respiratory distress. steroids, therefore muscle relaxants should be avoided unless
absolutely necessary due to increased risk of myopathy.Ventilator
NON-INVASIVE VENTILATION with in-built nebuliser should be preferred, otherwise provision
Non-invasive ventilation (NIV) is accomplished with an airtight for attaching a nebuliser should be made.
interface, e.g. facemask, nasal mask or NIV helmet and invasive Chronic Obstructive Pulmonary Disease
airways like tracheal tubes are not used. Two methods of NIV
COPD patients are better managed with NIPPV using CPAP
are available, one employs positive airway pressure and the
or BiPAP modes. ePEEP should be 75% to 80% of auto-PEEP or
other applies negative pressure to the chest wall (for complete
6 to 8 cm H 2O. Since these patients are accustomed to
review, refer to the chapter on NIV).
hypercapnoea, PaCO2 ≤ 90 mmHg with a pH ≥7.2 may be
OTHER METHODS OF VENTILATION allowed with vigil for CO2 narcosis and cardiac arrhythmias.
High Frequency Jet Ventilation Ketamine and lignocaine as described above should be
preferred for laryngoscopy and tracheal intubation. The VT of 8
High frequency jet ventilation employs a jet of gas into the to 10 mL/kg and RR of 10 to 12 per minute with moderate FiO2
upper airway with air entrainment and is based on Bernoulli’s
is usually sufficient. Ventilator is disconnected briefly in case of
principle.
hypotension. Improvement in pulse volume and blood pressure
High Frequency Positive Pressure Ventilation indicates air trapping and the need for reduction of PEEP, VT or
High frequency positive pressure ventilation delivers RR RR to prolong exhalation.
between 60 to 180 per minute and VT ≥ anatomical dead space Cardiogenic Pulmonary Oedema (CPO)
(VD). Administer high FiO2, morphine and keep the patient propped
High Frequency Oscillations up during transport, intubation and ventilation. Initial ventilator
High frequency oscillations deliver RR 180 to 3000 per minute settings should include VT of 8 to 10 mL/kg, RR of 12 to 15 per
and VT ≤ VD. minute, high FiO2 usually 100% and PEEP of 10 cm. Bladder
catheterisation should precede administration of diuretics and
The above three are un-conventional modes, require different aggressive treatment of underlying cardiac defect should
types of ventilators and mechanism of gas exchange is not commence along with. Role of NIPPV continues to be controversial
clear. Various mechanisms, like Taylor dispersal, gas velocity, in CPO despite certain reports of successful oxygenation.
convection, pendelluft, mass diffusion, and mixing due to
cardiac pulsations may be responsible for gas exchange. Interstitial Fibrosis
Successful oxygenation has been reported in some patients These patients have fast time constants for inflation and
268 where conventional ventilation proved ineffective. emptying of lungs along with severe diffusion block. Ventilator
should include VT of 5 to 6 mL/kg, RR of ≥ 16 per minute (I:E

Mechanical Ventilation
pediatric breathing circuits should be used below 25 kg
ratio 1:1 and IRV is well tolerated) and high FiO2 are required body weight. Neonates and infants require different types of
along with PEEP of 5 to 10 cm. Treatment of interstitial fibrosis ventilators.
comprises of immunosuppressants and steroid administration.
Muscle relaxants should be avoided and strict aseptic COMPLICATIONS OF MECHANICAL VENTILATION
precautions are needed. MV can result in or contribute to a number of complications.
Normal Lungs Major complications are listed in Table 3 and discussed below.
This group of patients includes poisoning, snake bite, tetanus, Respiratory System
head injury and Guillain-Barré syndrome, etc. These patients The diseased lung units have low compliance and or high
have normal lung mechanics and maintain oxygenation with resistance. MV is preferentially delivered to normal lung units,
FiO2 of 30% to 40%. PaCO2 of 35 to 40 mmHg (30 to 35 mmHg in which may be damaged by excessive pressure or volume
head injury patients) and a basal PEEP of 5 cm is usually sufficient. delivered by mechanical ventilators. Rupture of alveoli can
High FiO2 reduces the half-life of carboxyhaemoglobin, therefore, lead to life-threatening conditions, like tension pneumothorax
CO poisoning should be treated with FiO2 of 100% oxygen the and pneumomediastinum. Surfactant depletion and
first few hours (6 to 8 hours). oxygen toxicity have also been implicated as reasons for
lung damage. Prolonged ventilation leads to disuse atrophy
Progressive Neurological Diseases
of respiratory muscles and may contribute to ventilator
Motor neuron disease and lateral sclerosis patients develop dependence.
nocturnal dyspnoea due to decreased muscle tone and fatigue.
These patients are managed with night time NIPPV using CPAP Cardiovascular System
or BiPAP modes. Ventilation eventually needs to be terminated Positive intrathoracic pressure impairs the venous return,
by observing ‘care of the dying patient’ protocols. increases right ventricular afterload and may cause left
ventricular dysfunction leading to reduced cardiac output
SPECIAL SITUATIONS and hypotension. Institution of MV relieves the respiratory
Pregnancy distress and levels of circulating catecholamines fall rapidly,
Institution of MV imposes stress and may result in premature leading to further hypotension and sometimes cardiac
expulsion of foetus. Obstetrician and paediatrician should also arrest. These cardiac effects are directly related to the mean
be involved in the management. Viable foetus may require airway pressure, and therefore, modes like PEEP/CPAP and
surgical extraction. IRV have more pronounced effect. This compromised
haemodynamic state with decreased cardiac output and low
Paediatric Patients perfusion pressure results in decreased delivery of oxygen
Paediatric patients are more vulnerable to ventilator-induced and nutritional substrates to vital organs and contributes to
lung injury. Usually pressure cycled ventilators are used and multi-organ failure.

Table 3: Complications of Mechanical Ventilation

Organ System Complications Prevention/Treatment
Respiratory system Volume trauma, tension pneumothorax, Use appropriate ventilator modes and settings
deterioration of blood gas status Optimise PEEP, flow rate, FiO2 and I:E ratio
Cardiovascular system Hypotension, cardiac arrest Optimise volume status, adjust ventilator settings, PEEP
Psychological Acute stress and post-traumatic stress disorder Sedation, communication and reassurance
(PTSD)
Immunological Infection, sepsis Use of VAP bundle approach handwashing, aseptic
precautions, good hygienic status, avoid re-use of
disposable items
Aspiration of gastric Pneumonia, gastric acid aspiration syndrome Early securing of airway, regularly check tracheal tube cuff
contents leakage, observe NPO before change of tracheal tubes,
regularly check Ryle’s tube position
Use of PPIs/ H2 Blockers/ sucralfate, Head end elevation
to 30-45°
Long-term complications
Prolonged intubation Vocal cord polyps and granulomas Use appropriate size tracheal tubes, early tracheostomy
Tracheostomy Tracheal stenosis Decanulation with gradually decreasing diameter of
tracheostomy tubes (while in hospital), tracheal dilatation
or resection of affected segment
Psychological PTSD Psychologist/Psychiatrist consultation
PEEP = Positive end-expiratory pressure; FiO2 = Fraction of inspired oxygen; NPO = Nil per os

269
 Psychological CONCLUSION
Artificial airways, mechanical breaths and suctioning are both In critical situations it is important to secure the airways at first
physically and emotionally distressing. Sleep deprivation, possible opportunity to prevent aspiration and its associated
invasive procedures, tones and alarms of monitors, inability to complications. Oxygen should be given till the time of start of
communicate and isolation from family impose additional ventilation. Use high (100%) concentration of oxygen before
stress. A state of post-traumatic stress disorder may follow even tracheal intubation. Once the ventilation has started, send
after discharge from hospital. ABG after 1 hour. Strictly avoid using the same catheter for suction
and its size be appropriate. Time of suction should preferably
Infection
be not beyond 5-10 second each time. Nasogastric suction
Nosocomial infections and ventilator-induced pneumonia are should be done before emergency interventions. In case of
well known. Patients are vulnerable to infection due to invasive ventilation malfunction use manual ventilation. Patient should
procedures, indwelling lines and catheters and stress. be kept NPO for 4-6 hours before change of tubes.
Aspiration Maintain and constantly monitor all pulmonary and circulatory
Despite tracheal intubation, the patients remain at high-risk for parameters.
aspiration of gastric contents. Checking of nasogastric tube
position and residual gastric residual volume (GRV) before RECOMMENDED READINGS
administration of feed or enteral drugs is important. Positive 1. Hough A. Physiotherapy in Respiratory Care: An Evidence-based Approach to
pressure NIV may cause gastric inflation especially in debilitated Respiratory and Cardiac Management; 3rd Ed. Cheltenham: Nelson Thornes;
and comatose patients. 2001.
2. Kovacs G, Law JA. Airway Management in Emergencies. New York: McGraw-
Long-Term Complications Hill Medical; 2008.
Prolonged intubation and tracheostomy may cause tracheal 3. Miller RD. Miller's Anesthesia; 7th Ed. Philadelphia. Churchill Livingstone -
stenosis, vocal cord polyps and granulomas in the long run. Elsevier; 2010.
There is no consensus as to whether tracheal intubation or 4. Pilbeam SP, Cairo JM. Mechanical Ventilation: Physiological and Clinical
tracheostomy is better. However, tracheostomy should be done Applications; 4th Ed. Philadelphia: Elsevier; 2006.
early if ventilation or airway protection is anticipated for longer 5. Wilkins RL, Stoller JK, Kacmarek RM. Egan’s Fundamentals of Respiratory
than 3 weeks. Care; 9th Ed. Philadelphia: Elsevier; 2009.

270
 7.9 Non-Invasive Ventilation

Dhruva Chaudhry, Inderpaul Singh

INTRODUCTION In the assist mode, a change in the set IPAP occurs in response
Non-invasive ventilation (NIV) is the delivery of the mechanical to the patient’s inspiratory efforts. In A/C mode, all respiratory
ventilation to the lungs using techniques that do not require efforts initiated by the patient are supported to the IPAP level,
an endotracheal airway. Three basic methods of applying NIV as in the assist mode, but a minimum breathing rate may also
are: negative pressure ventilation, abdominal displacement be set. If a patient fails to make an inspiratory effort within a set
ventilation and positive pressure ventilation (PPV). However, for interval, the machine triggers inspiration to set the IPAP.
practical purposes, NIV now refers to PPV administered via mask The control mode delivers pressure support breaths based on
or interface that directs pressurised gas into the upper airway. control settings, not patient’s efforts. The clinician sets the IPAP
The use of PPV goes back as far as 1780, when the first bag-mask and EPAP, the number of breaths per minute and the inspiratory
apparatus was designed for resuscitative efforts. Over the years, time percentage. The breaths are time triggered to the IPAP,
it has evolved as being used as a means to deliver aerosolised based on the rate set. IPAP then cycles to EPAP based on the
medications periodically, to being used in patients with acute IPAP percentage. In all modes, delivered tidal volume (V T)
respiratory failure (ARF) due to chronic obstructive pulmonary depends on the gradient between the IPAP and the EPAP, the
disease (COPD) and asthma. Today NIV is used in both acute and inspiratory time, patient’s inspiratory effort, and the patient’s
chronic care settings, like COPD, asthma, neuromuscular diseases, lung characteristics. PTVs ability to deliver flow in response to
heart failure, obstructive sleep apnoea, etc. patient demand is the same as or superior to that of intensive
care unit (ICU) adult ventilators and portable volume ventilators.
EQUIPMENT FOR NON-INVASIVE POSITIVE PTV’s also allow adjustment of the amount of time required to
PRESSURE VENTILATION (NPPV) reach the IPAP. Two other comfort features of PTVs include
RAMP and delay time controls. RAMP allows positive pressure
The equipment needed for NPPV generally includes ventilators,
to increase gradually over a set interval (delay time) of time.
humidifiers and the interfaces or masks.
The RAMP rate generally can be set in increments of 1, 2, or 3
Types of Ventilators cm H2O, and delay time can be set in 5 minutes increments from
NPPV has been successfully applied using portable volume 5 to 30 minutes.
ventilators, adult intensive care ventilators and portable Portable PTVs have certain limitations that may restrict their
pressure support (pressure-targeted) ventilators. The choice of use in ARF. The oxygen delivery is not standard on most portable
ventilator depends on the level of support required and the PTVs. Therefore, fraction of inspired oxygen (FiO2) can vary and
advantages and disadvantages of the appropriate machines. is affected by flow rate, type of leak port in the system, site where
Pressure targeted ventilators oxygen is bled into the circuit, and IPAP and EPAP. Higher oxygen
flow rate results in higher oxygen concentrations. Lower IPAP
Portable pressure-targeted ventilators (PTVs) are also known and EPAP levels also yield higher oxygen concentrations. If leak
as continuous positive airways pressure (CPAP) ventilators, port is in the circuit, higher oxygen concentrations can be
pressure support ventilators or bilevel pressure ventilators. obtained, if the oxygen is bled into the patient’s mask.
These ventilators are microprocessor controlled, electrically
powered units that use a blower to regulate gas flow into the Rebreathing of carbon dioxide (CO2) is a concern with any type
patient’s circuit to maintain the preset pressure at the patient’s of PTVs that use a single circuit gas delivery system. The flow of
connection. PTVs have a single circuit gas delivery system that gas through the leak port depends upon the EPAP settings and
uses an intentional leak port for patient exhalation instead of a the patient’s inspiratory to expiratory ratio. At low EPAP settings
true exhalation valve. (< 4 cm H2O) and at a high respiratory rate, flow may not be
adequate to flush CO2 from the circuit.
PTVs are pressure limited, flow and time triggered, flow and
time cycled ventilators. These are designed to increase minute Portable volume ventilators
ventilation and improve gas exchange capabilities with the Portable volume ventilators were designed originally for
delivery of an inspiratory positive airway pressure (IPAP), and invasive ventilation in home and extended care facility. These
an expiratory positive airway pressure (EPAP). Most portable are patient or time triggered, pressure limited and volume
PTVs offer the CPAP, assist mode, assist/control (A/C), control cycled.
(or timed) mode of ventilatory support.
The newer generation of these ventilators has both volume and
In CPAP mode, the patient breathes spontaneously at a set pressure targeted modes with positive end-expiratory pressure
baseline pressure and controls both the rate and depth of (PEEP) capabilities. These ventilators are more responsive to
breathing. Flow sensors and pressure transducers respond to patient flow needs and can be used for either invasive or NIV.
patient’s inspiratory and expiratory efforts, and increased or These are not equipped with an internal blender, hence precise
decreased flow through circuit to maintain a stable pressure. oxygen concentrations are not possible and like portable PTVs 271
 oxygen must bled into the system through an adaptor from a RATIONALE OF VENTILATION
separate oxygen source. As such they are ideal for achieving a In ARF, NPPV is considered a life-saving application that offers a
seamless transition from the extended care facility to the home. number of benefits over invasive ventilation (Table 2). The most
Adult acute care ventilators significant is the avoidance of intubation. The physiological goal
of NPPV in ARF is to improve gas exchange by resting respiratory
Ventilators used in adult critical care settings offer more
muscles and increasing alveolar ventilation. NPPV reduces
ventilator support options, more alarms, a precise FiO2 and more
diaphragmatic swings, which suggests that respiratory muscles
monitoring features than portable PTVs. Although pressure
are being rested. In addition, when PEEP is applied during the
support mode is the most commonly used to administer NPPV,
pressure support ventilation, it helps offset intrinsic PEEP (PEEPi),
volume or pressure controlled modes combined with PEEP can
thereby reducing the work to initiate inspiration. Like-wise
also be administered via mask interface.
pressure support facilitates inspiration, thus increasing VT.
The most significant disadvantage of these ventilators is the Resting of respiratory muscles and improved VT lead to a lower
inability of some machines to compensate for leaks. Although arterial partial pressure of CO2 (PaCO2), better oxygenation and
studies have demonstrated no significant differences in gas decreased respiratory rate (Figures 1 and 2).
exchange between volume and pressure targeted modes,
volume control modes are seldom used to deliver NPPV in Table 2: Benefits of Non-invasive over Invasive Ventilation
acute care settings. However, volume control modes are more Acute care
likely to be used in the chronic care settings in patients with Reduces need for intubation
neuromuscular disorders. Reduces incidence of hospital acquired pneumonia
Humidification during Non-Invasive Pressure Ventilation Shortens ICU and hospital stay
Reduces mortality
Excessive drying of the nasal mucosa with the administration
Preserves airway defenses
of nasal CPAP or NPPV has been associated with nasal congestion
Improves patient comfort
and increased resistance. This is a leading cause of patient’s
Reduces need for sedation
discomfort and non-compliance. Humidification can prevent
and improve mucosal dehydration. A passover type of heated Chronic care
humidifier should be used because heated bubble humidifiers, Alleviates symptoms of hypoventilation
and heat and moisture exchangers, increase airway resistance Improves sleep quality
in the ventilator circuit and may also interfere with patient Improves functional capacity
triggering. Prolongs survival

Interfaces INDICATIONS AND CONTRAINDICATIONS OF

The effectiveness of NPPV is greatly influenced by the interface NON-INVASIVE VENTILATION
chosen to deliver the PPV. Various commonly used interfaces The goals of NPPV and the indications for its use are based upon
are described in Table 1. decades of clinical expertise and systemic research. The various

Table 1: Various Interfaces in Non-Invasive Positive Pressure Ventilation

Interface Advantages Disadvantages
Nasal mask Easy to fit Mouth leaks
Less feeling of claustrophobia Eye irritation
Low-risk of aspiration Facial skin irritation
Allows patient to cough and clear secretions Ulceration over nose bridge
Maintains ability to speak and eat Oral dryness
Less mechanical dead space Nasal congestion
More useful for chronic lung conditions Increased resistance through nasal passages
Not used in acute lung conditions
Full face (oronasal) mask Reduces air leakage through the mouth Increased risk of aspiration
Less airway resistance Increased risk of asphyxia
Used in acute lung conditions Increased dead space
Claustrophobia
Difficult to secure and fit
Facial skin irritation
Ulceration over nasal bridge
Patient must remove mask to eat, speak, or
expectorate secretions
Nasal pillows or seals Same as for nasal mask Pressure sores around nares
Mouth piece Facilitates communication Nasal air leakage
Less feeling of claustrophobia Hypersalivation
Low-risk of aspiration Possibility of orthodontic deformity
Allows patient to cough and clear secretions
Low-risk of carbon dioxide rebreathing
No head gear requirements
272
 Non-invasive Ventilation
SPECIFIC INDICATIONS
Acute Indications
Chronic obstructive pulmonary disease
The main objective of NIV in acute exacerbation of COPD is
not only to relieve symptoms of the disease but also to
reduce associated mortality and morbidity. During an acute
exacerbation, there is an increase in airway resistance and an
increased respiratory rate which together lead to hyperinflation
and development of PEEPi. As hyperinflation increases,
respiratory muscle activity also increases leading to an increase
in the work of breathing, and hence, oxygen consumption. This
together with impaired diaphragmatic mechanics leads to a
vicious cycle of hypoventilation, air trapping and muscle fatigue.
Figure 1: Mechanism of action of NPPV in obstructive airway disease. By combining high inspiratory pressure with low expiratory
pressure, NIV effectively reduces the diaphragmatic work
1. Augments tidal volume; 2. Decreases inspiratory threshold
PEEPi : Intrinsic Positive end-expiratory pressure; IPAP = Inspiratory positive airway of breathing, and hence, benefit the patient during acute
pressure; EPAP = Expiratory positive airway pressure; CPAP = Continous positive exacerbations by acting as a crutch to support the patient while
airway pressure; NPPV = Non-invasive positive pressure ventilation medical treatment is given time to work.
Unless contraindicated, NIV is to be preferably given to patients
with acute exacerbations having respiratory distress and
respiratory failure instead of conventional therapy alone, as NIV
has been shown to reduce respiratory rate, improve dyspnoea
and gas exchange, cause improvement of arterial blood gas levels,
shortens duration of hospital and ICU stay, reduces intubation
rate by three-fourth as well as complication and mortality rates.
The indications of NPPV are mentioned in Table 4.

Table 4: Indications of Initiating NPPV in Acute Exacerbations

of Chronic Obstructive Pulmonary Disease*
Respiratory distress with moderate-to-severe dyspnoea
Use of accessory muscles of respiration
Abdominal paradox
Respiratory rate > 30/min
pH <7.35; PaCO2 >45 mmHg; PaO2 <60 mmHg
* Any two of the above if present, NPPV should be initiated.
Figure 2: Mechanism of action of NPPV in hypoxaemic respiratory failure.
NIV can also facilitate early weaning in those intubated patients
1. Improves FRC/Oxygenation; 2. Decreases work of breathing, rests muscles,
decreases CO2
with COPD who could not be extubated due to multiple failed
“T” piece breathing trials. By facilitating early extubation in such
indications both in acute as well as chronic respiratory failure patients, NIV reduces occurrence of nosocomial pneumonias,
are mentioned in Table 3. improves breathing rates, and shortens duration of ventilator
use, NIV cap prevent re-intubation when used immediately after
Table 3: Indications for Non-Invasive Ventilation extubation for COPD patients at high risk of extubation failure
Obstructive Diseases Hypoxaemic Respiratory and also reduce hospital stay and mortality.
Failure
Acute cardiogenic pulmonary oedema
COPD (A) Acute pulmonary oedema (A)
Asthma (B) Pneumonia (B) CPAP has been in use to treat acute cardiogenic pulmonary
Cystic fibrosis (C) ARDS (C) oedema (CPE) since 1930s. The increased intrathoracic pressure
Upper airway obstruction (C) Trauma (C) reduces transmyocardial pressure, as well as the pre-load and
Restrictive diseases Categories of acute after-load; thereby enhancing cardiac function in patients with
(mainly long-term setting) respiratory failure left ventricle dysfunction who are dependent on after-load.
Kyphoscoliosis (C) Facilitation of weaning (A) CPAP leads to an increase in functional residual capacity,
Neuromuscular disease (C) Immunocompromised patients (A) secondary to opening of collapsed alveoli and rapidly improves
Obesity-hypoventilation Post-operative respiratory failure (B) compliance and oxygenation. It is highly effective in improving
syndrome (C) Extubation failure (B) oxygenation, lowering respiratory rate, decreasing sensation of
Do not intubate patients (C) dyspnoea, and thereby, helps in avoiding intubation.
Letter in parenthesis indicate level of evidence: A = Multiple controlled trials;
B = A single supportive controlled trial; C = Uncontrolled trials, case reports Studies comparing NPPV with CPAP demonstrated more rapid
COPD = Chronic obstructive pulmonary disease; ARDS = Acute respiratory improvement in PaCO2 and pH in the former, but the mortality
distress syndrome and intubation rates were almost similar. A disconcerting finding 273
 was a higher incidence of myocardial infarction in NPPV group should be monitored closely and if intubation is needed, delay
(71% versus 31%). The current recommendation is to use CPAP should be avoided.
(10-12 cm H2O) initially for the treatment of CPE and that NPPV Do not intubate
be used only in patients who continue to be hypercapnic and
dyspnoeic thereafter. The argument in favour of NPPV with “do not intubate status” is
that NPPV may relive severe dyspnoea and preserve patient
Hypoxaemic respiratory failure comfort. It may also reverse the acute process in disorders,
Evidence of the efficacy of NPPV in the treatment of hypoxic such as COPD or pulmonary oedema, and allow the patient to
respiratory failure has been inconsistent. Various studies live longer. The argument against NPPV is that it could actually
comparing NPPV plus usual medical care have shown better prolong the dying process, adds to patient discomfort and
gas exchange, reduced need for ventilation and decreased consume valuable resources, and may be deemed unethical. It
mortality rate. On the other hand, some studies found no is necessary for patients’ family and care-givers to understand
significant improvement in the patients’ overall outcomes these goals and to cease promptly if the goals are not being
unless the patients were also hypercapnic. Due to heterogeneity accomplished.
of disorders in this group, these findings cannot be applied to Long-Term Indications
individual patients and need further studies for application of
Chronic respiratory failure due to restrictive thoracic diseases
NPPV in these patients.
Patients with restrictive thoracic diseases presenting with features
Acute respiratory distress syndrome of chronic respiratory failure like symptoms of hypoventilation
Mixed success has been reported in patients with acute such as morning headache or day-time hypersomnolence, severe
respiratory distress syndrome treated with NIV. It can be tried pulmonary dysfunction may benefit from NIV. NIV ameliorates
in patients with mild oxygenation defects, but otherwise stable decline in lung function and improves gas exchange, cognitive
with only a single organ dysfunction. NIV should be started only function and overall survival in such patients.
in carefully selected patients within this group and intubation Guidelines for initiating NIV in patients with chronic respiratory
should be contemplated if there is no substantial improvement failure due to restrictive thoracic diseases are mentioned in
in oxygenation within the first hour. Table 5.
Pneumonia
Table 5: Guidelines for Non-Invasive Positive Pressure
Use of NIV in community-acquired pneumonia is becoming Ventilation Therapy in Restrictive Lung Disease on Long-term
more common. Various studies have outlined significant Basis*
benefits of early use of NIV in patients with severe community- 1. Symptomatic despite optimal medical therapy AND
acquired pneumonia which include reducing the need for
2. Severe pulmonary dysfunction OR
intubation, shortening stay in ICU and decreasing nosocomial
infections. However, the advantages of NIV in community- FVC ≤50% predicted
acquired pneumonia are seen mostly in patients with underlying MIP ≥60 cm H2O
COPD. Further studies are needed to define the optimal mode of 3. Gas exchange disturbance
ventilation and the specific patient population (especially, Chronic CO2 retention (PaCO2 >45) or
patients without COPD) who might benefit the most. Nocturnal hypoventilation (as evidenced by O2 saturation
<88% for ≥5 consecutive minutes while breathing room air)
Chest trauma
* 1 plus any of 2 or 3 if present, NPPV is indicated
Rapid improvement in gas exchange and low intubation rates
are expected among patients with chest trauma. NIV can also Patients with chronic hypoventilation syndromes due to
be used to facilitate extubation in such patients. neuromuscular diseases, chest wall or spinal deformity and
Post-operative patients obesity hypoventilation syndrome also respond gradually over
a few weeks after initiation of mechanical NIV. Amelioration of
NIV in post-operative patients has the potential to improve
nocturnal hypoventilation and improvement of sleep quality
many physiological parameters without apparent serious side-
are the major consequences of this therapy and probably the
effects. After high-risk surgeries, especially of thorax and upper
major reasons for daytime improvement.
abdomen, NIV can be used to prevent complications like
hypoxaemia, pneumonia and atelectasis, and reduces the rate Chronic respiratory failure due to chronic obstructive
of intubation. NIV can also be used to treat frank respiratory pulmonary disease
failure in these patients. Evidence of the efficacy of long-term nocturnal NPPV is vague
Difficult to wean/facilitation of weaning and often contradictory in patients with severe stable COPD.
Although evidence is inconclusive, the current professional
NIV can be used to facilitate weaning as well as in supporting consensus and guidelines recommend that patients with severe
patients who develop ARF after extubation. Current data day-time CO2 retention (PaCO 2 >52 mmHg) and nocturnal
support the use of NIV in patients with risk factors for extubation hypoventilation despite nocturnal oxygen therapy should be
failure, particularly if they have co-existing COPD, congestive considered for NPPV therapy.
heart failure and/or hypercapnia. However, early indiscriminate
use of NIV in patients who have risk factors for extubation failure, Obstructive sleep apnoea
but do not meet standard criteria for initiation of NIV should be Obstructive sleep apnoea is a life-threatening condition where
274
discouraged. Patients with extubation failure treated with NIV nasal CPAP is the treatment of choice. Positive pressure may
 Non-invasive Ventilation
provide a mechanical stent to the upper airway in such patients level and maintains oxygenation. Slowly increasing IPAP to
and prevent apnoea in all sleep stages, preferably in supine and maintain an exhaled VT at 5 to 7 mL/kg or higher may result in
lateral positions. As higher pressure can be uncomfortable for decrease in the respiratory rate. If EPAP is increased, IPAP may
sleep, the minimal pressure that reasonably eliminates most also need to be increased to maintain the same gradient between
respiratory disturbances like snoring and arousal together IPAP and EPAP, and thus ensure adequate VT delivery.
with elimination of oxygen desaturation is recommended. The
American Academy of Sleep Medicine guidelines for CPAP Monitoring during Non-Invasive Positive Pressure Ventilation
recommend its use in patients who have apnoea-hypopnoea Several studies have identified possible indicators of success of
index (AHI) greater than 20 and for symptomatic patients who NPPV in both the acute and chronic care settings (Table 8). A
have an AHI or respiratory arousal index greater than 10. patient of ARF must be closely monitored in ICU/emergency
department so that if NPPV is unsuccessful, patient can be
CONTRAINDICATIONS immediately intubated (Table 9). The indications of intubation
NIV should not be used in unconscious patients or in patients and termination of NPPV in favour of invasive ventilation are
unable to protect upper airways, intractable hypotension and mentioned in Table 10.
facial burns (Table 6).
Table 8: Indicators of Successful Non-Invasive Positive Pressure
Table 6: Contraindications of Non-Invasive Positive Pressure Ventilation
Ventilation Higher level of consciousness
Respiratory arrest or need for intubation Younger age
Haemodynamic instability Less severe illness
Inability to protect the airway Less severe gas exchange abnormalities (pH 7.10–7.35; PaCO2 < 92
Excessive secretions mmHg)
Agitated and confused patient Minimal air leakage around interface
Facial deformities or conditions that prevent mask from fitting Intact dentition
Uncooperative or unmotivated patient Synchronous breathing efforts with ventilator
Brain injury with unstable respiratory drive Lower quantity of secretions
Severe respiratory acidosis Absence of pneumonia
Facial trauma or burn Positive response to NPPV within 1 to 2 hours
Correction of pH
INITIATION OF NON-INVASIVE VENTILATION Decreased respiratory rate
After selecting the ventilator and interface, the physician is Reduced PaCO2
responsible for initiating NPPV. Steps for initiation of NIV have
Table 9: Parameters to be Monitored during Non-Invasive
been described in Table 7. The initial ventilator settings usually
Positive Pressure Ventilation
consist of an IPAP of 10 cm H2O and an EPAP of about 4 to 5 cm
H2O. The difference between the IPAP and EPAP is the level of Subjective responses
inspiratory support. IPAP augments the tidal volume and hence Patient comfort
alveolar ventilation, increases airway pressures and decreases Discomfort related to the mask
fatigue. EPAP prevents airway and alveolar collapse, prevents Respiratory distress
atelectasis and maintains functional residual capacity at increased Vital signs and physical findings
Respiratory rate
Table 7: Steps for Initiating Non-Invasive Positive Pressure Blood pressure
Ventilation Ability to cough and raise secretions
Accessory muscle use
1. Place the patient in an upright or sitting position. Carefully
explain the procedure for NPPV, including goals and possible Ventilator function
complications. Patient-ventilator synchrony
2. Using a sizing gauge, make sure a mask is chosen that is the Tidal volume ≥ 6 ml/kg
proper size and fit. Air leaking
3. Attach the interface and circuit to the ventilator. Turn on the Waveforms (if available)
ventilator and adjust it initially to low pressure settings (e.g. Gas exchange
IPAP 10 cm H2O/ EPAP 4 cm H2O). Continuous oximetry
4. Hold or allow the patient to hold the mask gently to the face Change in PaCO2 if hypercapnic
until the patient becomes comfortable. Encourage the patient Change in pH
to use proper breathing technique.
5. Monitor oxygen saturation; adjust the FiO2 to maintain saturation Table 10: Indicators to Terminate Non-Invasive Positive
above 90%. Pressure Ventilation and Switching to Invasive Ventilation
6. Secure the mask to the patient
Worsening pH and PaCO2
7. Titrate the IPAP and EPAP to achieve patient comfort, adequate
Tachypnoea (> 30/min)
exhaled tidal volume. Do not allow peak pressures above 20
cm H2O. Haemodynamic instability
8. Check for leaks and adjust the straps, if needed. Oxygen saturation > 90%
9. Monitor heart rate, respiratory arte, level of dyspnoea, minute Decreased level of consciousness
ventilation and exhaled tidal volume. Inability to clear secretions
10. Obtain blood gas within 1 hour. Inability to tolerate interface 275
 Complications decompensation and need for emergency intubation. Another
NPPV is considered much safer than invasive ventilation. approach to wean is to gradually reduce the level of pressure
Complications with NPPV usually are related to mask discomfort, support to a minimum level, allowing the patient to assume
air pressures or gas flows (Table 11). more of the work of breathing. Regardless of the method of
weaning, the reversibility of the disease process that caused
Table 11: Complications Associated with NPPV/CPAP Therapy respiratory failure is the most important factor for successful
Complications Corrective Action weaning.

Mask discomfort Check mask for correct size and fit CONCLUSION
Excessive leak around Minimise headgear tension Evidence supports the use of NPPV in the treatment of
mask
respiratory failure secondary to COPD, CPE, immuno-
Pressure sores Use spacers or change to another style
of mask compromised state in acute care settings and weaning in COPD.
Use wound care dressing over nasal Evidence is weak for use of NPPV in other indications and should
bridge not be used routinely, patients should be selected carefully.
Nasal and oral dryness or Add or increase humidification NPPV is used to avoid intubations and not replace it. Therefore,
nasal congestion Irrigate nasal passages with saline threshold for intubation should be low in acute care settings.
Use chin strap to keep mouth closed It should be avoided in patients having multiple organ
Apply topical decongestants dysfunction syndrome, unconscious patients and patients with
Change to full face mask burn and facial trauma; whereas in chronic care, NPPV is the
Mouthpiece/lip seal Use nose clips modality of choice in managing respiratory failure in patients
leakage Use custom made oral appliances having thoracic disorders and neuromuscular disorders.
Aerophagia, gastric Use lowest effective pressures for
distention adequate tidal volume delivery Proper fitting of interface is essential for the success of NPPV.
Use simethicone agents Proper ventilator settings and mask are more important than
Aspiration Make sure patients are able to protect ventilation for patient comfort and compliance.
the airway
Mucous plugging Ensure adequate patient hydration RECOMMENDED READINGS
Ensure adequate humidification 1. Agarwal R, Agarwal AN, Gupta D, et al. Role of non-invasive positive
Avoid excessive oxygen flow rates pressure ventilation in post-extubation respiratory failure: A meta-
(>20 L/min) analysis. Respiratory Care 2007; 52: 1472-9.
Allow short breaks from NPPV to 2. Ambrosino N, Vagheggini G. Non-invasive positive pressure ventilation
permit directed coughing techniques in the acute care setting: where are we? Eur Respir J 2008; 31: 874-86.
Hypotension Avoid excessively high peak pressures 3. Barreiro TJ, Gemmel DJ. Non-invasive ventilation. Crit Care Clin 2007; 23:
(≤ 20 cm H2O) 201-22.
4. Garpestad E, Brennan J, Hill NS. Non-invasive ventilation for critical care.
Patient Weaning and Discontinuation of Non-Invasive Chest 2007; 132: 711-20.
Positive Pressure Ventilation 5. Prasad SBN, Chaudhry D, Khanna R. Role of non-invasive ventilation in weaning
The duration of ventilator assistance with NPPV depends on from mechanical ventilation in patients of chronic obstructive pulmonary
disease: An Indian experience. Indian J Crit Care Med 2009; 13: 207-12.
how quickly the cause of respiratory failure can be reversed.
6. Simmonds AK. Non-Invasive Respiratory Support: A Practical Hand Book;
The most common approach involves increasing periods of time
Hodder Arnold (Blackwell); 2007.
off mask ventilation. If signs of respiratory distress occur, the
7. Ward S, Chatwin N, Heather S, et al. Randomised controlled trial of non-
patient is placed back on mask ventilation immediately. invasive ventilation (NIV) for nocturnal hypoventilation in neuromuscular
Prolonging the periods of ventilator interruption, when the and chest wall disease patients with daytime normocapnia. Thorax 2005;
patient is experiencing respiratory distress, may lead to rapid 60:1019-24.

276
 7.10 Hypotension and Shock

Anil Dhall, Sanjat S Chiwane

DEFINITION pressures as in cardiac tamponade; or to increased RV filling

Definition of shock includes the following haemodynamic pressures with low PCWP in the case of pulmonary embolism.
parameters to be identified: CO is usually decreased with an increase in SVR.
1. Persistent hypotension [systolic blood pressure (SBP) <80 Table 1: Classification of Shock
to 90 mmHg or mean arterial pressure (MAP) 30 mmHg
Hypovolaemic (Oligaemic)
lower than baseline]. Haemorrhagic
2. Severe reduction in cardiac index (CI) <1.8 L/min/m2 Fluid Depletion (Non-haemorrhagic)
without support or <2.0 to 2.2 L/min/m2 with support. Extensive fluid loss (dehydration)
Vomiting
3. Adequate or elevated filling pressure [(e.g. left ventricular
Diarrhoea
(LV) end-diastolic pressure >18 mmHg or right ventricular Polyuria
(RV) end-diastolic pressure >10 to 15 mmHg].
Interstitial Fluid Redistribution
The diagnosis is usually made with the help of pulmonary Thermal injury
artery catheterisation; however, echocardiography may also Trauma
be used to confirm elevation of LV filling pressures. The clinical Anaphylaxis
manifestations are due to hypoperfusion such as cold extremities, Cardiogenic
decreased urine output, and/or alteration in mental status. Myopathic:
Myocardial infarction
CLASSIFICATION Myocarditis
Cardiomyopathy
Hinshaw and Cox classification based on cardiovascular Septicaemia
characteristics, is the most practical classification of shock. It Mechanical:
divides the syndrome into four major categories: hypovolaemic, Valvular
cardiogenic, extracardiac obstructive, and distributive (Table 1). VSD
Arrhythmia:
Hypovolaemic Shock
Severe bradycardia
It is characterised by a loss in circulatory volume which results Marked prolonged tachycardia
in decreased venous return, decreased filling of the cardiac Extracardiac Obstructive
chambers, and decreased cardiac output (CO) which leads Cardiac tamponade
to increase in the systemic vascular resistance (SVR). The Constrictive pericarditis
haemodynamic profile on monitoring of flow pressure variables Post-MI rupture of ventricular wall
shows low central venous pressure (CVP), a low pulmonary Vena caval obstruction
capillary wedge pressure (PCWP), low CO and CI, and high SVR. Acute pulmonary hypertension
The arterial blood pressure may be normal or low. Impaired Systolic Contraction
Pulmonary embolism
Cardiogenic Shock Aortic dissection
This is primarily dependent on poor pump function. Cardiogenic Distributive
shock (CS) due to acute catastrophic failure of LV pump function Septic shock
is characterised by high PCWP, low CO and CI, and generally a Anaphylaxis
high SVR. Neural spinal shock
Adrenal crisis
Distributive or Vasogenic Shock Toxic
This type of shock is associated with not only poor vascular MI = Myocardial infarction; VSD = Ventricular septal defect
tone in the peripheral circulation but maldistribution of blood
flow to organs within the body also. The CO varies, but is usually Parameters in various types of shock are shown in Table 2.
raised. A common haemodynamic profile is a low or normal Table 2: Haemodynamic Parameters in Various Types of Shock
PCWP, a high CO, a low arterial blood pressure, and a low SVR.
CO PCWP ABP SVR
Extracardiac Obstructive Shock Hypovolaemic ↓ ↓ ↓ ↑
It is associated with reduced forward circulatory flow involving Cardiogenic ↓ ↑ ↓ ↑
mechanisms different than primary myocardial or valvular Vasogenic Nor ↑ Nor ↓ ↓ ↓
dysfunction.The haemodynamic patterns observed, depend on Extracardiac ↓ Nor ↓ ↓ ↑
the cause, from significant decrease in filling pressures (as in CO = Cardiac output; PCWP = Pulmonary capillary wedge pressure; ABP =
mediastinal compression of great veins); to equalisation of Arterial blood pressure; SVR = Systemic vascular resistance; Nor = Normal. 277
 PATHOPHYSIOLOGY Table 3: Compensatory Responses to Shock
Shock of all forms involve common pathophysiological
Volume
mechanisms that end in cell injury, organ failure and death. The
Fluid redistribution to vascular space
pathogenesis of shock involves multiple inter-related factors From interstitium (Starling effect)
including cellular ischaemia, circulating or local inflammatory From intracellular space (Osmotic effect)
mediators, and free radical injury. Decreased renal fluid losses
Decreased glomerular filtration rate (GFR)
1. Hypoperfusion decreases the delivery of nutrients to the
Increased aldosterone
cells leading to diminished ATP production. Essential ATP Increased vasopressin
dependent intracellular metabolic processes that may be
Pressure
affected include maintenance of transmembrane potential,
Decreased venous capacitance
mitochondrial function and other energy-dependent
Increased sympathetic activity
enzyme reactions. Increased circulating (adrenal) epinephrine
Liver and kidney are particularly sensitive as intracellular Increased angiotensin
levels of ATP fall and ATP-dependent processes are impaired. Increased vasopressin
Maximise Cardiac Performance
2. The effect of inflammatory mediators on cellular metabolism
Increased contractility
is of prime importance in organ dysfunction resulting from
Sympathetic stimulation
sepsis and septic shock and also haemorrhagic shock Adrenal stimulation
associated with extensive trauma. Generally, it is the
Redistribution of Perfusion
endotoxin from Gram-negative bacteria that triggers the
Extrinsic regulation of systemic arterial tone
inflammatory cascade but bacterial antigens and cell injury
Dominant autoregulation of vital organs (heart, brain)
itself can also initiate the cascade. Macrophage production
Optimise Oxygen Unloading
of cytokines such as tumour necrosis factor-alpha (TNF-α)
Increased RBC 2, 3 DPG
and interleukin-1beta (IL-1β) appear to be the prime
Tissue acidosis
mediators. Other substances involved in the inflammatory Pyrexia
process include IL-2, IL-6, interferon-γ, endothelin-1, Decreased tissue PaO2
leukotrienes, thromboxanes, prostaglandins and
complement fragments C3a and C5a. Two other mediators, Diagnostic Approach and Evaluation
i.e. circulating myocardial depressant substance and nitric
It is imperative, that clinicians recognise the early stages of shock
oxide have a role to play in septic shock.
at a time when it is more responsive to treatment. A monitored
3. Free radical injury induced by reperfusion or neutrophil physiologic approach to therapy provides the best opportunity
activity is another mechanism by which cell and organs for successful outcome and avoidance of organ dysfunction. Not
suffer a damage. Tissue ischaemia leads to accumulation of only is the initial resuscitative technique important but also
adenosine, inosine and hypoxanthine. With resuscitation, continuous evaluation of the patient’s condition.
reperfusion of ischaemic areas occurs.
Clinical Presentation
The availability of O2 generates superoxide (O2-) by xanthine
This varies with the previous level of organ function, compensatory
oxidase which is converted to hydrogen peroxide (H2O2) which
mechanisms, severity of organ dysfunctions and the cause of
further reacts to produce the highly reactive tissue damaging
shock syndrome. Impending shock is characterised by the
hydroxyl radicals. These in turn interact with critical cell targets
typical compensatory response to cardiovascular stress.
resulting in cell lysis and tissue injury. Oxidant activity, directly
Tachycardia, tachypnoea and oliguria are the hallmark. Cold
and through endothelial damage attracts and activates
extremities are seen in hypodynamic shock. With progression,
neutrophils causing amplification of superoxide generation and
blood pressure falls and frank hypotension (MAP < 60 to 65
further tissue damage due to neutrophil protease release.
mmHg) ensues. With further progression, anuria, mottled, dusky
Other microvascular pathologic processes occurring in shock extremities and altered sensorium occurs. (Detailed in Table 4).
include disruption of integrity of endothelial cell barrier leading
to loss of plasma proteins, decrease in plasma oncotic pressure, Laboratory Studies
interstitial oedema and fall in circulating volume. In addition, These are used not only for the confirmation of diagnosis of
there is microvascular clotting and microthrombi leading to shock but also to know the aetiologic factors. Initial laboratory
further inadequate distribution of perfusion within tissue. tests should include a complete blood count. Leucocyte count
is frequently elevated early in shock and leucopaenia is found
COMPENSATORY RESPONSES TO SHOCK in sepsis and late shock. Haemoglobin level varies with the type
Various compensatory mechanisms are detailed in Table 3. of shock. Stress of circulatory shock increases platelet count
With the onset of haemodynamic dysfunction, hemostatic initially, but with progression thrombocytopaenia occurs.
compensatory mechanisms engage to maintain adequate Complete chemistry profile with serum electrolytes, creatinine,
tissue perfusion. These responses are similar for varying classes blood urea nitrogen (BUN), liver function tests, calcium,
of shock and are divided into four categories: (a) maintenance magnesium and phosphate levels, serum lactate levels,
of mean circulatory pressure, (b) maximising cardiac function, prothrombin and activated partial thromboplastin times,
(c) redistributing perfusion to vital organs, and (d) optimising urinalysis with a detailed sediment analysis, serum amylase level,
278 unloading of oxygen at tissues. and arterial blood gases (ABG) must be done. BUN and creatinine
 Hypotension and Shock
Table 4: Organ System Dysfunction in Shock catheters should be instituted in those indicated, laboratory
tests as mentioned before should be performed at the earliest
Central Nervous System: Encephalopathy (ischaemic or septic), possible. Management of shock can be divided into specific
cortical necrosis
therapy for triggering injury and general therapy of the shock
Cardiovascular System: (Heart) tachycardia, bradycardia, syndrome.
supraventricular tachycardia, ventricular ectopy, myocardial
depression Therapeutic Goals
Pulmonary: Acute respiratory failure, adult respiratory distress 1. Haemodynamic MAP >60 to 65 mmHg (higher in the
syndrome presence of coronary artery disease or chronic
Kidney: Prerenal failure, acute tubular necrosis hypertension)
Gastrointestinal: Ileus, erosive gastritis, pancreatitis, acalculous 2. PCWP = 12 to 18 mmHg (may be higher for cardiogenic
cholecystitis, colonic submucosal haemorrhage shock)
Liver: Ischaemic hepatitis‘Shock’ liver, intrahepatic cholestasis 3. CI >2.1 L/min/m2 for cardiogenic and obstructive shock
Haematologic: Disseminated intravascular coagulation, dilutional >3.0 to 3.5 L/min/m2 for septic and resuscitated traumatic/
thrombocytopaenia haemorrhagic
Metabolic: Hyperglycaemia, glycogenolysis, gluconeogenesis,
4. Optimisation of haemoglobin >8 g/dL
hypoglycaemia (late), hypertriglyceridaemia
Immune System: Gut barrier function depression, cellular immune
5. Oxygen delivery arterial saturation >92%, SvO2 > 60%
depression, humoral immune depression 6. Normalisation of serum lactate (<2.2 mEq/L)
7. Maintain urine output >0.5 mL/kg/hr
rarely change after the acute onset of shock, even if renal injury
is present. ABG determines the adequacy of oxygenation and The basic goal of circulatory shock therapy is the restoration of
acid-base status. Serial serum lactate levels are used in the effective perfusion and oxygen supply to vital organs and
assessment of prognosis and levels of > 2 mEq/L represent tissues before the onset of cellular injury.
tissue ischaemia. A 12-lead electrocardiogram (ECG) is critical
Airway management and mechanical ventilation
for diagnosis of ischaemic cardiac injury. Chest radiograph is
also a must. Other studies should be considered in specific A critical first step in the treatment of shock is to ensure
conditions and may include detailed imaging studies like adequate alveolar ventilation and oxygenation. Most patients
computed tomography (CT ), abdominal radiographs or with the fully developed shock syndrome require tracheal
ultrasound, surface or transoesophageal echocardiography, intubation and mechanical ventilatory support, even if acute
ventilation/perfusion scan, angiograms and cardiac isoenzymes respiratory failure has not yet occurred. Mechanical ventilation
may be ordered for as and when required. allows blood flow to be redistributed, tends to reverse lactic
acidosis and supports the patient until other therapeutic
Invasive Haemodynamic Monitoring measures can be effective. Tracheal intubation also is indicated
Arterial pressure line is a must for all patients. Marked peripheral if mental status changes make airway unprotected or for
vasoconstriction makes the assessment of pressure by manual inadequate respiratory compensation for metabolic acidosis.
or non-invasive techniques inaccurate. Flow directed balloon- Positive-pressure ventilation and positive-end expiratory
tipped pulmonary artery catheter with thermodilution cardiac pressure (PEEP) may produce further haemodynamic
output determination capability have become the standard compromise, if volume status of the patient is not maintained.
practice for the haemodynamic assessment of circulatory shock. PEEP may also be desirable in patients with acute respiratory
Continuous monitoring of central venous and pulmonary artery distress syndrome (ARDS) or pulmonary oedema to ensure
waveforms and pressures is also provided by them. Mixed adequate oxygenation.
venous oxygen saturation provides an assessment of adequacy
Acid-base balance
of resuscitation of low output states before the presence
of anaerobic metabolism. Oxygen delivery and oxygen The previous standard practice of administering bicarbonate
consumption variables can also be determined using to patients with shock and lactic acidosis has been revised. The
pulmonary artery catheter-derived data. But, the utility of this optimal approach to the management of lactic acidosis is to
data is controversial when applied to individual patients. improve organ and systemic perfusion so that anaerobic
metabolism is limited and the liver as well as kidneys can clear
Ancillary Monitoring Techniques the accumulated lactate. If not effective, it has been suggested
Echocardiography in the intensive care unit (ICU) not only to restrict the use of sodium bicarbonate to situations with pH
detects the anatomic lesions but also allows direct less than 7.1 to 7.15.
measurement of cardiac output, stroke volume, pre-load,
Fluids
systolic contractility, diastolic function and regional motion
abnormalities. There are other promising non-invasive Common to all aetiologies of haemodynamic instability and
monitoring devices, i.e. near-infrared spectroscopy to detect shock is the need to provide optimal intravascular volume to
oxygen availability and utilisation at tissue level. ensure adequacy of pre-load. Thus, it is appropriate to begin
fluid administration in all shock patients who lack signs of
Management and Therapy pulmonary oedema and LV overload. Substantial controversy
Patients in shock should be managed in an ICU with continuous exists regarding the appropriate use of crystalloid and colloid
ECG monitoring and close nursing support. Invasive fluids for resuscitation. What is most important when either
haemodynamic monitoring with arterial and pulmonary artery type of fluid is used is to determine responses to these fluid 279
 challenges. Optimal therapy generally means administering the 3. Mixed pressor agents:
quantity of fluid that maximises DO2 while avoiding LV overload Dopamine, a precursor of norepinephrine, is commonly used
and pulmonary oedema. Also, sufficient preload should be there as an initial pressor agent, acting at several receptors in a
before or during institution of pharmacologic therapy for dose-related manner. It can be titrated towards achieving
hypoperfusion. different aims of therapy: dopaminergic effects at less than
Vasopressor agents 4 to 5 mcg/kg/min (e.g. vasodilatation of renal and
splanchnic vascular beds), β effect at 5 to 10 mcg/kg/min
The term pressor refers to any substance that raises blood
(e.g. augmentation of cardiac contractility and heart
pressure (BP). These agents are divided into 3 categories:
rate) and α effects at more than 10 mcg/kg/min (e.g.
(i) lnotropes/chronotropes (i.e. drugs that increase CO
vasoconstriction). There has been a decreased enthusiasm
by increasing cardiac contractility and heart rate);
for its routine use to protect the kidneys from hypoperfusion
(ii) vasoconstrictors (i.e. agents that raise BP by increasing systemic
insults or as a means to promote urine output in post-
vascular resistance); (iii) mixed pressor agents (i.e. drugs that act
hypoperfusion oliguria. However, at a dose of 2 to 3 mcg/kg/
through both mechanisms).
min, it can reverse vasoconstrictor—induced increases in
1. Inotropic/chronotropic agents: renal vascular resistance during vasoconstrictor infusion.
Dobutamine hydrochloride, a synthetic β1, β2 receptor Norepinephrine exerts both powerful inotropic (cardiac α
agonist is often used for inotropic support in cardiogenic and β1 adrenoreceptors) and peripheral vasoconstriction
shock. It increases myocardial contractility and CO, reduces effects (α adrenoceptors). It can be used for persistent
afterload through peripheral vasodilatation and decreases hypotension despite high-dose dopamine during septic and
LV filling pressures with improvement in diastolic coronary obstructive shock. It may also improve splanchnic oxygen
blood flow. It also prevents increase in infarct size in patients dynamics in patients with sepsis. Epinephrine is occasionally
with acute myocardial infarction by improved collateral used when other inotropes/vasopressors have failed to
blood flow and balance between oxygen supply and support blood pressure and/or cardiac output in circulatory
demand. Because of β2-mediated vasodilatation caution shock. It is the first-line agent for management of anaphylactic
should be observed if it is administered to hypotensive shock. All currently used vasopressor agents ultimately
patients, especially with coexistent hypovolaemia. produce their effects by increasing intracellular ionised
Milrinone lactate, a selective phosphodiesterase III inhibitor calcium concentration. Thus, normal ionised calcium
increases ionotropy and decreases systemic vascular concentration should be maintained in patients who are on
resistance by preventing the degradation of cyclic vasopressor support.
adenosine monophosphate. The haemodynamic The American College of Cardiology/American Heart
effects are similar to those of dobutamine. Amrinone, is Association (ACC/AHA) guidelines recommend norepin-
rarely used because of excessive vasodilatation and ephrine for more severe hypotension because of its high
thrombocytopaenia following long-term use. Dopexamine, potency. Although both dopamine and norepinephrine
a synthetic catecholamine, augments cardiac performance have inotropic properties, dobutamine is often needed
through both β2-mediated afterload reduction and in addition. Pharmacological treatments that warrant
baroreceptor reflex-mediated inotropy. Also, added benefit further investigation include vasopressin, levosimendan
is its dopaminergic-mediated increase in renal blood flow. —a calcium-sensitising agent that has so far shown
Isoproterenol hydrochloride, a pure β receptor agonist little additional value in randomised heart failure trials,
produces CO augmentation by increasing both heart rate and/or activated protein C, which has been tried in
and contractility. Dysrhythmias and increased myocardial conjunction with mechanical support in myocarditis
oxygen requirement limit the use. Digitalis has limited use patients.
in treating acute states of hypoperfusion due to its slow
onset of action and lower potency. Vasodilator agents
These drugs reduce afterload and improve CO in acute and
2. Vasoconstrictor agents:
chronic ventricular failure. For acute vasodilatation and preload
Phenylephrine is a pure adrenergic agonist. It causes reduction, nitroglycerin is the agent of choice; for afterload
vasoconstriction, thereby increasing BP, generally reduction, sodium nitroprusside, nitroglycerin, hydralazine
decreasing CO and often reflex slowing of heart rate. It hydrochloride, angiotensin converting enzyme inhibitors
should be used as a first-line agent in neurogenic shock. and fenoldopam are preferable. Patients with right-sided
It can also be useful in patients who, despite maximal fluid heart failure may benefit from pulmonary vasodilators, i.e.
and ionotropic support, remain hypotensive with prostacyclin, prostaglandin E1 and inhaled nitric oxide.
evidence of organ hypoperfusion. Pure vasoconstrictors
may compromise flow and perfusion, thus attention to Steroids
renal function, acid-base balance, serum lactate and DO2 Prospective, double-blind, randomised, multicentre studies
is imperative. Vasopressin is used as an alternative therapy have demonstrated no benefit of steroid administration in
for vasodilator shock especially where a stimulation does hyperdynamic/septic shock. Thus, the practice of routine
not produce a satisfactory vasoconstrictor response. administration of high-dose steroids was abandoned. Stress
Most studies have used doses between 0.01 and 0.1U doses of glucocorticoids are appropriate for treating shock
per minute. Other vasoconstrictor is noradrenaline when it is associated with adrenal insufficiency, hypothyroidism,
(norepinephrine). in patients with impaired adrenal pituitary axis, or in those who
280
 Hypotension and Shock
require steroids for treatment of an underlying immunologic hours after symptom onset was associated with the lowest
disease (e.g. vasculitis). Conversely, steroids are relatively mortality among CS patients undergoing primary PCI
contraindicated in patients with cardiogenic shock as they alter in the Arbeitsgemeinschaft Leitende Kardiologische
the healing process of the myocardium and predispose to Krankenhausarzte (ALKK) registry, in which door-to-
myocardial rupture. But recent reports also suggest a decrease angiography times was 90 minutes in approximately three-
in the endogeneous production of stress steroids in sepsis, fourths of patients. In the SHOCK trial, there appeared to be
causing vasopressor dependence and failure to respond to increasing long-term mortality as time to revascularisation
therapy. Administration of 50 mg of hydrocortisone 6 hourly increased from 0 to 8 hours. However, there is a survival benefit
indicates benefit. The mechanism for benefit may be reversal as long as 48 hours after myocardial infarction and 18 hours
of catecholamine receptor down regulation or prevention of after shock onset.
inflammatory mediated induction of nitric oxide synthase.
Total Circulatory Support: LV Assist Devices and
Patients with shock, who require increasing doses of
Extracorporeal Life Support
vasopressors or do not respond within 24 hours of therapy, may
be administered steroids. However, this topic still remains Temporary mechanical circulatory support with LV assist
controversial. devices (LVADs) is theoretically appealing to interrupt the
vicious spiral of ischaemia, hypotension and myocardial
Mechanical support: intra-aortic balloon pump (IABP) dysfunction, allowing for recovery of stunned and hibernating
Intra-aortic balloon counterpulsation has long been the myocardium and reversal of neurohormonal derangements.
mainstay of mechanical therapy for cardiogenic shock. Use of Device-related complications and irreversible organ failure
an IABP improves coronary and peripheral perfusion via remain major limitations. LVAD support involve circulation of
diastolic balloon inflation and augments LV performance via oxygenated blood through a device that drains blood from the
systolic balloon deflation with an acute decrease in afterload. left-side of the heart and returns blood to the systemic arteries
Accurate timing of inflation and deflation provides optimal with pulsatile or continuous flow. Surgically implanted
support. Not every patient has a haemodynamic response to LVADs remove blood through a cannula placed at the LV apex
IABP; response predicts better outcome. IABP support should and return blood to the ascending aorta. Percutaneous LVADs
be instituted as quickly as possible, even before any transfer for are also available. Extracorporeal life support involves
revascularisation if a skilled operator is available and insertion extracorporeal circulation of blood through a membrane
can be performed quickly. In the large US National Registry of oxygenator, which relieves both the right and left heart
Myocardial Infarction, IABP use was independently associated and the lungs of part of their workload. Anticoagulation is
with survival at centres with higher rates of IABP use—whether required for extracorporeal life support and for percutaneous
PCI, fibrinolytic therapy, or no reperfusion had been used; LVADs but may be optional with surgically placed LVADs.
however, no completed trials demonstrate benefit. Complications Extracorporeal life support and LVADs have been used
associated with IABP are less common in the modern era; in sequentially in CS patients, usually as a bridge to heart
the largest series, the overall and major complication rates were transplantation. In the largest reported LVADs series to date, 74%
7.2% and 2.8%, respectively. Risk factors for complications of 49 patients survived to transplantation, and 87% of
include female sex, small body size, and peripheral vascular transplanted patients survived to hospital discharge after
disease. receiving a variety of surgical LVADs. These devices need further
large trials for different use.
Reperfusion
The survival benefit of early revascularisation in CS, reported in RECOMMENDED READINGS
several observational studies, was shown convincingly in the 1. Henriques JP, Remmelink M, Baan J Jr, et al. Safety and feasibility of elective
randomised SHOCK trial, which found a 13% absolute increase high-risk percutaneous coronary intervention procedures with left
ventricular support of the Impella Recover LP 2.5. Am J Cardiol 2006; 97:
in 1-year survival in patients assigned to early revascularisation. 990-92.
This corresponds to a number needed to treat 8 patients to 2. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularisation and long-
save 1 life.The benefit was similar in the incomplete, randomised term survival in cardiogenic shock complicating acute myocardial
Swiss Multicenter Study of Angioplasty for Shock. Numerous infarction. JAMA 2006; 295: 2511–5.
registry studies have confirmed the survival advantage of early 3. Hoefer D, Ruttmann E, Poelzl G, et al. Outcome evaluation of the bridge-to-
revascularisation, whether percutaneous or surgical, in the bridge concept in patients with cardiogenic shock. Ann Thorac Surg 2006;
young and the elderly. Thrombolytic therapy is less effective 82:28-33.
but is indicated when PCI is impossible or if a delay has occurred 4. Leshnower BG, Gleason TG, O’Hara ML, et al. Safety and efficacy of left
ventricular assist device support in postmyocardial infarction cardiogenic
in transport for PCI and when myocardial infarction and CS shock. Ann Thorac Surg 2006; 81:1365-70.
onset were within 3 hours.
5. Tayara W, Starling RC, Yamani MH, et al. Improved survival after
Timing of PCI acute myocardial infarction complicated by cardiogenic shock with
circulatory support and transplantation: comparing aggressive
As in myocardial infarction without shock, earlier revas- intervention with conservative treatment. J Heart Lung Transplant 2006;25:
cularisation is better in cardiogenic shock. Presentation 0 to 6 504-9.

281
 7.11 Cardiopulmonary Resuscitation

Ashit M Bhagwati

INTRODUCTION observed that outcome of the victim is better with VF than

Sudden cardiac arrest is a leading cause of death worldwide. asystole or pulseless electrical activity (PEA), which in turn is
Recognition of this emergency is imperative to initiate prompt influenced by the cause of the arrest and the promptness in
resuscitation of the victim. It was in the 19th Century, Doctor the availability of resuscitation.
HR Silvester described a method (The Silvester Method) of
artificial respiration in which the patient was laid on his back, MANAGEMENT
with arms raised above the head to aid inhalation and then Survival of the victim depends on the chain of interlinked
pressed against the chest to aid exhalation. The procedure was processes referred to as ‘chain of survival’. The 2010 AHA
repeated 16 times per minute. A second technique, called the guidelines emphasise the importance of post-cardiac care, and
Holger-Neilson technique, was described in the first edition of hence, a fifth chain has been added to the chain of survival. The
the Boy Scout Handbook in the United States (US) in 1911. It is chain of survival for adults is now given below in Figure 1.
essentially the Silvester Method with the patient flipped over. When these links are implemented, survival rates can approach
This form was well used into the 1950s. The technique was later 50% following witnessed out of hospital VF arrest.
banned from first-aid manuals in the United Kingdom.
The 2010 AHA guidelines for CPR and emergency cardiovascular
However, it was not until the middle of the 20th Century that care (ECC) are based on an extensive international evidence
artificial respiration combined with chest compressions as a key evaluation process. The ILCOR 2010 International Consensus on
part of resuscitation following cardiac arrest was recognised. In CPR and ECC Science with treatment recommendations
1957, Peter Safar wrote the book ABC of Resuscitation. In USA, it summarises the international consensus after interpreting a
was first promoted as a technique for the public to learn in the vast number of peer reviewed resuscitation studies. The
1970s. modifications recommended are for both BLS and ACLS to
Artificial respiration was combined with chest compressions provide effective resuscitation outcomes.
based on the assumption that active ventilation is necessary to The modifications in the protocols and resuscitation in children
keep circulating blood oxygenated, and the combination was and infants, including current modifications, will not be
accepted without comparing its effectiveness with chest discussed in this chapter.
compressions alone. However, research over the past decade
has shown that assumption to be faulty, resulting in the Adult Life Support
American Heart Association’s (AHA) acknowledgement of the Adult life support involves two sequences, viz. adult basic life
effectiveness of chest compressions alone. support and adult advance life support. Here, the discussion will
be restricted to techniques meant for healthcare personnel only.
PATHOPHYSIOLOGY
Most of the cardiac arrest cases occur as a result of ventricular Adult basic life support
fibrillation (VF) precipitated by an acute coronary event. This involves resuscitation of the victim without any specialised
Needless to say that timely recognition and defibrillation of the equipment or complex understanding of the pathophysiology
victim leads to excellent survival results. However, it needs to of cardiac arrest. The objective is to maintain adequate
be realised that the goal of CPR is not just a functioning heart, circulation and ventilation of vital organs until specialised
but a functioning heart in a functioning person, i.e. revival of assistance is available. This minimises anoxic damage to the vital
heartbeat with intact neurological function. It has been organs.

Figure 1: AHA ECC adult chain of survival.

282
 Cardiopulmonary Resuscitation
Prompt Recognition of Arrest airway or use of a defibrillator. When two or more rescuers are
Before approaching the victim the rescuer should ensure present switch chest compressors approximately every 2
scene safety. Thereafter, the rescuer should check for response. minutes or after 5 cycles of compressions and ventilations at a
Tap the victim on the shoulder and shout ‘Are you alright’. The ratio of 30:2. This is done to avoid rescuer fatigue. This switch
healthcare provider should also check for no breathing or should be accomplished in less than 5 seconds.
abnormal breathing (i.e. only gasps) while checking for Managing the airway
responsiveness. If unresponsive, then activate emergency
Also the 2010 AHA guidelines regarding airway management
medical system, get AED/defibrillator or ask second rescuer (if
has eliminated ‘Look, Listen and Feel’ from BLS algorithm.
available to get it).
Open airway
Circulation
The healthcare rescuer should open airway using head-tilt chin
Pulse check
lift manoeuvre after ruling out head and neck trauma. If cervical
The 2010 AHA guidelines for CPR and ECC do not emphasise spine injury is suspected then open airway using ‘jaw thrust
the pulse check as a mechanism to identify cardiac arrest. This without head extension’. If this method fails to open the airway,
is because studies have shown that both lay person and then use head-tilt chin lift method. Maintaining a patent airway
healthcare providers have difficulty in detecting a pulse. and providing adequate ventilation is a priority in CPR.
Healthcare providers may take too long to appreciate a pulse,
thereby delay in initiating chest compressions. To avoid this, Rescue breathing
healthcare provider should not take more than 10 seconds. If Rescue breaths can be given through either mouth-to-mouth,
no pulse is felt during that period then proceed to closed chest mouth-to-barrier device, mouth-to-nose and mouth-to-stoma
compression immediately. ventilation with bag and mask. Each rescue breath should
ensure the following:
The ABC approach has been replaced by CAB approach, i.e.
initiation of chest compressions before ventilation, since setting 1. Deliver each rescue breath over 1 second.
up of airway equipment takes time. 2. Give sufficient tidal volume to produce visible chest rise.
Closed chest compression 3. Use compression to ventilation ratio of 30:2.
The process involves effective application of closed chest 4. When advance airway is in place, during two person CPR,
compression to maximise the quality of CPR. If done properly give 1 breath every 6 to 8 seconds without attempting to
and cyclically, nearly 25% to 30% cardiac output is maintained. synchronise breaths between compressions (i.e. delivery of
Closed chest compressions cause forward flow by direct 8 to 10 breaths/min). There should be no pause in chest
pressure on the cardiac chambers (cardiac pump) or by the compressions for delivery of ventilations.
cyclical evacuation of the pulmonary vasculature (thoracic The algorithms presented in Figure 2 summarise the adult BLS
pump). The low flow that is generated provides protective sequence.
circulation to the brain for a brief period and enhances coronary
Defibrillation
perfusion. The adequacy of the latter is the best predictor of
successful restoration of spontaneous cardiac activity and Early defibrillation is critical for survival in sudden cardiac arrest
circulation. Properly performed closed chest compression can (SCA) victims for several reasons: (1) most frequent rhythm in SCA
produce systolic arterial pressure of 60 to 80 mmHg, diastolic is VF,(2) treatment for VF is defibrillation, (3) probability of successful
pressure is low and mean arterial pressure in the carotid artery defibrillation diminishes rapidly with passage of time, and (4) VF
seldom exceeds 40 mmHg. tends to deteriorate to asystole within a few minutes. The success
of defibrillation is time-dependent, with rates of failure increasing
Changes from 2005 guidelines regarding compression by about 10% for every minute of delay after the cardiac arrest.
stipulates that the compression rate should be at least
100 per minute and not ‘approximately’ 100 per minute. The Defibrillation works by depolarising all the myocardium and
compression depth should be at least 2 inches (5 cm) in adults eliminating fibrillatory activity. This enables the patient’s
and not 1½ to 2 inches as was being practised earlier for adults. intrinsic pacemaker to take over and establish a stable rhythm.
Allow complete chest recoil after each compression. Minimise Also, the current has to be delivered in a mode that minimises
interruptions in chest compressions, i.e. continuous chest trans-thoracic impedance, which can be achieved by: (a) applying
compressions for effective outcomes. Also, there is need to avoid firm pressure to assure contact with the skin (8 kg in adults), and
excessive ventilation. (b) using a conducting gel to minimise resistance at the skin
interface (Avoid ultrasound gel as it has poor conductance).
Method
Appropriate size of the defibrillator paddle (12 cm diameter is
To give effective chest compressions, push hard and push fast.
ideal for adults) and shaving of the chest if possible, without
Compress the adult chest at a rate of at least 100 compressions
delaying the initial shocks. Alternately, electrode pads should
per minute, with a depth of 2 inches (5 cm). Allow the chest
be placed. Alternately electrode pads should be placed on
to recoil completely after each compression, and allow
the exposed chest in an antero-lateral position. Alternate
approximately equal compression and relaxation times. Please
acceptable positions are antero-posterior, anterior-left
minimise/avoid interruptions in chest compressions and avoid
infrascapular, and anterior-right infrascapular.
excessive ventilation. Healthcare providers should interrupt
chest compressions as infrequently as possible and try to limit Conventional defibrillators deliver the current as a monophasic
it to no longer than 10 seconds, except for insertion of advanced waveform (current flows in one direction between electrodes), 283
 of return of spontaneous circulation (ROSC) with drug therapy,
advance airway management, and physiological monitoring. It
is essentially a team-work carried out by trained healthcare
workers/providers in ACLS and not by a single individual.
Various steps in ACLS process as per the guidelines of AHA 2010
are shown in Figure 3 and described below.

Figure 2: Adult basic life support (BLS) algorithm with AED.

VF = Ventricular fibrillation; VT = Ventricular tachycardia; PEA = Pulseless electrical
activity

but biphasic currents (flowing first in one direction between

paddles and then returning in the reverse direction) are more
effective at cardioversion using much lower levels of energy.
The resulting reduction in myocardial injury is of benefit.
In the absence of biphasic defibrillators, use of monophasic
defibrillators can be permitted. For monophasic defibrillators,
recommended energy is 360 Joules. However, the ideal
recommendation is to use a biphasic defibrillator. The energy Figure 3: Advanced cardiovascular support pulseless arrest algorithm.
recommendation as per manufacturer is 120 to 200 Joules; if BLS = Basic life support; AED = Automated external defibrillation; VF = Ventricular
unknown then to use maximum available. Second and fibrillation; VT = Ventricular tachycardia; PEA = Pulseless electrical activity; CPR =
subsequent doses should be equivalent. Cardiopulmonary resuscitation; IV = Intravenous; IO = Intraosseous; ROSC = Return
of spontaneous circulation
Recovery Position
The recovery position is used for unresponsive adult victims Effective Steps as Recommended in BLS
who clearly have normal breathing and effective circulation.
This position is designed to maintain a patent airway and 1. After defibrillator is attached, check cardiac rhythm.
reduce the risk of aspiration. The victim is placed on his or her 2. Rhythm: VF/VT or PEA or asystole.
side with the lower arm in front of the body. Unfortunately no 3. If VT/VF, treatment of choice is defibrillation with
single position is perfect for all victims. As there are several continuous CPR. For refractory VF/VT use amiodarone.
variations of the recovery position, the goal is to see that the Drug therapy prior to amiodarone during CPR includes
patient should be stable, near a true lateral position, with the epinephrine every 3 to 5 minutes with vasopressin to
head dependent and no pressure on the chest to impair replace 1st or 2nd dose of epinephrine.
breathing.
4. For PEA/asystole shock is not indicated. Only drug therapy,
Advance Cardiac Life Support i.e. epinephrine every 3 to 5 minutes with vasopressin to
Cardiac arrest can be caused by four rhythms; VF, pulseless replace 1st or 2nd dose of epinephrine is indicated.
ventricular tachycardia (VT), PEA, and asystole. Neither of these 5. Check for any treatable/reversible causes of cardiac arrest
rhythms generate cardiac output. For a victim to survive this (Table 1).
catastrophe a well coordinated BLS and a system of advanced
cardiovascular support (ACLS) with integrated post-cardiac 6. During CPR it is important to check rhythm after every 2
arrest care is essential. ACLS interventions are based on the minutes to analyse whether the rhythm is shockable or non-
foundation of efficient BLS intervention, namely, immediate shockable.
recognition and activation of the emergency response system, 7. Consider after 2 minutes of CPR, advance airway
284 early CPR, rapid defibrillation to further increase the likelihood management and physiological monitoring of the patient.
 Cardiopulmonary Resuscitation
Table 1: Treatable Causes of Cardiac Arrest: The Hs and Ts Medications for Cardiac Arrest Rhythms
Drugs Routinely Administered in CPR
Hs Ts
Vasopressors
Hypoxia Toxins
Hypovolaemia Tamponade (Cardiac) Vasopressors are the only drugs routinely indicated in prolonged
Hydrogen ion (Acidosis) Tension pneumothorax arrests irrespective of the rhythm. They enhance coronary
Hypo- or Hyperkalaemia Thrombosis perfusion by raising aortic root pressures and help in restoration
– Pulmonary of spontaneous circulation. However, till date no placebo-
Hypothermia Thrombosis controlled trials have shown that administration of any
– Coronary vasopressor agent at any stage during management of VF/PVT,
PEA, or asystole increases the rate of neurological integrity and
Adult Cardiac Arrest survival leading to hospital discharge. However, there is evidence
Advance airways that they are associated with an increased rate of ROSC.
During CPR, breathing is normally maintained with bag-mask
Epinephrine hydrochloride: Epinephrine hydrochloride produces
ventilation as a part of BLS algorithm, which during ACLS
beneficial effect due to its alpha-adrenergic receptor
advance invasive airway placement is done to deliver effective
stimulating (i.e. vasoconstrictor) effect. This effect increases
oxygenation. The problem with this is interruption of chest
coronary and cerebral perfusion pressure during CPR. However,
compressions and the need for the healthcare provider to be
the value and safety of the β- adrenergic effects of epinephrine
sufficiently trained in insertion of the advance airway. Also the
are controversial as it may increase myocardial work and reduce
choice of the airway depends on the skill of the healthcare
subendocardial perfusion.
provider and the condition of the victim. Accordingly, there
are two types of advance airways as descried below: The recommended dose is 1 mg intravenous/intraosseous (IV/
(a) Supraglottic airways IO) every 3 to 5 minutes during adult cardiac arrest until ROSC
(b) Endotracheal intubation is achieved. Endotracheal route at a dose of 2 to 2.5 mg is used
if IV/IO access is delayed or cannot be established.
Supraglotic airways: Insertion of supraglottic airways is easier,
as it does not require direct visualisation of the glottis and can Vasopressin: Vasopressin is a non-adrenergic peripheral
be done without interruption of chest compressions. These are vasoconstrictor that acts on smooth muscle V-1 receptors and
very effective in maintaining an open airway, thereby facilitating increases cerebral and coronary perfusion without increasing
ventilation. The commonly used supraglottic airways are myocardial oxygen demand. Despite its seeming benefit, current
laryngeal mask airway, oesophageal-tracheal tube (combitube), evidence is inadequate to support its use as an alternative to
and the laryngeal tube. epinephrine in CPR. A recent meta-analysis showed no statistically
significant differences between vasopressin over epinephrine for
Endotracheal intubation: This is ideal for a variety of reasons
return of spontaneous circulation, 24-hour survival, or survival to
including to keep the airway patent, permits effective
hospital discharge.
respiratory toilet, and effective for providing invasive ventilation
and an alternative route for cardiac arrest drug administration. One randomised controlled trial (RCT) found that repeated
However, the drawback is in the hands of untrained healthcare doses of vasopressin during cardiac arrest did not improve
worker who could cause complications like oropharyngeal survival rates compared with repeated doses of epinephrine.
trauma, prolonged interruptions in chest compressions or Since effects of vasopressin have not been shown to differ from
oesophageal intubation. those of epinephrine in cardiac arrest, it is recommended that
one dose of vasopressin 40 U IV/IO can replace either the first
Clinical confirmation of the tube placement can be done by
dose or second dose of epinephrine in the treatment of cardiac
visual confirmation during intubation by noticing the tube
arrest.
passing through the vocal cords and bilateral chest expansion
following bagging the victim by attaching an Amboss bag to Other vasopressors: There are no alternative vasopressors
the ET, 5 point auscultation (presence of air over the chest (norepinephrine, phenylephrine) with proven survival benefit
bilaterally and absence over the epigastric region). Various compared with epinephrine.
devices are used for tube placement confirmation, viz.
oesophageal detector device and non-wave-form exhaled Antiarrhythmics
carbon dioxide (CO2) detector if waveform capnography is not There is no evidence that any antiarrythmic drugs given during
available. cardiac arrest can increase survival to hospital discharge. However,
amiodarone has been shown to increase short-term survival to
Once advance airway is in place with confirmation, the two
hospital admission when compared to placebo and lidocaine.
healthcare providers should no longer follow cycles of CPR, but
provide continuous chest compressions at the rate of 100 per Amiodarone: Amiodarone is a membrane-stabilising drug that
minute. Ventilation should continue at the rate of 1 breath every significantly slows conduction over the AV nodal and accessory
6 to 8 seconds, i.e. 8 to 10 breaths per minute with the same pathways. It has complex actions on sodium, potassium,
criteria to avoid excessive ventilation. To avoid fatigue of the and calcium channels along with effects on alpha and beta-
compressor and subsequent deterioration of CPR quality, the adrenergic receptors. It produces both hypotension and
two healthcare providers should rotate the compressor role bradycardia. It is effective in enhancing responses to
every 2 minutes. defibrillation in refractory VF/PVT.
285
 Amiodarone is administered for VF or PVT unresponsive to CPR, cardiac arrest victims does not improve the likelihood of ROSC
defibrillation, and vasopressors at initial dose of 300 mg IV/IO or survival outcomes regardless of the timing of pacing
bolus followed by an additional 1 dose of 150 mg IV/IO only. administration or location of arrest. As a result, electrical pacing
is not recommended for routine use in cardiac arrest.
Lidocaine: Initial animal studies did support the use of
lidocaine for ventricular arrhythmias, however subsequent Monitoring during CPR
studies showed that compared with amiodarone; amiodarone Physiological monitoring to optimise CPR quality and detect
was superior to lidocaine in restoring spontaneous circulation ROSC now plays an important role in the new 2010 AHA
with improved rate of survival to hospital admission and guidelines. Needless to say with ROSC the victim is shifted
that lidocaine was associated with more asystole after to intensive care unit (ICU) or if the event has occurred
defibrillation. in the ICU setting monitoring of physiological parameters
Lidocaine should be considered as an alternative to amiodarone is done aggressively, using clinical parameters and
only, if amiodarone is not available. The initial dose is 1 to 1.5 sophisticated equipments. The age-old arterial pulse
mg/kg IV. If VF/pulseless VT persists, additional doses of 0.5 to palpation, manual or intra-arterial BP monitoring, 12-lead
0.75 mg/kg IV push may be given at an interval of 5 to 10 minute ECG including rhythm monitoring on bedside monitor
to a maximum dose of 3 mg/kg. cannot be ignored.

Magnesium: Use of magnesium sulphate is considered only in The 2010 AHA guidelines emphasise particularly the use of
refractory VF, torsades de pointes, in chronic alcoholics with PETCO2 for monitoring in ACLS once advance airway placement
unresponsive VF/pulses VT and digoxin toxicity. has been done. Other parameters include coronary perfusion
pressure (CPP), central venous oxygen saturation (SVO2), SpO2
Interventions and Drugs Not Recommended for Routine monitoring, and arterial blood gas analysis (ABG).
Use during Cardiac Arrest
Continuous Quantitative Waveform Capnography
Atropine
The 2005 AHA guidelines laid emphasis on 5 points auscultation
The drug reverses cholinergic-mediated decrease in heart rate, for ET placement and confirmation with an exhaled CO 2
systemic vascular resistance and blood pressure. Lower level detector or an oesophageal detector device to confirm
clinical studies provide conflicting evidence regarding the placement of ET. The continuous quantitative waveform
benefit of routine use of atropine in cardiac arrest. In fact as capnography monitoring was being referred to as a useful non-
per available evidence, routine use of the drug during PEA and invasive indicator of cardiac output that is generated during
asystole is unlikely to have a therapeutic benefit. Therefore, CPR.The 2010 AHA guidelines for CPR and ECC now recommend
atropine has been removed from the cardiac arrest algorithm.
continuous quantitative waveform capnography monitoring for
Sodium bicarbonate confirmation and monitoring of endotracheal tube placement
During cardiac arrest and resuscitation tissue acidosis with include in algorithm for ACLS once advance airway placement
resulting acidaemia occur due to absence of blood flow during is done. The advantage of PETCO 2 monitoring is also for
arrest with low blood flow during CPR. ROSC following high monitoring quality of CPR and detection of ROSC based on
quality CPR restores acid-base balance. Except for two studies, ETCO2 values.
majority of the studies have shown no benefit or found to have The rationale is that PETCO2 provides a continuous waveform
poor outcomes with the use of sodium bicarbonate during CPR. with ventilation to confirm the presence of ET. Also, it serves to
However, use of it can be made in special resuscitation play a major role in the 5th chain of survival, i.e. in post-cardiac
circumstances, like pre-existing metabolic acidosis, hypothermia, arrest care. It plays a vital role in detecting the effectiveness of
hyperkalaemia, or tricyclic antidepressant overdosage. chest compressions and cardiac output in the recovery phase.
Calcium Falling PETCO2 during chest compressions indicate ineffective
chest compressions and during ROSC may indicate falling
Routine use of calcium for the treatment of in-hospital and out-
cardiac output or rearrest.
of-hospital cardiac arrest is not recommended, as routine use
of calcium has not been proved to be of beneficial value in Central Venous Oxygen Saturation (SVO2)
survival in any trials. Measurement of SVO2 is done by placing oximetric tipped
Intravenous fluids central venous catheters in the superior vena cava. The normal
Administration of normothermic fluid, hypertonic and chilled values are 60% to 80%. It is an effective tool for assessing the
fluids during CPR has no advantage in survival benefit of the adequacy of blood flow during cardiac arrest, because during
victim, as observed in various animal and small human studies. cardiac arrest the SVO2 is between 25% to 35% indicating poor
However, volume administration should be promptly given, if blood flow. The advantage of SVO2 during cardiac arrest is to
cardiac arrest is associated with severe volume losses because detect ROSC as it is a useful indicator of cardiac output and
these patients develop signs of circulatory shock advancing to oxygen delivery without interruption of chest compressions for
PEA. pulse and rhythm checks. If during CPR, SVO2 is > 30% it indicates
the need to improve CPR quality by improving the chest
Pacing compressions. Limitations in the use of SVO2 monitoring is the
No studies have shown survival benefits from pacing in availability of the catheter and knowledge of use in all ICUs,
cardiac arrest. Existing evidence suggests that pacing by and particularly its accuracy depends on oxygen consumption,
286 transcutaneous, transvenous, or transmyocardial means in SaO2 values and haemoglobin levels.
 Cardiopulmonary Resuscitation
Coronary Perfusion Pressure and Arterial Relaxation 9. Adopt measures to reduce the risk of multi-organ injury by
Pressure assessing routine biochemical parameters.
Coronary perfusion pressure (CPP) is defined as aortic 10. Assess prognosis for recovery.
relaxation pressure minus right atrial relaxation pressure. 11. Provide rehabilitation services to survivors.
Measured during CPR it correlates well with myocardial
blood flow and ROSC. It requires simultaneous recording, Brain injury is a common cause of morbidity and mortality of
measurement and calculation of both aortic and central post-cardiac arrest victims. Studies have shown that brain injury
venous pressures. Unfortunately, in our set-up its availability accounts for around 68% deaths of victims in out-of-hospital
is a problem. Alternatively intra-arterial pressure monitoring cardiac arrest and around 23% deaths in in-hospital cardiac
is preferred to detect ROSC during chest compression or when arrest. Presentations of post-cardiac arrest brain injury include
organised rhythm is restored. coma, seizures, myoclonus, various degrees of neurocognitive
dysfunction (ranging from memory deficits to persistent
Post-Cardiac Arrest Care vegetative state) and brain death.
A healthy brain and a functional patient are the primary goals
Management of seizures involves prompt EEG with
of CPR. Post-effective CPR, significant haemodynamic
interpretation and frequent EEG monitoring or continuous
instability as well as laboratory abnormalities can occur. Every
monitoring in comatose patients. Treatment regimens for post-
organ system is at risk during this time and patients may
cardiac arrest seizures follow the same pattern as with seizures
develop multi-organ dysfunction. Therefore, optimise
due to other causes. However, no studies have shown that
cardiopulmonary function to provide effective systemic
anticonvulsant therapy improves the outcome after cardiac
perfusion, particularly perfusion to the brain. This is best
arrest; with several studies showing that post-cardiac arrest
achieved in critical care unit. Therefore, transport the victim
seizures were refractory to traditional anticonvulsant therapy.
to the hospital in the ICU for monitoring and management.
Post-admission management measures include the Unfortunately, large clinical studies of brain resuscitation
following: (BRCT trials) have shown that administration of barbiturates
1. Identify the precipitating cause of arrest. (thiopental), steroids (glucocorticoids) or calcium channel
2. Adopt measures to prevent recurrence of arrest. blockers (lidoflazine, nimodipine), diazepam and magnesium
sulphate during the resuscitation have no effect on neurological
3. Institute measures to treat neurological complications and
recovery. One trial using coenzyme Q10 in patients receiving
measures to improve long-term neurological function hypothermia failed to show improved survival with good
including control of body temperature to optimise survival neurological outcomes. Hence, routine use of it in patients with
and neurological recovery. hypothermia is uncertain.
4. Do serial 12-lead ECG and cardiac biomarkers for the
PROGNOSIS
detection of acute coronary syndromes.
While ACLS can result in the restoration of circulation in over
5. Do serial ABGs. Provide adequate mechanical ventilation
40% of victims, less than 5% of pre-hospital arrests and about
to minimise lung injury.
15% of in-hospital sudden cardiac arrest (SCA) survive to be
6. Assess acid-base and fluid electrolyte imbalances and discharged alive from the hospital. Survival-to-discharge is
correct the same. strongly correlated with recovery of neurological function and
7. Monitor HGT/blood glucose levels to prevent hypoglycaemia. prognostication of such recovery is a major concern after CPR.
If hypoglycaemia is present, correct it. Maintain HGT around Though this is predominantly a clinical exercise, a few diagnostic
140 to 180 mg/dL. tests have been added, with little impact on predicting good
8. Avoid hypotension. Monitor central venous pressure (CVP). outcomes. In general, it is difficult to predict good neurological
If low, give fluid challenge. If CVP normal and low blood outcomes after CPR, but poor outcomes can be identified by
pressure, start vasoactive/inotropic/inodilator drugs as the clinical/investigational features.
case may be, dose titrated to optimise BP, cardiac output A recent meta-analysis of 11 studies involving 1,914 patients
and systemic perfusion (Table 2). documented 5 clinical signs that were found to strongly predict

Table 2: Drugs for Management of Hypotension

Drug Dose Remarks
Epinephrine 0.1 mcg/kg/min Used in severe hypotension
Norepinephrine 0.1 to 0.5 mcg/kg/min Used in severe hypotension, contraindicated in
hypovolaemia (low CVP)
Phenylephrine 0.5 to 2 mcg/kg/min Used in severe hypotension and low total peripheral
resistance
Dopamine 5 to 20 mcg/kg/min Used in hypotension particularly with symptomatic
bradycardia. Avoid in patients with low CVP
Dobutamine 5 to 20 mcg/kg/min Used in hypotension with cardiogenic shock
Milrinone 50 mcg/kg over 10 minutes as loading dose Used for low cardiac output states. Causes less tachycardia
then infuse at a rate of 0.375 mcg/kg/min than dobutamine
287
 death or poor outcomes, with 4 out of 5 predictors detectable hospital emergency department for advanced support. Proper
at 24 hours after resuscitation, as given below: intensive care management with proper post-cardiac arrest care
1. Absent corneal reflex at 24 hours. can contribute to restoration of a healthy brain and a functional
patient which are the primary goals of CPR. Therefore, the
2. Absent pupillary response at 24 hours.
comprehensive treatment of diverse problems after cardiac
3. Absent withdrawal response to pain at 24 hours. arrest involves multi-disciplinary aspects of critical care,
4. Absent motor response at 24 hours. cardiology, and neurology. It is for this reason it is mandatory to
5. Absent motor response at 72 hours. manage such victims in fully equipped critical care units.

In another meta-analysis, it was observed that bilateral absence RECOMMENDED READINGS

of cortical responses to median nerve somato-sensory evoked 1. American Heart Association 2010. American Heart Association Guidelines
potentials was associated with a poor outcome in normo- for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.
Circulation 2010; 122 (Suppl 3): S640-S656, S685-S705, S706-S719,S729-
thermic patients who were comatose for at least 72 hours. S767,S768-S786.
2. European Resuscitation Council Guidelines for Resuscitation 2010.
CONCLUSION www.erc.edu, www.CPRguidelines.eu
The primary aim of CPR is to rigidly follow the chain of survival, 3. Fang Gao Smith, Joyce Yeung. Post-resuscitation care, Garvin Perkins. Core
prompt CPR with defibrillation, rapid transport of the victim to Topics in Critical Care Medicine 2010; 22: 170-5.

288
 7.12 Brain Death and Support of the
Brain-Dead Organ Donor
Rajesh Chawla, Guneet Singh

INTRODUCTION 3. Confirmation of absence of drug intoxication or poisoning.

Recent advances in resuscitative and life support techniques have 4. Core body temperature ≥32°C (90°F)
led to the definition of death and its concept. The progress in
Testing of brainstem function can proceed only after these pre-
organ transplantation and the increasing number of patients
requisites have been fulfilled.
who have a living body but non-functioning brain, which is a
consequence of discoveries in resuscitative and life support Cardinal findings in brain death which need to be established
techniques, has led to study brain death more precisely. Such are: coma or unresponsiveness, absence of brainstem reflexes,
refinements in critical care medicine mean that neurologists, and apnoea. Figure 1 gives the algorithm for evaluation of
neurosurgeons, and anaesthesiologists must be able to make coma and brainstem function.
an appropriate diagnosis of death. The cultural and religious
diversity may lead to great differences in attitudes toward brain
death and there is no global consensus in diagnostic criteria.
The concept of brain death as defining the death of an individual
is widely accepted, and many countries have published
recommendations or legal requirements for the diagnosis of
brain death as a necessary pre-requisite for organ donation.

DEFINING BRAIN DEATH

Brain death has been traditionally defined as irreversible
cessation of all brain functions including brainstem. The advent
of effective artificial cardiopulmonary support for severely brain
injured persons, however, created some confusion about the
determination of death. Loss of heart and lung function was an
easily observable and sufficient basis for the diagnosis of death.
However, with availability of measures to support circulation
and respiration by a mechanical respirator and other medical
interventions, it is important to diagnose individuals who have
lost all brain functions, i.e. have a dead brain in an otherwise
living body. This diagnosis of determining neurological death
is also important in view of the developments in transplant
Figure 1: Testing algorithm for evaluation of coma and brainstem function.
surgery raising ethical and legal attention on the desirability of
agreeing on the medical criteria of brain death. CSF = Cerebrospinal fluid; PCO2 = Partial pressure of carbon dioxide

CRITERIA FOR CLINICAL DETERMINATION OF BRAIN DEATH Coma or Unresponsiveness

Determination of brain death clinically should include the Motor responses of the limbs
following: Testing: Motor responses of the limbs to painful stimuli should
1. Eliminate error in classifying a living individual as dead. be absent after supraorbital pressure and nail-bed pressure
2. Allow as few errors as possible in classifying a dead body stimulus.
as alive.
Pitfalls: Motor responses (“Lazarus sign”) may occur
3. Allow a determination to be made without unreasonable spontaneously during apnoea testing, often during hypoxic or
delay. hypotensive episodes, and are of spinal origin. Neuromuscular
4. Be acceptable to a variety of clinical situations. blocking agents can produce prolonged weakness. If neuro-
5. Be explicit and accessible to verification. muscular blocking agents have recently been administered,
Pre-Requisites for Clinical Determination examination with a bedside peripheral nerve stimulator is
needed. A train of – four stimuli should result in four thumb
1. Clinical or neuroimaging evidence of an acute catastrophic twitches.
cerebral event consistent with clinical diagnosis of cerebral
death. Absence of Brainstem Reflexes
2. Exclusion of conditions that may confound clinical Pupils
assessment of brain death, e.g. acute metabolic or endocrine Testing: The response to bright light should be absent in both
derangements, hypothermia and shock. eyes.
289
 Round, oval or irregularly shaped pupils are compatible with Pitfall
brain death.
Severe facial trauma may limit interpretation of all brainstem
Most pupils in brain death are in middle position (4 mm to 6 reflexes.
mm), but the size of the pupils may vary from 4 mm to 9 mm.
Pharyngeal and Tracheal Reflexes
Dilated pupils are compatible with brain death.
Testing
Pitfalls: Many drugs can influence pupil size, but light response
The gag response, tested by stimulation of the posterior
remains intact. In conventional doses, atropine given intra-
pharynx with a tongue blade, should be absent. Lack of cough
venously has no marked influence on pupillary response.
response to bronchial suctioning should be demonstrated.
Because nicotine receptors are absent in the iris, neuromuscular
blocking drugs do not noticeably influence pupil size. Topical Pitfall
ocular instillation of drugs and trauma to the cornea or In orally intubated patients, the gag response may be difficult
bulbous oculi may cause abnormalities in pupil size and to interpret.
can produce non-reactive pupils. Pre-existing anatomic
abnormalities of the iris or effects of previous surgeries should Apnoea
be excluded. Apnoea test (guidelines for the test)
Ocular Movements Pre-requisites: Important changes in vital signs (e.g. marked
hypotension, severe cardiac arrhythmias) during the apnoea
Testing
test may be related to lack of adequate precautions. Therefore,
Ocular movements are absent after head - turning and caloric the following pre-requisites are suggested:
testing with ice water (testing is done only when no fracture or
1. Core temperature greater than or equal to 36.5°C (4.5°C
instability of the cervical spine is apparent, and in patients with
higher than the required 32 °C for clinical diagnosis of brain
head injury, the cervical spine must be imaged to exclude
death).
potential fractures or instability or both) the oculocephalic
reflex, elicited by fast and vigorous turning of the head from 2. Systolic blood pressure greater than or equal to 90 mmHg.
middle position to 90° on both sides, normally results in eye 3. Euvolaemia (option: preferably positive fluid balance in the
deviation to the opposite side of the head-turning. Vertical eye previous 6 hours).
movements, should be tested with brisk neck flexion. Eyelid 4. Eucapnia (option: arterial PCO2 ≥ 40 mmHg).
opening and vertical and horizontal eye movements must be 5. Normoxaemia (option: arterial PO2 ≥ 200 mmHg). A pulse
absent in brain death. oximeter is connected to the patient.
Caloric testing Testing (Figure 2)
It should be done with the head elevated to 30° during irrigation 1. Ventilate with FiO2 of 100% for 10 minutes.
of the tympanum on each side with 50 mL of ice water.Tympanum
irrigation can be best accomplished by inserting a small suction 2. Disconnect the ventilator.
catheter into the external auditory canal and connecting it to a 3. Deliver 100% oxygen at a rate of 6 L/min by placing a
50 mL syringe filled with ice water. Tonic deviation of the eyes cannula at the level of the carina.
directed to the cold caloric stimulus is absent. The investigator 4. Look closely for respiratory movements. Respiration is
should allow up to one minute after injection and the time between defined as abdominal or chest excursions that produce
stimulation each side should be at least five minutes.
Pitfalls
Drugs that can diminish or completely abolish the caloric
response are sedatives, aminoglycosides, tricyclic anti-
depressants, anticholinergics, antiepileptic drugs, and
chemotherapeutic agents. After closed head injury or facial
trauma, lid oedema and chemosis of the conjunctiva may
restrict movement of the globes. Clotted blood or cerumen
may diminish the caloric response, and repeat testing is
required after direct inspection of the tympanum. Basal
fracture of the petrous bone abolishes the caloric response
only unilaterally and may be identified by an ecchymotic
mastoid process.
Facial Sensation and Facial Motor Response
Testing
Corneal reflexes should be tested with a cotton swab. Corneal
reflex and jaw reflex should be absent. Grimacing to pain can be
tested by applying deep pressure with a blunt object on the nail Figure 2: Procedure for the apnoea test in brain death.
beds, pressure on the supraorbital ridge, or deep pressure on both
FiO2 = Fraction of inspired oxygen; PCO2 = Partial pressure of carbon dioxide
condyles at the level of the temporomandibular joint.
290
 Brain Death and Support of the Brain-Dead Organ Donor
adequate tidal volumes. If present, respiration can be Result
expected early in the apnoea test. When the result is in No electrical activity occurs above 2 µV at a sensitivity of 2 µV/
doubt, a spirometry can be connected to the patient to mm with filter setting at 0.1 or 0.3 second and 70 Hz. Recording
confirm that tidal volumes are absent. should continue for at least 30 minutes.
5. Measure arterial PO2, PCO2 and pH after approximately
EEG
8 minutes and reconnect the ventilator.
Nevertheless in one consecutive series of patients fulfilling the
6. If respiratory movements are absent and arterial PCO2 ≥ 60
clinical diagnosis of brain death, 20% of 56 patients had residual
mmHg (option: 20 mmHg increase in PCO2 over a baseline
EEG activity that lasted up to 168 hours.
normal PCO2), the apnoea test result is positive (i.e. it
supports the clinical diagnosis or brain death). Disadvantage
7. If respiratory movements are observed, the apnoea Considerable artifacts in the intensive care unit can limit
test result in negative (i.e. it does not support the clinical interpretation.
diagnosis of brain death). Isotope Angiography
8. If during apnoea testing, systolic blood pressure becomes <90 Technique: Rapid intravenous injection of serum albumin
mmHg, the pulse oximeter indicates marked desaturation, and labeled with technetium 99m is followed by bedside imaging
cardiac arrhythmias occur, immediately draw a sample, with portable gamma camera.
connect the ventilator, and analyse arterial blood gas. The
apnoea test result is positive if arterial PCO2 is ≥60 mmHg or Results: Intracranial radioisotope activity is absent. Filling of
PCO2 increase is equal ≥20 mmHg above baseline normal PCO2. saggittal and transverse sinuses may occur in delayed images
If arterial PCO2 is < 60 mmHg or PCO2 increase is <20 mmHg from connections between the extracranial circulation and
over baseline normal PCO2, the result is indeterminate. venous system.
9. If no respiratory movements are observed, PCO2 is <60 mmHg Technetium 99m Hexamethylpropylenamineoxime
and no significant cardiac arrhythmia or hypotension is (99m TcHMPAO)
observed,the test may be repeated with 10 minutes of apnoea. Technique
DURATION OF OBSERVATION The procedure can be performed at the bedside and takes
approximately 15 minutes. The isotope should be injected
Brain death is a clinical diagnosis and irreversibility should be within 30 minutes of reconstitution. A portable gamma camera
documented by an extended period of observation. The patient produces planar views within 5 to 10 minutes. Correct intra-
must undergo two brain death determinations at least 6 hours venous injection can be checked by taking additional chest and
apart. However, this internal decision is arbitrary. The two abdominal images.
examinations must be performed by different licensed physicians.
Result
CONFIRMATORY LABORATORY TESTS No uptake occurs in brain parenchyma.
A repeat clinical evaluation 6 hours later is advised (option), Disadvantage
but a firm recommendation cannot be given and the interval is
The tracer should be injected immediately. Because the costs
arbitrary. A confirmatory test is not mandatory in most
are currently high and technique is not widely available,
situations. All clinical tests are needed to declare brain death
experience is limited.
and are likely equally essential. A confirmatory test is needed
for patients in whom specific components of clinical testing Transcranial Doppler Ultrasonography
cannot be reliably evaluated. Clinical experience with Technique
confirmatory tests other than EEG, transcranial Doppler
A portable 2 MHz pulsed Doppler instrument can be used at
ultrasonography, and conventional angiography is limited.
bedside. Intra-cranial arteries should be insonated bilaterally
Many tests need costly equipment and well-trained technicians.
(e.g. main carotid artery through the temporal bone above
Conventional Angiography zygomatic arch and vertebral or basilar arteries through the
Technique suboccipital transcranial window). Alternatively a combination
of one ophthalmic artery through transorbital window and the
A selective four-vessel angiogram is done in the radiology suite.
MCA can be tried.
Iodinated contrast medium is injected under high pressure in
both the anterior and the posterior circulations. Results
Transcranial Doppler signals that have been reported in brain
Result
death are as follows:
Intra-cerebral filling is absent at the level of carotid bifurcation
1. Absent diastolic or reverbating flow that indicates flow only
or circle of willis. The external carotid circulation is patent, and
through systole or retrograde diastolic flow. This pattern is
at times delayed filling of the superior longitudinal sinus is seen.
caused by contractive forces of the arteries.
Electroencephalography (EEG) 2. Small systolic peaks in early systole indicate very high
Technique resistance. This pattern is associated with greatly increased
Usually a 16- or 18-channel instrument is used with guidelines intracranial pressure. Lack of transcranial Doppler signals
developed by the American Electroencephalo-graphic society cannot be interpreted as confirmatory of brain death,
for recording brain death. because 10% of patients may not have temporal insonation 291
 windows. An exception possibly can be made in patients Respiratory Support
who had transcranial Doppler signals during admission that Ventilatory support should continue to maintain a normal blood
disappeared at the time of brain death. gas picture. Intravenous steroids should be given in case lung
Disadvantage transplant is planned. Lung protective strategy in ventilation
to maintain P/F ratio is advisable. A minimum SpO 2 of 95%
Transcranial Doppler velocities can be affected by marked
should be maintained.
changes in PCO2, hematocrit and cardiac output. Transcranial
Doppler ultrasonography requires practice and skill. Endocrinal Support
Somatosensory Evoked Potentials Injury to the hypothalamic-pituitary axis impairs the release of
arginine vasopressin. The sequelae of this damage leads to
Technique
occurrence of Diabetes Insipidus as most common abnormality.
A portable instrument can be used at bedside. Median nerve
stimulation is performed on both sides. The evaluation of the organ donor should be carried out in a
step-wise approach as depicted in Figure 3.
Result
N20-P22 response is bilaterally absent.
Miscellaneous Tests
Many of these tests have been done in small series of patients
only and are not widely adopted as confirmatory tests.
Contrast computed tomograph with bolus of meglumine
diatrizoate, 1 mL/kg of body weight, does not visualise intra-cranial
vessels. A good correlation with cerebral angiography has been
demonstrated in a few anecdotal reports.
Many other confirmatory tests are variants or modifications.
Experience is limited, as these tests produce similar results in
patients with neurological catastrophes who do not fulfil the
clinical criteria for brain death.

COMMUNICATION WITH THE FAMILY

Critical care nurses and resident doctors should become
familiar with the concept of brain death and its medical and
legal criteria, because they may need to explain brain death
to family members who are confused and in crisis. Sometimes
the use of certain terminology appears to conflict with reality
when the terminology is applied to cases in which patients
are pronounced dead on the basis of neurological criteria.
In order to avoid confusion, it is more helpful to tell family
that their loved one is ‘dead’ because use of this word can
help the family understand that neurological death has
occurred. A clear definition of brain death must be given and
reinforced.
Figure 3: Stepwise approach for evaluation of organ donor patient.
SUPPORT OF THE POTENTIAL ORGAN DONOR
PA = Pulmonary artery; PCWP = Pulmonary capillary wedge pressure; CVP = Central
Once established, a brain dead case who is a potential donor venous pressure; CI = Cardiac index; MAP = Mean arterial pressure; SVR = Systemic
is to be handled very carefully so as to prevent any organ vascular resistance
damage before procuring them. After brain death since central
regulation to circulation is lost, invasive haemodynamic RECOMMENDED READINGS
monitoring is mandatory to avoid fluctuations and help guide 1. Guidelines for the determination of brain death in children. Report of
fluid and vasopressor therapy. special task force. Paediatrics 1987; 80: 298-300.

Circulation 2. Guidelines for the determination of death. Report of the medical

consultants on the diagnosis of death to the Presidents commission for
Inotropes and vasopressors both can be used to maintain the study of ethical problems in medicine and biomedical and behavioural
haemodynamic parameters. Vasodilator infusion should be research. JAMA 1981; 246: 2184-6.
avoided in hypertension; rather short-acting beta blockers can 3. Kenneth EW, Bryan N Becker, John G McCartney et al. Care of potential
organ donor. N Engl J Med 2004; 351:2730-9.
be used. In patients with decreased left ventricle function and
acute respiratory distress syndrome, pulmonary artery catheter 4. Okagaki JF. Practice parameters for determining brain death in adults
(Summary statement). Neurology 1995; 45: 1012-4.
is advocated. Targets to be maintained are: (i) systolic blood
5. Report of the ad hoc committee of the Harvard medical school to examine
pressue >90 mmHg; mean arterial pressure >65 mmHg; (iii) the definition of brain death. JAMA 1968; 205: 337-40.
central venous pressure 8 cm to 12 cm H2O; pulmonary capillary 6. Wijdicks EFM. Determining brain death in adults. Neurology 1995;45:
292 wedge pressure <12 mmHg. 1003-11.
Section 8
Bone Disorders
Section Editor: S.N.A. Rizvi
8.1 Bone and Mineral Metabolism in Health and Disease 294
Deepak Khandelwal, Ravinder Goswami
8.2 Investigations and Diagnosis of Bone Disorders 299
Sukumar Mukherjee
8.3 Rickets and Osteomalacia 305
Bindu Kulshreshtha, Sachin K. Jain
8.4 Osteoporosis 309
S.N.A. Rizvi
8.5 Developmental Disorders of Bone 313
Rakesh K. Sahay
8.6 Miscellaneous Bone Disorders 316
C.V. Harinarayan
 8.1 Bone and Mineral Metabolism
in Health and Disease
Deepak Khandelwal, Ravinder Goswami

PHYSIOLOGY OF THE BONE can be helpful in diagnosis and management of metabolic bone
Bone is a special form of connective tissue with a collagen diseases. These biochemical markers of bone remodelling are
framework impregnated mineralized matrix in the form of summarised in Table 1.
hydroxyapatite crystals and also small, but highly active
Table 1: Biochemical Markers of Bone Formation and Resorption
cellular fraction. Bone is involved in overall Ca 2+ and PO43–
homeostasis. It also protects vital organs, permits locomotion Bone formation Serum bone specific alkaline phosphatase
with its rigidity, involved in acid-base balance, and provides markers Serum osteocalcin
the environment for hematopoiesis within the marrow spaces. Serum propeptide of type 1 procollagen
Bone is of two types: compact or cortical bone, and trabecular Bone resorption Urine and serum cross linked
or spongy bones. Cortical bone is the dense bone that is found markers N-telopeptides
Urine and serum cross linked C-telopeptides
in the shafts of long bones, whereas trabecular bone is
Urine deoxypyridinoline
composed of a honeycomb like network interspersed in the
bone marrow compartment. The adult human skeleton is
CALCIUM PHYSIOLOGY
composed of 80% cortical bone and 20% trabecular bone.
Bone is composed of 50% to 70% mineral, 20% to 40% organic Calcium is involved in important cellular functions like cell
matrix, 5% to 10% water and less than 3% lipids. The mineral division, cell adhesion, integrity of plasma membrane, muscle
content of bone is mostly hydroxyapatite [Ca10(PO4)6(OH)2]. contraction, neuronal excitability, secretion of proteins and
Approximately 85% to 90% of bone protein is composed of coagulation cascade. A normal adult body contains about 1 kg
collagenous proteins and the noncollagenous proteins is of calcium, of which approximately 99% is present in the
composed of rest 10% to 15%. skeleton as hydroxyapatite [Ca10(PO4)6(OH)2] and 1% in soft
tissues and extracellular fluids. A normal calcium balance is
There are three cell types in bone: (1) bone forming osteoblasts, summarised in Figure 1.
(2) osteocytes, and (3) bone resorbing osteoclasts. Osteoblasts
are derived from mesenchymal cells, whereas osteoclasts are
derived from mononuclear precursor cells of the monocyte-
macrophage lineage. Bone undergoes modelling and
remodelling during life. Longitudinal and radial growth occurs
during childhood and adolescence. Modelling is the process
by which bones change their overall shape in response to
physiologic influences or mechanical forces, leading to gradual
adjustment of the skeleton to the stress that it has to face. During
bone modeling, bone formation and resorption are not tightly
coupled. Bone remodelling is the process by which bone is
renewed to maintain bone strength and mineral homeostasis.
The bone remodelling units (BRUs) or bone multicellular units
(BMUs) are composed of a tightly coupled group of osteoclasts
and osteoblasts that sequentially carry out continuous removal
of discrete packets of old bone and replacement of these
packets with newly synthesised proteinaceous matrix and
subsequent mineralisation of the matrix to form new bone. The
remodelling cycle can be divided into four steps: (1) activation,
Figure 1: Normal calcium balance.
(2) resorption, (3) reversal, and (4) formation.
The process of bone remodelling is highly regulated by In spite of large movements of calcium between body
mechanical forces, hormones and cytokines. One of the most compartments, serum calcium is maintained constant at about
important cytokine in osteoclastogenesis is receptor activator 10 mg/dl (2.5 mgm). The essential fraction is the biologically
of nuclear factor-κB ligand (RANKL), which is a member of the active free, ionized one which equals 50% of the total serum
tumor necrosis factor (TNF) family and is expressed in the bone- calcium (1.3 mgm). Forty percent of total serum calcium is
lining cells or osteoblast precursors that support osteoclast protein-bound, principally to albumin, and the remaining 10%
recruitment. Interaction of RANKL with its receptor (RANK) on of calcium is complexed with various anions such as citrate,
osteoclast progenitors and osteoclasts then stimulates their sulfate, bicarbonate, lactate and phosphate. A decrease in serum
recruitment and activation, and delays their degradation. albumin of 1 g/dl results in a decrease in total serum calcium of
294 Measurement of product of osteoblast and osteoclast activity 0.8 mg/dl without affecting the ionized fraction significantly.
 Bone and Mineral Metabolism in Health and Disease
As calcium is bound to carboxyl groups on albumin, pH changes is restricted to a few dietary items. Also, dietary phosphorus is
affect ionised calcium. Acidosis decreases binding and increases absorbed almost twice as efficiently as dietary calcium. Thus,
ionized calcium, whereas alkalosis increases binding and phosphorus absorption, unlike calcium, is rarely a nutritional
decreases ionised calcium. The constancy of extracellular fluid problem. The normal range for serum phosphate level in
concentration of calcium is maintained by hormonal regula-tion adults is 2.5 to 4.5 mgm/dL. In children, serum phosphate levels
of the absorption of calcium from the gastrointestinal tract, the are higher and decrease with age. Unlike plasma calcium,
mobilization of skeletal calcium and the reabsorption of filtered phosphorus is not protein bound and is filtered almost
calcium in kidney tubules. Vitamin D, parathyroid hormone (PTH) completely at the glomerulus.
and calcitonin are the regulators of these processes.
Intestinal Phosphate Absorption
Intestinal Calcium Absorption The average adult ingests approximately 1,000 mg/day of
Intestinal calcium absorption occurs through both an active phosphorus, with 80% being absorbed by the intestine and the
transcellular pathway and a passive paracellular pathway. The remaining 20% being excreted directly into the stool. Intestinal
paracellular pathway is dependent on calcium moving through absorption of phosphorus can be either through paracellular
tight junctions in the intestinal epithelium, which is a passive, or transcellular pathways. Paracellular absorption is largely
nonsaturable process and is favored during states of high dependent on the luminal concentration of phosphorus and
calcium intake. However, transcellular pathway, an active does not appear to be saturable. Transcellular absorption occurs
transport, is particularly important at low and normal calcium through the sodium-phosphate type IIb cotransporters, which
intake. It is summarised in Figure 2. have been shown to be upregulated by increasing 1,25(OH)2D.
Renal Handling of Phosphate
Approximately 70% of filtered phosphate is reabsorbed within
the proximal tubule, which involves uptake across the brush
border membrane, translocation across the cell and efflux at
the basolateral membrane. The overall rate-limiting step in
the reabsorptive process is phosphate uptake at the apical
membrane; where the sodium-phosphate cotransporters (NPT)
Figure 2: Intestinal absorption of Ca2+ via the transcellular pathway. Ca2+ enters IIa and IIc actively transport phosphate from the lumens of
through Ca2+ channel TrPV5 or TrPV6, in the luminal membrane of the enterocyte. nephrons into proximal tubular cells. Parathyroid hormone
Once absorbed, the transcellular movement of calcium to the basolateral
membrane is dependent on binding to an intracellular protein known as
decreases the expression of the NPT IIa and IIc and decreases
calbindin-D 9k. The egress of calcium from the intestinal epithelium occurs phosphate reabsorption. There are several other recently
through the actions of the plasma membrane calcium-dependent ATPase identified factors, termed phosphotonins like fibroblast growth
(PMCA1b). This transcellular movement of calcium is closely regulated by factor 23 (FGF23), which induce renal phosphorus wasting
1,25(OH)2D3, which regulates the gene transcription of TRPV6, calbindin and
PMCA1b.
by decreasing the expression of the NPT IIa and IIc. Human
disorders associated with increased circulating concentrations
of FGF23 are characterised by hypophosphataemia, and
Renal Handling of Calcium
disorders associated with reduced FGF23 bioactivity, like
Approximately 98% to 99% of the filtered Ca2+ is reabsorbed in tumoral calcinosis, are characterised by hyperphosphataemia.
kidney. About 60% of the reabsorption occurs in the proximal
tubules via a passive, paracellular route, which follows sodium PARATHYROID HORMONE
reabsorption. Rest of active calcium reabsorption takes place Structure and Biosynthesis
in the thick ascending limb of the loop of Henle and in the distal The parathyroid glands develop from the endodermal lining of
convoluted tubule and the connecting tubule. About 20% to
the third and fourth branchial pouches. There are usually four
25% of the filtered calcium is reabsorbed in the loop of Henle
parathyroid glands in man, two superior and two inferior each
through both transcellular and paracellular routes. The primary
weighing about 40 mg, and located behind the thyroid gland.
site for PTH regulation of renal calcium reabsorption is the distal
The predominant cell type in the parathyroid gland is the chief
nephron, which normally reabsorbs nearly all of the remaining
(also called principal) cell, which are primary endocrine cell.The
10% of filtered calcium by a unique transcellular active transport
primary function of parathyroid hormone (PTH) is to maintain
mechanism.
extracellular calcium concentration in a narrow normal range.
PHOSPHORUS PHYSIOLOGY The hormone acts directly on bone and kidney and indirectly
on intestine, by increasing the synthesis of 1,25(OH) 2D to
Phosphate, comprises 1% approximately of total body weight,
increase serum calcium concentration. Rapid feedback effect
is widely distributed in the soft tissues of the body. It is both in
on PTH secretion and production along with biological actions
inorganic form and as a component of organic molecules
in multiple target tissues makes PTH as most important
including nucleic acids, membrane phospholipids and other
regulator for minute-to-minute control of extracellular calcium.
phosphoproteins. However, 85% of body phosphate is stored
In contrast, vitamin D is of importance in long-term, day-to-day,
in the bone matrix. Calcium and phosphorus are regulated by
and week-to-week regulation of calcium balance.
the controlled interactions of the intestine, renal tubules and
bone. However, there are several important differences between PTH is synthesised as a part of the larger precursor protein
phosphorus and calcium balance. Dietary phosphorus is present containing a 25-amino acid hydrophobic residue-rich signal
in abundance in most foods. This is in contrast to calcium, which sequence and a 6-amino acid prosequence preceding the 295
 amino terminus of PTH. These portions of the precursor are elevations in PTH thus result in hypophosphataemia in addition
sequentially removed within the cell and mature 84-amino acid to hypercalcaemia. Both PTH and hypophosphataemia stimulate
PTH is secreted from storage granules. A portion of the PTH l α-hydroxylase activity to increase formation of l,25(OH)2D.
secreted from parathyroid glands consists of carboxy-terminal
Regulation of Synthesis and Secretion
PTH fragments. The carboxy-terminal fragments of PTH do not
activate the PTH/PTHrP (parathyroid hormone-related protein) The parathyroid gland has multiple methods for adaptation
receptor and might even block bone resorption. Secreted intact to change in extracellular calcium. Most rapid is secretion of
PTH (1-84) is metabolised by liver and kidney and disappears preformed hormone, which occurs within minutes. Second,
from the circulation with a half-life of 2 minutes. However, rate intracellular degradation of newly synthesised PTH provides
of clearance of carboxy-terminal fragments occurs principally an important regulatory mechanism by increasing the fraction
by glomerular filtration and much slower, with a half life of 20- of biologically inactive carboxy-terminal fragments of PTH.
40 minutes and these fragments accumulate in patients with Third, PTH production is also regulated at the level of gene
renal failure. Older assays for PTH detected both intact 1-84 PTH transcription and lastly, prolonged hypocalcaemia also elicits
and also carboxy-terminal fragments and therefore detected an increase in both the size and number of parathyroid cells.
unreliably high levels of PTH, especially in patients with renal Secretion of PTH is primarily regulated by the concentration
failure. These problems largely circumvented by use of current of ionized calcium in serum. Critically important to the process
assays which utilise two antibodies recognising epitopes from of calcium homeostasis is the G-protein-coupled calcium
both ends of the molecule, reliably measuring only intact PTH. sensing receptor (CaSR), which is located on the surface of
parathyroid chief cells. Increased serum ionised calcium leads
Biological Effects to activation of CaSR causing activation of downstream
PTH/PTHrP-receptor (PTHR1) binds both PTH and parathyroid signaling pathway leading to decrease in PTH secretion.
hormone-related protein (PTHrP) and is primarily coupled to Heterozygous and homozygous inactivating mutations in
Gs, and via this heterotrimeric G protein activates adenylyl CaSR cause familial hypocalciuric hypercalcaemia (FHH) and
cyclase. PTHR1 is expressed on osteoblasts in bone and neonatal severe hyperparathyroidism respectively. In these
proximal and distal tubules of the kidney. A second PTH receptor, patients, CaSR fails to inhibit PTH secretion in hypercalcaemia
which can be activated by PTH but not by PTHrP, called the PTH2 because of defective calcium sensing in parathyroid and
receptor (PTH2R), is expressed in multiple tissues including also inappropriate hypocalciuria occurs in presence of
brain, vascular endothelium and smooth muscle, endocrine cells hypercalcaemia because of defective calcium sensing at renal
of the gastrointestinal tract, and sperm. The functional role of level. Conversely, activating mutations in CaSR cause familial
the PTH2R is not clearly known. hypoparathyroidism with hypercalciuria. 1,25(OH)2D has no
direct effect on PTH secretion, but it dramatically suppresses
PTH has multiple actions on bone, some direct and some
PTH gene transcription. In hypomagnesaemia, in addition to
indirect. PTHR1 is expressed on osteoblasts, but not on
impaired responsiveness of target tissues to PTH action, PTH
osteoclasts.Therefore, PTH stimulates osteoblast activity directly,
secretion is decreased.
whereas osteoclasts are stimulated indirectly through paracrine
factors secreted by osteoblasts. PTH-mediated bone calcium Parathyroid Hormone-Related Protein
release can occur within minutes. The chronic effects of PTH Parathyroid hormone-related protein (PTHrP) is peptide with
are to increase number of osteoblasts and osteoclasts, and PTH like activity. PTHrP and PTH have marked homology at their
to increase in bone remodelling. As PTH can increase both amino terminal ends and they both bind to the PTH1R, yet their
bone formation and bone resorption, net effect on bone mass physiologic effects are very different. PTHrP is primarily an
varies according to whether PTH is administered continuously autocrine or paracrine factor, acting close to where it is produced.
or intermittently, and also on type of bone. When PTH Other than important function during breast development
concentrations are persistently elevated like in primary and systemic calcium metabolism during lactation, it is also
hyperparathyroidism, significant bone loss occurs mainly in involved in Ca2+ transport in the placenta. Normally it appears to
cortical bone with subperiosteal resorption, formation of bone have little influence on calcium-phosphate homeostasis in an
cysts and spontaneous fractures. However, intermittent adult. However, secretion of PTHrP by a wide variety of tumors
administration of low doses of PTH causes net increase in bone contributes to the humoral hypercalcaemia of malignancy by
formation and increase in trabecular bone mass, with little effect mimicking the systemic action of PTH.
on cortical bone mass and this concept has been utilised as
use of PTH as anabolic therapy in patient with osteoporosis. VITAMIN D
PTH has two major effects on the kidney: to increase calcium Structure and Biosynthesis
reabsorption in the distal nephron and to decrease proximal Although initially discovered as a fat-soluble vitamin, vitamin
tubular reabsorption of phosphate. Calcium excretion depends D is a classical steroid hormone having both dietary and
both on the amount of calcium which reaches the distal tubule endogenous precursors. Vitamin D3, cholecalciferol, is formed
and on the concentration of circulating PTH. In hypercalcaemia, by solar ultraviolet B radiation (wavelength, 290-315 nm) of
the filtered load of calcium increases so that more calcium is precursor 7-dehydrocholesterol in skin, which is present in large
delivered to the distal tubule. In hyperparathyroidism, PTH amounts in keratinocytes of the basal or spinous epidermal
increases fractional reabsorption of calcium, but because of the layers (Figure 3). Adequate exposure to UV light is necessary,
large calcium load delivered, hypercalciuria results. PTH with more exposure being required for darker skinned races.
decreases proximal tubular reabsorption of phosphate, so that Ergocalciferol, vitamin D2 is the compound formed in plants
296 increased urinary excretion of phosphate occurs. Sustained from precursor ergosterol and differs from vitamin D3 by the
 Bone and Mineral Metabolism in Health and Disease
the retinoid receptor and binds to a vitamin D responsive
element on responsive genes and followed by their
transcription and translation. Recently, it has been
demonstrated that other than these genomic actions, vitamin
D may have certain nongenomic actions, and may work through
a plasma membrane receptor and second messengers such
as MAP kinase or cAMP. The intestine is the principal target
for 1,25(OH) 2D, where it enhances calcium and phosphate
absorption as discussed above. Bone is the second major target
for vitamin D. By increasing intestinal absorption of calcium
and phosphate, vitamin D provides sufficient calcium and
phosphate to initiate the crystallisation process at bone
surfaces. l,25(OH)2D also directly affects bone cells to facilitate
mineralisation even without measurable changes in the
plasma concentrations of calcium and phosphate. Vitamin D
Figure 3: Biosynthesis of 1,25(OH)2D .
deficiency is characterised by defective mineralisation of
bone osteoid. Vitamin D receptor (VDR) are expressed on
presence of a double bond between carbon 22 and 23 and a parathyroid cells and 1,25(OH) 2D inhibits the transcriptional
methyl group at carbon 24. Best dietary sources of vitamin D activity of PTH gene and prevents proliferation of parathyroid
are fatty fish and its liver oils, although small amount is present gland. In recent years, there has been great interest in the role
in egg yolk and dairy products. Both vitamin D2 and D3 are of vitamin D in non-classical actions like decreasing the risk
prohormones and require subsequent modification to yield of many chronic illnesses, including autoimmune diseases like
active hormone. As hormones derived from either vitamin D2 multiple sclerosis and Type 1 diabetes, infectious diseases,
or D3 are equally active in man, the generic term vitamin D is cardiovascular disease and even common malignancies. Brain,
generally used. In the liver, vitamin D is hydroxylated at C-25 by prostate, breast and colon tissues, among others, as well as
cytochrome P450 vitamin D 25-hydroxylases, resulting in the immune cells, have a vitamin D receptor. 1,25(OH) 2D has been
formation of 25-hydroxyvitamin D [25(OH)D]. In the proximal found to have potent immunomodulator action, inhibits
renal tubule, 25(OH)D is further hydroxylated, resulting in the renin synthesis, increases insulin production and increases
hormonally active 1,25-dihydroxyvitamin D (1,25(OH)2D), which myocardial contractility. Table 2 summarises the major
is responsible for most of the biologic actions of vitamin D. In biological actions of PTH and 1,25(OH)2D, in relation to calcium
addition to 1,25(OH)2D, the kidney can also produce 24,25- and phosphate homeostasis.
dihydroxyvitamin D3 (24,25(OH) 2D), a relatively inactive
metabolite. Human vitamin D binding protein (DBP) is a 52 kd Table 2: Actions of PTH and 1,25(OH)2D on Calcium/Phosphate
α globulin synthesised in the liver. Approximately 88% 25- Homeostasis
hydroxyvitamin D (25(OH)D) circulates bound to DBP, 0.03% is Hormone Small Bone Kidney Parathyroid
free and the rest circulates bound to albumin. In contrast, 85% intestine gland
of the circulating 1,25(OH)2D3 binds to the vitamin D binding PTH No direct Promotes Stimulates No direct
protein, 0.4% is free and the rest binds to albumin. action osteoblastic 1α hydroxylase action
growth and Stimulates
The most plentiful and stable metabolite of vitamin D is 25(OH)D survival Ca2+ reabsorption
and 25(OH)D level in the serum is the best indicator of vitamin
Chronic Inhibits
D status in an individual. A 25(OH)D level of 30 ng/ml (75 nmol/ high levels phosphate
L) or greater is considered indicating sufficient vitamin D for an promotes reabsorption
individual. Vitamin D deficiency is defined as a 25(OH)D level bone
less than 20 ng/ml (50 nmol/L), while a level between 20 ng/ml resorption
and 29 ng/ml is considered to indicate a relative insufficiency. 1,25(OH)2D Increases Sensitises Increases Directly
Reports from across the world in last decade indicate that Ca2+ and osteoblasts phosphate inhibits
vitamin D deficiency and insufficiency is widespread and is re- phosphate to PTH reabsorption PTH gene
absorption expression
emerging as a major health problem globally. Regulates Minimal
Regulation of 1,25(OH)2D Formation osteoid effect on Ca2+
production reabsorption
The renal 1α(OH)ase represents a key target of vitamin D and
regulation. Low dietary calcium and phosphate result in calcification
enhanced activity of 1α(OH)ase. Elevated PTH resulting from
hypocalcemia is a primary signal stimulating the transcription CALCITONIN
of 1α(OH)ase. The 1α(OH)ase gene is negatively regulated
Structure and Biosynthesis
by 1,25(OH)2D and fibroblast growth factor 23 (FGF23), a
phosphaturic factor. Calcitonin is a 32-amino acid polypeptide, whose two major
biological effects are to lower serum calcium and phosphate. It is
Biological Effects synthesised by the parafollicular cells of the thyroid gland, also
The active metabolite 1,25(OH)2D enters the cell and binds to known as the clear or C cells, which originate from the neural
the vitamin D receptor. This complex forms a heterodimer with crest. It has a circulatory half-life of about 10 minutes. Interestingly, 297
 salmon calcitonin is 10 to 100 times more potent than concentrations remain normal. In addition, it has a central
mammalian hormone and is the one that is used therapeutically. analgesic effect, directly in cells of hypothalamus and related
structures. Calcitonin is used in treatment of bone disorders
Regulation of Synthesis and Secretion
associated with accelerated rate of bone turnover like
Synthesis and secretion of calcitonin is controlled by the Paget’s disease and osteoporosis, and in the treatment of
concentration of ionised serum calcium. The stimulus for hypercalcaemia of malignancy. Calcitonin can serve as a tumour
calcitonin synthesis is thus opposite to that for PTH secretion. marker in medullary carcinoma of the thyroid as well as other
Thus, its secretion is increased, when ionised serum calcium tumours, including insulinomas, VIPomas and lung cancers,
rises and vice versa. The calcium-sensing receptor cloned
which can secrete calcitonin ectopically. In addition, high
initially from parathyroid cells is also expressed in C cells and it
molecular weight forms of calcitonin may be elevated in acute
contributes to the regulation of calcitonin secretion.
pancreatitis, burns and infections.
Biological Effects
Calcitonin reduces bone resorption by inhibiting osteoclast RECOMMENDED READINGS
function, through its receptors on these cells. Thus it has a direct 1. Bergwitz C, Juppner H. Regulation of phosphate homeostasis by PTH,
action on osteoclasts in contrast to PTH, whose effects are vitamin D, and FGF23. Ann Rev Med. 2010; 61: 91-104.
mediated through osteoblasts. In spite of the reproducible 2. Clarke B. Normal bone anatomy and physiology. Clin J Am Soc Nephrol. 2008;
effects of calcitonin on bone and serum mineral content, the 3: S131-9.
hormone does not appear to be a major physiological regulator. 3. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266-81.
After removal of the thyroid-containing C cells and documented 4. Peacock M. Calcium metabolism in health and disease. Clin J Am Soc Nephrol.
calcitonin deficiency or after development of medullary thyroid 2010; 5: S23-30.
carcinoma, a neoplasm of C cell origin which results in markedly 5. Potts JT. Parathyroid hormone: past and present. Journal of Endocrinology.
elevated calcitonin production, serum calcium and phosphate 2005; 187: 311-25.

298
 8.2 Investigations and Diagnosis
of Bone Disorders
Sukumar Mukherjee

Bone is a highly dynamic tissue. About 70% of all bone mass Bone markers are reliable indicators of therapeutic success as
contains inorganic material (calcium and phosphates) and 30% early as three months after start of therapy. PINP (propeptide
is of organic material (collagen and osteocalcin). Remodelling of type I procollagen) is the marker of osteoblastic activity
is a continuous process involving bone resorption and bone for bone formation. The normal value is 26-110 microgram/L.
formation. The evaluation and diagnosis of metabolic bone Osteocalcin is a bone turnover marker and useful for therapy
disorders require the systematic elucidation of clinical history adherence and drug efficacy in bone diseases.
and thorough physical examination of musculo-skeletal
Serum Calcium
system and other extra-skeletal features. The characteristics
of bone pain, muscular weakness, anaemia, posture of In circulation, the calcium is present in three forms namely
the patient and deformities, linear-height, check-list of ionised calcium (48% to 50%), protein-bound fraction (40%) and
drug consumption and pre-existent risk factors need to be rest as complex calcium. The estimated normal value of calcium
stressed; however, laboratory and radiological workup are is around 9 to 10.6 mg/dL and because of diurnal variation, it
usually necessary to clinch a diagnosis, even in early and reaches its peak value in mid-day and nadir in early morning. It
asymptomatic stage of illness. is essential to correct serum calcium values to serum albumin
levels as per formula.
The laboratory aids for diagnosis and assessment are many but
each one of them needs tailoring on the background of clinical Free Serum Calcium
information and risk factors assessment. These tests are: Serum calcium (mg/dL) + [4 – serum albumin (gm%) × 0.8]. It is
I. Bone mineral profile advisable to avoid tourniquet while drawing blood for serum
II. Calcitropic hormone profile calcium estimation irrespective of fasting or non-fasting state.
III. Imaging Ionised Calcium
IV. Bone biopsy and histomorphometry It comprises 48% to 50% of total serum calcium, and is primarily
responsible for physiological functions like muscle contraction,
BONE MINERAL PROFILE
coagulation and bone mineralisation. The normal value of
The bone mass of women declines earlier than in men. Men ionised calcium is around 4.5 to 5.2 mg/dL in fasting state (1.12
have 30% to 50% more bone mass and are far less osteoporotic to 1.3 micromoles/L) with maximum at 10.00 hours and
than woman. Preliminary workup consists of measurement minimum at 18.00 to 20.00 hours. In heparinised samples,
of serum calcium, phosphorus, magnesium and alkaline binding of calcium with heparin leads to low ionised calcium
phosphatase. The newer biochemical markers (bone level. The significance of ionised calcium is of value in critical
markers) are classified depending upon their role on bone care patients with low albumin, altered acid-base balance and
formation or bone resorption as in Table 1. following massive blood transfusion.
Table 1: Newer Biochemical Markers of Bone Formation and The clinical disorders with hypercalcaemia and hypocalcaemia
Bone Resorption are mentioned as in Tables 2 and 3.
Bone Formation Bone Resorption
Table 2: Clinical Disorders with Hypercalcaemia
Bone specific alkaline Urinary deoxypyridinoline (DPD)
Hyperparathyroidism – Primary, tertiary
phosphatase
Prolonged immobilisation
Osteocalcin Urinary N-telopeptide (NTX)
Renal failure, Milk-alkali syndrome
N - terminal propeptide of Serum C-terminal telopeptide (CTX)
Malignancies – Lung, Breast, Kidneys, Myeloma, Lymphoma
type 1 procollagen (PINP) or β cross laps
Endocrine – Thyrotoxicosis, Addison’s disease, Pancreatic islet
cell tumour
These biochemical markers are sometimes useful in monitoring Granulomas – Tuberculosis, Sarcoidosis
the response to treatment. They assess the risk for fracture in Drugs – Vitamin D toxicity, Lithium, Thiazides, Foscarnet and
the stage of osteopaenia earlier than osteoporosis. The urinary Aluminium toxicity
NTX excretion, an indicator of bone resorption is to be
determined on the second morning voiding, to predict early Table 3: Clinical Disorders with Hypocalcaemia
response to anti-resorptive therapy when compared to bone
Hypoparathyroidism, pseudohypoparathyroidism
mineral density (BMD) follow-up every 1-2 years. The fall of NTX
value by 35% from baseline is characteristic of effective anti- Vitamin D deficiency – Nutritional, malabsorption, renal diseases
resorptive therapy. The resorption markers are also useful to Drugs – Anti-convulsants (phenytoin and phenobarbitone),
identify patients with high risk of developing fractures. However, doxorubicin, bisphosphonates, cisplatin, calcitonin
the limited availability of these newer markers are major Miscellaneous – Acute pancreatitis, tumour lysis syndrome,
acute severe illness, toxic shock syndrome 299
hindrance towards their regular use in daily clinical practice.
 Serum Phosphate —a marker of osteoblastic activity is raised in Paget’s disease
Out of total phosphorus in plasma, inorganic phosphate or of bones, metastatic bone disease, osteomalacia, osteoporosis.
phosphorus constitutes 1/3 fraction, the measurement of which However, it is important to exclude hepatobiliary disease where
is clinically useful for assessment of metabolic bone disorders. ALP level is also high, especially in patients with cholestasis.
The normal range of inorganic phosphate is 2.5-4.5 mg/dL with The bone specific alkaline phosphatase fraction has better
higher values in elderly male and postmenopausal women. The predictive value in evaluating bone disorders.
inorganic phosphate is 20% protein bound and rest is free ionic
CALCITROPIC HORMONE PROFILE
form.The serum phosphorus level is higher in infants and children.
Serum phosphorus level is measured by spectrophotometry from Parathyroid Hormone (PTH)
fasting plasma sample. The best index of phosphorus excretion The major 84-amino acid polypeptide hormone from parathyroid
is the maximal tubular reabsorption of phosphorus expressed glands is metabolised in liver and present as intact PTH (iPTH)
as a function of GFR or TmP/GFR. This is decreased in primary in circulation. PTH is measured by radioimmunoassay and the
hyperparathyroidism. normal value ranges from 10-55 pg/mL (1-6.1 picomol/L). The
The clinical disorders associated with hyperphosphataemia and sample for PTH assay is stored at –4oC and should be transported
hypophosphataemia are listed below in Tables 4 and 5. to laboratory in ice and centrifuged as early as possible and
kept at –20oC or lower. The iPTH assay is indicated in: (a) to
Table 4: Clinical Disorders Associated with Hyperphosphataemia distinguish between PTH dependent versus PTH independent
causes of hypercalcaemia; (b) to find out the cause of
Disorders Mechanism
hypocalcaemia; (c) to evaluate Paget’s disease and in
Acute and chronic renal failure Poor renal excretion hypophosphatemic rickets where iPTH level is normal.
Hypoparathyroidism
Pseudohypoparathyroidism Parathyroid Hormone-Related Protein (PTHrP)
Bisphosphonate therapy The PTH-related peptide (PTHrP) is mainly significant in
Hypothermia Intracellular to extracellular hypercalcaemia of malignancy. On the other hand, PTHrP
Acidosis shift of phosphorus levels are essentially normal in primary hyperparathyroidism
Rhabdomyolysis and non-malignant causes of hypercalcaemia. This is measured
Haemolysis
by two-site isotopic immunoassay (IRMA) or by ELISA method.
Table 5: Clinical Disorders Associated with Hypophosphataemia Calcitonin
Disorders Mechanism This 32-amino acid polypeptide is secreted by the parafollicular
or C-cells of thyroid gland. It reduces bone resorption by
Hyperparathyroidism Increased renal excretion
inhibiting osteoclastic activity; and also reduces tubular
Hypovitaminosis D
resorption of both calcium and phosphorus and hence it has
Alcoholism
Renal tubular acidosis
hypocalcaemic effect. Its estimation is useful in the diagnosis
of hypercalcitoninaemia and medullary carcinoma of thyroid.
Respiratory alkalosis Extracellular to intracellular
The normal value is less than 0.08 microgram/L. The provocative
Sepsis shift of phosphorus
Recovery from diabetic ketoacidosis tests for calcitonin estimation are done with calcium infusion
Salicylate toxicity and pentagastrin stimulation; calcitonin is the only hormone
to actively lower serum calcium.
Diuretics Drug related adverse effect
Steroids Vitamin D and Metabolites
Calcitonin
Both vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol)
Beta agonists
are prohormones and are inert until activated in the liver and
Malabsorption Diminished intestinal
kidney through sequential hydroxylation. The major transport
Antacid abuse absorption of phosphates
form of vitamin D is 25(OH)D (calcidiol) hydroxylated in liver
Vitamin D deficiency
and its circulating concentration reflects nutritional status of
vitamin D. This is further hydroxylated in kidney to produce the
Serum Magnesium
active form of the hormone 1, 25 dihydroxy D (Calcitriol).
Magnesium is present mostly in ionised form (55%), protein
bound (30%) and rest in complex form. The normal value of In clinical disorders with vitamin D deficiency or excess the best
serum magnesium is 1.7 to 2.6 mg/dL. The hypomagnesemia is method for assessing vitamin D status is measurement of serum
observed in metabolic acidosis, prolonged diuretic therapy, 25(OH)D level and its normal value is between 8 and 50 ng/mL
by RIA. The levels of 25(OH)D reflect the body stores of vitamin D
prolonged nasogastric aspiration, hypoparathyroidism, acute
more accurately than 1,25(OH)2D. The level rises in summer and
pancreatitis, extensive bowel resection. Increase in serum
declines in winter and more so in elderly.
magnesium level is seen in haemolysis. Severe and prolonged
hypomagnesemia inhibits parathyroid hormone (PTH) release Estimation of 25(OH)D is indicated in vitamin D deficiency/toxicity
and induces resistance to PTH action on bones. and in some subsets of hypercalcaemia with low PTH level. The
value is low in clinical osteomalacia and subclinical vitamin D
Serum Alkaline Phosphatase deficiency states. The cut-off value for overt osteomalacia is less
The normal value in adults is 40-150 IU/L and in children than 5 ng/mL whereas values less than 15 ng/mL is suggestive
11-306 IU/L. The bone specific serum alkaline phosphatase (ALP) of subclinical deficiency. The estimated values also vary
300
 Investigations and Diagnosis of Bone Disorders
periodically with the quality of diet and duration of sun exposure
in an individual.In patients with vitamin D toxicity serum 25(OH)D
level is high along with hypercalcaemia but low PTH level.
The measurement of most biologically active form serum
1,25(OH) 2D (normal value 20-60 pg/mL) is indicated in
hypercalcaemic states with normal iPTH, PTHrP and 25(OH)D,
e.g. sarcoidosis, lymphoma and William’s syndrome.

IMAGING
Standard Radiographs in Metabolic Bone Disease
This remains a useful and simple modality for the diagnosis of
metabolic bone diseasae. The regions of the skeleton meant for
diagnostic radiology are skull (lateral view), thoraco-lumbar spine
(lateral view), pelvis with both hips (AP view), hands (AP view)
and long bones (AP and lateral). Mostly conventional radiology
is indicated in Paget’s disease, primary hyperparathyroidism, Figure 1: Paget’s disease of skull.
osteomalacia, osteoporosis, fluorosis and osteosclerosis. However,
the standard x-rays are unable to pick up decreased bone mass
until there is 40% to 50% reduction of bone mass. However,
these X-rays are useful to pick up compression fractures and
other minimal injury fractures. The characteristic features are
summarised as in Table 6 (Figures 1 to 5).

Table 6: Summary of Characteristic Radiological Features in

Common Disorders
Disease Radiological Anatomical
features areas
Paget’s disease Cortical thickening, areas Femur, skull, tibia,
(Figure 1) of sclerosis and lucencies, pelvis and spine
bowing of legs and
kyphosis of spine
Primary Subperiosteal resorption, Radial border of
hyper- osteitis fibrosa cystica middle phalanges
parathyroidism pathological fractures, long bones, Figure 2: Bone cyst left femur in primary hyperparathyroidism.
(Figure 2) tufting of distal phalanges femoral neck, distal
and salt and pepper skull clavicle, skull
Osteomalacia Symmetrical pseudo- Pubic rami, ribs,
(Figures 3 and 4) fractures or Looser’s scapula, femoral
zones demineralisation, neck shafts of
deformities, radiological long bones
features
Osteoporosis Demineralisation, Thoraco-lumbar
thin cortex, prominent spine, pelvis with
trabecular lines, femoral neck and
spinal deformities wrists
and stress fractures
Fluorosis Diffuse osteosclerosis Long bones, pelvis
(Figure 5) interosseous membrane
calcification
Osteosclerosis Diffuse thickening of Spine, long bones
(Renal osteody- cortices with gradual
strophy, bone obliteration of medulla
metastasis
and hyper- Figure 3: Pseudofracture or Looser’s zone in osteomalacia.
vitaminosis
A and D) accumulation of radioactive material in areas of bone
depending upon blood flow and osteoblastic activity. The
Bone Scan or Scintigraphy imaging is done with radioactive diphosphonates (DPN)
The principle behind metabolic bone scan is functional labelled with technetium 99m. The bone scan is diagnostic in
mapping of bone turnover and essentially it consists of bone metastasis and vertebral fractures which are not always 301
 hypertension and risk of stroke. It is estimated that 10%
reduction of BMD doubles the risk of fracture.
There are number of methods to assess the BMD in a given
individual which are mentioned in Table 7.

Table 7: Methodologies of BMD Measurement

Method Common Anatomical Sites

Plain X-ray Phalanges (hands)

Thoracolumbar spine
Single energy X-ray absorptiometry (SXA) Calcaneum, Radius/ulna
Dual energy X-ray absorptiometry (DEXA) Lumbar spine
Proximal femur
Forearm
Quantitative computed tomography (QCT) Lumbar spine
Broadband ultrasound attenuation (BUA) Calcaneum, tibia
Figure 4: Pseudofracture in right pubic ramus in osteomalacia.
Out of all these modalities, DEXA is more accurate and
consistent when compared with other methods.
The BMD measurement is recommended in several clinical states
according to sex and age of the individuals as below in Table 8.

Table 8: Indications for BMD Measurement

1. Premenopausal women (Caucasian or Asian)
(a) Long-term therapy with steroids, thyroxine, heparin
(b) Primary or secondary amenorrhoea
(c) Post-oophorectomy, organ transplantation
(d) Malabsorption, chronic renal failure, hyperparathyroidism
2. Postmenopausal women
(a) Patients not on oestrogen therapy
(b) Vertebral or hip deformities or fractures plus premenopausal
indications as above
3. Men
(a) Hypogonadism
(b) Unexplained fractures
(c) Recurrent falls

Interpretation of BMD Measurement

The BMD reports express the standard deviation from the mean
Figure 5: Fluorosis of spine bone mass of normal 30-year-old young adults as the ‘T’ score
and standard deviation from age and sex matched control as
characteristic in conventional radiology (Figure 6). The ‘hot the ‘Z’ score.
spots’ of vertebral fractures have time frame of two weeks to WHO has established the following BMD-based diagnostic
twelve months after the onset of fracture. criteria for women:
The metabolic ‘superscan’ with increased uptake in long bones,  Normal—a BMD value within 1 (one) SD of the young adult
axial skeleton, skull, mandible is quite characteristic in primary mean.
hyperparathyroidism and renal osteodystrophy with secondary  Osteopaenia—a BMD value more than 1 (one) SD but less
hyperparathyroidism. But this is negative in hypercalcaemia than 2.5 SD below the young adult mean.
of malignancy. Bone scan is invaluable in Paget’s disease for  Osteoporosis—a BMD value of 2.5 SD or more below the
diagnosis and extent of disease; similarly it is useful to pick up young adult mean.
Looser’s zones in osteomalacia.  Established or severe osteoporosis—a BMD value 2.5 SD or
Bone Densitometry more below the young adult mean with one or more
fragility fractures.
The reduced bone mineral density (BMD) is the ‘gold standard’
for diagnosis with osteoporosis, yardstick of bone fragility Bone markers do not replace BMD, but are complimentary tools
and consequent risk of fracture. The correlation of BMD with as they provide information about the rate of bone loss and
risk of fracture is strong and sustained and comparable to not the patients’ current bone mineral density.
302
 Investigations and Diagnosis of Bone Disorders
Plain X-ray Single Energy X-ray or Photon Absorptiometry (SXA)
It is insensitive to measure bone loss unless 30% to 50% of bone In this method the photon source is the digital X-ray system.
density has been lost. However, it is good to pick up fractures. The sites measured are the distal (90% cortical) and ultradistal
(65% trabecular bone) radius of the forearm in prone position.
However, it is inadequate to reflect the bone loss of BMD
measurement.
Dual Energy X-ray Absorptiometry (DXA or DEXA)
(Figure 7)
It is the gold standard for the diagnosis and monitoring treatment
of patients with osteopaenia and osteoporosis. The sites
commonly chosen are PA and lateral lumbar spine, hip, forearm
and whole body. The positioning of femoral neck is critical to
maintain good precision. The follow-up DXA after treatment is
advisable after 1-2 years. Because of cost and non-availability of
portable machines, its liberal use is somewhat limited.
Quantitative Ultrasound (QUS)
This method is portable, without any radiation risk which
provides information both about bone quality and trabecular
connectivity unlike DXA.The broadband ultrasonic attenuation
(BUA) describes the increase in ultrasound attenuation and may
be used for determination of bone density of calcaneum. The
precision of this method is modest and the standardisation and
quality control remains controversial. However, it can be utilised
for community screening.
Quantitative Computed Tomography (QCT)
It takes the cross-sectional image of the vertebra and measures
trabecular component in T 12 to L4 using regular CT scanner.
Figure 6: Bone metastasis in prostatic carcinoma in bone scintigraphy.
Besides, volumetric QCT improves the spinal measurement.

Figure 7: DEXA scan of right femur neck in osteoporosis.

303
 The peripheral QCT gives higher spatial resolution which study is useful in follow-up of drug trial and other research
renders superior-modality when compared with other purposes.
techniques.
Lastly, in disease specific states with bone disorders additional
Magnetic Resonance Imaging (MRI) tests may be carried out like serum protein electrophoresis,
This is also valuable to recognise trabecular pattern more renal profile, serum thyroid hormones, cortisol, gonadal
precisely but it is not cost effective for regular use. hormonal profile, genetic study on individual basis to settle the
comprehensive diagnosis.
BONE BIOPSY AND HISTOMORPHOMETRY
Bone biopsy is hardly indicated in metabolic bone disorders RECOMMENDED READINGS
for diagnosis. In difficult situations of osteoporosis or 1. Favus MJ. Primer on the Metabolic Bone Disorders of Mineral Metabolism;
osteomalacia of undetermined origin, it may be attempted to 4th Ed. Philadelphia: Lippincott, Williams and Wilkins; 1999.
study the bone architecture under microscope with special 2. Mittal A. Investigation and diagnosis of bone disorder. API Textbook of
Medicine; 7th Ed; 2003: pp 1206-10.
histomorphometry. The biopsy is done through transilial
3. Teotia SPS, Teotia M, Singh KP. Metabolic bone diseases: changing
approach on anterior superior iliac spine and processed in an perception. In: Thakur BB, editor Post Graduate Medicine. (APICON 2002 API,
undecalcified state prior to histologic evaluation. Rarely biopsy Vol 16; 501-14).

304
 8.3 Rickets and Osteomalacia

Bindu Kulshreshtha, Sachin K Jain

OSTEOMALACIA AND VITAMIN D DEFICIENCY IN INDIA regulated by PTH. 1,25 dihydroxy vitamin D enhances calcium
A large amount of literature is available indicating a widespread and phosphorus absorption from the intestine. Reduction in
occurrence of vitamin D deficiency, osteopaenia and osteoporosis the absorption of calcium in vitamin D deficiency and the
among Indians. Studies from India have reported a high prevalence resulting hypocalcaemia stimulates parathyroid glands to
(84% to 90%) of hypovitaminosis D among healthy Indians across increase PTH secretion. PTH acts on osteoclasts to mediate
all age groups including pregnant population. Genetic factors resorption of the bone. At the renal level, PTH facilitates
are also believed to play a role in causation of osteomalacia. calcium reabsorption and phosphorus excretion through the
tubules. PTH also stimulates the renal conversion of 25 hydroxy
Osteomalacia and rickets are widely prevalent in India. Due to vitamin D to 1,25 dihydroxy vitamin D which in turn stimulates
widespread occurrence of 25(OH)D deficiency, 25(OH)D levels more calcium and phosphorus absorption from the gut.
may not be considered the hallmark for diagnosing osteomalacia Histopathology of osteomalacic bone shows an incompletely
in Indian population. Also, financial constraints and lack of mineralised osteoid, an increase in the osteoid volume and
laboratory support make it difficult to get the 25 hydroxy thickness and a decrease in the calcification or mineralisation front.
vitamin D and parathormone (PTH) levels in all patients. Instead,
an integrated approach taking into consideration the Osteomalacia and rickets are disorders characterised by
socioeconomic background and history, serum biochemistry and defective mineralisation of the bony matrix. Rickets occurs in
24-hour urinary calcium estimation can help in the diagnosis. the growing skeleton of children and both the long bones and
the cartilaginous matrix of the growth plate are involved.
AETIOPATHOGENESIS Osteomalacia is defective matrix mineralisation of the bones in
Vitamin D is the major steroid hormone involved in bone adults, in whom the epiphyseal bony fusion has occurred. The
mineral homeostasis. The sources of calcium include milk and most common cause of these diseases in Indian population
milk products like butter, ghee, curd and animal products like remains nutritional vitamin D deficiency. Inadequate sunlight
eggs and meat. Vegetable sources of calcium include pulses due to purdah as practiced by Muslim women coupled with
and gram. Some fruits like coconut, apricot, guava, banana borderline vitamin D reserves could also result in osteomalacia.
and pumpkin are also rich in calcium. Though not regularly Other causes are enlisted in Table 1. Another common disorder
calculated, spices are also rich source of calcium with dhaniya, in India is fluorosis. Excess fluoride mainly from water sources
asafoetida, cloves, coriander and cumin seeds accounting for interferes with mineralisation of hydroxyapatite in bone.
about 100 mg of daily calcium intake among Indians.
Table 1: Aetiologic Profile of Osteomalacia
Sunlight is a good source of vitamin D. Vitamin D is naturally
Vitamin D deficiency Inadequate dietary intake
obtained in the animal products like cod liver oil and fish liver Malabsorption
oil. Other sources are meat, fish, eggs and milk. Thus, there is Impaired cutaneous production
a tendency for vitamin D deficiency in pure vegetarians. Impaired 25 hydroxylation Liver disease
Activation of inactive vitamin D to its active vitamin D3 form Drugs like isoniazid
occurs under the influence of ultraviolet light. This activation ? Inherited mutation of 25 alpha
may be prevented by melanin in the skin which explains hydroxylase
occurrence of vitamin D deficiency in dark skinned individuals. Impaired 1-alpha Renal failure
The first step in the activation of vitamin D is 25 hydroxylation hydroxylation Renal tubular disorders, Fluorosis
in the liver followed by 1-alpha hydroxylation in the kidney. Vitamin D dependent rickets type 1
The active 1,25 dihydroxy vitamin D exerts its effects by Oncogenic osteomalacia
binding to the vitamin D receptor, a member of steroid/ X-linked hypophosphatemic rickets
thyroid hormone superfamily. The major actions of vitamin D Accelerated vitamin D Drugs, like phenobarbitone, primidone,
metabolism phenytoin, rifampin, glutethimide
include mineralisation of the bony matrix and growth
Vitamin D resistance Vitamin D dependent rickets type II
plates. It is also known to have immunomodulatory and anti-
(receptor mutation)
proliferative effects. The absence of biologic effects of vitamin
D could be due to a lack of dietary intake, deficient production
Vitamin D dependent rickets type I (VDDR I) is a rare genetic
of active form of vitamin D in the skin, impaired vitamin D
disorder of mutation in the 1-alpha hydroxylase gene inherited
activation or resistance to the biologic effects of 1,25 dihydroxy
in autosomal recessive fashion.Vitamin D dependent rickets type
vitamin D.
II (VDDR II), another inborn error of metabolism inherited in an
For skeletal mineralisation, adequate calcium and phosphate autosomal recessive fashion, is due to mutations of the vitamin D
must be present at mineralisation sites. Calcium levels in the receptor and is characterised by alopecia, vitamin D deficiency
blood are regulated by vitamin D mediated absorption from and lack of response to the conventional doses of vitamin D.
the gut and resorption of calcium from the bone that is Oncogenous osteomalacia is another rare cause of osteomalacia 305
 where phosphaturic factor is secreted by tumours (usually of the
mesenchymal origin) resulting in deficient mineralisation.
Calcipenic Rickets
Decrease in calcium intake or decrease in the intestinal calcium
has also been associated with rickets. Such cases were reported
from South Africa, also from India where children consumed
no milk or dairy products and the intake of calcium was
estimated to be less than 200 mg. Consumption of cereals and
grain products high in phytate could lead to formation of
intraluminal calcium phytate complexes and consequent
calcium malabsorption. Other features and biochemistry is
similar to vitamin D deficiency rickets except for 25 hydroxy
vitamin D levels which are normal.

Clinical Features
Clinical signs may differ according to the age at presentation.
Infants may present with hypotonia, feeding difficulties, irritability,
or hypocalcaemic seizures. Clinical signs in infants include
craniotabes (softened calvaria), widened fontanelle, frontal
bossing, hypotonia, divarication of the recti and umbilical hernia.
As the disorder progresses, the child finds increasing difficulty
in walking and a progressive proximal muscle weakness.
Pathological fractures may occur, growth is stunted. In children,
the weight bearing joints may present with bowing deformities
(genu valgum and varum) and wrist widening. Prominence of
the costochondral junction (also known as rachitic rosary and
indentation of the lower ribs (Harrison’s groove) due to softening
of skeleton may be present. Dentition is delayed and enamel
hypoplasia may occur. Deformity of the back including kyphosis
and lordosis along with limb bowing (Figure 1) can contribute
to waddling gait. Patients with VDDR I and VDDR II usually present
during infancy or childhood. Those with VDDR II also present with
alopecia, multiple milia and epidermal cysts, milder defect could
present during adolescence also. Figure 1: Spinal, wrist and foot deformities in a child with rickets.

Adult patients with vitamin D deficiency may be asymptomatic

or present with varying degrees of bony aches along with features
of proximal muscle weakness. History of repeated fractures even
on trivial trauma may be present. In severe cases, long bones may
show bowing deformities (Figure 2). Seizures in adults due to
hypocalcaemia caused by vitamin D deficiency are extremely rare.
This is possibly due to PTH excess which prevents extreme decline
in calcium levels and a relative metabolic alkalosis (PTH effect).
Axial osteomalacia and resulting microfractures of the vertebrae
may cause loss of the adult height. Rib involvement could result
in a deformed chest. Enthesopathy and ligamentous calcification
as occurs in X-linked hypophosphatemic osteomalacia or
fluorosis could result in joint stiffness.
Investigations
Routine investigations including haemogram, renal function
tests, liver function tests and urine routine examination
are important to rule out a systemic cause of metabolic
bone disease. The basic investigation for a metabolic bone
disease work-up includes calcium, phosphorus and alkaline
phosphatase, 24-hour urinary calcium and fractional excretion
of phosphorus as assessed by tubular reabsorption of
phosphorus (TRP) and TmpGFR. Serum albumin is also needed
to make appropriate corrections for the serum calcium level. A
24-hour urinary creatinine is also needed along with 24-hour
Figure 2: Photograph showing bowing of lower limbs.
306 urinary calcium to assess for adequacy of urine collection.
 Rickets and Osteomalacia
In osteomalacia, serum calcium levels are low to normal, ligamentous joints is usually seen with fluorosis. Rarely, patients
phosphorus levels are low and alkaline phosphatase is high. In with fluorosis may masquerade as ankylosing spondylitis.
the initial stages, phosphorus levels may be low and normal Figure 4 shows a female with florid osteomalacia and
calcium levels due to secondary hyperparathyroidism. A 24-hour hypocalcaemic tetany in Figure 5.
urinary calcium level in patients with osteomalacia is low (normal
calcium excretion is 2.5 to 4 mg/kg/day).This helps in distinguishing
osteomalacia from other metabolic bone disorders like
normocalcaemic hyperparathyroidism and renal tubular
acidosis where the 24-hour urinary calcium levels are high. In
osteomalacia, 25(OH)D levels are low and PTH levels are high.
There is no utility of 1,25(OH) 2D in patients with nutritional
osteomalacia since these levels are usually normal due to the
enhanced 1-alpha hydroxylase activity, an action mediated by
PTH. 1,25(OH)2D levels are low in patients with osteomalacia due
to renal causes, fluorosis or oncogenous osteomalacia. Table 2
gives the differential biochemical parameters in patients with
metabolic bone diseases due to different causes.
Table 2: Biochemical Parameters in Metabolic Bone Diseases
Calcium Phosphorus Alkaline 24-hour Diagnosis
Phos- Urinary
phatase Calcium
Figure 3A: Radiograph of pelvis showing osteopaenia, pubic diastasis and
Normal Decreased Increased Decreased Osteomalacia pseudofractures of the pubic rami.
Decreased Decreased Increased Decreased Osteomalacia
Normal Decreased Normal Decreased Osteomalacia
Increased Decreased Increased Increased Hyperpara-
thyroidism
Normal Decreased Increased Increased Normocalcaemic
hyperpara-
thyroidism, Renal
tubular acidosis
Decreased Increased Normal Decreased/ Hypopara-
normal thyroidism
Decreased Increased Increased Decreased/ Renal failure,
normal selective renal Figure 3B: Pseudofractures in forearm bones (looser zone).
resistance to
PTH action

Asymptomatic/Subclinical Osteomalacia
Some healthy Indian adults or some patients who report mild
non-specific bony aches and pains have normal calcium,
phosphorus and alkaline phosphatase vitamin D and PTH levels
but low 25(OH)D levels. It is difficult to detect this subgroup since
most of them have normal calcium, phosphorus and ALP levels.
PTH levels are also within the normal range albeit high normal, a
finding difficult to explain. A 24-hour urinary calcium in these
patients is usually low.
A comprehensive evaluation of a patient with metabolic bone
disease demands radiographs of the pelvis, skull, dorsolumbar
spine (anteroposterior and lateral views), chest and bilateral
forearms and hands. There is usually a generalised osteopaenia
with coarsening of the trabeculae.Widening, fraying and cupping
of the distal ends of the shaft and disappearance of the zone
of provisional calcification is seen. Pseudofractures (thin cortical
radiolucent lines at right angle to the shaft) may be present.
The common sites of pseudofractures includes medial margins
of the neck of femur, pubic rami (Figures 3A and 3B) borders of
scapulae, ribs and rarely margins of forearm bones. Secondary
hyper-parathyroidism manifests as diastasis of the pubic rami,
though presence of cysts, pepper pot appearance of the
skull, subperiosteal resorption and tufting of the phalanges
points towards a diagnosis of primary hyperparathyroidism. Figure 4: Photograph shows a female with florid osteomalacia.
Interosseous membrane calcification and calcification of the 307
 Management expensive. These patients could be given monthly
Treatment of osteomalacia or rickets should be tailored to the cholecalciferol for 2 to 4 months. In more severe cases, where
underlying disorder. In almost all cases treatment with calcium depleted vitamin D stores have to be replenished
1 to 3 g daily is required. Patients with nutritional osteomalacia, cholecalciferol 60,000 IU weekly for a month and then monthly
where activation pathway is intact, could be supplemented for 3 to 6 months , sometimes per year are required. In patients
with cholecalciferol instead of calcitriol which is more with osteomalacia due to a renal cause or hypoparathyroidism
or VDDR I where 1-alpha hydroxylation is defective, active
metabolite, calcitriol in the dose of 0.25 to 0.5 mcg should be
supplemented. In cases of malabsorption, vitamin D could be
administered parenterally. In our practice, development of
hypercalcaemia or nephrocalcinosis is extremely rare. This is
possibly due to poor vitamin D stores which take a long time
to normalise.
In the initial stages of vitamin D therapy, bone pains may worsen
and alkaline phosphatase levels may increase, thereby
indicating active bone remodelling. There is a gradual increase
in phosphorus levels as the PTH levels come down. The
radiologic healing takes around 4 to 6 weeks. It is also important
to reinforce the patients to ensure a healthy nutrition and a
minimum exposure to sunlight (290-315 nm) for 30 minutes of
unprotected skin per day.
It is advisable to check calcium, phosphorus and alkaline
phosphatase levels of other unaffected family members,
especially siblings. Similarly, dietary advice should be reinforced
for the whole family.

RECOMMENDED READINGS
1. Goswami R, Kochupillai N, Gupta N, et al. Presence of 25(OH) D deficiency
in a rural North Indian village despite abundant sunshine. J Assoc Physicians
India. 2008; 56: 755-7.
2. Goswami R, Mishra SK, Kochupillai N. Prevalence and potential significance
of vitamin D deficiency in Asian Indians. Indian J Med Res. 2008; 127: 229-
38.
3. Ray D, Goswami R, Gupta N, Tomar N, et al. Predisposition to vitamin D
deficiency osteomalacia and rickets in females is linked to their 25(OH)D
Figure 5: Photograph shows hypocalcaemic tetany. and calcium intake rather than vitamin D receptor gene polymorphism.
Clin Endocrinol (Oxford). 2009; 71: 334-40.

308
 8.4 Osteoporosis

SNA Rizvi

INTRODUCTION AGE-RELATED OSTEOPOROSIS (POSTMENOPAUSAL

Osteoporosis is the second most common metabolic bone AND SENILE)
disease in India. The term describes a group of bone disorders Normally, bone mass is lost gradually in both sexes, but in
in which the absolute bone mass is less than normal. There is women, the rate of bone loss is accelerated at the time of
deterioration of micro-architecture of the skeleton leading to menopause. The suggested aetiopathogenesis of age-related
increased bone fragility and risk. The mineral-to-matrix ratio is (involutional) osteoporosis is shown in Figure 1.
reduced. Histologically, it is characterised by a decrease in the
The differentiating features between types I and II involutional
number and size of the trabeculae,with normal width of the osteoid
osteoporosis are summarised in Table 2.
seams. It is a silent underlying condition which often remains
asymptomatic until a fracture occurs. The actual prevalence of
osteoporosis remains unknown because of its asymptomatic Table 2: Types of Involutional Osteoporosis
nature. In India it has been presumed that 35% of post- Postmenopausal Age-related senile
menopausal women are at the risk of developing osteoporosis. (Type I) (Type II)
Osteoporotic bone fractures commonly occur at the spine, hip
Age (years) 51-70 >70
and wrist. On an average a post-menopausal woman has 40% to
50% chance of developing a fracture including 15% chance of Sex ratio (F : M) 5:2 2:1
hip fracture in her lifetime. More than 10% of hip fracture victims Type of bone loss Mainly trabecular Cortical and trabecular
die within one year from various complications and nearly 50% Rate of bone loss Accelerated Not accelerated
of the survivors are incapacitated, some of them permanently. Fracture sites Vertebrae (crush), Vertebrae (multiple
distal radius wedging), hip
Clinically, osteoporosis has been classified into two categories (extracapsular)
(Table 1).
Parathyroid function Decreased Increased
Bone mass is the result of the amount of bone achieved during Calcium absorption Decreased Decreased
growth and at maturity, and the subsequent rate of bone loss. Renal conversion of Decreased secondary Decreased due to
The remodelling of bone (its formation and resorption) is a 25(OH)D to to decreased PTH decreased 25(OH)D
continuous process throughout life. In normal individuals, for 1,25(OH)2D secretion α activity
many years after closure of the epiphyses, skeletal mass remains Main cause Factors related to Factors related to
constant and the rates of bone formation and resorption (bone menopause to aging
remodelling) are approximately equal. In osteoporosis the
rate of bone resorption exceeds that of bone formation.
Table 1: Classification of Osteoporosis
A. Primary osteoporosis
I. Postmenopausal (Type I) II. Idiopathic
Senile (Type II) Juvenile
In adults (premenopausal women, middle aged or young men)
B. Secondary osteoporosis
IV. Iatrogenic (prolonged drug administration)
I. Genetic (heritable disorders of connective tissue) Steroids
Osteogenesis imperfecta Heparin
Homocystinuria Anticonvulsants
Marfan’s syndrome
V. Disorders with associated osteoporosis
II. Nutritional Other metabolic bone diseases
Calcium deficiency Adult hypophosphatasia
Protein deficiency Mast cell disease
Scurvy Rheumatoid arthritis
Malabsorption Endemic skeletal fluorosis
Malnutrition Alcoholism
III. Endocrine VI. Regional osteoporosis
Hypogonadism Immobilisation
Cushing’s syndrome Post-traumatic (reflex sympathetic dystrophy)
Thyrotoxicosis Transient
Hyperparathyroidism Migratory
Acromegaly
Diabetes mellitus
309
 Figure 1: Mechanisms of bone loss in involutional osteoporosis.

CLINICAL FEATURES X-rays are the easiest but evident only after loss of 30% to 50%
Most patients are asymptomatic until they develop a of bone mass. The radiological changes are more marked in the
complicating fracture which often occurs after minimal trauma. bones of the axial skeleton and consist of loss of bone density,
Fractures are most common in the hip, humerus, ribs and wrists. reduction in the number and size of the trabeculae, and thinning
The most frequent symptoms are pain in the back, deformity of of the cortex. The lumbar and thoracic vertebrae become
the spine (kyphosis) and loss of height. Pain usually results from biconcave, and later compression or collapse causes anterior
collapse of the vertebral bodies, especially in the lower dorsal and wedging.
upper lumbar regions; it is typically acute in onset. Generalised Some of the risk factors are shown in Table 3.
bone tenderness would suggest coexisting osteomalacia. Impaired
movement of thoracic cage can produce cardiopulmonary Table 3: Risk Factors for Osteoporosis
embarrassment and exercise intolerance and disablility. Age (advanced : 50 years or more)
DIAGNOSIS Sex (female)
Race (caucasian or oriental ethnic origin)
The calcium, phosphorus, and alkaline phosphatase levels in the
Habitus (petite or thin)
blood are normal. In the past, osteoporosis used to be diagnosed
Menopause (premature, surgically induced)
after manifestation of fracture in old age but now can be achieved
by Bone Densitometry which include dual energy X-ray Positive family history for osteoporosis
absorptiometry (DEXA), quantitative computed tomography, Reduced weight for height
quantitative ultrasound, radiographic absorptiometry and single Diet
energy X-ray absorptiometry. DEXA is being most preferred Calcium (low)
Caffeine (excess)
densitometry technique for diagnosis of osteoporosis. The
Alcohol (excess)
results are interpreted in terms of T-Scores and Z-Scores. T-
Protein (low)
Scores represent the bone mass of the patient compared to the
Phosphate (low)
mean peak bone mass of the young adult reference population
Sedentary life-style
using standard deviations. Z-Scores compare the patients bone
Cigarette smoking
mineral density (BMD) with the mean BMD for the person of
Multiparity
the same age. According to WHO osteoporosis is diagnosed
Other disorders affecting mineral metabolism
using T-Scores as follows:
Medications
BMD within 1.0 SD – Normal Steroids
BMD between 1.0 and 2.5 SD – Osteopaenia Anti-epileptics
Thyroid supplements
BMD below 2.5 SD or more – Osteoporosis
Anti-coagulants
BMD beyond 2.5 SD with one or – Severe osteoporosis Hypogonadism
310 more fragility fractures
 Osteoporosis
PREVENTION OF OSTEOPOROSIS resorption and promotes absorption of intestinal calcium and
Prevention or early treatment of osteoporosis is still the most stimulates osteoblast function. Adverse affects of HRT include
certain way to maintain a sound skeleton. The various elements vaginal bleeding, breast tenderness and upper gastrointestinal
for prevention are summarised in Table 4. It involves symptoms. It also increases the risk of breast and endometrial
maintenance of normal oestrogen levels, high calcium intake, malignancy. It is no longer first line of treatment for post-
exercise, sensible weight and lifestyle modification (avoiding menopausal osteoporosis.
cigarette smoking, excess of alcohol and coffee).
Table 5: Drug Treatment for Osteoporosis
Table 4: Elements of Osteoporosis Prevention Anti-resorptive agent
Calcium intake 1.0-1.5 g per day HRT/Oestrogen, progesterone
Moderate phosphorus intake Bisphosphonates
Moderate vitamin D intake, 400-800 IU per day or calcitriol Etidronate, alendronate, pamidronate, tiludronate,
0.25 µg/day risedronate, zolendronate (transdermal formulation)
Appropriate exercise programme Calcitonin
Avoidance of alcohol and cigarette Calcium
Periodic assessment of skeletal status Tibolone
Prophylactic agents when indicated, Alendronate 5 mg or Raloxifene Stimulators of bone formation
60 mg per day Fluoride
Parathyroid hormone
Clinical deterioration due to further bone loss can generally Agents with unknown action
be prevented by administration of oestrogens and anabolic Vitamin-D and analogues
steroids combined with calcium supplementation, small doses Anabolic steroids
of vitamin D, and maintenance of physical activity. A typical Ipriflavone
programme consists of oral administration of 0.625 mg to 1.25 mg Newer therapies
of conjugated oestrogen or the equivalent dosage of another Selective oestrogen receptor modulators (SERMS)
natural oestrogen daily for the first 25 days of the month, with raloxifene, idoxifene, tamoxifene, droloxifene.
administration of medroxyprogesterone acetate 10 mg daily Activator of non-genomic estrogen like signalling (ANGELS)
during the last 10 days of the month to complete shedding of the Growth factors (TGF-β , IGF-1 and 2)
endometrium. The 19-nortestosterone derivatives (desogestrel,
norgestinate) have negligible side-effects. Hormonal replacement Tibolone
therapy (HRT) slows down bone loss, helps to maintain bone mass
It is a synthetic steroid with simultaneous weak oestrogenic,
and skeletal integrity and protects against osteoporosis.
androgenic and progestational activity. It is given in the dose
Pelvic examination, vaginal smear for cytology and possibly of 2.5 mg daily with its beneficial affect on the lumbar spine.
endometrial biopsy, manual examination of breasts and
Bisphosphonates
mammography are indicated at frequent intervals for evidence
of carcinoma. Any bleeding other than that associated with They are synthetic analogues of pyrophosphate with potent
oestrogen withdrawal should be investigated. History of ischaemic anti-resorptive properties. First generation include etidronate
heart disease or of venous thrombosis is a contraindication for and clodronate. Second generation agents are alendronate,
hormone replacement therapy. Recently, a new agent Tibolone pamidronate and tiludronate and third generation includes
(2.5 mg) with oestrogenic and progestogenic activity has been risedronate. It inhibits bone resorption by inhibiting osteoclasts.
launched as an alternative to traditional HRT. Alendronate is approved by US Food and Drug Administration
(FDA). It reduces vertebral fracture rate by 50% at a daily dose
TREATMENT OF ESTABLISHED OSTEOPOROSIS of 10 mg. It is avoided in abnormalities of oesophagus such as
The primary goals of treatment are: stricture or achalasia, inability to stand or sit for at least 30
1. Increasing bone mass minutes and hypocalcaemia. An alternative to oral preparation
2. Reducing the incidence of osteoporotic fractures is now available as transdermal formulation of zolendronate.
3. Arresting and reversing bone loss by inhibiting bone It has been shown that alendronate and risedronate have
resorption and stimulating bone formation profound effects on reduction of vertebral fractures and non-
4. Symptom relief vertebral fractures of hip.
Symptom relief from fracture pain is provided by analgesics. Calcitonin
Calcitonin has an analgesic action mediated by endorphins.
It is a peptide hormone which is an effective interesting
Salmon calcitonin, the most potent injectable form, is given in
antiresorptive agent with excellent safety profile. The principal
doses of 50 to 100 MRC unit daily two-three times a week. It is
side effects are nausea, nasal irritation, and dizziness. It is costly
also available as nasal spray.
and should be reserved for treatment of osteoporosis when HRT
Various drugs used in the treatment of osteoporosis are outlined or bisphosphonates are contraindicated or ineffective 50-100
in Table 5. MRC units daily to three times a week is used.
Hormonal Replacement Therapy Calcium
Oestrogen alone or in combination of progesterone may be Calcium supplementation has significant beneficial effect on
used. It inhibits osteoclasts and decreases the rate of bone bone mass irrespective of age. Dietary calcium derived mostly 311
 from dairy products slows bone loss in post-menopausal IDIOPATHIC OSTEOPOROSIS
women. Combining with oestrogen or calcitonin offers an even This is the term used to describe the disorder in children,
greater benefit. The recommended dose for calcium in post- younger men or premenopausal women in whom no
menopausal women is 1500 mg/day and in men and women aetiological factor is detected. Juvenile osteoporosis is a rare
on HRT is 1000 mg/day. disorder with onset usually between the ages of 8 and 14 years;
Fluoride it is characterised by abrupt appearance of bone pains and
occurrence of fractures after minimal trauma. Investigations
It stimulates bone formation and substantially increases bone
show malabsorption of calcium and/or a high urinary calcium
density. In view of potential toxicity and inconsistent anti-
loss. Bone resorption is generally high and vertebrae reveal
fracture effect, it is not approved for the treatment of
regular biconcavity with large disc spaces. In many cases the
osteoporosis even in USA.
disorder is self-limited. It differs from osteogenesis imperfecta
Parathyroid Hormone (PTH) which occurs since birth, lasts life-long and has associated
It prevents bone loss upto 3.4% in lumbar spine with daily connective tissue defects such as blue sclerae and abnormal
injection of 500 units of hPTH subcutaneously. The drug has to teeth. It does not respond to treatment with vitamin D and
be administered parenterally and is costly too. calcium.
Teriparatide is given by subcutaneous injection. It acts on In idiopathic adult osteoporosis, present in a young man or a
osteoblast cell and increases the bone density at spine and is premenopausal woman, malabsorption of calcium is frequently
given for 18 months and effect lasts another 18 months after present and symptomatic improvement often follows
stopping the therapy. It is given only in severe osteoporosis treatment with calcium and vitamin D.
with spine fracture. It is contraindicated in hypercalcaemia,
STEROID-INDUCED OSTEOPOROSIS
kidney disease, Paget’s disease and radiation therapy.
Osteoporosis commonly accompanies Cushing’s syndrome,
Combination Therapy both exogenous and endogenous, and in some instances is
PTH and bisphosphonate combination was tried but no rapidly progressive, especially in children and women over the
substantial improvement in prevention of fractures and change age of 50 years. Osteoporosis in conditions of glucocorticoid
in BMD was noted. excess is accounted for by a combination of low rates of bone
formation accompanied by high rates of bone resorption.
Strontium Ranelate
This results partly from glucocorticoid-induced secondary
New modality for treatment of osteoporosis has dual action hyperparathyroidism and alteration in the metabolism
which increases bone formation and uncoupling of bone of vitamin D 3 . Treatment consists of withdrawal of
remodelling. glucocorticoids or decrease in its dose, and treatment with
Vitamin D and its Analogues vitamin D in doses of 1.25 mg three times a week with
It has been shown that vitamin D and its active metabolite supplemental oral calcium 1 g per day. The use of vitamin D
calcitriol and its analogue alfacalcidol have beneficial effects metabolites such as 25(OH)D3 or 1,25(OH)2D3 may prove to be
on bone mass in osteoporosis. Calcitriol decreases rate of more effective. Alendronate can be prescribed in men with
vertebral fracture and improves vitamin D deficiency which is steroid induced osteoporosis. Testosterone may be given if
not very uncommon in old age. Recommended dose for vitamin testosterone level is low. Calcitonin can be prescribed if
D supplementation is 400-800 IU / day or 0.25 μg calcitriol daily. bisphosphonate is contraindicated.

Phytoestrogens OSTEOPOROSIS IN MEN

These are plant derived molecules that have oestrogenic actions Primary osteoporosis is seen in 50% where no aetiological factor
and obtained from dry soyabeans and all soya based products. is detected (idiopathic) whereas secondary (50%) is commonly
Ipriflavone has been shown to increase bone mass in associated with glucocorticoid excess (15%), hypogonadism
established osteoporosis, its safety is yet to be established. (10%), alcoholism (7%), hypercalciuria (2%), smoking,
immobilisation and some gastrointestinal disorder.
Selective Oestrogen Receptor Modulators (SERMS)
Raloxifene, has recently been approved for the treatment of Treatment in cases of secondary osteoporosis consists of
post-menopausal osteoporosis. It has mixed oestrogen treatment of the cause, androgen, limitation of corticosteroid
agonist and antagonist activity. The usual dose is 60 mg orally therapy, alcohol or smoking and use of thiazides for
once a day. Side effects are leg cramps and worsening of hot hypercalciuria. Idiopathic osteoporosis is treated with most
flushes. BMD of spine and hip increased by approximately prescribed modalities, includes exercise and prevention of falls,
2% to 3%, but it does not increase the risk of breast cancer or calcium and vitamin-D supplements, PTH (teriparatide) and
endometrial cancer. alendronate.

In recent years , a number of new agents have been devised RECOMMENDED READINGS
with little effects on endometrium and breast. These include 1. Avioli LV, Lindsay R. The female osteoporotic syndrome. In: Avioli LV, Krane
tamoxifen, droloxofen and idotoxifen. Their potential for SM, editors Metabolic Bone Disease and Clinically Related Disorders, (2nd Ed.)
Philadelphia: WB Saunders. 1990; 397-451.
treatment of osteoporosis remains to be assessed.
2. Consensus Development Conference. Diagnosis, prophylaxis and
Clinical trials are on to see the potential application of GH and treatment of osteoporosis. Am J Med. 1993; 94: 646-50.
TGF-β and IGF-1 and 2 in the management of osteoporosis. 3. PK Dave. Osteoporosis: The silent epidemic. JIMSA. 2000; 13: 5-8.
312
 8.5 Developmental Disorders of Bone

Rakesh K Sahay

A wide variety of inherited disorders affect the skeletal Adult (benign) osteopetrosis type II is an autosomal dominant
development. They affect the bone growth and remodelling disease that is usually diagnosed by the discovery of typical
and may also produce derangements in mineral homeostasis. skeletal changes in young adults who undergo radiologic
From a practical clinical standpoint these disorders can be evaluation of a fracture. The fractures may be accompanied
classified as sclerosing and non-sclerosing bone dysplasias by loss of vision, deafness, psychomotor delay, mandibular
(Table 1). An overview of some of the common clinically osteomyelitis, and other complications usually associated
relevant developmental bone disorders has been provided. with the juvenile form. The milder form of the disease does not
usually require treatment.
Table 1: Developmental Disorders of Bone
Radiography
Sclerosing bone dysplasias
Osteopetrosis Generalised symmetric increases in bone mass with thickening
Carbonic anhydrase II deficiency of both cortical and trabecular bone. The diaphyses and
Pycnodystosis metaphyses are broadened (Erlenmeyer deformity), and
Engelmann’s disease alternating sclerotic and lucent bands may be seen in the iliac
Endosteal hyperostosis crests, at the ends of long bones, and in vertebral bodies. The
Osteopoikilosis cranium is usually thickened, particularly at the base of the skull,
Osteopathia striata
Melorheostosis
and the paranasal and mastoid sinuses are underpneumatised.
The thickened cranium along with the vertebral end plate
Non-sclerosing bone dysplasias
Osteogenesis imperfecta
sclerosis gives the appearance of Rugger-Jersey spine.
Fibrous dysplasia Laboratory Findings
Osteochondrodysplasias Elevated serum levels of osteoclast-derived tartarate-resistant
Multiple epiphyseal dysplasia
acid phosphatase (TRAP) and the brain isoenzyme of creatine
Spondylo-epiphyseal dysplasia
Handigodu disease kinase are characteristic. Serum calcium may be low in severe
Achondrodysplasia disease, and parathyroid hormone and 1,25-dihydroxy vitamin D
Metaphyseal chondrodysplasia levels may be elevated in response to hypocalcaemia.
Enchondromatosis
Osteochondromatosis Treatment
Mucopolysaccharidosis Allogenic HLA-identical bone marrow transplantation has been
Dysostosis multiplex successful in some children. Following transplantation, the
Morquio’s syndrome marrow contains progenitor cells and normally functioning
Hurler’s syndrome osteoclasts. A cure is most likely when children are transplanted
before age of four years. Marrow transplantation from non-
SCLEROSING BONE DYSPLASIAS identical HLA-matched donors has a much higher failure rate.
Osteopetrosis Limited studies in small numbers of patients have suggested
Osteopetrosis (Marble bone disease, Albers-Schonberg disease): variable benefits following treatment with interferon gamma-
These disorders are caused by severe impairment of osteoclast- 1b, 1,25-dihydroxy vitamin D (which stimulates osteoclasts
mediated bone resorption. Mostly two types of osteopetrosis directly), methylprednisolone, and a low calcium/high-
include type I which is malignant (severe, infantile, autosomal phosphate diet. Decompression of the optic or auditory nerve
recessive) and type II osteopetrosis, which is benign (adult, compression may be needed. Orthopaedic management is
autosomal dominant). A rare autosomal recessive has a more required for the surgical treatment of fractures and their
benign prognosis. This is also known as intermediate form. complications including malunion and post-fracture deformity.
Clinical Presentation NON-SCLEROSING BONE DYSPLASIAS
Type I osteopetrosis presents in early childhood, and untreated Osteogenesis Imperfecta
is often fatal before age of five year. As bone and cartilage fail
to undergo modelling, paralysis of one or more cranial nerves Osteogenesis imperfecta (OI), characterised by generalised
may occur due to narrowing of the cranial foramina and patient osteopenia and brittle bones (hence called brittle bone disease)
can at times present with resultant sensorineural deafness and is the most common genetic bone disorder and its prevalence
blindness as initial complaints. Failure of skeletal modelling also is estimated around 1 in 10,000-20,000 births. The disorder is
results in inadequate marrow space, leading to extramedullary frequently associated with blue sclerae, dental abnormalities
haematopoiesis with hypersplenism and pancytopaenia. (dentinogenesis imperfecta), progressive hearing loss, and a
Hypocalcaemia due to lack of osteoclastic bone resorption may positive family history. The clinical manifestations based on the
occur in infants and young children. mode of inheritance of OI are summarised in Table 2. 313
 Table 2: Clinical Features of Osteogenesis Imperfecta Based on mitral incompetence, and fragility of large blood vessels can
Mode of Inheritance also be seen. Short stature is the most prevalent secondary
feature of OI.
OI Major clinical Inheritance
Type features Cardiopulmonary complications of osteogenesis imperfecta are
I Normal stature, blue sclerae, hearing AD the major cause of mortality directly related to the disorder.
loss in about 50% of patients There is a high frequency of basilar invagination (BI) in patients
II Lethal in perinatal period, minimal AD with severe osteogenesis imperfecta, which is an upward
calvarial mineralisation, long bone (new mutation) displacement of vertebral elements into the foramen magnum.
deformities, platyspondyly AR (rare) It may lead to static or dynamic stenosis of the foramen
III Short stature, bone deformities, variable AD or AR magnum, and compression of the medulla oblongata. Children
hue in sclerae, Dentigerous imperfecta should be screened by CT every 2-3 years, and followed annually
(DI) and hearing loss common by MRI if radiographic signs of BI develop.
IV Normal sclerae, bone deformity, AD Pathogenesis
DI common, short stature and
hearing loss variable OI results from a qualitative or quantitative defect in the type 1
collagen, which is the most abundant protein in bone. This is
AD = Autosomal dominant; AR = Autosomal recessive.
generally caused by mutations in the genes encoding for type 1
Skeletal Changes procollagen.
Radiographs of the skull in patients with mild disease may show Diagnosis
a mottled appearance because of small islands of irregular Diagnosis is usually made on the basis of clinical criteria. The
ossification. In type II OI, bones and other connective tissues presence of fractures together with blue sclerae, dentinogenesis
are so fragile that massive injuries can occur in utero or during imperfecta, or family history of the disease is usually sufficient
delivery. Ossification of many bones is frequently incomplete. to make the diagnosis. The characteristic radiological features
Continuously beaded or broken ribs and crumpled long bones are decreased bone density, modelling defects of long bones
(accordina femora) may be present. In types III and IV, multiple and deformities caused by recurrent fractures. Osteogenesis
fractures from minor physical stress can produce severe imperfecta is frequently associated with either relative or
deformities. Kyphoscoliosis can impair respiration, cause cor absolute macrocephaly. Individuals with OI frequently have
pulmonale, and predispose to pulmonary infections. On relatively long arm span for length and a shortened lower
radiographs the appearance of “popcorn-like” deposits of segment (pubis to floor). Elevated serum alkaline phosphatase,
mineral on the ends of long bones is an ominous sign. In all hypercalciuria and increased urinary excretion of hydroxy-
forms of OI, bone mineral density in unfractured bone is proline have also been noted. The mutation in type I
decreased. However, the degree of osteopenia may be difficult procollagen gene can also be identified and if done in an
to evaluate because recurrent fractures limit exercise and individual patient, a simple test based on the polymerase chain
thereby worsen already reduced bone mass. Surprisingly, reaction (PCR) can be used to screen family members at risk
fractures appear to heal normally. and for prenatal diagnosis. A lateral view of the skull should also
Ocular Changes be obtained to detect wormian bones.
The sclerae can be normal, slightly bluish, or bright blue. Treatment
Thinning of the collagen layers of the sclerae allows the The recurrent fractures require orthopaedic care including
choroid layers to be seen. Blue sclerae may also be seen in other surgical management, and in some instances, physical and
conditions. rehabilitative therapy.
Dentinogenesis Imperfecta Treatment with bisphosphonates to decrease bone loss has
Improper deposition or deficiency of dentine leads to yellowish been found to be helpful although long-term effects are not
brown or translucent bluish grey colour of teeth. The enamel completely understood. Systemic infusion of stromal cells from
generally appears normal. The deciduous teeth are usually bone marrow that can differentiate into osteoblasts and bone
smaller than normal, whereas permanent teeth are frequently marrow transplantation from a HLA compatible donor have
bell-shaped and restricted at the base. These discoloured teeth been tried. Growth hormone therapy has been found to
may also fracture and need to be extracted. increase growth in a small number of children with OI.
Management of pneumonia and cor pulmonale is done as in
Hearing Loss any other patient but more aggressively. For severe hearing
The middle ear usually exhibits maldevelopment, deficient loss with stapedectomy or replacement of the stapes with a
ossification, persistence of cartilage in areas that are normally prosthesis may be required.
ossified, and abnormal calcium deposits. This usually presents
Prenatal Diagnosis
as hearing loss beginning during the second decade of life and
occurs in more than 50% of individuals over age 30. The loss It can be diagnosed by ultrasonography at 18 to 24 weeks’
can be conductive, sensorineural or mixed and varies in severity. gestation. DNA sequencing on chorionic villus sample (CVS)
biopsies is possible. Cultured CVS cells can be used for DNA or
Associated Features RNA extraction and detection by either PCR and restriction
Thinning of skin that scars extensively, joint laxity, cardiovascular enzyme digestion or sequencing. Appropriate genetic
314 manifestations such as aortic regurgitation, floppy mitral valves, counselling is then required.
 Developmental Disorders of Bone
Fibrous Dysplasia The disease is caused by a mutation of the fibroblast growth
It is discussed in Chapter on ‘Miscellaneous Bone Disorders’. factor receptor 3 (FGFR3) gene that results in a gain-of-function
state. The primary defect is abnormal chondrocyte proliferation
Achondroplasia at the growth plate that causes development of short but
Achondroplasia is the commonest form of short-limb dwarfism. proportionately thick long bones. Other regions of the long
It is characterised by the presence of short limbs (particularly bones may be relatively unaffected. This disorder has an
the proximal portions), normal trunk, large head, frontal and autosomal dominant inheritance, but sporadic mutations also
parietal bossing and flattening of the occiput, saddle nose, and may be seen. Pseudo-achondroplasia clinically resembles
an exaggerated lumbar lordosis. The tip of the nose is fleshy, achondroplasia but has no skull abnormalities.
with upturned nostrils. All the bones are affected but abnormal
configuration of the skull, lumbar spine and pelvis are hallmarks RECOMMENDED READING
of the disease. Radial heads may be dislocated and posterior 1. Monti E, Mottes M, Fraschini P, Brunelli P, Forlino A, et al. Current and
scalloping of the vertebral bodies and dorsolumbar kyphosis is emerging treatments for the management of osteogenesis imperfecta.
seen. Severe spinal deformity may lead to cord compression. Ther Clin Risk Manag. 2010; 6: 367-81.

315
 8.6 Miscellaneous Bone Disorders

CV Harinarayan

PAGET’S DISEASE (OSTEITIS DEFORMANS) are seen. Paget’s disease can lead to wide pulmonary artery
Paget’s disease of bone is a chronic skeletal disorder which pressure and high output failure.
may result in enlarged and/or deformed bones in one or Biochemical Features
more regions of the skeleton. The disease is characterised by
Calcium and phosphorus levels are within normal range with
abnormal bone turnover, structure and architecture. It was
raised alkaline phosphatase levels. Markers of bone turnover
first described by James Paget in 1877. This disorder is quite
such as urinary N-telopeptide, urinary hydroxyproline/creatinine
common in Europe, North America, Australia and New Zealand.
and urinary and serum deoxypyridinoline, C-telopeptide are
There are occasional cases reported from India.
increased. Hyperuricaemia may be present.
Definition
Radiological Features
It is a focal disorder of accelerated (anarchic) skeletal
The most commonly affected bones are the pelvis, lumbar
remodelling due to increase in osteoclastic activity and bone
vertebrae, skull, femur and tibia. Small bones in the hands and
resorption followed by excessive bone formation resulting in
feet are seldom affected. The disease may be uni- or multi-focal
an abnormal highly vascularised bone that is structurally
(mono-ostotic or poly-ostotic) in distribution. Radiologically,
disorganised, with an excess of fibrous connective tissue. It is
Paget’s bone consists of focal area of osteolysis which has blade
the second most common disease after osteoporosis in
of grass or candle-flame appearance. Unique radiological
Western population. Raised alkaline phosphatase in the
features differentiate Paget’s disease from other bone diseases.
presence of classical radiological picture is diagnostic of
The radiological features follow the histological findings on light
Paget’s disease and is further substantiated by bone scan and/
microscopy. The correlation of the different phases with the
or bone histology.
clinical, radiological and pathological features of Paget’s disease
Aetiology allows accurate diagnosis and treatment. These features can be
Genetic and environmental factors are implicated in the divided into three phases: initial phase, mid phase, and late
pathogenesis. Environmental factors may be due to viral phase.
pathogen belonging to paramyxovirus group, such as measles In the initial or active phase (osteolytic), skull shows osteoporosis
virus. This disease has a strong genetic predisposition and circumscripta, especially of the frontal and occipital bones. In the
several genetic loci have been linked to familial Paget’s disease. long bones, there is a well-defined, advancing radiolucency
It has autosomal dominant transmission. Different pre- with a V-shaped margin which begins subarticularly. In the mid
disposition loci have been identified on chromosome 18 and phase, there are osteolytic and sclerotic lesions of the skull,
on chromosome 6. Recently, many susceptible loci (2q36, 5q31, pelvis and long bones. In the late or inactive (osteosclerotic) phase,
5q35, 10p13) have been described. there are ‘cotton wool’ areas of sclerotic bone. The spine shows
Pathogenesis enlargement of the vertebrae. Cortical thickening produces the
‘picture frame’ vertebral body or the ‘Ivory vertebra’. Affected
Little is known about its pathogenesis. Characteristic feature is
vertebral bodies have an almost ‘bone within bone’ appearance.
increased resorption of bone accompanied by increased
Pelvis shows widening and coarsened trabeculation of pelvic ring
formation. In early phase, bone resorption predominates and
with splitting of iliopectineal line. In late phase, the long bones
bones are very vascular. Excessive bone resorption is followed
show sclerosis with coarse and thickened trabeculae. Cortical
closely by formation of new pagetic bone. With decline in
thickening gradually encroaches the medullary canal and the
disease activity, there is decrease in bone resorption relative to
epiphysis is nearly always involved.
formation leading to development of hard, dense, less vascular
bone. The unusual radiological presentations of Paget’s disease
include unusual disease progression, massive post-
Clinical Features
immobilisation lysis, metastatic spread to Pagetic bone, and
The disease affects both sexes with male predominance. Age vertebral end-plate destruction that mimics infection. The
at presentation is fourth and fifth decades of life. The clinical radiological picture of Paget’s disease before and after
features include bone pains, joint pains, skeletal deformities, low treatment is shown in Figure 1. The bone involvement as seen
backache, fractures, painless swellings, skull enlargement, in Indian population is given in Table 1.
headache, deafness, visual impairment, loss of facial sensation,
difficulty in biting, ataxic gait, neurogenic claudications and Bone Scan Features Tc-99m (MDP)
renal stones. Paget bones are fragile and susceptible to fractures The scintigraphic uptake pattern ranges from diffuse uptake in
with trivial trauma. In patients with skull involvement increase a relatively early mixed phase to a mottled uptake pattern of
in size of head as reflected by increase in hat size, increased the late sclerotic phase (Figure 2). Bone lesions begin at
sweating and warmth over skull due to increased vascularity metaphyseal region and extend into diaphysis towards the
316
 Miscellaneous Bone Disorders
other end. Intense uptake in long bones involving one end to
mid-shaft or further suggests Paget’s disease. The ‘butterfly’
pattern of vertebral involvement suggests Paget’s disease,
which affects the entire vertebral body rather than metastatic
disease, which has predilection for the pedicles.

Figure 2: Nuclear scan of patient with Paget’s disease before and 6 months
Figure 1: Radiological appearance in Paget’s—pre- and post-therapy. after the treatment.

Table 1: Skeletal Site Involvement in Patients with Paget’s etidronate, tiludronate, alendronate and risedronate given
Disease orally. Zolendronic acid is said to produce more rapid, more
Site of bone involvement Cases (Percentage) complete and more sustained response. Calcitonin is now
infrequently used. Non-pharmacological measures for pain
Skull 60
management and surgery are used when indicated.
Spine 60
Prognosis
Pelvis 40
Femur 35 The disease is slowly progressive and the course can vary from
stable to rapid progression. The outlook is good if the treatment
Tibia 18
is given early before major complications set in. The treatment
Fibula 8-10
can control the symptoms but not cure the disease and duration
Ulna 9 of the disease.
Radius 10
Scapula 10 McCUNE-ALBRIGHT SYNDROME (FIBROUS DYSPLASIA)
Sacrum 10 McCune-Albright syndrome (MAS) is a triad of poly-ostotic
Clavicle 6 fibrous dysplasia (FD), Café-au-lait skin pigmentation and
endocrine disorder. The disease may present as mono-osototic,
Complications poly-ostotic or MAS and its variants or even panosteotic (entire
skeleton). Mono-osototic form is the commonest.
Hyperuricaemic gout and deafness are relatively common. An
enlarged skull can lead to headaches or hearing loss. If the spine Pathophysiology
is involved, enlarged vertebrae may cause compression of the It is mediated by activating mutation in the receptor associated
spinal cord or nerve roots. Secondary osteoarthritis, radiculopathy heterotrimeric G protein G sα. The effect of Gs α results in
and renal stones are also seen. Bones can soften and lead on to hyperphosphaturic hypophosphataemia leading on to rickets
bowed bones, basilar invagination and protrusio acetabuli. and osteomalacia. The pathological effects of Gsα mutation in
Transverse fractures with a predilection for the convex aspect of osteogenic cells are most pronounced during the rapid phase
the bone, osteomyelitis and extra-medullary haematopoiesis are of growth. Thus, the disease is commonly present in childhood
seen. Osteosarcomas or other types of sarcomas occur in less than or adolescence.
1% of patients with Paget’s disease and carries a poor prognosis.
High output cardiac failure can occur. The multiple endocrine hyperfunction and possibly fibrous
dysplasia is due to defect in the G protein-cyclic AMP-protein
Treatment kinase A-dependent pathway. Activating mutation in the
Since the major defect is exaggerated bone remodelling, G protein stimulates adenyl cyclase Gsα. This signal transduction
the treatment is based on the use of bisphosphonates. induces end-organ hyperfunction. It is of interest to note that
Bisphosphonates suppress or reduce bone resorption by the defect in Albright’s hereditary osteodystrophy (pseudo-
osteoclasts. These include pamidronate given intravenously or hypoparathyroidism) is converse to that found in MAS.
317
 In Albright’s hereditary osteodystrophy, the mutation in be assessed to predict the functional outcome. The metabolic
G s α proteins results in deficient activity and decreases derangements especially hypophosphataemia and growth
responsiveness to hormones mediated through cAMP- hormone excess worsen the clinical outcome and should
mediated signal transduction. be assessed. Calcitonin may be effective in treatment of
widespread disease associated with bone pain and high serum
Clinical Picture
alkaline phosphatase.
Clinical course is variable and depends on the skeleton involved.
The disease is detected because of localised pain, deformities OSTEONECROSIS OF THE JAW
or fractures. The base of the skull and the proximal metaphysis Osteonecrosis of the jaw is an extremely painful condition,
of the femur are the sites commonly involved. Symptoms related characterised by bone erosions and exposure of the bone
to bone involvement include headache, seizures, hearing loss, which affects the mandible or maxillary bones. Inhibition of
narrowing of the external ear canal or even spontaneous scalp osteoclasts by bisphosphonates is hypothesised to disrupt
haemorrhages. Cutaneous pigmentation consisting of isolated the critical balance between the osteoclast and the
dark-brown to light-brown macules on one side of the midline osteoblast. In situations where healing of the bone is
is seen. The borders are irregular or jagged (coast of Maine) in necessary, after chronic inflammation and infection
contrast to smooth borders of macules in neurofibromatosis associated with gum disease, disruption of the dynamic
(coast of California).The macules range from 1 cm to large areas, process of bone resorption and formation could contribute
particularly the back, buttock or sacral region. When present in to the development of osteonecrosis of the jaw. In addition
the scalp, the overlying hair may be more deeply pigmented to chronic bisphosphonates therapy, it is associated with oral
than the remaining areas of the scalp. fungal infections, trauma, herpes zoster and radiation
Sexual precocity is common in females. Premature vaginal therapy.
bleeding and development of breast, axillary and pubic hair
BONE LOSS WITH CANCER THERAPIES
are the main features. Hyperthyroidism is a common associated
endocrine abnormality. Sexual precocity and adrenal and Chemotherapy, hormonal therapy and radiation have improved
thyroid hyperfunctions associated with fibrous dysplasia are the survival rates in patients suffering from malignancies but
due to autonomous end-organ activity and not due to pituitary they carry significant side effects.
or hypothalamic dysfunction. Some subjects can have features Oestrogens play a key regulatory role in bone remodelling
of high cardiac output similar to Paget’s disease. through oestrogen receptors (ER). Current breast cancer
Radiology therapies decrease the circulating oestrogen levels by
blocking or downregulating the receptor itself. Some agents
Radiographically, the lesion is limited to metaphysis or extends
do disrupt the oestrogen-skeleton axis leading to decreased
along the diaphysis for variable length. In children and
bone mineral density, and increased risk of osteoporosis and
adolescents, the picture consists of expansile, deforming
fracture. There are two major classes of aromatase inhibitors;
medullary lesion with cortical thinning and an overall ‘ground-
the non-steroidal reversible inhibitors, anastrozole and
glass’ density. Femoral disease can present with fracture and
letrozole; and steroid irreversible inhibitors, exemestane. Both
deformity ranging from coxa vara to the classical ‘Shepherd’s
classes of aromatase inhibitors result in bone loss to some
crook deformity’ of the femur, bowing of tibia, Harrison’s grooves
extent.
and protrusio acetabuli. Advanced skeletal age is correlated
with skeletal precocity. Before puberty the lesion spares the Prostate cancer patients with metastasis often receive
epiphyseal region but involves the epiphysis in older individuals. palliative therapy in the form of androgen deprivation therapy
Sclerosis in the lesion suggests less active disease. Involvement (ADT) which includes surgical castration, pharmacological
of facial bones usually with increased radiodensity may create castration with LHRH agonists and antiandrogen therapy
leonine appearance (leontiasis ossea). The presentation in with agents like flutamide, nilutamide, bicalutamide or
childhood may be with facial asymmetry or a‘bump’ that persists, cyproterone. One of the potential complications with
but symmetrical expansion of the malar prominences and/or castration or LHRH agonist therapy is the decrease in bone
frontal bosses may also be seen. Abnormal growth and mineral density.
deformity of the craniofacial bones may result in encroachment Radiotherapy is also known to induce fractures. Rib-fracture
of cranial nerves. Involvement of temporal bones can cause after X-ray exposure is a potential complication of radiotherapy
progressive loss of hearing. Malignancy is very rare. Fibrous used for breast cancer. Brachytherapy (radiotherapy) for non-
dysplasia and Paget’s disease of the bone are two disorders that metastatic carcinoma prostate patients can lead to pelvic
can cause a bone to become larger than normal. fracture.
Diagnosis and Management RECOMMENDED READINGS
Diagnosis is based on expert assessment of clinical, radiological 1. Collins MT, Bianco P. In: Favus. M. Fibrous Dysplasia; 6th Ed; 2006; 415-8.
and histopathological features. The extent of the disease must 2. Mithal A. Paget’s disease in India. J Assoc Physicians India. 2006; 54: 521-2.

318
Section 9
Diabetes Mellitus
Section Editor: Anil Bhansali
9.1 Epidemiology and Basic Considerations of Diabetes 321
A. Ramachandran, C. Snehalatha
9.2 Pathogenesis of Type 1 Diabetes Mellitus 324
V. Mohan, Rakesh Parikh
9.3 Pathogenesis of Type 2 Diabetes Mellitus 327
Hemraj B. Chandalia
9.4 Clinical Features and Diagnosis of Diabetes Mellitus 331
D. Maji
9.5 Lifestyle Modifications in Management of Diabetes 336
B.K. Sahay
9.6 Oral Anti-Diabetic Drugs 339
Anil Bhansali, Viral Shah
9.7 Insulin Therapy 343
Rama Walia
9.8 Newer Modalities of Treatment in Type 2 Diabetes Mellitus 347
Anil Bhansali, G. Shanmugasundar
9.9 In-Hospital Management of Diabetes Mellitus 350
Nihal Thomas, Rahul Ramnik Baxi
9.10 Hypoglycaemia 354
Siddharth N. Shah
9.11 Diabetic Ketoacidosis, Hyperosmolar Hyperglycaemic State and Lactic Acidosis 359
Rajesh Rajput
9.12 Infections in Diabetes Mellitus 364
Samar Banerjee
9.13 Macrovascular Complications of Diabetes 368
Murlidhar S. Rao
9.14 Microvascular Diseases—Pathogenesis of Chronic Complications 372
Suman Kirti
9.15 Diabetes and Kidney Disease 375
Jamal Ahmad
9.16 Diabetic Retinopathy 377
Amod Gupta, Reema Bansal
9.17 Diabetic Neuropathy 382
Manish Modi
9.18 Sexual Dysfunction in Diabetes 385
Shashank R. Joshi
 9.19 The Diabetic Foot 387
Pendsey Sharad Purushottam
9.20 Diabetes and Pregnancy 390
V. Seshiah
9.21 Prevention of Diabetes Mellitus 393
Yash Pal Munjal

320
 9.1 Epidemiology and
Basic Considerations of Diabetes
A Ramachandran, C Snehalatha

DEFINITION OF DIABETES MELLITUS unless hyperglycaemia is severe while ketosis is rare. Familial
Diabetes mellitus is a metabolic disorder of multiple aetiology, inheritance is very common.This form of diabetes usually begins
characterised by chronic hyperglycaemia with disturbances of with insulin resistance and initially there is a counter regulatory
carbohydrate, fat and protein metabolism resulting from defects hyperinsulinaemia. With time, the pancreas loses its ability
in insulin secretion, insulin action, or both. The long-term effects to secrete enough insulin in response to meals and clinical
of diabetes include damage, dysfunction, and failure of various diabetes develops.
organs. The long-term effects include progressive development
Table 1: Values for Diagnosis of Diabetes – (WHO 1999)
of retinopathy with potential blindness, nephropathy that
may lead to renal failure, neuropathy with risk of foot ulcers, Venous Whole Whole
amputation, Charcot joints, and features of autonomic Plasma Blood Blood
Venous Capillary
dysfunction, including sexual dysfunction. People with diabetes
are at increased risk of cardiovascular, peripheral vascular, and Glucose Concentration in mg/dL
cerebrovascular diseases. Diabetes Mellitus:
Fasting ≥126 ≥110 ≥110
DIAGNOSIS OF DIABETES 2-hour PG ≥200 ≥180 ≥200
Clinical diagnosis of diabetes is made if a person has the Impaired glucose tolerance (IGT):
symptoms, viz. polyuria, polydipsia, polyphagia, recurrent Fasting (if measured) <126 <110 <110
2-hour PG ≥140 to <200 ≥120 to <180 ≥140 to <200
infections, unexplained weight loss and in severe cases
Impaired fasting glucose (IFG):
drowsiness, coma and a casual plasma glucose concentration of
Fasting ≥110 to <126 ≥100 to <110 100 to <110
≥ 200 mg/dL or a fasting plasma glucose (FPG) of ≥ 126 mg/dL or 2-hour PG (if measured) <140 <120 <140
a two hours post-glucose (2hPG) (75g load) of ≥ 200 mg/dL during
To convert mg/dL to mmol/L, divide mg/dL by 18.
an oral glucose tolerance test (OGTT). For clinical purposes, the
diagnosis should always be confirmed by a repeat blood test on
another day, unless there is unequivocal hyperglycaemia with Gestational Diabetes
acute decompensation or obvious symptoms. Gestational diabetes is carbohydrate intolerance resulting
Table 1 shows the diagnostic criteria for diabetes, impaired in hyperglycaemia of variable severity with onset or first
glucose tolerance (IGT) and impaired fasting glucose (IFG) using recognition during pregnancy. It does not exclude the possibility
capillary or venous plasma or whole blood. The diagnostic that the glucose intolerance may antedate pregnancy but has
criteria are the same for adults or children. For children, a glucose not been previously recognised.
load of 1.75 g per kg is used. For epidemiological studies, a single Other Types of Diabetes
plasma glucose value measured after an overnight fast and/or A number of other types of diabetes exist which develop due to:
2hours after a glucose load can be used. In some populations,
 Genetic defects of the β-cell,
such as the Asians, the diagnostic sensitivity of the FPG is lower
than that of the 2 hours PG. Pregnant women, who meet the  Genetic defects in insulin action,
WHO criteria for diabetes or IGT are classified as having  Diseases of the pancreas,
gestational diabetes mellitus (GDM). After the pregnancy ends,  Excess amounts of counter regulatory hormones,
the women should be tested with an OGTT, six weeks or more  Infections,
after delivery to reclassify the glucose tolerance.  Rare autoimmune disorders, and
 Genetic syndromes associated with diabetes.
CLASSIFICATION OF DIABETES MELLITUS
Type 1 Diabetes AETIOLOGY AND RISK FACTORS
Type 1 diabetes, formerly called juvenile diabetes, is usually Diabetes, either type 1 or type 2, has equally strong genetic and
diagnosed in children, teenagers, and young adults. Type 1 environmental risk factors, an interaction of which leads to the
diabetes may develop in adults also. This is an autoimmune clinical expression of the disease. The genetic susceptibility for
disease causing specific destruction of β-cells of pancreas which type 1 is associated with certain human leucocyte antigen (HLA)
results in an absolute insulinopaenia. combinations (DR3+DR4) and the environmental insults are
Type 2 Diabetes rather ill defined. Possibility of some aspects of diet and viral
infections triggering an autoimmune exposure causing specific
Type 2 diabetes, formerly called adult onset diabetes, is the
destruction of the β-cells of pancreas has been proposed.
most common form and has an insidious onset. It remains
asymptomatic for many years. It is commonly seen in adults, Type 2 diabetes has a more complex aetiopathology. Though it
but can occur even in childhood. Weight loss is uncommon has a strong genetic basis, as shown by its hereditary nature, 321
 the major susceptibility genes have not yet been identified. dependent on the duration and hence, there are no data
Racial predisposition as seen in Asian populations, also is available in children. Data from Japanese and Pima Indian
common. The environmental factors showing strong association children indicate presence of microvascular diabetic
with diabetes are increasing age, family history of diabetes, complications even at the time of diagnosis and with a short
obesity, unhealthy diet, physical inactivity, insulin resistance, period of follow-up.
adverse intrauterine environment, and stress factors.
Gestational Diabetes
The pathophysiology of type 2 diabetes includes, impaired Gestational diabetes mellitus (GDM) is common in many
insulin secretion, impaired insulin action, insulin resistance populations, including Asian Indians. Pregnant women should be
and impaired incretin effect on the β-cell function and non- tested for GDM, in 24 to 28 weeks of gestation. GDM is a pre-diabetic
suppression of the action of α-cells, with rising blood glucose state with an increased risk of development of the disorder in the
levels. subsequent pregnancies, in 60% to 90%. It is also known that
women with GDM have a high-risk (up to 30%) of developing
EPIDEMIOLOGY diabetes within 7 to 10 years after the index pregnancy.
Type 1 Diabetes Asian Scenario
Type 1 diabetes is one of the most common metabolic disorders The rising trend in prevalence of diabetes is evident globally.
which occurs due to an absolute insulin deficiency. The disease The changes are marked in developing countries, particularly
shows an acute onset, with severe symptoms including weight in the Asian continent. Increasing levels of urbanisation,
loss. Positive family history of diabetes is rare and ketonuria industrialisation and economic advancements adversely affect
is common. The patients are dependent on exogenous insulin the biological, and environmental risk factors for diabetes and
for metabolic control and survival. The Diabetes Mondiale other non-communicable diseases. Unhealthy diet, physical
Study (DIAMOND) and the Europe and Diabetes Study have inactivity and stress factors cause overweight/obesity and
established population based national registries using insulin resistance. Asian populations, particularly people of the
standardised methods. There are wide geographic differences Indian subcontinent have a strong genetic predisposition for
in the prevalence and incidence of type 1 diabetes. Finland has diabetes. They also have high levels of insulin resistance and
the highest number of patients with type 1 diabetes. The also have a low threshold for risk factors such as age, body mass
estimated global number of children (0 to 14 years) with type 1 index, and upper body adiposity. Both thrifty genotype and
diabetes is 4,80,000 and annually approximately 76,000 children thrifty phenotype appear to operate in them. Clustering of
develop the disease. Data from developing countries is sparse. cardiovascular risk factors, the metabolic syndrome is common
Type 2 Diabetes in these populations, at a young age itself.
The global burden due to diabetes is mostly contributed by type PREVALENCE OF DIABETES IN INDIA
2 diabetes which constitutes 80% to 95% of the total diabetic
The prevalence of diabetes in India in 1970’s was 2.3% in urban
population. Diabetes mellitus is the most common metabolic
and 1.5% in rural areas, as shown by the multi-centric study by
disease which is prevalent in every part of the world and is a
the Indian Council of Medical Research (ICMR). In 2000s, the
major public health challenge of the twenty-first century. The
prevalence has risen to 12% to 19% in urban areas and to 4% to
explosive increase in the prevalence of diabetes seen in the last
9% in rural areas. A study from rural Andhra Pradesh reported a
three decades poses huge clinical and economic burden in
prevalence of 13.2%. Though, the studies are not strictly
many countries. The estimates by the International Diabetes
comparable due to methodological differences (Table 2) the
Federation (IDF) show that 285 million adults (20 to 79 years)
rising trend in prevalence of diabetes in urban and rural areas
are affected by the disorder in 2010. Epidemiological trends
in India, is evident. The narrowing of urban, rural divide in the
indicate that without proper control and prevention, its
prevalence is due to the rapid urbanisation and socio-economic
prevalence will increase further to 438 million in 2030. This
transitions occurring in rural areas also.
accounts for a global increase by 54%, i.e. a rise from a
prevalence of 6.6% to 7.8% in 20 years. Nearly 70% of the people India which has a large pool of pre-diabetic subjects (IGT and
with diabetes live in developing countries; the largest numbers IFG) shows a rapid conversion of these high-risk subjects
are in the Indian subcontinent and China. Nauru has the highest to diabetes. The Indian Diabetes Prevention Programme-1
prevalence of diabetes (30.9%) and will continue to be so in (IDPP-1) has shown an annual incidence of approximately 18%
2030 (33.4%). Many Arab countries, Tonga, and Malaysia are among subjects with IGT.
among the top ten countries having high percentages of people National studies or population based studies on diabetic
with diabetes. There is little gender difference in the distribution complications are sparse in India. A few population based
in the number affected with diabetes. The largest numbers with studies indicate the prevalence of retinopathy to be 18% to
diabetes are in the 40 to 59 age groups (132 million, in 2010) 27.0% and overt nephropathy to be about 2.2% with a large
which is expected to rise further. By 2030, there will be more percentage (27%) having microalbuminuria. Peripheral vascular
diabetic people in the 60 to 79 age groups (196 millions). disease is prevalent in 6.3%, peripheral neuropathy in 26%, and
Children with Type 2 Diabetes coronary artery disease (CAD) is detected in 21%.
Type 2 diabetes in children is becoming common in many The major contributory factors for the high prevalence of the
countries, especially so among Asian populations. There is little complications are; delayed diagnosis of diabetes, inadequate
data about the onset and progress of complications in these control of glycaemia, hypertension, and lack of awareness about
322 children. Occurrence of cardiovascular diseases (CVD) is the disease among majority of the public.
 Epidemiology and Basic Considerations of Diabetes
Table 2: Prevalence of Diabetes in Rural and Urban India Since stage of diabetes. There is a long asymptomatic pre-diabetic
2000 stage(s) before the development of diabetes. These stages are
easily identifiable by OGTT. For the development of diabetes,
Reference (Year) Diabetes Prevalence (%)
Urban Rural
both the basic pathophysiological defects, i.e. insulin resistance
and β-cell secretory defect have to co-exist.
National
Ramachandran et al (2000) 12.1 — The definition of IGT has been stable. The American Diabetes
Reddy et al (2003) 8.4 — Association (ADA) recommends that the normal cut-off for
Sadikot et al (2004) 5.9 2.7 FPG of < 100 mg/dL. Both IGT and IFG have heterogeneous
Northern India pathogenesis and hence may have different rates of progression
Delhi (2000) 11.6 — to diabetes. People with combined IFG and IGT have
Delhi (2001) 10.3 — approximately double the rate of conversion to diabetes than
Delhi (2005) 15* —
those with any one of the abnormalities. Both the states are
Kashmir (2000) — 4.0
Jaipur (2003) 8.6 — associated with insulin resistance and other cardiovascular risk
Rajasthan (2004) — 1.8 factors such as dyslipidaemia and hypertension. IGT is shown
Maharashtra (2006) — 9.3 to be a stronger risk predictor than IFG.
Southern India
Chennai (2000) 13.9 — PREVENTION OF DIABETES
Kerala (2000) 12.4 2.5 Several systematic long-term prospective studies from different
Chennai (2003) — 6.4 parts of the world have shown that type 2 diabetes is largely
Chennai (2004) 14.3 — preventable. Although the genetic factors cannot be modified,
Kerala (2005) 19.5 —
its interaction with the diabetogenic environmental factors can
Mysore (2005) — 3.8
Andhra Pradesh (2006) — 13.2 be prevented by modifying obesity, diet, and physical activity.
Chennai (2006) 18.6 9.2 Indian Diabetes Prevention Programmes (IDPP-1 and IDPP-2)
have shown that by improving physical activity and by using
* Study in industrial workers (men only)
healthy diet, incidence of diabetes can be significantly reduced
with a relative risk reduction of ~ 30%, in persons with IGT.
ECONOMIC BURDEN DUE TO DIABETES
Metformin in small doses was also found to be effective in
The cost of diabetes care is high and is escalating world wide. It primary prevention of diabetes.
is estimated by the WHO that the global expenditure for
diabetes care would increase from 234 billions in 2007 to 411 Lifestyle changes due to urbanisation and modernisation have
billions in the next 20 years. The WHO estimate is based on lost caused unhealthy diet habits, lack of physical activity, and
productivity due to diabetes, heart diseases, and stroke together increased stress leading to overweight or obesity with higher
show that over the next 10 years, lost national income in billions levels of insulin resistance. India and many other developing
of USD will amount to 555.7 in China, 303.2 in Russian countries are going through this scenario and as a result, we
Federation, 336.6 in India, 49.2 in Brazil, and 2.5 in Tanzania. notice more of chronic metabolic disorders than communicable
diseases posing increasing challenge to the national health.
A study by us in India showed that the median expenditure
had risen from INR 4,200 (USD 95) to INR 9,000 (USD 203) RECOMMENDED READINGS
between 1998 to 2005. The indirect cost is more difficult to 1. International Diabetes Federation. Diabetes Atlas; 4th Ed; 2009.
assess and is much higher than the direct cost. The proportion 2. Joshi SR, Das AK, Vijay VJ, Mohan V. Challenges in diabetes care in India:
of annual income spent on health care is about 25% to 30% by Sheer numbers, lack of awareness and inadequate control. JAPI 2008; 56:
the poor people. The cost increases many fold when diabetic 443-50.
complications are present. 3. Ramachandran A, Ma RC, Snehalatha C. Diabetes in Asia. Lancet 2010;
375:408-18.
PRE-DIABETES 4. Ramachandran A, Snehalatha C. Current scenario of diabetes in India.
J Diabetes 2009; 1: 18-28.
Type 2 diabetes is a lifestyle disorder and an interaction of 5. World Health Organization. Definition, diagnosis and classification of
genetic and environmental factors precipitates the metabolic diabetes mellitus and its complications. Report of a WHO consultation.
abnormalities existing in pre-diabetic subjects to the clinical Part 1. Geneva; 1999.

323
 9.2 Pathogenesis of Type 1 Diabetes Mellitus

V Mohan, Rakesh Parikh

Understanding the pathogenesis of type 1 diabetes mellitus chromosome 11p15 and these are labelled as IDDM 1 and
(type 1 DM) is crucial for developing preventive strategies. IDDM 2, respectively.
However, despite much research, it still remains largely unclear.
As per current understanding, type 1 DM develops in people Table 1: Genetic Loci Associated with Type 1 Diabetes Mellitus
who are genetically predisposed. In addition, certain Locus Chromosome Candidate Genes Markers
environmental triggers start the process of autoimmune IDDM1 6p21.3 HLA DR/DQ TNFA
destruction leading to complete β cell destruction and IDDM2 11p15.5 Insulin VNTR D11S922
insulinopaenia that is characteristic of type 1 DM. IDDM3 15q26 D15S107 D15S107
It is estimated that 50% to 90% of type 1 DM patients have IDDM4 11q3.3 MDU1, ZFM1, RT6, IC, FGF3, D11S1917
evidence of auto-antibodies and they are labelled as type 1A LRP5, FADD, CD3
DM or autoimmune type 1 DM while the remaining are called IDDM5 6q25 SUMO4, MnSOD ESR, a046×a9
type 1B DM or idiopathic type 1 DM. The prevalence of type 1B IDDM6 18q21-21 JK (Kidd), ZNF236 D18S487, D18S64
DM is reported to be 5% to 10% in Caucasian populations. IDDM7 2q31-33 NEUROD D2S152, D251391
Though limited data is available on type 1 DM from India, in IDDM8 6q25-27 — D6S-281,-264,
-446
one study as much as 45% of recently diagnosed subjects were
IDDM9 3q21.25 — D3S1303, D10S193
found to have idiopathic or type 1B DM. Though the exact
IDDM10 10p11.q11 — D10S565
pathophysiology is unknown for this subtype, various factors
IDDM11 14q24.3.q31 ENSA, SEL-1L D14S67
like viral infection, toxins, subclinical pancreatitis or some
IDDM12 2q33 CTLA4 (AT)n 3’UTR,
unidentified genetic defects might be responsible.
A/G,Exon1
The pathogenesis of type 1 DM will be discussed here under IDDM13 2q34 IGFBP2, IGFBP5, D2S137, D2S164,
the subheadings of genetic factors, environmental triggers and NEUROD, HOXD8 D2S1471
autoimmune destruction. As per the current understanding IDDM15 6q21 — D6S-283, -434,
most of the type 1 diabetic subjects have some or the other -1580
genetic predisposition, though alone it is not sufficient to cause IDDM16 14q32 IGH —
type 1 DM. In such genetically predisposed subjects, one or the IDDM17 10q25.1 — D10S1750,
D10S1773
other environmental trigger sets the process of insulitis. Its only
IDDM18 5q31.1.33.1 IL-12B IL-12B
after the β-cells are destroyed critically enough to cause
IDDM19 2q24.3 IFIH1 —
insulinopaenia, that the subject might present with classical
1q42 — D1S1617
symptoms of type 1 DM. As the environmental triggers are 16p12-q11.1 — D16S3131
highly unpredictable, routine screening in genetically 16q22-q24 — D16S504
predisposed subjects (first degree relatives of type 1 DM 17q25 — —
patients) have not been shown to be cost effective. 19q11 — —
3p13-p14 — D3S1261
GENETIC FACTORS 9q33-q34 — D9S260
12q14-q12 — D12S375
Several studies have shown familial clustering of type 1 DM with 19p13.3-p.13.2 — INSR
siblings of type 1 diabetic subjects having a risk of 5% to 6%, PTPN22 1p13 PTPN22(LYP) SNP = R620W
while the risk of transmission of type 1 DM from parents is about CLEC16A 16p13 — rs2903692
10%. The greatest risk is provided by an identical (monozygotic)
IDDM = Insulin-dependent diabetes mellitus; HLA = Human leucocyte antigen;
twin with type 1 DM.The concordance rate even for monozygotic TNFA = Tumour necrosis factor; VNTR = Variable number tandem repeat.
twins is only in the range of 25% to 50% while that of dizygotic
twins is much lower. This suggests that in addition to genetic HLA MOLECULE AND IDDM1 GENE
factors, there is a strong role for environmental factors in the
development of type 1 DM. IDDM 1 (genes encoded within HLA region) remains the most
powerful determinant of type 1 DM accounting for
The inheritance pattern of type 1 DM is complex and polygenic. approximately 40% of familial inheritance of the disorder.
Ongoing research over the last few decades has identified at
least 20 candidate genes associated with type 1 DM. Different HLA Molecules
candidate loci are named with a prefix of IDDM, viz. IDDM 1, HLA are glycoproteins found on the surface of cells. They are
IDDM 2 and so on (Table 1). Among these, two chromosomal comprised of class I and class II, both being encoded by different
regions have emerged consistently across multiple studies. genes within the HLA region of chromosome 6. Class I molecules
These are the human leucocyte antigen (HLA) region located are found on surface of all nucleated cells and are involved in
324 on chromosome 6p21.3, and the Insulin gene region on the ‘restriction’ of cytotoxic T lymphocyte activity. The antigen
 Pathogenesis of Type 1 Diabetes Mellitus
peptides are recognised by CD8+ T lymphocytes only when Europe there has been an overall increase of 3.4% per year
they are presented along with HLA molecule. Class II molecules and even higher increase (6.3% per year) in children below 5
are normally confined to antigen presenting cells such as years of age. This sharp rise in incidence rates over a short
macrophages, B lymphocytes and activated T lymphocytes. period of time suggests the role of changing environmental
Class II molecules are comprised of α and β chains which bind factors operating in early life. Finally, seasonal variations in
to foreign and self antigens in a cleft on the surface of molecule occurrence of new onset type 1 DM also suggest the role of
to be presented to CD4+ helper T lymphocytes. environmental triggers for type 1 DM. Among the various
environmental factors studied viruses and dietary factors have
Owing to the crucial role played by HLA molecules in immune
been reported and these are discussed below.
response, any alterations in their structure might influence the
predisposition to autoimmune disorders. The genes for class I Viruses
HLA are encoded in HLA, A, B and C loci while that for class II are Recently diagnosed type 1 DM patients may show serological
located on HLA, DP, DQ and DR regions. or other evidence of viral infection. There are a few case reports
The first evidence of allelic association between the HLA of type 1 DM being diagnosed during or soon after viral
complex and type 1 DM was reported for the HLA-B15 allele infection. Viruses can damage β-cells either directly by cytolytic
and was based on serology. In subsequent studies, a positive effects or indirectly by an autoimmune response that is initiated
association of type 1 DM with HLA-B8 and a negative association or enhanced by a viral infection. In certain patients in whom β-
with HLA-B7 were established. Higher risks were shown to be cell destruction is going on, viral infection can act as a terminal
associated with HLA class II specificities, namely DR3 and DR4, insult destroying a critical number of residual β-cells. A few of
whereas DR2 (now renamed DR15) was shown to be protective. the viruses implicated in development of type 1 DM are
More than 90% of white Caucasian patients with type 1 DM have described below.
DR3 and/or DR4 as compared with 40% to 50% of controls. The Mumps virus
greatest risk of type 1 DM is conferred by the simultaneous
This was one of the first viruses implicated in the development of
presence of DR3 and DR4, which are found together in 30% to
type 1 DM. Some children with mumps parotitis develop islet cell
50% of patients but in only 1% to 6% of controls.
antibodies suggesting an autoimmune basis.
Recent molecular studies indicated that the primary susceptibility
Coxsackievirus B
genes are situated in the HLA-DQ rather than the DR region. In
white Caucasians, the DQA1*0301, DQB1*0302 (DQ8) allele Coxsackievirus B is the virus implicated more often. It has
(associated with DR4) and DQA1*0501-DQB1*0201 (DQ2) allele been shown to have cytolytic activity on β-cells in animal
(associated with DR3) have the strongest association with type 1 experiments. Autoimmune mechanisms have also been
DM. In contrast, DR2 and DQ6 (DQA1*0102-DQB1*0602) provide suggested through cross reactivity of the virus with specific β-
protection against the development of type 1 DM. cell antigens. An alternative hypothesis of the virus acting as a
‘bystander’ activating autoreactive T cells against islet antigens
North Indian data suggests the strongest association is with DR3 has also been suggested.
unlike in south Indians where both DR3 and DR4 are associated
with type 1 DM. Data from Orissa shows that DRB1*03 and DQ2 Other viruses, like rubella, cytomegalovirus, retroviruses,
(DQA1*501, DQB1*0201), but not DR4 and DQ8, was significantly Epstein-Barr virus, echoviruses, hepatitis A virus, varicella zoster,
increased in patients with type 1 DM. measles, polio, influenza and rotavirus have also been suggested
to be associated with type 1 DM based on circumstantial
IDDM2 evidence. Some viruses, such as lymphocytic choriomeningitis
IDDM2 has been mapped to 5’ end of insulin gene with variable virus (LCMV) and mouse hepatitis virus also have been shown
number of tandem repeats (VNTR). IDDM2 contributes to 10% to be protective against type 1 DM in animal experiments.
of familial inheritance. The class I allele of IDDM2 is associated
Overall, the role of viruses causing type 1 DM is less recognised
with development of type 1 DM while class III is protective.
nowadays.
As shown in Table 1, there are several other genes associated
with type 1 DM but these play a relatively minor role. Dietary Factors
Nitrites and nitrates are common components in food and can
ENVIRONMENTAL FACTORS react with amines and amides to produce nitrosamines and
Identification of the exact environmental trigger in any nitrosamides. The high incidence of type 1 DM in Sicily and
given case of type 1 DM is difficult owing to the larger number Finland has been reported to be due to these compounds in
of environmental triggers. Epidemiological studies have drinking water. An increased incidence of type 1 DM in Icelandic
suggested differences in incidence rates even among boys was observed and linked to the consumption of smoked
countries with similar genetic make-up, like Finland and and cured mutton.
Estonia or Norway and Iceland. Pointing to the role of
Exposure to cow milk early in life has been linked to the
environmental factors, it is of interest that children of Asian
development of type 1 DM in humans particularly in Scandinavia.
origin who moved to UK (traditionally having a low risk of type
Some studies have suggested milk powder based diets to be
1 DM) now have incidence rates approaching that of local
diabetogenic.
white population strongly suggesting that environmental
factors modulate the risk of developing type 1 DM. The Five to ten per cent patients with type 1 DM have coeliac disease.
incidence of type 1 DM is increasing in many countries, e.g. in Wheat gluten has been found to be diabetogenic in BB rats.
325
 In a Finnish study dietary supplementation of children with produced. These antibodies can be detected in the subject
vitamin D was found to be protective against type 1 DM. Cod long before development of type 1 DM as insulitis is slowly
liver oil which is a good source of vitamin D, when taken during progressive disease. However, all subjects with ICA or GAD – Ab
pregnancy has also been shown to be beneficial. do not necessarily develop type 1 DM. Insulin antibodies carry
a very small risk of type 1 DM, but its presence along with ICA
Other Factors increases the 5-year risk of type 1 DM to 50% to 70% particularly
Bafilomycin A1 produced by Streptomyces (which are ubiquitous in childhood type 1 DM below 5 years of age. Presence of
bacteria found in soil and tubers) could be a source of β-cell two or more antibodies suggests a greater risk of type 1 DM.
toxins. Other bacteria may also act as adjuvant to food antigens. Approximately 80% of patients with type 1 DM express two or
It has been observed that heat killed bacteria or microbial more autoantibodies. Although around 3% of normal subjects
products can act as an adjuvant. might express one or more antibodies, the chances of having
two or more antibodies being present in a normal subject, is
AUTOIMMUNE DESTRUCTION less than 0.3%. Indians have a high prevalence of type 1B DM
The strongest evidence to support autoimmunity as the ultimate and hence absence of these antibodies does not rule out type
pathogenesis comes from the presence of insulitis (presence of 1 DM.
inflammatory cells consisting of T lymphocytes, B lymphocytes,
and macrophages) around the islets in recently diagnosed CONCLUSION
patients of type 1 DM. Fifty per cent to ninety per cent of type 1 In subjects who are genetically predisposed to type 1 DM,
DM patients have presence of antibodies against, islet cells (ICA), certain, as yet, poorly defined environmental triggers initiate
glutamic acid decarboxylase (GAD) 65, and IA2. Moreover type 1 T-cell mediated immune response. With the development
DM has a strong association with other autoimmune disorders, of insulitis, autoantibodies are produced, which can be
like Hashimoto’s thyroiditis, Grave’s disease, pernicious anaemia, detected long before the development of clinical type 1 DM.
coeliac disease, etc. Subjects with genetic predisposition to type Insulitis is a slowly progressive disease and over a period of
1 DM, if exposed to certain environmental trigger, autoimmune months or years, may cause complete destruction of β-cells
destruction of β-cells starts. If the β-cells are destroyed to such (insulinopaenia) leading to clinical manifestation of type 1
an extent that the patient becomes insulinopaenic, he or she DM (Figure 1).
would develop hyperglycaemia and present with classical
features of type 1 DM.
Cellular Immune Response
Type 1 DM is a T cell mediated disease. β-cells can become the
target of CD8 T cells due to their close resemblance with other
foreign antigens (e.g. virus), the immune response being
directed towards the foreign antigen. Alternatively some virus
may infect β cells and the viral proteins may get expressed over
the β cells. In this case, the CD8 T cells directed against the virus,
would attack the β-cells.
Humoral Response Figure 1: Pathogenesis of type 1 diabetes mellitus.
Humoral response does not cause type 1 DM per se but is
considered to be the result of insulitis. In the process of insulitis, RECOMMENDED READINGS
islet cell antigens leak out of the damaged β-cells and initiate a 1. Joslin’s Diabetes Mellitus; 14th Ed. Lippincott Williams and Wilkins; 2005.
humoral immune response. Islet cell antibodies (ICA), GAD 65 2. Type 1 Diabetes Mellitus: Pathogenesis and metabolic alterations. In : RSSDI
antibodies, IA-2 antibodies, and insulin autoantibodies (IAA) are Textbook of Diabetes Mellitus; 2nd Ed; 2008.

326
 9.3 Pathogenesis of Type 2 Diabetes Mellitus

Hemraj B Chandalia

INTRODUCTION Of a variety of candidate genes, calpain-10, Kir 6.2, peroxisome

Simply stated, type 2 diabetes is caused by the interaction of proliferator activated receptor-γ, hepatocyte nuclear factor-4α
certain genetic abnormalities with adverse environmental factors. gene and transcription factor 7-like 2 gene are important. Many
To further identify the genetic and environmental factors and of these genes predispose to obesity, thus leading to diabetes.
unravel the pathogenetic mechanisms is a daunting task. A clear However, an interesting gene, ENPP-1 K121Q causes insulin
picture is emerging in certain areas, while it is blurred in others. resistance in the non-obese Asian Indians and is one of the
However, elucidation of these mechanisms holds the key to vast susceptibility genes in this population.
opportunities for therapeutic interventions.
Table 1: Monogenic Forms of Type 2 Diabetes
GENETIC FACTORS Phenotype characterised by defective insulin secretion
Type 2 diabetes is a polygenic disorder, caused by a cluster of Maturity-onset diabetes of the young (MODY)
susceptibility genes. It is very difficult to pinpoint these genes, MODY 1: Mutation in hepatic nuclear factor 4α (HNF-4α) gene
as they may be present without the phenotypic manifestations MODY 2: Mutation in glucokinase gene
or the disease may be seen at times in the absence of these MODY 3: Mutation in hepatic nuclear factor 1α (HNF-1α) gene
genes. It is also possible that these genes vary in various ethnic MODY 4: Mutation in insulin promoter factor 1 (IPF-1) gene
groups. The classic method of candidate gene identification has MODY 5: Mutation in hepatic nuclear factor 1β (HNF-1β) gene
been unsuccessful in unravelling these genes. The problem has MODY 6: Mutation in neurogenic differentiation-1 transcription
also been approached by studying the functional candidate factor (Neuro D1/β-2)
genes, tracing back the functional or biochemical abnormality Mutations in the insulin or proinsulin genes
to the genetic abnormality. Further, linkage analysis and micro Mitochondrial gene mutations
satellite genotyping technique followed by positional cloning Phenotype characterised by insulin resistance
has been tried with limited success. Mutations in the insulin receptor gene
The genetic aetiology is clear in a group of monogenic type 2 Type A insulin resistance
diabetes (Table 1). Here the gene is clearly identifiable and the Leprechaunism
phenotypic presentation and treatment approaches well Rabson-Mendenhall syndrome
elucidated. Some of these genes operate by producing insulin Lipoatrophic diabetes
resistance while others do so by producing a β-cell secretory Mutations in the PPAR-γ gene
defect. These forms of diabetes show an autosomal dominant
inheritance, identified by a vertical transmission. Mitochondrial ENVIRONMENTAL FACTORS
diabetes is maternally transmitted diabetes, caused by an A to Physical inactivity and excessive caloric intake are well
G transition in the mitochondrial tRNA Leu (UUR) gene at base recognised environmental factors producing type 2 diabetes.
pair 3,243. The disease is associated with sensorineural hearing These factors can produce the disease independently in a
loss. The same genetic anomaly at times produces a syndrome genetically susceptible person, but usually work via production
of Mitochondrial myopathy, encephalopathy, lactic acidosis and of obesity.
strokes (MELAS), the different phenotypic expression of the
Obesity and type 2 diabetes are inextricably interrelated. They
same genetic anomaly is not yet well understood. Although the
further coexist in the form of metabolic syndrome, together
prevalence of these varieties of diabetes would vary in various
with other anomalies like hypertension, high triglycerides, and
ethnic groups, it is estimated that they do not make more than
low HDL-cholesterol. It is estimated that 25% to 30% of the
about 5% to 10% of young-age diabetes. Some rare genetic
population in India and elsewhere suffers from the metabolic
abnormalities described are insulin gene abnormality which
syndrome. In the shadow of a global spurt of obesity, type 2
produces an abnormal insulin or a convertase deficiency which
diabetes is emerging as an epidemic.
impairs the conversion of proinsulin to insulin.
Obesity results from the interaction of multiple susceptibility
Abnormalities of insulin receptor are rare. They produce
genes with environmental factors. By various estimates,
syndromes of extreme insulin resistance (type A insulin
aetiologically hereditary factors account for 50% to 70% of the
resistance, Leprechaunism, Rabson-Mendenhall syndrome;
obesity. Obesity is characterised by insulin resistance, an
Table 1). If all these anomalies are put together, they may not
important feature of type 2 diabetes.
make more than 1% of all type 2 diabetes.
The search for genetic abnormalities in the common form of GENE-ENVIRONMENT INTERACTIONS
type 2 diabetes has been very intense but not very fruitful. Most The mechanism of interaction of gene and environment is a
susceptibility genes described increased the hazard ratio in very complex issue. The environmental factors interact by
diabetics versus the normal population only marginally. altering the expression of genes. There is also a gene-gene 327
 interaction. Intrauterine environment also may influence would limit the glycogen synthesis through the HMP shunt.
the subsequent development of many non-communicable Recently, a defect in glucose transport has been described in
diseases like diabetes, obesity, and hypertension. Low birth the milieu of high fatty acids. In insulin resistant state, fatty acid
weight, presumably due to poor maternal nutrition leads to oxidation or re-esterification leading to triglyceride synthesis
development of insulin resistance in childhood and adult life. is also impaired, thus leading to high levels of intra-myocellular
This is further exacerbated by over-nutrition in the post-natal FFA. On exercise, many of the abnormalities, including the
period. diminished amount of glycogen synthase gets corrected, thus
improving insulin sensitivity. Exercise increases glucose
Epigenetic phenomenon, where unchanged DNA sequence
transporter activity, improves capillary density, increases
can lead to altered phenotype, probably due to enhanced or
mitochondrial mass, and increases type 2 A muscle fibres
suppressed expression of certain genes that may be responsible
which are involved in the glycolytic process.
for obesity and diabetes Environmental factors may operate
through epigenesis.

BIOCHEMICAL PERTURBATIONS
The biochemical perturbations in type 2 diabetes were
described earlier than the genetic factors. Of these, the most
well known abnormalities are of peripheral and hepatic insulin
resistance, and impaired β-cell function.
Peripheral and Hepatic Insulin Resistance
With the advent of radioimmunoassay, massive data on serum
insulin levels in obesity and diabetes became available.
Hyperinsulinaemia was described first in obesity and later in
type 2 diabetes, including type 2 normal weight diabetic. Thus,
the concept of insulin resistance emerged. In spite of high
insulin levels, there is poor glucose utilisation and insulin
Figure 1: Diminished glucose utilisation in type 2 diabetics, primarily in the
inaction in the muscle, adipose tissue, and liver.
skeletal muscle.
In type 2 diabetes, adipose tissue in general and visceral fat in Courtesy: DeFronzo RA. Lilly Lecture 1987: The triumvirate: beta cell, muscle, liver.
A collusion responsible for NIDDM. Diabetes 1988; 37: 667-87.
particular, exhibits a decreased inhibition of lipolysis and
increased lipoprotein lipase activity, both resulting in a
The hepatic insulin resistance leads to enhanced gluconeo-
heightened flux of fatty acids in the liver and other tissues. High
genesis and glycogenolysis. Thus, increased hepatic glucose
fatty acids levels are known to inhibit glucose utilisation, as
production is a hallmark of uncontrolled diabetes. Type 2
demonstrated by Randle (glucose-fatty acid cycle). In type 2
diabetes is often associated with a fatty liver, with or without
diabetes and obesity, the adipose tissue also expresses
elevated liver enzymes and evidence of hepatic necrosis. It is
increased amounts of 11β-hydroxysteroid dehydrogenase
also a manifestation of hepatic insulin resistance and is often
type 1 (11 β HSD-1), leading to increased cortisol levels and
reversed by weight loss and the use of insulin sensitisers.
increased lipolysis locally. Adipose tissue is known to cause
insulin resistance by secreting TNF-α and interleukins. Of the The molecular mechanism of insulin resistance has been a subject
multiple adipose tissue hormones, resistin is responsible for of intensive studies (Figure 2). The resistance is very rarely due
insulin resistance, while adiponectin and leptin ameliorate to an abnormal insulin or insulin receptor. Sustained hyper-
insulin resistance. Although leptin levels are high in type 2 glycaemia produces glucotoxicity, probably by a failure to
diabetes, there is also a state of leptin resistance. These enhance hexosamine pathway, leading to increased glucosamine
biochemical abnormalities are accentuated in the abdominal levels. Increased glucosamine levels can produce insulin
adipose tissue, which is known to be abundant in type 2 resistance in adipose tissue and skeletal muscle. Sustained
diabetes. Interestingly, Asian Indians have increased adiposity hyperinsulinaemia also down-regulates the insulin receptor and
even at a relatively low BMI, which may be one of the reasons further aggravates insulin resistance. The main locus of the
for the increased type 2 diabetes. For this reason, the BMI above resistance appears to reside at the post-receptor level. Insulin
23 kg/m2 is also considered overweight in the Asian Indians, signalling is initiated by the binding of insulin to alpha subunits
unlike the cut-off point of 25 kg/m 2 in the Caucasians. of the receptors.This initiates a cascade of auto-phosphorylation
and dephosphorylation through the intra-cellular tyrosine kinase,
The skeletal muscle glucose utilisation is impaired to a greater
insulin receptor substrates (IRS-1, 2, 3, 4) and other signal
degree than adipose tissue in type 2 diabetes (Figure 1). In the
regulatory protein family (Gab-1,Cb-1, CAP, APS).
post-prandial state, the glucose is primarily deposited as
glycogen in the muscle. Hyperinsulinaemic-euglycaemic clamp The β subunit of insulin receptor has been shown to undergo
studies have shown that the non-oxidative glucose disposal, besides tyrosine auto-phosphorylation, a serine-threonine
like that in hexose monophosphate (HMP) shunt is severely phosphorylation. The latter type of phosphorylation increases
impaired in type 2 diabetes and other insulin resistant states. insulin resistance and impairs insulin signal transduction. The
The cause of this resistance is a high free fatty acid (FFA) insulin signal is terminated by dephosphorylation of the β
concentration in the myocytes, as demonstrated in several subunit of receptor by tyrosine phosphatases, the activities of
studies by using a nuclear-magnetic resonance imaging. This which is increased in insulin resistant states.
328
 The genetic factors that determine β cell differentiation, growth

Pathogenesis of Type 2 Diabetes Mellitus

and apoptosis are being intensively studied at present. The
growth factors and their biology is yet to be elucidated. It
obviously holds the key to a fruitful avenue for intervention.
However, it is characterised by an early apoptosis of β cells. The
insulin resistance and β cell failure exist and progress pari
passu. In early phases there is predominately a resistant state.
Subsequently, β cell failure dominates the scene. The β-cell is
able to compensate by increased insulin secretion in the face
of rising blood glucose, but at about 140 mg/dL of blood glucose
the insulin secretion levels off and a further rise in blood glucose
results in diminishing insulin secretion (Figure 3).
In about 10% of type 1 diabetics, the β cell failure may be due
to auto immunity. This is called latent autoimmune diabetes of
adults (LADA) and aetiologically represents a forme fruste of
type 1 diabetes.
Figure 2: Molecular mechanisms of insulin resistance. Altered post-receptor
events, tyrosine kinase phosphorylation, IRS and other signal regulatory proteins
are responsible for the resistance.
Source: Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and
lipid metabolism. Nature 2001; 414: 799-806.
aPKC = Atypical protein kinase C; GSK3 = Glycogen synthase kinase 3; IGF= Insulin-
like growth factor; MAP = Mitogen activated protein; PI (3)K = Phosphatidyl inositol 3
kinase; PPI = Protein phosphatase 1; PTEN = Phosphatase and tensin homologue
deleted on chromosome 10; SH1P2 = SH2-domain-containing inositol-5-phosphatase

Following the insulin receptor phosphorylation a number of

down stream events, including an increase in phosphatidyl
inositol-3 kinase (Pl-3 kinase) leads to the translocation of GLUT-
4. In insulin resistant state, the GLUT-4 is not depleted, but its
translocation is hampered. The glucocorticoid-induced insulin
resistance is also associated with a reduced insulin stimulated
IRS-1 associated Pl-3 kinase.
Insulin Secretory Defects in Type 2 Diabetes
In a non-diabetic individual, besides the meal-related insulin
Figure 3: Natural history of type 2 diabetes. The plasma insulin response depicts
secretion, there are rapid oscillations in insulin secretion every the classic Starling’s curve of the pancreas. Upper panel, : insulin-mediated
8 to 15 min, without any glycaemic stimulus. There is also a glucose uptake, : plasma insulin response.
circadian rhythm occurring every 80 to 150 min. Overall, about (DeFronzo, RA. From the triumvirate to the ominous octet: a new paradigm for the
18 to 32 units of insulin are secreted daily and about 50% is treatment of type 2 diabetes. Diabetes 2009; 58: 773-95).
extracted by the liver for local action during its first passage.
In type 2 diabetes, the rapid meal-related insulin secretion, which OTHER PATHOGENETIC MECHANISMS
primarily occurs in about 30 min post-meal and mostly represents
Besides the role of β cell, skeletal muscle, adipose tissue, and
the preformed insulin, is attenuated. The post-meal response for
liver in the genesis of type 2 diabetes, a few other important
the 2-hour period post-meal appears to be exaggerated but in
pathogenetic mechanisms have been described. The gastro-
relation to the high glycaemic levels is indeed also impaired. In
intestinal tract secretes a group of important hormones,
obesity and impaired glucose tolerance group, absolute amounts
collectively labelled as incretins.This includes two extremely well-
of insulin secreted may be excessive. The molecular mechanism
known members: glucagon like peptide (GLP-1) and glucose-
of this phenomenon is probably an overexpression of hexokinase
dependent insulinotropic peptide (GIP). The former is secreted
gene as compared to the glucokinase gene. As the former has a
from the L-cells of the ileum and the latter from the K-cells located
low Michaelis constant (K m) for glucose, hypersecretion is
in the proximal small intestine. These hormones account for the
produced.The circadian rhythm of both types of non-meal related
enhanced insulin secretory response upon ingestion of glucose
insulin responses is also altered or attenuated.
orally, as compared to that obtained by intravenous glucose
The β-cell mass appears to be slightly reduced at the time of administration. This has been termed the incretin effect. In type
diagnosis of diabetes; however, the functional capacity is 2 diabetes, the incretin effect is blunted, which can be corrected
impaired out of proportion to its mass and hence in many by injecting GLP-1 or its longer acting analogue, like exenatide
studies, a 50 % reduced insulin response has been described at or liraglutide. GLP-1 is normally destroyed by a group of enzymes
the onset of type 2 diabetes. Subsequently, the β cell mass called dipeptyl peptidases, of which dipeptyl peptidase-IV (DPP-
declines further in a relentless fashion with increasing IV) is the predominant one. Compounds inhibiting DPP-IV
insulinopaenia. This is at time correlated to fibrillary amylin inhibitors prolong the effect of endogenous GLP-1 and are being
deposition in the β-cells. used therapeutically at present. 329
 Although non-suppressibility of glucagon following a meal was by a high capacity glucose transporter called SGLT2. Remaining
described in type 2 diabetes almost 4 to 5 decades ago, it gained 10% of the filtered glucose is absorbed in the straight
further relevance recently, with the availability of therapeutic descending part of the proximal tubule by another glucose
tools to correct this anomaly. GLP-1 analogues and DPP-IV transporter SGLT-1. It has been demonstrated that in type 1
inhibitors described above correct this defect by suppressing diabetes the tubular maximum for the glucose absorption is
glucagon levels post-prandially. Tachy-alimentation has also increased. Although it is not clear whether the same holds true
been described to aggravate diabetes by exposing the body of type 2 diabetes, the levels of SGLT-2 mRNA is four-fold
to sudden surge of nutrients. GLP-1 analogues and DPP-IV increased in the proximal tubular renal cells. This may account
inhibitors are known to retard gastric emptying, thus offering for increased glucose resorption and hence, hyperglycaemia.
an additional mechanism of action. Inhibition of SGLT has provided another avenue to treat type 2
diabetes.
The hypothalamic neurons and neurotransmitters have been
considered in the pathogenesis of type 2 diabetes. There are In summary, type 2 diabetes originates from a complex
numerous changes described in the neurotransmitter secretion interaction of genetic and environmental factors, which express
in obesity and type 2 diabetes. The rapid first phase insulin themselves in the form of myriad biochemical abnormalities.
response is mediated through these pathways. It has been
demonstrated that the hypothalamic nuclei regulating appetite RECOMMENDED READINGS
are also insulin resistant. After the ingestion of glucose, the 1. Abate N, Chandalia M, Satija P et al. ENPPIK121Q polymorphism and genetic
elevated plasma insulin levels are unable to exert the inhibitory susceptibility to type 2 diabetes. Diabetes 2005; 54: 1207-13.
response in these nuclei in obese, insulin resistant individuals. 2. Boshell BR, Chandalia HB, Kreisberg RA, Roddam RF. Serum insulin in obesity
Hence, pharmacological manipulation of these neurons by and diabetes mellitus. Am J Clin Nutr 1968; 21: 1419-28.
promoting satiety can be utilised in type 2 diabetes. More 3. Hales C, Barker D. Type 2 (non-insulin-dependent) diabetes mellitus: the
recently, dopamine agonists, like bromocriptine have been thrifty phenotype hypothesis. Diabetologia 1992; 35: 595-601.
shown to improve hyperglycaemia in type 2 diabetes. 4. De Fronzo RA. Lilly Lecture 1987: The triumvirate: beta cell, muscle, liver. A
collusion responsible for NIDDM. Diabetes 1988; 37: 667-87.
Another new pathogenetic mechanism described shows 5. De Fronzo RA. From the triumvirate to the ominous octet: A new paradigm
involvement of kidney in the pathogenesis of type 2 diabetes. for the treatment of type 2 diabetes. Diabetes 2009; 58: 773-95.
Normally about 160 g of glucose is filtered in the glomerular 6. Saltiel AR, Kahn CR. Insulin signaling and the regulation of glucose and
filtrate; 90% of it is absorbed in the proximal convoluted tubule lipid metabolism. Nature 2001; 414: 799-806.

330
 9.4 Clinical Features and Diagnosis of
Diabetes Mellitus
D Maji

Diabetes mellitus is a group of metabolic disorder involving is rapid destruction of β-cells of pancreas; in a susceptible
carbohydrate, lipid and protein metabolism, characterised by subject due to viral mediated autoimmune process. A typical
chronic hyperglycaemia, as a result of defects in insulin secretion type 1 diabetes patient is below 30 years, is underweight
from the β-cells of pancreas or peripheral action of insulin (insulin and present with frank symptoms, e.g. polyuria, polydipsia,
resistance) or both. During the course of the disease the diabetic polyphagia, weakness, weight loss, restlessness and if continued
subjects are at risk of development of microvascular (retinopathy, for some period, may lead to diabetic ketoacidosis with altered
nephropathy, neuropathy) and macrovascular (coronary artery, sensorium and severe dehydration. Occasionally a child with
cerebrovascular and peripheral vascular disease) complications similar clinical presentation in a remote area may die before
later in the course of the disease. The features of long term the diagnosis is made. Any comatose child presenting with
complications then become a part of the diabetic phenotype. severe dehydration without diarrhoea; a diagnosis of type 1
diabetes should be in the list of diagnostic consideration. In
CLINICAL FEATURES some type 1 diabetic subjects; β-cell destruction is slower and
Clinical features of diabetes mellitus are variable and depend may mimic a type 2 diabetes in clinical presentation (latent
upon the type of diabetes and the stages of the natural history autoimmune diabetes in adult; (LADA). After initial treatment
of diabetes at which it is seen (Figure 1). with insulin, a type 1 diabetic may recover some residual β-cell
function (the so-called ‘honeymoon phase’) when they can be
In the earlier part of development of diabetes, the patient may
maintained with a small daily dose of insulin; rarely, they do not
remain asymptomatic for a long period of time; on the other
even need insulin for some period of time. However, this phase
hand in the later part of the disease the features of long-term
of recovery of residual β-cell function is temporary and the
complications of diabetes may manifest and become part of
autoimmune process ultimately destroys the remaining β-cells
the diabetic syndrome. There are four major types of diabetes—
and the subject becomes completely insulin deficient and
type 1 diabetes, type 2 diabetes, other specific types of diabetes
require insulin for survival.
and gestational diabetes (Figure 2).
TYPE 2 DIABETES
As the clinical manifestations of these types of diabetes may
be different, they will be considered separately. Type 2 diabetes constitutes almost 98% of diabetic population
in India. Age, obesity, lack of physical activity, and family history
TYPE 1 DIABETES
of diabetes are the predisposing factors for type 2 diabetes.
Type 1 diabetes constitutes less than 2% of total diabetic Other risk factors are – hypertension, dyslipidaemia, and past
population in India. In majority of type 1 diabetes patients; there history of gestational diabetes mellitus (GDM). Some may

Figure 1: The natural history of diabetes mellitus.

IGT = Impaired glucose tolerance; IFG = Impaired fasting glucose; HDL = High density lipoprotein; ICA = Islet cell antibody; IAA = Insulin autoantibody;
GADA = Glutamic acid decarboxylase antibody
331
 Figure 2: Four major types of diabetes.
Disorders of glycaemia: aetiologic types and stages.
* Even after presenting in ketoacidosis, these patients can briefly return to normoglycaemia without requiring continuous therapy (i.e.‘honeymoon remission’).
** In rare instances patients in these categories (e.g. Vacor toxicity, type 1 diabetes presenting in pregnancy) may require insulin for survival.

present with the characteristic symptoms of polyuria, Diagnostic criteria includes age of 30 years or older, no insulin
polydipsia and polyphagia with weakness and weight loss, treatment required for six months after diagnosis and the
many type 2 diabetics are asymptomatic and remain silent presence of antibodies to glutamic acid decarboxylase (GAD), islet
for many years and at diagnosis may have features of long- cells (ICA), tyrosine phosphate (IA 2α and IA 2β), or insulin (IAA).
term complications like neuropathy (tingling, numbness, OTHER SPECIFIC TYPES
paraesthesia of lower limbs), retinopathy or even nephropathy.
A middle-aged female often consult gynaecologist for pruritus These group of diabetes refers to glucose intolerance that
vulva, a male subject may consult physician for balanitis; develops in association with other disorders other than those
because chronic hyperglycaemia makes a subject prone to currently defined as type 1 or type 2 diabetes.
several type of bacterial or fungal infections. Asymptomatic Genetic Defect of the β -Cell
patients are diagnosed during routine health check-up for LIC Several forms of diabetes are associated with monogenic
policy, or job recruitment or before surgery. In spite of this, defects in β-cell. They are characterised by early onset in young
about half of the type 2 diabetic population in India remain age before 25, inheritance is autosomal dominant and they have
undiagnosed. impaired insulin secretion from β-cell with minimal insulin
LATENT AUTOIMMUNE DIABETES IN ADULTS (LADA) resistance, they are called maturity onset of diabetes in young,
(MODY ). Six different chromosomal locations have been
LADA includes a heterogeneous group of conditions that are
identified (Table 2).
phenotypically similar to type 2 diabetes, but patients have
autoantibodies that are common to type 1 diabetes (Table 1). Table 2: Classification of Currently Recognised Genetic Defects
of β -cell Function: Maturity-Onset Diabetes of the Young
Table 1: Characteristic of Special Tests for the Diagnosis of (MODY)
Diabetes Mellitus
MODY Chromo- Defective Molecular Most
Type of Diabetes Type some Gene Defect Common
Test Type 1 Type 2 LADA Product Therapy
1 20q HNF-4α β-cell mass, Oral hypoglyc-
C-peptide <1.51 ng per mL <1.51 ng per mL:
insulin secretion aemic agent,
(0.5 nmol per L): NPV for diagnosis
Insulin
PPV of 96% for in adults and
diagnosis in adults children 2 7p Glucokinase Glucose Diet and
and children phosphorylation exercise
GADA 60% prevalence in 7% to 43% Presence: PPV of 92% 3 12q HNF-1α β-cell mass, Oral hypogly-
adults and children prevalence in adults for requiring insulin insulin secretion caemic agent,
and children at 3 years Insulin
73% prevalence NPV of 94% for Absence: NPV of 49% 4 13q IPF-1 β-cell develop- Oral hypogly-
in children requiring insulin at for requiring insulin
(PDX-1) ment and caemic agent,
6 yrs in adults at 3 years
function Insulin
IA-2α 40% prevalence in 2.2% prevalence in PPV of 75% for
and adults and children adults requiring insulin at 3 5 17 cen-q HNF-β β-cell mass, Insulin
IA-2β years in persons 15 to insulin secretion
34 years of age 6 2q Neuro D1/ β-cell develop- Insulin
ICA 75% to 85% 4% to 21% PPV of 86% for β-2 ment and function
prevalence in adults prevalence requiring insulin at 3%
and children in adults in persons 15 to 34 Endocrinopathy
years of age
Hormone like growth hormone, cortisol, glucagon and
GADA = Glutamic acid decarboxylase antibody; ICA = Islet cell antibody;
LADA = Latent autoimmune diabetes in adults; NPV = Negative predictive value;
epinephrine are diabetogenic. Syndromes associated with the
PPV = Positive predictive value excess of these hormones are associated with hyperglycaemia
332 leading to secondary diabetes, e.g. Cushing, syndrome,
 Clinical Features and Diagnosis of Diabetes Mellitus
acromegaly glucagonoma, phaeochromocytoma. Apart from accepted any more. Today there is wide acceptance of the fact
symptoms of hyperglycaemia, they will have clinical features that there is a continuous spectrum of glucose levels between
related to respective endocrine disorder. those considered normal and those to be considered as
diabetic.
Drugs
Some drugs affect β-cell functions, e.g. Vacor (a rat poison), ORAL GLUCOSE TOLERANCE TEST
pentamidine, glucocorticoids (quite often used in pharma- Oral glucose tolerance test (OGTT ) should be done in the
cologic doses), can cause or precipitate diabetes. Some of morning after fasting for 10 to 16 hours before the test;
the anti-psychotic drugs also have diabetogenic effect, e.g. having unrestricted carbohydrate diet for 72 hours. No
clozapine, olanzapine, risperidone, quetiapine, ziprasidone, smoking should be done during the test. Any concomitant
aripiprazole. medication or illness should be noted. The test should be
performed with 75 g of anhydrous glucose in 150 to 300 mL
Other syndromes of water taken over 5 minutes time. Children to be given 1.75
Many genetic syndromes, are associated with increased gm/kg body weight, up to total of 75 gm of glucose. It is
incidence of hyperglycaemia; chromosomal disorders like recommended in asymptomatic individuals to reconfirm the
Klinefelter’s syndrome, Turner’s syndrome, and Down’s results on another occasion. Interpretation of OGTT is
syndrome. Wolfram’s syndrome, an autosomal recessive described in Table 3.

Table 3: WHO Diabetes Criteria-Interpretation of OGTT

Glucose levels Normal Impaired fasting Impaired glucose Diabetes
glycaemia (IFG) tolerance (IGT) Mellitus
Venous Plasma Fasting 2 hrs Fasting 2 hrs Fastin;g 2 hrs Fasting 2 hrs
(mmol/L) <6.1 <7.8 ≥6.1 & <7.8 <7.8 <7.0 ≥7.8 ≥7.0 ≥11.1
(mg/dL) <110 <140 ≥110 & <126 <140 <126 ≥140 ≥126 ≥200
To convert mmol/L to mg multiply by 18

disorder, is associated with insulin deficient diabetes and HbA1c AND DIAGNOSIS OF DIABETES MELLITUS
absence of β-cells seen at autopsy. HbA1c is an index of mean blood glucose in fasting and post-
Chronic Pancreatic Disease prandial state and is well established, and widely used as a
Chronic calcific pancreatitis develop hyperglycaemia, along clinical measure of chronic glycaemia, in the follow-up
with defects of exocrine function of pancreas. Fibrocalcific monitoring of diabetes. Several studies indicate that HbA1c
pancreatic disease (FCPD) which was earlier considered as a may show a glycaemic threshold with microvascular
separate type, are now put in this category of secondary complications, suggesting it may additionally be useful as
diabetes. a diagnostic test for diabetes (Table 4). The main factors in
support of using HbA1c as a screening and diagnostic
Haemochromatosis test include: (1) HbA1c does not require patient to remain
Abnormal glucose intolerance occurs in 75% to 80% of fasting, (2) HbA1c reflects longer-term glycaemia than
haemochromatosis patients where iron deposition is found in does plasma glucose, (3) HbA1c laboratory methods
different tissues of the body including liver and pancreas. The are now well standardised and reliable, and (4) errors
severity of cirrhosis and iron load is correlated with the degree caused by non-glycaemic factors affecting HbA1c such as
of glucose intolerance. Characteristic bronze colour skin and haemoglibinopathies are not frequent and can be minimised
hepatospl-enomegally are prominent clinical features in this by confirming the diagnosis of diabetes with a plasma glucose
condition. specific test.

DIAGNOSIS Table 4: Interpretation of HbA1c Test in Hyperglycaemic States

as Proposed by Experts
Diagnosis of diabetes should be made in the early stage of
development of the hyperglycaemic state, as several reports Normal <5.7%
including that of Diabetes Control and Complication Trial Pre-diabetes 5.7% to 6.4%
(DCCT), United Kingdom Prospective Diabetes Study (UKPDS) Diabetes 6.5% or more
and Steno 2 trial, clearly suggest that long-term complications
of diabetes can be prevented or delayed if treatment is Gestational Diabetes Mellitus (GDM)
started early. In clinical practice, however, diabetes is When hyperglycaemia is just recognised during pregnancy, it
diagnosed late. is defined as gestational diabetes. Majority of GDM are
A plethora of diagnostic criteria existed before the publication asymptomatic and diagnosed on routine check-up in the
of National Diabetes Data Group (NDDG) in 1979 and WHO obstetric clinic. In general glucose intolerance resolves after
Expert Committee Report, 1980. WHO has published several the pregnancy is over, but in those who continue to have
technical reports relating to diabetes in 1965, 1980, 1985,1994, hyperglycaemia after delivery might have had unrecognised
and 1999. The diagnostic criteria used over this period are not diabetes before pregnancy.
333
 Table 5: Interpretation of OGTT for GDM Plasma Sugar Value Given Below in mg/dL
100 gm 3 hours OGTT 100 gm 3 hours OGTT 100 gm 3 hours OGTT 75 gm 2 hours OGTT 75 gm 2 hours OGTT
O‘Sullivan and NDDG Carpenter and ADA WHO
Mahan 1973 1979 Couston ‘ 82 ADA 1997 1998 1999
Fasting 90 105 95 95 126
1 hours 165 190 180 180 —
2 hours 145 165 155 155 140
3 hours 125 145 140 — —
Any two Any two Any two Any two

DIAGNOSIS OF GESTATIONAL DIABETES diabetes; but as a screening test for diabetes it is insensitive
Diversity of opinion exists for the diagnosis of gestational specially when the value is on the lower side (Tables 6 and 7).
diabetes. O’Sullivan was the first to use the term Gestational
Table 6: Sensitivity and Specificity of Achieved in Screening for
Diabetes in 1961. In 1964 O’Sullivan and Mahan suggested the
Diabetes Based on Random Plasma Glucose of Various Levels
100 gm 3 hours OGTT in the 2nd and 3rd trimester of pregnancy
to diagnose GDM. Random Plasma Glucose Sensitivity Specificity
(mg/dL) (%) (%)
In 1979, the NDDG recommended a 15% upward adjustment
≥110 84 65
of the diagnostic threshold using the venous plasma glucose
≥120 76 77
in place of whole blood glucose. In 1982, Carpenter and ≥130 63 87
Loustan modified the O’Sullivan and Mahan criteria using new ≥140 55 92
enzymatic glucose oxidase method. The present American ≥150 50 95
Diabetes Association (ADA) criteria recommends both 100 gm ≥160 44 96
and 75 gm OGTT done between 24 and 28 weeks of gestation. ≥170 42 97
The WHO criteria is based on the 75 gm OGTT. The International ≥180 39 98
Association of Diabetes and Pregnancy Study Group also The following ADA guidelines are widely accepted for screening
recommends that all women with no prior history of diabetes of diabetes.
undergo a 75 gm 2 hours OGTT between 24 and 28 weeks.
Additional Risk Factors for Diabetes
SCREENING FOR DIABETES  Physical inactivity
Diabetes is a common disease and associated with significant  Hypertension
morbidity and mortality. It has an asymptomatic phase that may  HDL cholesterol <35 mg/dL
be up to 7 to 10 years before the diagnosis is made. If treated  Triglyceride >250 mg/dL
early, the long-term complications may be preventable, so  History of cardiovascular disease
testing is rationale for screening diabetes. Both fasting plasma  Previous IFG or IGT
glucose (FPG) and 2 hours post-glucose values (after 75 gm  First degree relative is diabetic
glucose) are now used widely in clinical practice as well as in  History of GDM
epidemiological studies. Though a casual plasma glucose more  Member of high-risk ethnic group
commonly called random plasma glucose (RPG) 200 mg/dL or  Delivery of baby >9 lb
greater with symptoms is an established diagnostic criteria for  History of PCOD

Table 7: Criteria for Screening and Diagnosis of Diabetes at a Glance

Screening Diagnosis
FPG ≥100 mg/dL FPG ≥126 mg/dL
A1c >6.0% A1c ≥6.5%
RPG ≥130 mg/dL RPG ≥200 mg/dL
If screening result is negative, screen again in 3 years 2-hour OGTT ≥200 mg/dL
If screening result is positive but below the diagnostic threshold, Diagnosis requires confirmation unless unequivocal symptoms
do another test for diagnosis, using a different method of hyperglycaemia are present
If screening result is above the diagnostic threshold but a second Diagnosis based on HbA1c requires confirmation using a glucose
test does not reach the threshold, test again in 1 year dependent test (FPG or OGTT) or, if first HbA1c is ≥7.0%, by a
second HbA1c ≥6.5%
In asymptomatic persons with Hba1c ≥6.5%, if FPG ≥126 mg/dL
or RPG ≥200 mg/dl, diagnosis is confirmed
If screening is positive but less than the diagnostic threshold,
two tests are required to reach the diagnostic threshold

334
 Clinical Features and Diagnosis of Diabetes Mellitus
Testing to detect type 2 diabetes should be considered in and diagnosing diabetes mellitus. J Clin Endocrinol Metab 2008; 93:
asymptomatic adults with BMI of 25 or greater and one or more 2447-53.
additional risk factors for diabetes. 3. DCCT Research Group: The effect of intensive treatment of diabetes on
the development and progression of long-term complication in insulin-
Screening for Gestational Diabetes (GDM) dependent diabetes mellitus. N Eng J Med 1993; 329: 977-86.
4. Fajans SS, Bell GI, Polonsky KS. Molecular mechanisms and clinical
Risk assessment at the 1st prenatal visit: High-risk GDM
pathophysiology of maturity onset diabetes of the young. N Eng J Med
 Marked obesity 2001; 345: 971-80.
 Previous GDM 5. Irene M Straton, Aamanda Adler, Andrew H, Neil W, David R Mathews, Susan
 F/H/O diabetes E Menley, Carole A Cutt, David Haden, Robber + C Turner, Rusy R Holton.
On behalf of the UK prospective study. Association of glycaemia with
 Glycosuria macrovascular and microvascular complication of type 2 diabetes (UKPDS
35) prospective observational study. BMJ 2000; 321: 405-12.
If testing is negative, re-testing should be done at 24 to 28 weeks
of gestation. 6. Maji D. Diabetes or prediabetes-when to start? Medicine Update 2010; 20:
131-4.
Women with GDM should be screened for diabetes 6 to 12 7. Maji D. Pathogenesis of diabetes mellitus. API Textbook of Medicine; 2008; 8:
weeks post-partum and subsequent screening for the pp1044-9.
development of diabetes. 8. National Diabetes Date Group: Classification and diagnosis of diabetes
mellitus and other categories of glucose intolerance. Diabetes 1939; 28:
CONCLUSIONS 1979.
9. O’Sullivan JB, Mahan C. Criteria for OGT in pregnancy. Diabetes 1964; 13:
In summary, diabetes is a heterogeneous metabolic disorder 278-85.
with varied manifestation. Prevention, timely diagnosis, and 10. Parita Patel, Allison Macerollo. Diabetes Mellitus: Diagnosis and screening.
early initiation of treatment are important in patients with American Family Physician 2010; 81: 863-70.
diabetes mellitus. Many of the complications associated with 11. Peter Gaxto, Pemla Vedel, Hans-Hranrik Paring, Otuf Pedersen. Intensified
multifactorial intervention in patients with type 2 diabetes mellitus and
diabetes such as nephropathy, retinopathy, neuropathy,
micro albuminuria: the steno type 2 randomised study. Lancet 1999; 353:
cardiovascular disease, stroke, and death can be delayed or 617-22.
prevented with early and appropriate treatment of elevated 12. Report of WHO Study Group: WHO Technical Series 844: 1994: Definition
blood sugar, blood pressure, and blood lipids. Based on diagnosis and classification: P11-35, WHO Geneva.
aetiology, diabetes is presently classified as type 1 diabetes, type 13. Sabanayagam C, Liew G, Tal ES, Shankar A, Lim SC, Subramaniam T, Wogn
2 diabetes, diabetes due to other illness and gestational TY. Relationship between glycated haemoglobin and microvascular
complications: Is there a natural cut-off point for the diagnosis of diabetes?
diabetes. At present there has been wide acceptance of the Diabetologia 2009; 52: 1279-89.
WHO criteria (1997) for the diagnosis of diabetes on the basis 14. Seshiah V. Gestational diabetes mellitus. Current guidelines for diagnosis
of fasting plasma glucose and modified oral glucose tolerance and treatment. Medicine Update 2010; 57-64.
test. Of late; estimation of HbA1c has been proposed by experts 15. Tabaci BP, Herman WH. Amultivariate logistic regression equation to screen
to diagnose and screen diabetes. The lack of availability of for diabetes: development and validation.Diabetes Care 2002; 25: 1999-2003.
HbA1c testing in more remote or underserved areas, the cost 16. The Expert Committee on the Diagnosis and Classification of Diabetes
of the test and lack of standardisation of the test are of Mellitus. Report of the Expert Committee on the Diagnosis and
Classification of Diabetes Mellitus. Diabetes Care 1997; 20: 1183-97.
legitimate concern. There is uniform agreement that earlier the
17. WHO/IDF (2006) Definition and diagnosis of diabetes mellitus and
diabetes is diagnosed and measures taken, the greater is the intermediate hyperglycaemia. Report of a WHO/IDF consultation. WHO,
benefit of the patient. Geneva.
18. WHO (1980) World Health Organization Expert Committee on Diabetes
RECOMMENDED READINGS Mellitus: second report. WHO Technical Report 646. WHO, Geneva.
1. American Diabetic Association: Diagnosis and classification of diabetes 19. Zhang P, Eugelgm MM, Valder R, Cardwel B, Benjakin SM, Naryan KM.
mellitus. Diabetes Care 2010; 33 Supplement January. Efficient cut-off points for the screening tests for detecting undiagnosed
2. Christopher D Saudek, William H Herman, David B Sacks, Richard M diabetes and prediabetes an economic analysis. Diabetes Care 2005; 28:
Bergenstal, David Edelman, Mayer B. Davidson. A new look at screening 1321-5.

335
 9.5 Lifestyle Modifications in
Management of Diabetes
BK Sahay

INTRODUCTION quantities separately), (c) use any of the above oils with alpha-
Lifestyle measures which combines increased physical activity linoleic acid containing oil like mustard oil or soyabean oil.
and dietary modifications are an important component in the Roughly the oil intake should be half a litre per person per month.
management of both type 1 and type 2 diabetes mellitus (DM). The salt intake should be between 5 to 6 g per day. Dietary
The role of exercise in the control of DM has been known since guidelines are summarised in Table 2.
ages. Our ancient ayurvedic physicians Sushruta and Charaka
Table 1: Calorie Requirements Based on Activity and Ideal Body
stressed on the role of exercise in the treatment of DM. Even
Weight (IBW)
after the advent of insulin, Joslin emphasised the importance
of exercise as one of the basic principles of management of Category Sedentary Moderately Strenuous
diabetic patients. All major guidelines for diabetes management Active Physical Activity
recommend lifestyle changes as part of the standard treatment Overweight/Obese 20 25 30
in all patients of DM. Ideal weight 25 30 35
Underweight 30 35 40
DIETARY THERAPY
IBW is calculated as (Height in cm -100) x 0.9
The goal of dietary therapy is to provide a nutritionally balanced
Grid for calculating the recommended caloric intake (Kcal/kg/day) based
diet to maintain the ideal body weight (IBW) of the patient to on physical activity and weight of the individual
achieve good glycaemic control along with correction of the
dyslipidaemia. The dietary planning is based on the type of Table 2: General Guidelines for Diet in Diabetes Mellitus
diabetes, weight of the patient, activity profile, and presence of
co-morbid conditions. Energy (Calories) 25 to 30 calories/kg IBW, reduce calories in obese
and increase in underweight individuals
Dietary macronutrient composition is one of the important Protein 0.8 g/kg body weight, supplement provided for
consideration for the dietary therapy in diabetes. Studies have pregnancy, lactation and growth. A small quota
shown that higher intakes of saturated and trans-fats are of animal proteins—fish, chicken, milk and
associated with an increased risk of diabetes, whereas higher yoghurt and appropriate food intake
intake of mono-unsaturated and poly-unsaturated fats is recommended, avoid cattle meat and eggs
associated with decreased risk of diabetes. The importance of Fats 20% to 25% of total calories
consuming minimally processed foods with low glycaemic Saturated 6% to 7% of total calories
index and glycaemic load is recommended in the management PUFA total 6% to 7% of total calories
of diabetes. Whole grain products such as whole wheat breads, N6/N3 ratio 1:1 to 4:1
brown unpolished rice, oats, and barley tend to produce lower MUFA 6% to 7% of total calories
glycaemic and insulinaemic responses than highly processed Cooking oil 0.5 kg/month/person
refined grains. Such unprocessed whole grains are also rich in Total fat intake, with cholesterol 300 mg per day
fibre, antioxidants, vitamins, and phytochemicals. Carbohydrates 55% to 60% of total calories
To encourage complex carbohydrates, i.e. mainly
The calorie requirements are calculated for each individual whole grain cereals, pulses, beans, vegetables, and
(Table 1) based on his weight and physical activity. These are salads. Avoid simple and refined carbohydrates
distributed into three principal meals and two snacks.The calories like bakery products or deep fried items
are derived mainly from carbohydrates 50% to 60%, 20% from Fruits Fresh fruits up to 400 g per day. Avoid juices
proteins and 20% from fats. The carbohydrates should be of low Dietary fibre 30 to 40 g per day preferably from natural
sources; avoid loss from refining and processing.
glycaemic index and should be rich in fibre, the source of fat
Indian diet is rich in fibre and generally does not
should be 7% each of saturated mono- and poly-unsaturated fats. require addition of fibre supplements
Three percent of total energy should be derived from essential Common salt Up to 5 to 6 g per day. Reduced intake to 4 g per
fatty acids. Cholesterol intake should be less than 300 mg per day in the presence of hypertension, renal failure
day. With regard to fat in the diet, one should take into account and hearing problems
the invisible fat in the diet derived from cereals and legumes and Condiments and Provides anti-oxidants, trace elements, minerals,
milk products which nearly contributes to 50% of the required spices and n-3 fatty acids
fat. As per the choice of oils in the diet, none of the available oils Artificial Use of saccharin and aspartame in limited quantity
are ideal, however the choice of cooking oil should be as follows: sweetners is acceptable. Avoid in pregnancy and lactation
(a) use an oil which has moderate quantity of linoleic acid like Alcohol Avoid if possible. If not, drastically restrict. It is
groundnut oil, rice bran or sesame, (b) use an oil which has high utilised as fats.
amounts of linoleic acid like safflower oil, sunflower oil, cotton 1 g = 7 calories (2 small drinks/one glass of wine/
pint of beer (preferably avoided)
336
seed or corn oil along with an oil which has relatively low levels
Tobacco Avoid smoking or its use in any form
of linoleic acid like palm oil (mix equal quantities or use equal
 Lifestyle Modifications in Management of Diabetes
Fresh fruits up to 400 grams per day are advisable. Consuming Hitherto it was thought that exercise should not be recommended
the whole fruit is better than the fruit juice which needs to be for type 1 DM, currently there is enough evidence that regular
avoided. Ideal fruits are citrus fruits, orange sweat lime, guava, physical exercise helps in improving the insulin sensitivity as
apple, papaya and pomegranate. They provide vitamins and well as cardiovascular risk factors.
fibre. Each one portion contains 40 to 50 calories.
Table 3: Summary of Exercise Recommendations for Patients
Indian diets traditionally are high in carbohydrate content. There with Type 2 Diabetes Mellitus
have been concerns expressed regarding difficulty in achieving
Screening Search for vascular and neurological complications
glycaemic control and an increase in the risk of development
including silent ischaemic heart disease
of complications with such diets. However, studies from India
Stress electrocardiogram in patients >35 years of
and Japan have shown that even with diet high in carbohydrate age or >10 years of diabetes
content, good glycaemic control can be achieved without
Exercise Aerobic
increasing the risk for complications.
programme Resistance
EXERCISE THERAPY and type Yogic practices

Adequate physical activity helps in correcting obesity which is Intensity 50% to 70% of maximum aerobic capacity
a major modifiable risk factor in type 2 DM. In addition, physical Duration 20 to 60 minutes with warm up and cool down
activity may independently enhance insulin sensitivity and Frequency Ideally daily or at least 5 times a week
glucose tolerance. Exercise increases the skeletal glucose Avoid Careful selection of exercise type and intensity
transporter protein GLUT4 which is responsible for insulin complications Patient education
independent glucose transport into the skeletal muscle. Monitoring of blood glucose by patient and
overall programme by medical personnel
Regular physical exercise is associated with changes in body
Compliance Make exercise enjoyable
composition with a reduction in body fat and increase in muscle Convenient location
mass, a reduction in triglycerides, increase of high density
lipoprotein 2 fraction. Exercise causes a reduction in blood Many of the elderly patients tend to avoid physical exercise.
pressure, corrects the endothelial dysfunction and brings about However, with increasing age there is a progressive decline in
improvement in the fibrinolytic activity. Exercise also induces insulin sensitivity, muscle mass and strength and loss of mineral
weight loss and subsequently helps in maintenance of the from bones. Regular physical exercise can prevent and reverse
weight. these changes. Exercise also improves the quality of life in the
To be effective, exercise should be performed regularly. An elderly diabetics.
exercise schedule that is enjoyable and suits the needs of an Upper body exercises should be routinely recommended for
individual should be chosen. Daily exercise of 30 to 45 minutes diabetic subjects with arthritis. Pregnant women with diabetes
is preferable. It should be done on an empty stomach either in should also be advised walking and if this is not possible they
the morning or evening. An exercise session should have a should be advised upper body exercises.
warning up and cooling down. Following a session of exercise,
there is an increase in insulin sensitivity which returns to For cardiovascular conditioning, the exercise intensity in healthy
baseline after 72 hours of cessation of exercise. This underlies adults should be such that 75% to 90% of the target heart
the importance of persistent and regular exercise. Apart from rate (THR) is achieved for at least 15 minutes (THR = 220-Age).
the aerobic exercises (isotonic exercises), resistance training However, for the diabetic subjects, the intensity of the exercise
exercises (isometric exercises) are also useful since they increase should achieve 50% to 70% of THR.
the muscle mass, particularly in the elderly patients. Missing exercise for more than 72 hours may increase the blood
Before an exercise programme is initiated a thorough clinical glucose by 80 to 100 mg in subjects on oral hypoglycaemic
evaluation of the patient should be made particularly in regard agents (Table 4).
to cardiovascular disease, neuropathy, autonomic neuropathy,
nephropathy and retinopathy. If any of these is present, suitable Table 4: Caloric Expenditure in a 60 kg Individual Performing
Various Forms of Exercise for 60 Minutes
precautions and modification should be made in the exercise
schedule. Treadmill exercise test should also be performed in all Type of Exercise Caloric Expenditure
cases in order to detect myocardial ischaemia. A fair degree of Aerobics 450+
glycaemic control has also to be achieved before initiating the Cycling, moderate 450+
exercise programme particularly in patients with type 1 diabetes, Jogging (5 m per hour) 500
wherein exercise done in the background of a poor glycaemic
Gardening, digging 500
control can precipitate diabetic ketoacidosis (Table 3).
Skipping with rope 700+
Presence of autonomic neuropathy may limit an individual’s Running 700+
exercise capacity and increase the risk of adverse cardiovascular Swimming, active 500+
events. Hypotension and hypertension are more likely to Walking (3 m per hour) 280
develop in patients with autonomic neuropathy. These patients Table Tennis 290
have difficulties in thermoregulation and should be advised to Gardening 350
avoid exercises in extremely hot or cold environments and to Tennis 350+
be careful about their hydration.
337
 Figure 1: Bhujangasana.

Figure 4: Ardha Matsyendrasana.

Figure 2: Dhanurasana.

Figure 5: Paschimotasana.

Figure 3: Naukasana.

ROLE OF YOGIC PRACTICES Figure 6: Shavasana.

Several recent studies have documented the beneficial effect
of yogic practices in both type 2 and type 1 DM yogic practices RECOMMENDED READINGS
improve glycaemic control, reduce blood pressure, correct
1. Lifestyle Changes in Management of Diabetes Mellitus in the Indian
dyslipidaemia, reduce insulin resistance and eliminate stress Diabetes Guidelines. J Assoc Physicians of India 2002; 50.
leading to effective control of diabetes and prevention of its 2. Management of diabetes mellitus: exercise and yoga. In: Ahuja MMS,
long-term complications. Some of the common yogic exercises Tripathi BB, Moses SGP et al, editors. RSSDI Textbook of Diabetes Mellitus.
are shown in (Figures 1 to 6). Research Society for Study of Diabetes in India 2002; 369-78.
338
 9.6 Oral Anti-Diabetic Drugs

Anil Bhansali, Viral Shah

INTRODUCTION (b) Second generation: glibenclamide, glipizide and

Oral anti-diabetic drugs (OADs) have been used for more than gliclazide
five decades in the management of type 2 diabetes mellitus (c) Third generation: glimepiride
(T2DM). T2DM is characterised by insulin resistance and insulin B. Non-sulphonylureas
deficiency. Therefore, there are two main classes of drugs, one
– Meglitinides: repaglinide and nateglinide
which decreases insulin resistance and the other which increase
insulin secretion. The basic mechanism and target organs have C. GLP-1 analogues
been illustrated in Figure 1. This chapter gives an overview of – Exenatide and liraglutide
different OADs and their brief details. D. DPP-IV inhibitors
HISTORICAL PERSPECTIVE – Sitagliptin, vildagliptin and saxagliptin
The quest for oral anti-diabetic agent began in the backdrop 2. Agents lowering insulin resistance (sensitisers)
of the discovery of insulin. Lacklustre introduced guanidine A. Biguanides: phenformin and metformin
derivative, synthalin A, in 1926 that marked the journey of B. Thiazolidinediones: pioglitazone and rosiglitazone
OADs. It was serendipity when chemist Marcel Janbon and co- 3. Agents reducing carbohydrate absorption
workers, who were studying sulphonamide antibiotics,
A. Alpha-glucosidase inhibitors: acarbose, voglibose and
discovered that the compound sulphonylurea can induce
miglitol
hypoglycaemia in animals. Sulphonylurea was first discovered
by Frank and Fuchs but later on withdrawn from market due 4. Agents decreasing renal reabsorption of glucose
to bone marrow suppression. Subsequently, number of drugs SGLT-2 inhibitors
came in the market. First synthesis of dimethylbiguanide
(metformin) is attributed to Werner and Bell in 1922 and it was SULPHONYLUREA
Sterne’s work that studied mechanism of metformin in great Structure
detail and popularised it. Thiazolidinediones were discovered Basically sulphonylureas have a benzene ring plus sulphonyl
in late 1970s when lipid lowering drug ciglitazone was found group plus urea. Differences in the para position of the benzene
to possess hypoglycaemic effects. Acarbose was isolated in ring and in addition of a group to the urea results in different
1975 from the strains of actinoplanes species and synthesised sulphonylurea compounds.
in laboratory in 1988 and found to be the inhibitor of alpha-
Mechanism of Action
glucosidase.
Insulin secretion is regulated by an ATP dependent K+ channel
CLASSIFICATION OF ORAL ANTI-DIABETIC DRUGS located in the plasma membrane of the β cell. Under fasting
1. Agents stimulating insulin release (secretagogues) conditions, most of the channels are open, and K + is actively
extruded from the β-cell. When the plasma glucose rises, glucose
A. Sulphonylureas
is transported into the β-cell through GLUT receptor and
(a) First generation: chlorpropamide and tolbutamide phosphorylated by glucokinase enzyme. This results in the
formation of ATP from ADP. Increase ATP/ADP ratio cause ATP
dependent K+ to close resulting into depolarisation of cell.Voltage
dependent Ca2+ channel opens and calcium moves from extra-
cellular space to β-cell cytosome causes the insulin granule to
migrate to cell surface whereas its contents are released by
exocytosis. ATP dependent K+ channel consists of two subunits
named SUR which is the binding site for various sulphonylurea
drugs, other is KIR channel. The potency of sulphonylurea is a
function of its binding affinity to the SUR receptor (Figure 2).
Indications
Sulphonylureas are drugs of choice after lifestyle modification
and metformin fails to achieve glycaemic target. However,
when A1c is more than 9%, sulphonylureas are usually to be
started in combination with metformin. Good responders to
sulphonylureas include: (a) short duration of diabetes, (b) normal
weight subjects, (c) fasting plasma glucose less than 200 mg/dL,
Figure 1: Site of action of different OADs. and (d) preserved β-cell mass. 339
 secondary failure are dietary indiscretion, lack of physical
activity, intercurrent illness and declining β-cell function.
NON-SULPHONYLUREA SECRETAGOGUES
Structure
The meglitinide analogues are non-sulphonylurea compounds
derived from the benzimido non-sulphonylurea portion
of glibenclamide. Table 2 shows the differences between
sulphonylureas and non-sulphonylureas.
Mechanism of Action
Mechanism of these agents are similar to that of sulfonylureas but
they bind to a site on the SUR 1 sub unit of the β-cell ATP dependent
K+ channel that is different from the binding site for sulfonylureas.
Characteristic of Each Agent
Figure 2: Mechanism of action of sulphonylureas. Repaglinide is a carbamoylmethyl benzoic acid derivative, which
can be safely used in patients with renal failure. Nateglinide is a

Table 1: Characteristics of Different Oral Anti-Diabetic Agents

Drug Dose Range Peak Level Half-life Duration of Route of Excretion Reduction in A1c
(mg) (hours) (hours) Action (hours)
Sulphonylureas
Tolbutamide 500 to 3,000 3 to 4 4.5 to 6.5 6 to 12 Kidney
Chlorpropamide 100 to 500 2 to 4 36 Up to 60 Kidney ⎫
Tolazamide 100 to 1,000 3 to 4 7 10 to 14 Kidney ⎪
⎪ 1% to 2% with
Glipizide 2.5 to 40 1 to 3 2 to 4 8 to 10 Kidney 80%, faeces 20% ⎬ almost all agents
Glyburide (Glibenclamide)
Gliclazide
1.25 to 20
40 to 240
~4
3 to 4
10
6 to 15
10 to 24
Up to 20
Kidney 50%, faeces 50%
Kidney 70%, bile 30%
⎪
Glimepiride 1 to 8 2 to 3 9 12 to 24 Kidney 60%, faeces 40%
⎪⎭
Non-sulphonylurea secretagogues
Repaglinide 0.5 to 4 1 1 to 2 3 to 4 Faeces 0.5% to 1%
Nateglinide 60 to 120 1.8 1 to 2 3 to 4 Kidney 80%, faeces 50%
Biguanide
Metformin 500 to 2,500 — 1.5 to 2.8 6 to 8 Kidney 1% to 2%
Thiazolidinediones
Pioglitazone 15 to 45 — 3 to 7 24 Kidney 35%, faeces 30% 0.5% to 2%
Rosiglitazone 2 to 8 — 3 to 4 12 to 14 Kidney 70%
Alpha-glucosidase inhibitors
Acarbose 50 to 300 — — — GIT 0.5% to 1%

Pharmacokinetic properties of different OADs are given in derivative of phenylalanine and very rapid acting insulin
Table 1. Adverse effects, contraindications and drug interactions secretagogue. Its rate of association and dissociation are much
of different OADs are listed in Table 3. Commonly used drugs more rapid. It has very low binding affinity for cardiovascular
which can enhance the effect of OADs are listed in Table 4. ATP dependent K+ channels.
Primary Sulphonylurea Failure These agents are generally indicated for the control of post-
prandial hyperglycaemia alone or as an adjuvant treatment
For unknown reasons, not all T2DM patients respond to the anti-
diabetic action of sulphonylureas and this is known as primary with other anti-diabetic agents. Their use is contraindicated in
sulphonylurea failure. hepatic insufficiency and pregnancy.

Secondary Sulphonylurea Failure Table 2: How Non-Sulphonylureas Differ from Sulphonylureas?

Most patients of T2DM who respond very well initially may have Sulphonylureas Non-Sulphonylureas
a loss of effective anti-diabetic response after several years of
treatment and this is known as secondary sulphonylurea failure. Act on SUR1 K+ channel Act on different channel
In the United Kingdom Prospective Diabetes Study (UKPDS), Intermediate or long acting Short acting
treatment with sulphonylureas achieved an A1c less than 7% To be taken before meal Taken along with meal
in 50% of patients at three years, 34% at six years and 24% at Major effect to decrease FPG Mainly reduce PPG
nine years. Six and nine year data from the UKPDS showed that and modestly PPG
this secondary failure is a characteristic of all anti-diabetic Hypoglycaemia is common Hypoglycaemia is rare
treatments and not just sulphonylureas. Still, the term secondary A1c reduction is good (1% to 2%) Modest A1c reduction
sulphonylurea failure remains in clinical practice. Secondary (0.5% to 1%)
340
failure is usually considered as a good initial response to the Weight gain is a problem Less weight gain
oral glycaemic agents for at least 1 month. The causes of this
 Oral Anti-Diabetic Drugs
Table 3: Contraindication, Adverse-events and Drug Interactions of Different OADs
Drug Contraindications Adverse Effects Drug Interactions
Sulphonylureas (a) T1DM Hypoglycaemia Drugs increase hypoglycaemic response:
Pregnancy Weight gain aspirin, fibrates, alcohol,
Major surgery Hypersensitivity reaction (rare) H2 blockers, allopurinol, probenecid
Severe infections ? Concern about cardiovascular Drugs decrease hypoglycaemic effects:
ill-effects barbiturate, rifampicin, steroid, oestrogen,
phenytoin, β-blockers
(b) Hypersensitivity to sulpha Chlorpropamide causes —
compounds hyponatraemia
Significant liver or kidney disease
Non-sulphonyl- Renal and liver disease Hypoglycaemia and weight Drugs increase repaglinide metabolism:
urea secretag- gain less common than rifampicin, barbiturate, carbamazepine
ogues sulphonylureas Drugs decrease metabolism: antifungal,
erythromycin NSAIDs, and sulphonamides
may increase its action
Biguanide Serum creatinine >1.5 mg/dL in males Nausea, vomiting, dysgeusia, Cimetidine increases the metformin level
and >1.4 mg/dL in females. occasional diarrhoea, lactic Nifedipine enhances absorption
Hepatic dysfunction acidosis and B12 deficiency
Congestive heart failure (CHF) are rare
class- III, IV Alcohol abuse/binge drinking.
Acute or chronic metabolic acidosis
Relative contraindications are acute my-
ocardial infarction, pregnancy, and severe
infections. It should be withheld 24 hours
prior to radiological procedure requiring
contrast agent and surgery
Thiazolidine- Liver disease (AST >3 times), CHF Weight gain, oedema, Rosiglitazone metabolised by CYP2C8 and
diones requiring treatment (class III and IV) precipitation of CHF, pioglitazone by CYP3A4, hence, drugs
hepatotoxicity (rare), anaemia metabolised by this pathway may interfere
decrease bone mineral density with its level
Alpha- Inflammatory bowel disease, Flatulence, diarrhoea, May increase level of sulphonylureas
glucosidase gastroparesis, serum creatinine abdominal discomfort, Resin and antacid decrease the effect
inhibitors >2 mg/dL and distension

Table 4: Drugs which Enhance the Effect of OADs Causing Hypoglycaemia

Drugs with Moderate-Quality Evidence Drugs with Low-Quality Evidence
Gatifloxacin Artesunate/artemisinin/artemether
Glucagon Chloroquine, oxaline, sulphonamide
Indomethacin IGF-I
Pentamidine Lithium
Quinine Propoxyphene and dextropropoxyphene

BIGUANIDES 6-phosphatase. Insulin-mediated glucose uptake is also

Structure enhanced by metformin. Metformin increases the translocation
of insulin sensitive GLUT4 into the cell membrane. It also
Metformin is chemically 1,1-dimethylbiguanide, derived from
suppresses fatty acid oxidation and reduces triglycerides. It also
herb Galega officinalis.
increases glucose turnover particularly in the splanchnic bed
Mechanism of Action which may benefit both glucose lowering and weight stabilising
Metformin decreases hepatic glucose production, principally effect.
due to reduced gluconeogenesis and also through reduced Indication of metformin as per American Diabetes Association
glycogenolysis, and thus, its main effect is reduction in fasting (ADA) guideline is‘it is to be given in all T2DM patients in absence
plasma glucose. At therapeutic concentrations, metformin of contraindications’.
suppresses hepatic gluconeogenesis by potentiating the
effect of insulin and increasing the activity of activated protein THIAZOLIDINEDIONES
kinase (AMP). It can also reduce hepatic extraction of lactate. Mechanism of Action
The rate of glycogenolysis is decreased by reducing the effect The thiazolidinediones were found to be ligands for an orphan
of glucagon and impeding the activity of hepatic glucose receptor known as peroxisome proliferator-activated receptor 341
 gamma (PPAR-γ). This receptor is a member of the nuclear Indication
receptor superfamily of ligand-activated transcription factors.The These can be used in both type 1 DM and type 2 DM. However,
specific genes that are PPAR-γ responsive are lipoprotein lipase, their main use is to treat postprandial hyperglycaemia. It can
fatty acid-binding proteins and, PEPCK which regulates lipid delay the progression of IGT to diabetes, and hence, can be used
metabolism, insulin action, and adipose tissue differentiation. to treat IGT. These can be used in combination with other drugs
The major pharmacological action includes; increased insulin to achieve glycaemic control.
mediated glucose uptake in muscle and to increase adipogenesis.
The beauty of this class of drugs is that it increases subcutaneous ADVERSE EVENTS
fat and not the visceral, and hence, despite increase in The side effects, contraindications and drug interactions
adipogenesis it increase insulin sensitivity. It converts the larger are summarised in Table 3. Table 4 gives a list of drugs which
adipocyte into smaller one. These convert small dense LDL into potentiates effect of OAD and induce hypoglycaemia.
large LDL, increases HDL, decreases TG, decrease plasma free fatty Cardiovascular Safety of OADs
acids. Their vascular actions include; improve endothelial Cardiovascular safety has become hot issue after a meta-analysis
dysfunction, reduce peripheral resistance, decrease plasma by Nissen in May 2007. He showed increased risk of myocardial
fibrinogen and PAI-1, and thus, improve procoagulant state, infarction with rosiglitazone. Since then FDA warned that it
decrease carotid intima media thickness. These are also is mandatory for all anti-diabetic drugs to establish their
shown to have inhibitory effect on neo-intimal proliferation cardiovascular safety. Among thiazolidinediones, rosiglitazone
after coronary stent. These also have shown to reduce β-cell but not the pioglitazone is associated with high cardiovascular
loss. risk. The large, pro active study clearly demonstrated the
cardiovascular safety of pioglitazone. Older studies, beginning
Rosiglitazone is surrounded with recent controversies.This drug
in the 1970s with the University Group Diabetes Programme trial
is found to increase cardiovascular mortality and also increase
have suggested that diabetic patients receiving sulphonylureas
in incidence of atypical bone fracture due to decrease in bone
were at increased cardiovascular risk compared with diabetic
mineral content. patients who did not receive such medications. Therefore, it was
Indication believed that sulphonylureas particularly glibenclamide
through SUR1 receptor on cardiac myocyte can adversely
These can be used as mono-therapy or in combination with
affect the ischaemic preconditioning. However, in the United
other drugs in type 2 DM patients. These are more useful in
Kingdom Prospective Diabetes Study (UKPDS), treatment with
patients with insulin resistance. sulphonylureas was not associated with increased risk of
ALPHA-GLUCOSIDASE INHIBITORS cardiovascular morbidity and mortality. Furthermore, a number
of studies did not show any adverse cardiovascular effect of
Mechanism of Action newer sulphonylureas. Metformin is the only drug shown to
Alpha-glucosidase inhibitors are competitive suppressants of reduce cardiovascular morbidity and mortality. A meta-analysis
small intestine brush border α-glucosidases, which are essential of eight different trials showed no increase in cardiovascular
to hydrolyse disaccharides, oligosaccharides, and polysaccharides mortality with the use of acarbose.
to monosaccharides. Therefore, carbohydrate absorption and
digestion is delayed and prolonged resulting in lowering of RECOMMENDED READINGS
postprandial hyperglycaemia. These agents do not interfere in 1. American Diabetes Association. Therapy for Diabetes Mellitus and related
disorder, 5th edition; 2009; pp 222-72.
absorption of lactose as they require β-glucosidase (lactase) for
2. Lebovitz HE. Management of hyperglycaemia with oral anti-
their digestion. Furthermore, these increase the secretion of
hyperglycaemic agents in type 2 diabetes. In: C Ronald Khan, Weir GC, King
GLP-1 and decrease secretion of GIP, significance of which still GL, editors. Joslin’s Diabetes Mellitus. 14th Ed; Lippincott Williams and
remains elusive. Willkins; 2005:pp 687-710.

342
 9.7 Insulin Therapy

Rama Walia

Insulin is one of the oldest, best studied and most effective Conventional Insulin
treatment for diabetes. Insulin therapy is a must and life saving Regular insulin is short-acting soluble crystalline zinc insulin.
for patients with type 1 diabetes while many patients with Regular insulin been modified by adding zinc with or without
advanced duration of type 2 diabetes also require insulin protamine to retard its absorption and prolong the duration of
therapy for optimal glycaemic control. Insulin was discovered action, e.g. neutral protamine Hagedorn (NPH) or isophane
by an orthopaedic surgeon, Frederick G. Banting (Figure 1) who insulin which is an intermediate acting insulin.
was assisted by a medical student Charles H. Best (Figure 2).
The first clinical trial took place on January 1922 on a patient, Insulin Analogues
Leonard Thompson. The rest is history of success of insulin. The self association of insulin molecules in a hexamer leads
to slow absorption with a lag period of 30 to 60 minutes. With
PHYSIOLOGY OF INSULIN SECRETION
recombinant DNA technology, rapid acting insulin analogues
Insulin is a two chain polypeptide having 51 amino acids have been synthesised which remain in monomeric form and
(Figure 3). A-chain has 21 amino acids while B-chain has 30 are, therefore, rapidly absorbed, e.g. insulin lispro, insulin
amino acids. Insulin is secreted in a pulsatile manner. There are aspart, and insulin glulisine. The action profile and structural
rapid oscillations occurring every 8 to 15 minutes that are change of various insulin preparations are shown in Table 1.
superimposed on slower oscillations occurring at a rate of once The use of rapid acting insulin analogues allows more
per 80 to 150 minutes. Fifty per cent of total insulin secreted by flexibility and convenience as these are to be injected only
pancreas is secreted under basal conditions and the remainder 5 to 15 minutes prior to meals, although overall glycaemic
is secreted in response to meals as postprandial bursts. control may not improve as assessed by HbA1c. Because of
Under basal conditions insulin secretion rate is 0.5 to 1 U/h. After the shorter duration of action than regular insulin (Table 1),
food intake insulin is released in two phases. First phase is the incidence of post-absorptive hypoglycaemia is
transient (2 to 5 minutes) followed by a second phase in which decreased by almost 25% thereby reducing the requirement
there is progressive increase in insulin secretion for 5 to 52 for inter-prandial snacking.
minutes. Currently available long-acting insulin analogues include insulin
glargine and insulin detemir (Table 1). Insulin glargine has a
INSULIN PREPARATIONS pH of 4 and it makes microprecipitates in subcutaneous tissue
Initially commercial preparations of insulin were derived from which insulin is slowly released. Insulin detemir is designed
from beef and pork pancreas. In 1980s, human insulins were to bind albumin in plasma after absorption (Table 1). These
produced by recombinant deoxyribonucleic acid (DNA) alterations result in prolonged duration of action with little peak
technology in Escherichia coli and yeast. In 1990s, insulin activity thereby reducing the incidence of hypoglycaemia.
was genetically engineered to produce various insulin Additionally, weight gain associated with insulin therapy may
analogues. be avoided particularly with insulin detemir. This probably

Figure 1: Dr. Frederirk G. Banting. Figure 2: Dr. Charles H. Best.

343
 Figure 3: Amino acid sequence of human insulin.

Table 1: Action Profile of Various Insulin Preparations

Insulin Preparations Structural Change pH Onset (h) Peak (h) Duration (h)
Conventional insulin
Short-acting insulin
Regular insulin(human) — N 0.5 to 1 2 to 3 6 to 8
Intermediate-acting insulin
Neutral protamine Hagedorn, Addition of protamine N 1.5 4 to 10 16 to 24
NPH (human)

Insulin analogues
Rapid-acting insulin
Lispro Lysine-proline conversion in B-chain N 0.2 to 0.5 0.5 to 2 3 to 4
Aspart Aspartic acid for proline substitution in B-chain N 0.2 to 0.5 0.5 to 2 3 to 5
Glulisine Lysine for asparagine substitution in B-chain N 0.2 to 0.5 1 4
Long-acting insulin
Glargine Glycine for asparagine substitution in A-chain and 4 2 to 4 none 20 to 30
a prolonged B-chain
Detemir Acylation of lysine in B-chain with saturated fatty acid N 1 to 2 none 20
N= Neutral

happens due to less snacking as hypoglycaemias are reduced Indications for Insulin Therapy
and secondarily due to a selective appetite modulating effect Insulin therapy is a must and life saving in patients with
of insulin detemir. type 1 diabetes. Therefore, omission of insulin in these patient
Insulin lispro and insulin aspart are approved for use during is suicidal. Insulin therapy is also treatment of choice for
pregnancy and marginally reduce glycosylated haemoglobin gestational diabetes mellitus. Indications for insulin therapy
(HbA1c) as well as incidence of hypoglycaemia with no in patients with type 2 diabetes at diagnosis include fasting
differences in gestational outcome when compared with plasma glucose >250 mg/dL, HbA1C >10%, patients having
human regular insulin. Insulin detemir and insulin glargine are severe osmotic symptoms, and weight loss and/or ketosis.
still not approved for their use during pregnancy. Patients During follow-up, insulin is to be initiated if patient has
having significant hyperglycaemia require higher proportion inadequate glycaemic control (HbA1c >7%) on maximal
of short/ rapid acting insulin. doses of two or more oral anti-diabetic drugs. Insulin also
344
 Insulin Therapy
needs to be started during inter-current illness and patients glucose in mg/dL. Insulin dosage needs to be individualised
undergoing surgery. in each patient to achieve satisfactory glycaemic control. The
reader is referred to chapter 7 Insulin Therapy in management
TIMINGS AND DOSAGES OF INSULIN THERAPY diabetic ketoacidosis.
Short-acting regular human insulin needs to be injected 30 to Site and Technique of Injection
60 minutes prior to meals while rapid acting insulin analogues
Conventionally, insulin is injected with syringe subcutaneously
can be injected 5 to 15 minutes prior to meals. However, if pre-
in anterior abdominal wall. Other sites like arms and thighs
prandial plasma glucose is higher, then short-acting analogues
are not preferred because of erratic absorption, especially if
are to be injected 30 minutes prior to meal to achieve adequate
patient undertakes any physical activity leading to increased
glycaemic control. If required, in case of children and in patients
blood flow to the limb and hence rapid absorption of the
with gastroparesis these can be injected even after meals.
insulin. After raising a skin fold the injection must be given
Insulin NPH is to be injected once or twice a day usually with perpendicular to the skin in obese individuals and at 45
regular insulin 30 minutes prior to meals. In basal bolus regimen, degrees in thin patients. The site of injection must be rotated
it can be drawn in the same syringe containing regular insulin to avoid lipodystrophy.
with out change in efficacy or pharmacokinetics reducing the
Insulin vials are available in two strengths, namely 40 and 100
number of injection. In this way, peak action of NPH insulin takes
units per mL. One should be careful that the ‘number’ of units/
care of post-lunch hyperglycaemia. Similarly, the night dose of
mL on insulin vial must match the ‘number’ of units/mL on
NPH insulin can be injected before dinner along with regular
insulin syringe. Insulin pen devices are certainly user-friendly
insulin. However, if the total dose of insulin being injected at
and convenient to carry. Insulin needs to be stored in
one time exceeds 30 units, then regular and NPH insulins need
refrigerator at 2 to 8 degree Celsius.
to be injected at separate sites. If a patient develops nocturnal
hypoglycaemia, then along with reducing the night dose of GLYCAEMIC TARGETS
insulin, the timing of the NPH insulin can also be shifted to 10
The targets for fasting and post-prandial plasma glucose
p.m. so that the peak activity of the NPH insulin overlaps with
are 70 to 130 mg/dL and <180 mg/dL, respectively for adult
the early morning surge of counter-regulatory hormones
population according to American Diabetes Association (ADA).
thereby avoiding hypoglycaemia.
The HbA1c needs to be targeted <6.5% to 7%. Glycaemic targets
Insulin glargine can be given once a day at fixed time, usually at for children are described in Table 2. The goals need to be
8 pm or 8 am Insulin detemir needs to be injected twice a day individualised, depending on the age of the patient, associated
at fixed timings, e.g. 8 am and 8 pm, as its duration of action is co-morbidities, and the risk of hypoglycaemia.
around 20 hours. Long-acting analogues cannot be mixed with
Table 2: Glycaemic Targets in Paediatric Age Group
rapid/short-acting insulins.
Age (year) Plasma Glucose (mg/dL) HbA1c
In patient having mainly fasting hyperglycaemia, intermediate
Before Meals Bedtime
or long-acting insulin can be injected at 10 pm It is convenient
and improves glycaemic control with lesser weight gain. The <6 100 to 180 110 to 200 <8.5% but >7.5%
dose can be modified according to fasting plasma glucose 6 to 12 90 to 180 100 to180 <8%
(FPG) every third day. If post-prandial glycaemic control 13 to 19 90 to 130 90 to 150 <7.5%
remains inadequate, short/rapid acting insulin is to be added
either in form of pre-mixed preparation insulin or as basal Self Monitoring of Blood Glucose on Insulin Therapy
bolus regimen. At this time insulin secretagogues should be Patients on insulin therapy need to monitor blood glucose three
stopped. Patients with FPG less than 200 mg/dL can be or more times daily as recommended by ADA. The blood
managed with pre-mixed insulin injected twice a day before glucose is monitored pre-prandially to adjust insulin dosage. If
meals. The usual preparation used is 30:70 or 25:75 ratio of HbA1c still remains high then post-prandial blood glucose
short/rapid acting insulin to intermediate acting insulin. needs to be targeted to achieve desired HbA1c.
Higher percentage of short/rapid acting insulin (50%) is
sometimes required to control post-prandial hyperglycaemia. INSULIN DELIVERY DEVICES
Usually 50% to 70% of the required daily dose is injected Conventionally, insulin is injected subcutaneously with the
before breakfast and 30% to 50% is injected before dinner. If help of syringe. Pen devices have the advantage of hidden
required short/rapid acting insulin can be injected prior to needles and convenience. Continuous subcutaneous insulin
lunch to control post-lunch hyperglycaemia. If FPG is more infusion (CSII) with insulin pump is another option. In this,
than 200 mg/dL, then the patient needs to be started on basal rapid-acting insulin provides basal as well as prandial cover.
bolus regimen which means short/rapid acting insulin being This improves glycaemic control with decreased incidence of
injected prior to meals while intermediate/long-acting insulin hypoglycaemia while reducing the number of pricks. Non-
injected separately at timings as described before. In this each invasive insulin delivery includes use of inhaled insulin, buccal
component of insulin therapy can be manipulated separately spray, and in form of tablets. The absorption of inhaled insulin
according to individual requirement but at the cost of starts immediately as that of rapid-acting insulin analogues
increased number of insulin injections. Insulin dose can be but its duration of action is similar to regular insulin. In
modified according to the rough 1,500 rule. 1,500/total insulin smokers, the bronchial tumour rate under inhaled insulin
dose per day is equal to the effect of 1 unit of insulin on blood seems to be increased. With buccal spray device, insulin
345
 particles get deposited in buccal cavity while oral insulin is in refuted it. This can be due to its higher affinity to IGF-1 receptor
tablet form and delivers insulin to gastro-intestinal tract. The which determines the mitogenicity of insulin. However, insulin
bioavailability of these preparations is approximately 10% and glargine is still not approved for pregnant patients and children
these mimic rapid-acting insulin in onset and duration of less than six years of age.
action. Other investigational routes of delivery include
transdermal iontophoretic transport, powdered insulin RECOMMENDED READINGS
delivery though skin using helium gas, liposome based 1. American Diabetes Association. Standards of Medical Care in Diabetes –
2010. Diabetes Care 2010; 33: S11-S61.
formulation for insulin delivery, etc.
2. Buse JB, Polonsky KS, Bruant CF. Type 2 diabetes mellitus. In: Larsen PR,
Adverse Effects of Insulin Therapy Kronenberg HM, Melmed S, Polonsky KS, editors. Williams Text Book of
Endocrinology; 10th Ed. Philadelphia: WB Saunders; 2002: pp1427-83.
The commonest problem with insulin therapy is hypoglycaemia
(blood glucose <70 mg/dL) and weight gain. Risk factors 3. Dejkhamron P, Menon RK, Sperling MA. Childhood diabetes mellitus: Recent
advances and future prospects. Indian J Med Res 2007; 125: 231-50.
for hypoglycaemia include-mismatched insulin syringe,
4. Eisenbarth GS, Polonsky KS, Buse JB, Type 1 diabetes mellitus. In:
mismatched meal timings, unusually vigorous exercise, Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, editors. Williams
impaired ability to defend against hypoglycaemia and Text Book of Endocrinology; 10th Ed. Philadelphia: WB Saunders; 2002:
hypoglycaemia unawareness in patients with autonomic pp1485-1505.
neuropathy. Weight gain happens partly due to improved 5. Glaser B, Cerasi E. Early intensive insulin treatment for induction of long-
glycaemic control and partly due to inter-prandial snacking to term glycaemic control in type 2 diabetes. Diabetes Obes Metab 1999; 1:
avoid hypoglycaemia. These can be reduced by carefully 67-74.
titrating insulin therapy and educating the patient about it. 6. Hirsch IB. Insulin analogues. N Engl J Med 2005; 352: 174-83.
Lipoatrophy, lipohypertrophy, and insulin allergy is rare now-a- 7. Oiknine R, Bernbaum M, Mooradian AD. A critical appraisal of the role of
days because of the availability of purified insulins. insulin analogues in the management of diabetes mellitus. Drugs 2006;
65: 326-40.
Although there were some reports of association of increased 8. Vajo Z, Fawdett J, Duckworth WC. Recombinant DNA technology in the
risk of malignancies with insulin glargine but other studies have treatment of diabetes: insulin analogues. Endocr Rev 2001; 22: 706-17.

346
 9.8 Newer Modalities of Treatment in
Type 2 Diabetes Mellitus
Anil Bhansali, G Shanmugasundar

INTRODUCTION glucose-lowering may even result in an increase in cardiovascular

Type 2 diabetes mellitus is characterised by multiple metabolic events if implemented late in the course of the disease. However,
abnormalities that result in hyperglycaemia. These include the long-term follow-up of UK Prospective Diabetes Study Group
obesity, insulin resistance in skeletal muscle, adipose tissue and (UKPDS) patients suggests persistent effects of good control if
liver, increased hepatic production of glucose, and dysfunction implemented early. The main limitations and unwelcome effects
of most commonly used drug therapies are hypoglycaemia, fluid
of the islet cells of the pancreas. Islet cell abnormalities include
retention and weight gain, all of which may theoretically increase
qualitative and quantitative defects of insulin secretion from
the risk of cardiac events (Table 1).
β-cells and dysregulated glucagon secretion from α-cells. It has
also been shown that patients with type 2 diabetes have an NEWLY AVAILABLE THERAPIES
impaired incretin effect. These multiple metabolic abnormalities
New therapies are emerging, some of them address the unwanted
lead to persistent hyperglycaemia unless intervened, results in
side-effects and limitations of older therapies (Table 2).
the long-term complications of type 2 diabetes including micro-
and macrovascular diseases. These long-term complications, in INCRETIN-BASED THERAPIES
turn, cause considerable morbidity, and are associated with Incretins are intestinal hormones that increase insulin release
reduced life expectancy and increased health care costs. from the pancreas and inhibit glucagon release. They are
Current treatment options have different mechanisms of action released after the ingestion of food from the L and K cells of
and are variably effective at lowering blood glucose levels. This the gastrointestinal tract. The main incretin that has found
includes biguanides, insulin secretagogues, thiazolidinediones, therapeutic use is glucagon-like peptide-1 (GLP-1). GLP-1
alpha-glucosidase inhibitors, and insulin. improves β-cell responsiveness to glucose and, unlike GIP,
inhibits gastric emptying and has a central nervous system
Challenges in Achieving Good Glycaemic Control in Type 2 effect, resulting in reduced food intake and a decrease in body
Diabetes weight. Endogenous incretin peptides are short-lived due to
Clinical and observational studies clearly link glycaemic control their degradation by the enzyme dipeptidyl-peptidase-4
to diabetes complications. However, while the beneficial (DPP-4). The discovery of the incretin-DPP-4 pathways led to
effects of glucose-lowering interventions are established for the development of GLP-1 analogues, which are resistant to the
microvascular disease, the data for macrovascular disease are actions of DPP-4 and DPP-4 inhibitors, which protect the natural
less convincing, with recent trials suggesting that very intensive incretin hormones from deactivation.

Table 1: Adverse Effects of Commonly Used Oral Hypoglycaemic Agents

Type Prototype Hypoglycaemia Fluid Retention Weight Homeostasis Typical Problems
Biguanide Metformin, No No Weight neutral Lactic acidosis;
Metformin SR or modest thus C.I in renal failure.
weight loss Do not use in CKD 4,
caution in CKD 3, liver
and heart failure,
GI intolerance
Sulphonylureas + Gliclazide, Particularly in No Weight gain No β- cell preservation
other insulin Glimeperide, the elderly
secretagogues Glipizide
Glibenclamide,
Repaglinide
Thiazolidenediones/ Rosiglitazone, Uncommon Frequent, Weight gain CI in heart failure; avoid
Glitazones Pioglitazone especially in rosiglitazone in IHD,
combination increased fracture risk
with insulin in women
Insulin Soluble, basal Frequent Occasional Weight gain Other drawbacks:
and biphasic injection. First inhaled
insulin preparations insulin withdrawn for
economic reasons; also
Detemir Weight neutral concerns regarding
lung function and
cancer risk
347
 Table 2: Summary of Newer Glucose Lowering Therapies
Drug Examples Mechanism of Dose Range HbA1c Advantages Adverse Effects/
Action Reduction Disadvantages
Incretin mimetics Exenatide ↑ Insulin, ↓ Glucagon, 5 or 10 µg BD 0.5% to 1.0% Weight loss Injection—nausea,
Liraglutide slow gastric emptying 1.2 or 1.8 mg OD pancreatitis
Incretin enhancers Sitagliptin Prolong endogenous 100 mg OD 0.4% to 0.9% Weight neutral, Nausea, pancreatitis, dose
Vildagliptin GLP-1 action 50 mg BD no hypoglycaemia reduction in renal failure
Saxagliptin Care while using in 5 mg OD
renal failure
SGLT-2 inhibitors Dapagliflozin Inhibits glucose 5 to 10 mg OD 0.5% to 0.9% Weight loss Polyuria, genital infections
re-absorption
Amylin agonist Pramlintide Slow gastric emptying, 60 to 120 µg TDS 0.3% to 0.5% Reduce postprandial Injection, nausea
↓ glucagon glycaemia, weight Hypoglycaemia with
loss insulin use

BD = Twice daily; OD = Once daily; TDS = Thrice daily; SGLT-2 = Sodium glucose transporters-2

INCRETIN MIMETICS in progressive weight loss (4 to 6 kg). Improvements in glycaemic

Exenatide control appear to be better with liraglutide than with exenatide,
probably because the former has a better effect on fasting plasma
It is the synthetic version of exendin-4, a specific agonist of the
glucose levels. Risk of hypoglycaemia is low.
GLP-1 receptor originally isolated from the salivary secretions
of the lizard Heloderma suspectum, otherwise known as the gila Incretin Enhancers
monster. Its duration of action is longer compared with GLP-1, Gliptins acts as inhibitors of the enzyme DPP-4, which is
largely due to its resistance to degradation by DPP-4. It is a DPP- responsible for the very rapid inactivation of the circulating
4 resistant peptide with a half-life of more than 2 hours, giving incretin GLP-1 and GIP. Thus, DPP-4 inhibitors have been
a therapeutic effect for 4 to 6 hours, it is administered twice developed to prolong the circulating half-life of incretins, and
daily by subcutaneous injection (5 or 10 µg) before main meals. thus, enhance the biological effects of endogenous incretins
It typically decreases HbA1c by 0.8% to 1.0% over 6 to 12
particularly GLP-1. Currently available gliptins include sitagliptin,
months, with substantially decreased postprandial glycaemic
vildagliptin and saxagliptin, which almost completely inhibit
excursion, modestly decreased basal glycaemia and weight loss
DPP-4 activity for about 12 to 18 hours causing increased
of 2 to 5 kg.
endogenous incretin concentration to two-to-three-folds.
The improvement in glycaemic control is due to enhanced
Sitagliptin
glucose-dependent insulin secretion, the suppression of
postprandial glucagon secretion and slower gastric emptying. The usual recommended dose of sitagliptin is 100 mg per day, but
In addition, GLP-1 analogues reduce food intake, with subsequent 25 mg and 50 mg tablets are available for dosing in patients with
weight reduction, and therefore, higher insulin sensitivity. moderate-to-severe renal impairment.The recommended doses for
Because their effect on insulin secretion is dependent on the patients with renal impairment are 50 mg per day if the creatinine
prevailing glucose concentration, incretin analogues have a low clearance is between 30 and 50 mL/min, and 25 mg per day if the
risk of hypoglycaemia when used alone or in combination with creatinine clearance is <30 mL/min. Sitagliptin can be taken with or
metformin or thiazolidinediones but can increase the risk of without food. It has been shown to be safe and efficacious in clinical
hypoglycaemia when used with sulphonylureas. trials, producing A1c reductions of 0.65% to 0.94%, with patients
who had higher A1c levels (>9.0%) receiving the most benefit. No
Nausea is the most commonly reported side-effect, affecting severe hypoglycaemia was reported with its use.
up to 44% of patients in clinical trials. This, however, tends to
Vildagliptin
reduce with time, and only 4% of patients in clinical trials
withdrew from treatment as a result of nausea. There are case Clinical trials show that vildagliptin is similar to sitagliptin for
reports of acute pancreatitis in association with exenatide use, dosing, efficacy, and safety profiles. A recent Cochrane review
but it is currently unclear whether this is a true side-effect or a 19 compared the efficacy and safety of vildagliptin and
chance association. Meanwhile, it seems wise to avoid the use sitagliptin in multiple studies, and concluded the following:
of this drug in patients with a history of pancreatitis or those at ‘Compared with placebo, A1c reductions of ~0.7% (sitagliptin)
high risk (e.g. with severe hypertriglyceridemia). and 0.6% (vildagliptin) were noted; there were improvements
in metabolic control when compared with other hypoglycaemic
Liraglutide agents; neither medication produced weight gain, both were
Liraglutide is another GLP-1 agonist which is now available. It is well tolerated, and there was no severe hypoglycaemia; and no
nearly identical to human GLP-1; consequently, the rate of antibody definite conclusion could be drawn from published data about
formation is low. Liraglutide has a significantly longer half-life (12 their effects on β-cell function’.
to 14 hours) than exenatide and can be dosed once daily. Like
exenatide, liraglutide appears to reduce HbA1c levels (0.7 to 1.2) in Saxagliptin
patients poorly controlled on oral anti-diabetic medications, This drug is also available. Dose is 5.0 mg OD. It has similar action
348 reduces fasting and postprandial plasma glucose levels,and results profile and effectiveness in glucose reduction. Other important
 Newer Modalities of Treatment in Type 2 Diabetes Mellitus
side-effects are pertaining to gastrointestinal tract like nausea, Sirtuins
flatulence and diarrhoea. Sirtuin deacetylases have been discovered with the study of
Pramlintide calorie restriction and resulting prolonged lifespan. SIRT1-
activators do not only increase mitochondrial activity but also
Pramlintide is an analogue of amylin, a small peptide improve insulin secretion and glycaemia. Human studies in
hormone that is released into the blood stream by the β- diabetic patients are in progress.
cells of the pancreas along with insulin, after a meal. Like
insulin, amylin is deficient in individuals with diabetes. By Other agents are expected to emerge from targeting gut
augmenting endogenous amylin, pramlintide aids in the hormones and appetite regulators, e.g. PYY3-36, ghrelin-
absorption of glucose by slowing gastric emptying, antagonists, melanocortin-4 (MC4)-antagonists and MTP-
promoting satiety via hypothalamic receptors (different antagonist (which limit gut absorption of fat) and various
receptors than for GLP-1), and inhibiting inappropriate combinations of the above.
secretion of glucagon, a catabolic hormone that opposes the Insulin Pumps
effects of insulin and amylin.
Rather than receiving multiple daily subcutaneous injections of
It is used as an adjunct to insulin therapy for type 1 and type 2 short- and either long- or intermediate-acting insulin, patients
diabetes. Although it has received only minor use, possibly due using an insulin pump receive a continuous subcutaneous
to the need for multiple daily subcutaneous injections infusion of short-acting insulin. These devices hold insulin
separately from insulin, it has been shown to benefit glycaemic reservoir and supply insulin via a plastic tube into subcutaneous
control while enabling a reduced insulin dose and a decrease tissue. Pumps are able to more precisely dose insulin compared
in body weight. to insulin syringes or pens. Pumps are also programmable to
provide different doses of basal insulin throughout the day. This
SGLT-2 Inhibitor feature allows patients to increase their basal insulin, for example,
The sodium glucose co-transporter-2 is located predominantly to counteract the ‘dawn phenomenon’ or to decrease their basal
in the first segment of the proximal tubules of the kidney, rate to compensate for increased physical activity.
where it acts as the conduit to re-absorb most of the filtered
Insulin pumps in some, but not all, studies have been
glucose. Dapagliflozin is a potent and highly selective SGLT-2
associated with improved metabolic control and lower risk
inhibitor. It causes urinary energy loss of up to 200 to 300 Kcal of mild and severe hypoglycaemia in patients with type 1
per day and can lower HbA1c up to 0.5% to 0.9% over 3 months diabetes. Most studies also show that the A1C improvement
with weight loss of 2.5 to 3 kg. Potential side-effects include is modest, usually less than one percentage point. Some of
polyuria and an increased risk of urinary and genital fungal the newest insulin pumps are also available with integrated
infections. Other drugs in this group are sergliflozin and continuous glucose monitoring devices mimick ing
remogliflozin. pancreas.
Glucokinase Activators
CONCLUSIONS
Glucokinase is the main ‘glucose sensor’ in the pancreas
Control of blood glucose in type 2 diabetes mellitus is
and liver. Defects in the glucokinase gene cause one form of
important to improve outcomes, but achieving long-term
maturity onset diabetes of the young, MODY 2. Glucokinase
control is challenging and all existing agents have limitations,
activators increase the sensitivity of glucokinase to high particularly as most of the older agents and insulin cause an
levels of glucose, leading to increased insulin secretion, increase in body weight and hypoglycaemia. Newer agents,
increased liver glycogen synthesis and a decrease in liver especially those that target body weight, have significant
glucose output. Potential concerns include hypoglycaemia potential, but their place in the therapeutic algorithm is not
due to increased insulin secretion. However, ‘liver-selective’ yet determined possibly because of lack of data on cardio-
glucokinase activators with lower potential for hypogly- vascular safety profile.
caemia have also been developed and tested in pre-clinical
models. RECOMMENDED READINGS
1. American Diabetes Association (ADA): www.diabetes.org.
Glucagon-Receptor Antagonists
2. Expanding Treatment Options for Type 2 Diabetes: The Old and the New,
The abnormal increase of liver-derived gluconeogenesis in Richard E. Pratley: The Diabetes Educator 2009; 35: 4S.
type 2 diabetes mellitus is targeted by glucagon-receptor 3. The Therapeutic Role of Incretin Mimetics and DPP-4 Inhibitors: Martha M.
antagonists, which are currently being tested in humans. Funnell: The Diabetes Educator 2009; 35: 12S.

349
 9.9 In-Hospital Management of Diabetes Mellitus

Nihal Thomas, Rahul Ramnik Baxi

INTRODUCTION Diabetes educator or diabetes specialist nurses

A study has shown that India has spent a mind-boggling Rs.1.5 They play a key role in patient and staff education and
trillions on diabetes care in 2010. A significant proportion of implementation of glycaemic control strategies and are able
inpatients with hyperglycaemia have undiagnosed diabetes to facilitate a smooth patient pathway from hospital to home.
and stress hyperglycaemia. Hospitalisation should be resorted The diabetes educator could also be the leader of the team.
to in diabetes patients only when absolutely necessary to cut
Diabetes specialist dietician
down on costs.
They play a pivotal role in those with complex nutritional needs
EVIDENCE OF HARM FROM IN-HOSPITAL HYPERGLYCAEMIA —those unable to swallow, those with renal failure, pregnancy,
AND BENEFITS OF GLUCOSE LOWERING cystic fibrosis, and the elderly.
There is compelling evidence that poorly-controlled glucose
Targets to be Achieved
levels are associated with a higher in-hospital morbidity
and mortality, prolonged length of stay, unfavourable post- 1. Initiate glucose monitoring in any patient not known to have
discharge outcomes and significant increase in healthcare costs. diabetes, but who receives therapy associated with high-risk
We have tried to stratify the impact of inpatient diabetes for hyperglycaemia, including high-dose glucocorticoid
management, relying on evidence-based norms. therapy and initiation of enteral or parenteral nutrition. If
hyperglycaemia is documented and persistent, treatment
Which Patient Requires Hospitalisation? is necessary. Such patients should be treated to the same
Hospitalisation for a patient for reasons related to diabetes may glycaemic goals as patients with known diabetes.
be indicated in specific situations. 2. A plan for treating hypoglycaemia should be established
1. Acute metabolic complications like diabetic ketoacidosis, for each patient. Episodes of hypoglycaemia in the hospital
hyperglycaemic hyperosmolar state and hypoglycaemia should be tracked.
with neuroglycopaenia. 3. All patients with diabetes admitted to the hospital should
2. Newly diagnosed diabetes in children and adolescents when have their glycosylated haemoglobin (HbA1c) obtained if
unstable or brittle, for the purpose of dose adjustment or the result of testing in the previous 3 months is unavailable.
monitoring (when not possible on outpatient basis).
4. Patients with hyperglycaemia in the hospital should have
3. Chronic poor metabolic control that necessitates close appropriate plans for follow-up testing and care documented
monitoring to determine the aetiology and modify therapy at discharge.
as in hypoglycaemia unawareness.
GOALS FOR BLOOD GLUCOSE LEVELS
4. Severe chronic complications requiring intensive treatment
Critically-Ill Patients
or other conditions unrelated to diabetes that significantly
affect its control, particularly wherein ambulation may be Insulin therapy should be initiated for treatment of persistent
a problem. hyperglycaemia starting at a threshold of 180 mg/dL (10
mmol/L). Once insulin therapy is initiated, a glucose range of
5. Uncontrolled insulin-requiring diabetes during pregnancy
140 to 180 mg/dL (7.8 to 10 mmol/L) is recommended for the
for rapid control.
majority of critically-ill patients.
6. The institution of insulin pump therapy or other intensive
insulin regimens. Non-Critically-Ill Patients
There is no clear evidence for specific blood glucose goals.If treated
Diabetes In-Hospital Team
with insulin, the pre-meal blood glucose target should generally
The patient be less than 140 mg/dL (7.8 mmol/L) and random blood glucose
The patient forms the core of the team and is encouraged to less than 180 mg/dL (10.0 mmol/L), provided these targets can be
participate in the formulation and conduct of their own care safely achieved.More stringent targets may be appropriate in stable
plan while admitted in the hospital. patients with previous tight glycaemic control and less stringent
targets in those with severe co-morbidities.
Consultant physician/diabetologist/endocrinologist
The primary role of the consultant is as a leader of the multi- Hospital Barriers to Glucose Control
disciplinary team. They work closely to provide clinical support This may seem to be a paradox. However, hospitalisation may
to diabetes specialist nurses and diabetes educators. The in fact hamper the efforts to achieve glycaemic control in some
practical knowledge of ‘on the spur of the moment’ innovation situations. Indeed, it may be more prudent to have good
is vital towards patient care, and over-rides theoretical educational facilities on an out-patient basis to enable patient
knowledge. self-emancipation.
350
 In-Hospital Management of Diabetes Mellitus
1. Majority of diabetes patients are hospitalised for reasons testing should be performed every 1 to 2 hours in patients on
other than diabetes, e.g. vascular complications. The care intravenous insulin infusions. In patients eating usual meals,
of diabetes per se becomes subordinate to care for the glucose levels should be monitored as fasting and 2 hours post-
primary diagnosis. prandial after three major meals. The common error in SMBC
2. Infection, fever, glucocorticoid therapy, surgical trauma and monitoring have to be kept in mind and taken care (Table 2).
general medical stress exacerbate hyperglycaemia due to Table 2: Sources of Errors in Bedside Blood Glucose Results
release of counter regulatory hormones.
Sources of analytical error Sources of use error
3. Decreased physical activity (in previously active patients)
False high Inadequate metre calibration
also exacerbates hyperglycaemia.
Low haematocrit Inadequate quality-control
4. Strict diet and supervised compliance with drugs may result Hyperbilirubinaemia Poor technique in finger prick
in hypoglycaemia in patients who were not compliant earlier. Severe lipaemia Poor technique of applying
False low blood drop on test strip
COMMON ERRORS IN MANAGEMENT High haematocrit
Test strip with unmatched
Admission Orders and Lack of Therapeutic Adjustment Either false high or false low meter code or that has
Hypoxia passed the expiration date
The out-patient treatment regimen is often continued Shock and dehydration
unchanged or withdrawn entirely upon admission. Although Drugs: acetaminophen overdose,
either of these choices may occasionally be indicated, dopamine, mannitol, salicylate
patients more commonly will require some modification of
their out-patient regimen. A patient may be treated with GLUCOSE CONTROL
regular insulin alone during the entire hospital stay, which General Recommendations
will deprive the treating physician of an opportunity to A key component of providing effective insulin therapy in the
observe the patient’s response to regimens that can be hospital setting is to determine whether a patient has the ability
transferred home. to produce endogenous insulin or not (Table 3).
High glycaemic targets
Table 3: Characteristics of Patients with Insulin Deficiency
Blood glucose levels are commonly allowed to be more than
Known type 1 diabetes
200 mg/dL. In-patient care is sometimes taken for granted to
History of pancreatectomy or pancreatic dysfunction
be superior; however, infrastructural limitations and nursing
History of wide fluctuations in blood glucose levels
staff inadequately trained in diabetes could work contrary.
History of diabetic ketoacidosis
Overutilisation of ‘sliding scales’ History of insulin use for > 5 years and/or diabetes for >10 years
There are opinions that sliding scales are illogical, as they are
designed to correct the therapeutic inadequacies of the Patients with type 1 diabetes will require some insulin at all
previous 4- to 6-hour period rather than anticipating future times to prevent ketosis, even when not eating. The insulin
requirements. Sliding scale is used frequently as the only means regimen should be revised frequently based on the values of
of insulin dosage, rather than concurrently with intermediate- glucose monitoring. Intermediate-acting insulin added once or
acting insulins, which may lead to fluctuations of insulin supply twice daily, even at small doses, will stabilise the control. Glucose
and erratic glucose control. Sliding scale may be used in certain levels should be maintained as close to the normal range as
situations outlined in Table 1. possible in the post-operative, post-myocardial infarction, and
intensive care settings. Conservative targets should be set in
Table 1: Situations in which Sliding Scales may be Useful patients prone to hypoglycaemia (e.g. brittle diabetes,
hypoglycaemia unawareness), in very elderly or in those with
To adjust pre-prandial insulin based on the pre-meal capillary
short life expectancy due to co-morbid conditions and with
glucose level and the anticipated carbohydrate consumption
inadequate nursing or monitoring support.
With basal insulin analogues, such as insulin glargine
To evaluate patient’s initial response to insulin Patient Specific Recommendations
In patients receiving parenteral nutrition, in whom each 6-hour Patient on oral agents and not consuming food
period is similar to the last In patients on sulphonylurea or other secretagogues, the
drugs should be withheld and a short-acting insulin sliding scale
Underutilisation of insulin infusions
should be used temporarily. Addition of intermediate-acting
Intravenous insulin is recommended for patients with insulin should be considered, if insulin is needed for more than
hyperglycaemic emergencies and also in the peri-operative 24 hours. Metformin may be withheld owing to concerns about
setting or when glucose control has deteriorated with altered renal function in the acutely ill. Avoid α-glucosidase
conventional subcutaneous insulin. The intravenous route inhibitors as these are effective only when taken with food.
provides predictable insulin delivery and enables quick control Thiazolidinediones are discontinued in patients with abnormal
of glucose levels. Adequate nurse training, staffing and hepatic or cardiac function.
supervision is required for their safe implementation.
Patient on oral agents and consuming food
Blood Glucose Monitoring In patients on oral agents with controlled sugars, continue the
In patients on enteral or parenteral nutrition, glucose medication but consider a dosage adjustment of 25% to 50%, due
monitoring is optimally performed every 4 to 6 hours. Glucose to the likelihood of better dietary adherence. Metformin should 351
 be withheld in peri-operative patients (general anaesthesia), in recommended with glucose targets according to severity of
those with standard contraindications, or when dehydration is illness.
suspected or anticipated and if radio-contrast studies are planned.
α-glucosidase inhibitors and thiazolidinediones may be continued. Glucocorticoid Therapy
Insulin should be started if sugars are uncontrolled. The best predictors of glucocorticoid-induced diabetes are
family history of diabetes, increasing age and glucocorticoid
Patient on insulin and not consuming food
dose and duration. For patients receiving high-dose intravenous
Intravenous insulin infusion should be strongly considered in glucocorticoids, an intravenous insulin infusion may be
type 1 diabetes patients. Alternatively, half to two-thirds of the appropriate. During steroid tapers, insulin dosing should be
patient’s usual dose of intermediate-acting insulin may be given proactively adjusted to avoid hypoglycaemia.
along with a short-acting insulin sliding scale.
Switching from Intravenous to Subcutaneous Insulin
Some patients with type 2 diabetes on insulin may have
improved control with diet restriction and require only short- It is important to administer short-acting insulin subcutaneously
acting insulin. A 5% dextrose solution intravenously at 75 to 1 to 2 hours before discontinuation of the intravenous insulin
125 mL per hour should be provided. infusion. Intermediate or long-acting insulin must be injected 2
to 3 hours before discontinuing the insulin infusion.
Patient on insulin and consuming food
Continue insulin, although consider dosage reduction (10% to Prevention of Hypoglycaemia
50%) in well-controlled patients because of the likelihood of Hypoglycaemia is the most important limiting factor in the
more rigid dietary adherence. management of diabetes, more so in patients on insulin.
Patient Scheduled for Surgery Institutions are more likely to have protocols for the treatment
of hypoglycaemia than for its prevention. Tracking such
Peri-operative instructions
episodes and analysing their causes are important quality
In general, patient’s treatment programme is least affected if improvement activities (Table 4).
surgeries are scheduled for early morning. Blood glucose levels
should be monitored every 1 to 2 hours before, during and after Table 4: Causes of Hypoglycaemia in Patients on Insulin
the procedure.
Sudden reduction in oral intake or nil per oral status
Type 1 diabetes Discontinuation of enteral feeding/TPN/IV dextrose
Insulin infusion should be given at a maintenance rate (1 to 2 Pre-meal insulin given and meal not ingested
units per hour) with a 5% dextrose solution at 75 to 125 mL per Unexpected transport from nursing unit after rapid acting insulin
hour, adjusted to maintain glucose levels between 100 and 150 given
mg/dL. Alternatively, give one-half to two-thirds of the usual dose Reduction/omission of corticosteroid dose
of intermediate-acting insulin on the morning of procedure.
Type 2 diabetes Medical Nutrition Therapy in the Hospital
If the patient is taking an oral anti-diabetic agent, hold the Current nutrition recommendations advise individualisation
medication on the day of procedure and resume when tolerating based on treatment goals, physiologic parameters, medication
a normal diet. usage and other co-morbid conditions, such as obesity,
If the patient is treated with insulin, give one-half of dyslipidaemia, hypertension and renal failure. A registered
intermediate-acting insulin on the morning of procedure. Do dietician, skilled in diabetic MNT, should serve as an in-patient
not give short-acting insulin unless the blood glucose level is team member.
>200 mg/dL. Alternatively, an insulin infusion can be used. DISCHARGE PLANNING
SPECIFIC CLINICAL SITUATIONS Patients (and their families) should be familiar with their
Insulin Pumps glucose targets and drug regimens after discharge from
Patients who use continuous subcutaneous insulin infusion hospital and should understand any changes made in their
(CSII) therapy in an out-patient setting can continue using it in treatment (Table 5).
the hospital, provided they are mentally and physically fit to do
Table 5: Issues to be Addressed Prior to Hospital Discharge
so. The availability of hospital personnel with expertise and
experience in CSII therapy is essential. Level of understanding related to the diagnosis of diabetes
Self monitoring of blood glucose and explanation of home blood
Enteral Nutrition
glucose goals
For intermittent enteral feedings, intermediate-acting insulin Recognition, treatment and prevention of hyperglycaemia and
with a small dose of regular insulin is adequate. For continuous hypoglycaemia
feeding, once or twice daily insulin glargine (or NPH) can be Identification of health care provider who will provide diabetes care
used. Start with a small basal dose and use correction-dose after discharge
insulin as needed while the glargine dose is being increased. Information on consistent eating patterns
Parenteral Nutrition When and how to take oral medications and insulin administration
Sick-day management
The high glucose loads in standard parenteral nutrition
Proper use and disposal of needles/lancets/syringes
352 frequently results in hyperglycaemia. Insulin therapy is
 In-Hospital Management of Diabetes Mellitus
RECOMMENDED READINGS 4. Lansang MC, Umpierrez GE. Management of inpatient hyperglycaemia in
noncritically ill patients. Diabetes Spectrum 2008; 21: 248-55.
1. American Diabetes Association. Standards of medical care in diabetes.
Diabetes Care 2011; 34: S11-S61. 5. Thomas N, Jeyaraman K, Velavan J, Vasan S. A Practical Guide to Diabetes
Mellitus; 5th Ed. New Delhi: Academa; 2010:pp. 178-347.
2. Clement S, Braithwaite SS, Magee MF et al. Management of diabetes and
hyperglycaemia in hospitals. Diabetes Care 2004; 27: 553-91. 6. Thompson CL, Dunn KC, Menon MC et al. Hyperglycaemia in the hospital.
Diabetes Spectrum 2005; 18: 20-27.
3. Hammersley MS, JJ. In-Hospital treatment and surgery in patients
with diabetes. In: Holt RIG, Cockram C, Flyvbjerg A, Goldstein BJ, editors. 7. Wolpert HA. Treatment of diabetes in the hospitalized patient. In: Kahn CR,
Textbook of Diabetes; 4th Ed. West Sussex: Wiley-Blackwell; 2010: King GL, Moses AC, Weir GC, Jacobson AM, Smith RJ, editors. Joslin’s Diabetes
pp. 514-27. Mellitus; 14th Ed. Boston: Lippincott Williams and Wilkins; 2005: pp. 1103-110.

353
 9.10 Hypoglycaemia

Siddharth N Shah

INTRODUCTION HYPOGLYCAEMIA AND THE BRAIN

Hypoglycaemia occurring several hours after meals was Glucose is an obligate oxidative fuel for the brain under
described for the first time in 1922. In 1927, hyperinsulinism as physiological conditions.The brain accounts for > 50% of whole-
a cause was recognised in a patient with malignant pancreatic body glucose utilisation. The brain can oxidize alternative
islet cell tumour who had episodes of severe hypoglycaemia. fuels, such as ketones, if their circulating levels are high enough
Hypoglycaemia is the major hazard of insulin treatment and to to enter the brain in a substantial quantity, but that is seldom
a lesser extent with OAD, while trying to achieve tight control. the case. Because it cannot synthesise glucose, it utilises
The patient may experience symptoms of hypoglycaemia when physiological levels of circulating non-glucose fuels effectively,
the blood glucose concentration is less than 50 mg/dL but or store more than a few minutes supply of glucose as glycogen.
individual susceptibility varies considerably. At its mildest it is no The brain requires virtually continuous supply of glucose from
more than a slight inconvenience, but at its severest uncon- the arterial plasma glucose concentration. This supply is
sciousness, it is both a hazard and an embarrassment. required for maintenance of neural function and integrity. At
Hypoglycaemia occurs commonly in patients on sulphonylureas some level of hypo-glycaemia (perhaps 50 to 55 mg/dL) (2.8 to
especially elderly patients on long-acting drugs like chlor- 3.1 mmol/L) since symptoms normally occur at that level, blood-
propamide and glibenclamide. Neonatal hypoglycaemia of to-brain glucose transport becomes limited to brain glucose
infants born to diabetic mothers is well known. metabolism and therefore, function is impaired.
Maintenance of Systemic Glucose Balance
DEFINITION
Falling plasma glucose concentrations elicit a sequence of
Hypoglycaemia or low blood glucose is a clinical state responses that normally prevent or rapidly correct hypo-
associated with low (less than 50 mg/dL) or relatively glycaemia. Because obligatory glucose utilisation by the brain
low plasma glucose concentration usually associated is fixed and exogenous glucose delivery from food is
with signs and symptoms of autonomic hyperactivity and intermittent, systemic glucose balance is maintained and
neuroglycopaenia. The Diabetes Control and Complications hypoglycaemia (as well as hyperglycaemia) is prevented by
Trial (DCCT) has defined hypoglycaemia as an event resulting dynamic regulation of endogenous glucose production by the
in seizure, coma, confusion, irrational or other prodromal liver (and the kidneys) and of glucose utilisation by non-neural
symptoms consistent with hypoglycaemia (e.g. sweating, tissues such as muscle.
palpitations, hunger or blurred vision) in conjunction with a
laboratory-determined or finger stick blood glucose less than The physiological defence against declining plasma glucose
50 mg% and amelioration by treatment that raises blood concentrations include: (1) a decrease in insulin secretion; (2)
glucose. Prodromal symptoms of hypoglycaemia remembered an increase in glucagon secretion, in absence of the latter, an
by the subject as occurring shortly before the event. Severe increase in epinephrine secretion. The behavioural defence is
the ingestion of carbohydrates prompted by awareness of
hypoglycaemic coma or seizure requires hospitalisation or
hypoglycaemia. The first physiological defence against
intravenous glucose or glucagon.
hypoglycaemia is a decrease in pancreatic islet β-cell insulin
AETIOLOGY secretion. That occurs as plasma glucose concentration decline
and within the physiological range and increase hepatic (and
The most common cause of hypoglycaemia is iatrogenic, i.e.
renal) glucose production with virtual cessation of glucose
drug-induced oral hypoglycaemic agents or insulin.
utilisation by insulin-sensitive non-neural tissues. The second
Hypoglycaemia secondary to alcohol, insulinoma, kidney and physiological defence is an increase in pancreatic islet
liver disease and that associated with endocrine dysfunction α-cell glucagon secretion that occurs as plasma glucose
and neonatal hypoglycaemia are among the other causes of concentrations fall just below the physiological range and
hypoglycaemia. increases hepatic glucose production (largely by stimulating
glycogenolysis). Increased glucagon secretion is signalled by a
PHYSIOLOGY OF GLUCOSE COUNTER-REGULATION
decrease in intra-islet insulin, perhaps among other β-cell
Energy requirements are made from the substrate derived from secretory products, in the setting of low plasma glucose
food and excess substrates stored as fat, protein and glycogen. concentration. The third physiological defence, which becomes
Insulin is the primary hormone mediating the anabolic phase critical when glucagon secretion is deficient, is an increase in
of metabolism when the counter-regulatory hormone levels are adrenomedullary epinephrine secretion that too occurs as
suppressed. The metabolic adjustment during the catabolic plasma glucose concentration through an array of mechanisms
phase includes the activation of liver for glycogenolysis and which include direct stimulation of hepatic (and renal) glucose
gluconeogenesis and use of free fatty acid from triglycerides production, limitation of glucose clearance by insulin-sensitive
354 stored in adipose tissue. tissues, mobilisation of gluconeogenic substrates such as lactate
 Hypoglycaemia
and amino acids from muscle and glycerol from fat, and leading to hypoglycaemia (reactive hypoglycaemia). Rapid gastric
limitation of insulin secretion. Unlike insulin and glucagon emptying in post-gastrectomy patients with brisk absorption of
secretion, which are regulated primarily by changes in glucose glucose results in excessive insulin release, leading to rapid fall of
concentrations within the pancreatic islets and only secondarily glucose concentration and hypoglycaemia symptoms.
by central nervous system-mediate autonomic inputs,
When the liver function is severely impaired, hypoglycaemia
sympathoadrenal activity, including epinephrine secretion, is
occurs because glycogen stores in liver are poor and perhaps
regulated with the central nervous system.
insulin destroying complex (insulinase) is deficient in hepatic
Hypoglycaemia-Associated Autonomic Failure in Diabetes disease. Recurrent hypoglycaemia can occur in patient with
The concept of hypoglycaemia-associated autonomic failure deteriorating renal function. Accumulation of serum insulin leads
(HAAF) in diabetes (Table 1) postulates that recent antecedent to fasting hypoglycaemia, (Table 2), diabetic type of glucose
hypoglycaemia as well as prior exercise or sleep, causes both tolerance test due to inability of the liver to store glucose as
defective glucose counter-regulation (by reducing increments glycogen, and poor glucose response to administration of
in epinephrine in the setting of absent decrements in insulin glucagon or epinephrine. Alcohol induces slowing of the Krebs
and absent increments in glucagon during subsequent cycle with impairment of gluconeogenesis, giving rise to reduced
hypoglycaemia) and hypoglycaemia unawareness (by reducing glucose output and hypoglycaemia. There is no rise of serum
sympathoadrenal and the resulting neurogenic symptom insulin during fed state hypoglycaemia (Table 3).
response during subsequent hypoglycaemia) and, therefore, a
Table 2: Causes of Fasting Hypoglycaemia
vicious cycle of recurrent iatrogenic hypoglycaemia. Perhaps
the most compelling support for the concept of HAAF is the Underproduction Overutilisation
finding, in three independent laboratories, that as little as 2 to 3 Hormone deficiencies Hyperinsulinism
weeks of scrupulous avoidance of hypoglycaemia reverses Hypopituitarism Insulinoma
hypoglycaemia unawareness and improves the attenuated Adrenal insufficiency Exogenous insulin overdose
epinephrine component of defective glucose counter- Catecholamine deficiency Sulphonylurea overdose
regulation in most affected patients. While HAAF is largely a Glucagon deficiency Insulin autoimmunity
functional, dynamic disorder that can induce and reverse, there Enzyme defects Inappropriate insulin level
may also be a structural (neuropathic) contribution to the Glucose-6-phosphatase Extrapancreatic tumours
Liver phosphorylases Carnitine deficiency
attenuated sympathoadrenal response.
Pyruvate carboxylase Cachexia with fat depletion,
Table 1: HAAF (Hypoglycaemia-Associated Autonomic Failure) Substrate deficiency e.g. advanced cancer
Ketotic hypoglycaemia of
Absolute endogenous insulin deficiency infancy
A history of severe hypoglycaemia, hypoglycaemia unawareness, Severe malnutrition,
or both as well as recent antecedent hypoglycaemia, prior muscle wasting (?)
exercise, and sleep Late pregnancy
Aggressive glycaemic therapy per se (lower AlC levels, lower Acquired liver disease
glycaemic goals) Hepatic congestion
Cirrhosis
The first defence against falling plasma glucose concentration Severe hepatitis
is decreased insulin secretion and the glucose counter Drugs
regulatory hormones are activated. Glucagon plays a primary Alcohol
role in the glucose counter-regulatory process. Epinephrine Propranolol
becomes important when glucagon is deficient. Other factors Salicylates
such as cortisol and growth hormone are involved in prolonged
hypoglycaemia; other hormonal neuro-transmitters and normal Table 3: Fed State (Reactive) Hypoglycaemia
physiological response to falling blood glucose concentration Underproduction Overutilisation
is the decline in insulin secretion and it occurs at a glycaemic
Early (alimentary) within 2 to Late (occult) diabetic 3 to
threshold of 83 mg/dL. The symptoms of hypoglycaemia are
3 hours after meals 5 hours after meals
felt at blood glucose of 54 mg/dL and those of cognitive
Alimentary hyperinsulinism Delayed insulin release due to
dysfunction at 49 mg/dL. β-cell dysfunction
PATHOGENESIS Post-gastrectomy (dumping Counter-regulatory deficiency of
syndrome) growth hormone, glucagon,
Hypoglycaemia is most commonly encountered due to over cortisone, epinephrine
dosage with insulin or oral hypoglycaemic drugs. This may be Hereditary fructose intolerance
due to any one or a combination of the following; if more than Galactosaemia
the required dose of insulin or oral drug is taken; if a meal is Leucine sensitivity
skipped, is inadequate or is unduly delayed after insulin
Non-specific reactive functional hypoglycaemia is the most
injection or oral antidiabetic drugs and; unusual heavy physical
frequent cause of hypoglycaemia in the normal population
exertion, after taking insulin.
and is associated with anxiety. These patients tolerate physical
In early diabetes with partial decompensation there is islet inertia exercise and prolonged fasting very well. In early diabetes,
and insulin is not released till blood glucose level reaches 200 mg/ hypoglycaemia is seen to occur 3 to 5 hours after a
dL. Blood sugar then falls rapidly due to sudden release of insulin, carbohydrate-rich meal. Specially in patients with a strong 355
 family history of diabetes. Fasting blood sugar is normal or producing Zollinger-Ellison syndrome may be associated. After
elevated and prolonged fast is well tolerated. In reactive a severe bout of alcohol, hypoglycaemia can occur especially if
hypoglycaemia due to leucine sensitivity which releases the patient takes very little food. Hypoglycaemia is intermittent
insulin from the β-cells, hypoglycaemic convulsions occur after and cannot be reproduced by fasting. Patients who have
an injection of leucine in infants and small children. There is a undergone gastrectomy complain of nausea, abdominal
fall in blood glucose within 20 minutes and marked rise of discomfort, diarrhoea, sweating, palpitation and giddiness
serum insulin levels. It is a self-limiting disease occurring in (dumping syndrome).
infants up to 5 months of age and is rarely seen in adults.
After ingestion of sugar or a fruit, severe vomiting and
Pseudohypoglycaemia hypoglycaemia occur in hereditary fructose intolerance. Liver
Pseudohypoglycaemia occurs in certain chronic leukaemias enlargement, jaundice, cirrhosis, albuminuria, aminoaciduria,
when the leucocyte counts are markedly elevated.This artefactual and mental retardation due to chronic hypoglycaemia have
hypoglycaemia reflects utilisation of glucose by leucocytes after been observed in children. Older children show strong dislike
the blood sample has been drawn. Such a hypoglycaemic for sugar and fruits.
condition, therefore, is not associated with symptoms. Other
artefactual hypoglycaemias may be seen with improper sample INVESTIGATIONS
collection or storage, errors in analytic methodology. Diagnosis of post-prandial hypoglycaemia, the only
unequivocal diagnostic test is the demonstration of low plasma
CLINICAL FEATURES glucose concentration (less than 50 mg/100 mL) during
The signs and symptoms of hypoglycaemia can be divided spontaneously developed symptoms. A 5-hour oral glucose
into those due to autonomic hyperactivity and those tolerance examination showing a plasma glucose value of 50
resulting from neuroglycopaenia, as shown in Table 4. The mg/mL or less is suggestive.
manifestations are varied and will depend mainly on the rate
Diagnosis of β-cell adenomas (insulinoma) is based on serum
of fall of blood glucose level and the ability of the patient’s
insulin level of 20 µg/mL or more in the presence of blood
endocrine system to counteract. For example, a patient on
glucose values below 40 mg/mL. Elevated circulating
insulin may complain of few symptoms despite very low
proinsulin level, differentiates between insulinoma and
glucose levels whereas a patient with Sheehan’s syndrome
factitious hyperinsulinism. The ratio of insulin to glucose and
may feel very uncomfortable even with moderately low
absence of suppression of C-peptides during hypoglycaemia
blood glucose level.
induced by 0.1 unit of insulin per kg body weight per hour
Table 4: Signs and Symptoms of Hypoglycaemia are diagnostic. A normal person would suppress the peptide
level to 50% or more during hypoglycaemia. Glucose tolerance
Autonomic Hyperactivity Neuroglycopaenia test is not helpful. CT scan may not pick-up the tumour and
Adrenergic Headache pancreatic arteriography may be required to locate the
Palpitation Fatigue tumour preoperatively.
Sweating Mental dullness
Anxiety Dizziness In normal persons, the insulin/glucose ratio is always less than
Tremors Blurring/clouding of vision 0.4. In insulinomas, the ratio is greater than 0.4 and often above
Parasympathetic Confusion 1.0. Multiple sampling is required because patients with
Hyperactivity Amnesia insulinoma may secrete insulin episodically. In islet cell
Nausea Seizure tumours, provocative tests with tolbutamide, glycogen or
Hunger Unconsciousness leucine may be of help but the overlap between normal and
insulinoma patients is so great as to render the tests of little
Patient may present with weakness, palpitation, nervous- value.
ness, sweating and mental confusion, progressing to
In factitious hypoglycaemia, the triad of low blood sugar,
unconsciousness. History of insulin being administered or
high immunoreactive insulin and low C-peptide level are
history of having consumed oral hypoglycaemic may be
pathognomonic of exogenous insulin administration. When
available. Short acting insulin may produce hypoglycaemia up
sulphonylureas are suspected as being responsible, a chemical
to 4 to 6 hours after injection whereas intermediate acting
test of the plasma to detect the drugs may be required.
insulin may produce hypoglycaemia in the evening or at
midnight. It is rare to find prolonged hypoglycaemia with short- DIFFERENTIAL DIAGNOSIS
acting oral drugs like tolbutamide and glipizide whereas
Hypoglycaemia may be misdiagnosed as hyperglycaemia
prolonged hypoglycaemia leading to coma is more commonly
and if not treated promptly may lead to death. Chronic
encountered in elderly diabetics who are on chlorpropamide
hypoglycaemia may lead to loss of memory, clouding of vision,
or glibenclamide. Whipple’s triad consisting of symptoms of
blunted mental activity, confusion, abnormal behaviour,
hypoglycaemia, low blood glucose values during this period
convulsions and coma.
and immediate relief of symptoms and signs after ingestion of
glucose is characteristic of β-cell tumours. Occasionally the Hypoglycaemia should be differentiated mainly from
tumour is associated with severe diarrhoea, muscle wasting or hyperglycaemia especially when a patient is in coma. Table 5
carcinoid syndrome. These patients get tired easily and do not shows differential diagnostic features of hyperglycaemia and
tolerate prolonged exercise. It may also present as a part of hypoglycaemia. Hypoglycaemia may also present as transient
356 multiple adenomatosis or neurofibromatosis. Even gastrin ischaemic attacks, giddiness, mental confusion, convulsion or
 Hypoglycaemia
Table 5: Differential Diagnosis of Hypoglycaemic and Hyperglycaemic Coma
Symptoms, Signs and Hypoglycaemic Coma Hyperglycaemic Coma
Laboratory Findings
Physical findings
Pulse rate Increased Increased
Pulse volume Full Weak
Temperature May be decreased May be decreased
Respiration Shallow or normal Rapid and deep (air hunger)
Blood pressure Normal, may be increased Decreased
Skin Clammy, sweating Dry
Tongue Moist Dry
Tissue turgor Normal Reduced
Eyeball tension Normal Reduced
Breath No acetone Acetone may be present
Reflexes Brisk reflexes Diminished reflexes
Laboratory tests
Urine glucose Negative to positive depending on time of last voiding Positive
Plasma glucose Negative* to positive** Positive** >200 mg/dL
Plasma acetone Negative Usually present
Plasma bicarbonate Normal Low <20 mg/L
Plasma CO2 Normal Diminished***
Blood pH Normal <7.35
* In case of diabetic ketoacidosis with very severe complicating lactic acidosis, urine and plasma acetone may be negative. Rarely, uraemic patients
with diabetic ketoacidosis have positive plasma acetone but negative urine acetone.
** Sometimes urine is negative for sugar but positive for acetone in patients with hypoglycaemic coma. This is due to starvation ketosis.
*** In patients with severe acute or chronic respiratory failure, plasma bicarbonate may be normal or increased despite concomitant presence of
metabolic acidosis or diabetic ketoacidosis.

coma and may be mistaken for a neurological illness. Although hypoglycaemia-induced glucagon response is invariably
food, especially free carbohydrates, will relieve symptoms reduced in patients with diabetes after 5 years, the main factor
regardless of the cause, persons without a hypoglycaemic responsible for unawareness of hypoglycaemia is inadequate
disorder may feel better after eating. A suspected patient has response of epinephrine. Autonomic neuropathy was initially
to undergo a 5-hour oral glucose tolerance test with plasma thought to be the main factor responsible for inadequate
sampling every half hour and at the time the symptoms occur. counter-regulation. However, many with inadequate response
A good history will clinch the diagnosis of iatrogenic have no evidence of autonomic neuropathy. It is postulated
hypoglycaemia. that the hypothalamus has a specialised area which detects
hypoglycaemia and triggers autonomic response. Exposure
COURSE AND PROGNOSIS of this area to hypoglycaemia would reset the trigger
If detected early, hypoglycaemia is reversible and can be threshold at a lower level resulting in diminished counter-
prevented. Surgical removal of β-cell tumour alleviates all regulation.
symptoms. If hypoglycaemia occurs only at night and is not
TREATMENT
detected, it might lead to loss of memory and mental
dullness. Hypoglycaemia associated with unconsciousness or stupor
should be treated as an emergency. The treatment of choice
SOMOGYI EFFECT is to give 25 to 50 mL of 50% glucose solution over a period
Insulin treated diabetic patients may show a rapid swing to of 2 to 3 minutes. One mg of glucagon injected IV is
hyperglycaemia after episodes of hypoglycaemia , the rebound preferable in an emergency where peripheral veins are
hyperglycaemia or Somogyi effect is thought to be caused by collapsed, the patient regaining consciousness within 15
actions of hormonal antagonists of insulin secreted in response min to permit ingestion of sugar. History of the
to hypoglycaemia. precipitating cause of hypoglycaemia must be ascertained
and the future course of action chalked out to prevent
HYPOGLYCAEMIA UNAWARENESS further episodes.
Some elderly long standing diabetics on sulphonylurea do The treatment of reactive hypoglycaemia of fed state is
not get adrenergic symptoms and present with severe alteration in dietary habits. Frequent small feeds are advised in
neuroglycopaenic symptoms such as convulsions or coma non-specific reactive hypoglycaemia; the diet should contain
during the hypoglycaemic episodes. About a decade back, some slowly absorbable carbohydrates and more protein.
when patients taking porcine insulin were shifted on human Anticholinergic drugs such as probanthine, 15 mg 3 times a day,
insulin in UK, some insulin-dependent diabetic patients also may be useful in reducing rapid gastric emptying. Tolbutamide
developed hypoglycaemia unawareness. It is characterised in small doses may be given twice daily before meals in patients
by low sympathetic response with insignificant increase with early diabetes. Reactive hypoglycaemia in leucine
in circulating epinephrine and glucagon. Since the sensitivity can be treated by avoiding leucine containing protein 357
 such as milk. Diazoxide has also been tried. Propranolol in small Table 6: Risk Factors for Hypoglycaemia in Diabetes
doses may be useful in both situations. Alcohol induced hypo-
glycaemia is prevented by reducing the intake of alcohol and Absolute or relative therapeutic insulin excess
increasing the ingestion of food. Hereditary fructose intolerance 1. Insulin or insulin secretagogue doses are excessive, ill-timed, or
requires avoiding foods containing sugar or fructose. Other of the wrong type
carbohydrates and milk can be taken without fear. 2. Exogenous glucose delivery is decreased (e.g. following missed
meals and during the overnight fast)
β -CELL TUMOURS 3. Glucose utilisation is increased (e.g. during and shortly after exercise)
Surgical removal, chemotherapy and irradiation help in 4. Endogenous glucose production is decreased (e.g. following
eradication of the tumour. If hypoglycaemia occurs it is treated alcohol ingestion)
symptomatically, e.g. carbohydrate feeding every 2 to 3 hours 5. Sensitivity to insulin is decreased (e.g. in the middle of the night
is usually effective in preventing hypoglycaemia. Glucagon and following weight loss, improved fitness or improved glycaemic
control)
should be available for emergency use. Diazoxide 300 to 600
6. Insulin clearance is decreased (e.g. with renal failure)
mg daily orally has been useful along with a thiazide diuretic.
Octreotide, somatostatin analogues have been used in
metastatic tumours. diabetes and their caregivers, adequate education of diabetic
patients and their relatives is necessary so that hypoglycaemia
NON-β β -CELL TUMOUR HYPOGLYCAEMIA can be avoided or treated effectively at an early stage. Patients
Mesenchymal tumours—45% to 64% of reported cases of non- should carry a card stating that they have diabetes and are
β-cell tumour cause hypoglycaemia. Histological types – fibro- treated with insulin or oral hypoglycaemic agents. Relatives,
sarcoma, lymphosarcoma, liposarcoma, rhabdom-yosarcoma, friends or colleagues at work or at school should be familiar
haemangiopericytomas, leiomyosarcoma, mesotheliomas. In with the signs of hypoglycaemia and its emergency treatment.
both sexes; 5th to 7th decade; 1/3 in chest, 2/3 in abdomen; The importance of regular meals and snacks must be
large and easily detectable, hepatomas, large adrenal tumours emphasised, and treatment should be adjusted appropriately
and carcinoma lung. These large tumours metabolise large for sporting activities or for special situations such as fasting
amount of glucose. They may secrete insulin like material. before radiological procedures or minor surgery. If Beta-
NEONATAL HYPOGLYCAEMIA blocking drugs are needed, cardioselective agents should be
used. The widespread use of highly purified human insulins
Hypoglycaemia in the immediate postpartum period needs should reduce the problem of hypoglycaemia associated with
recognition, as this phenomenon is transient. Associated
high titres of insulin antibodies. The therapeutic goal has to
with hypoglycaemia there are other parameters like
be modified in diabetic patients with autonomic neuropathy,
hypocalcaemia, hyperbilirubinaemia, polycythaemia and
hypoglycaemia unawareness of severe diabetic complications.
hyperviscosity, respiratory distress syndrome and necrotising
Very strict glycaemic control should be avoided where the
enterocolitis which must be recognised and treated. Every
risks of hypoglycaemia outweighs any potential benefit,
newborn of diabetic mothers must be given a 5% glucose
such as in long-standing, type 1 patients who have impaired
infusion for the first six hours and subsequently blood glucose
glucose counter-regulation, or in elderly or mentally
monitored to prevent fatal hypoglycaemia and hypoglycaemic
subnormal patients. Intensive insulin therapy may also be
convulsions.
impractical in treating infants or very young children.
AUTOIMMUNE HYPOGLYCAEMIA Moderate hyperglycaemia may have to be accepted in these
This may be associated with insulin antibodies or insulin individuals to avoid the greater risks of low blood glucose
receptor antibodies. The age of onset varies from a few days concentrations. Although there is no evidence in humans that
to the elderly. Hypoglycaemia occurs at any time and is hypoglycaemia causes foetal damage in early pregnancy, very
often limited. Insulin receptor antibodies are observed in tight glycaemic control reduces the ability to perceive
diabetic patients with type B insulin resistance associated with hypoglycaemic symptoms and increases the risk of coma and
acanthosis nigricans. Most of these patients have pre-existing convulsions, which are clearly undesirable for foetal
insulin resistant diabetes and evidence of autoimmune disease development. Rapid tightening of glycaemic control is now
before the development of hypoglycaemia. considered to have an initial potentially adverse effect on
established microangiopathy and also increase vulnerability
Hypoglycaemia risk factor reduction. It is, of course, preferable to hypoglycaemia. Because of the potential risk of hypogly-
to prevent rather than treat iatrogenic hypoglycaemia. The caemia, type 1 individuals are usually advised not to
prevention of hypoglycaemia requires the practice of participate in high-risk sporting activities such as hand-gliding,
hypoglycaemia risk factor reduction (Table 6). parachute jumping or scuba-diving. They may also be
excluded from certain types of employment. They are usually
PROPHYLACTIC MEASURES debarred from driving public-service vehicles, fly aeroplanes
Minimising the risk of hypoglycaemia while maintaining and may not be permitted to operate some forms of
meaningful glycaemic control is a challenge for people with machinery.

358
 9.11 Diabetic Ketoacidosis, Hyperosmolar
Hyperglycaemic State and Lactic Acidosis
Rajesh Rajput

INTRODUCTION of phosphoenolpyruvate carboxykinase and, thus, promoting

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycaemic gluconeogenesis. Ketosis results from marked increase in free
state (HHS) are potentially life-threatening complications in fatty acid release from adipocytes secondary to insulin deficiency
patients with diabetes mellitus representing two extremes in and increases ketone body (acetoacetate and β-hydroxybutyrate)
the spectrum of uncontrolled diabetic state. DKA happens formation in the liver through activation of carnitine palmitoyl-
predominantly in those with type 1 diabetes, while HHS is seen transferase I secondary to hyper-glucagonaemia. This enzyme is
in patients with type 2 diabetes under certain circumstances. crucial for regulating fatty acid transport into the mitochondria,
HHS differs from DKA in the magnitude of dehydration, ketosis, where β-oxidation and conversion to ketone body occurs. The
and acidosis. In as many as one-third of cases, the clinical features ketone bodies, however, have a low pH and cause metabolic
of HHS and DKA overlap and are observed simultaneously acidosis. The absence of ketosis in HHS is not completely
(overlap cases). understood. Contributing factors include availability of insulin in
amounts sufficient to inhibit ketogenesis but not sufficient to
PATHOPHYSIOLOGY prevent hyperglycaemia. Additionally, hyperosmolarity itself may
In both DKA and HHS, the underlying metabolic abnormality decrease lipolysis, limiting the amount of free fatty acids available
results from combination of absolute or relative insulin deficiency for ketogenesis. Also, lower levels of counter-regulatory
and increased amount of counter-regulatory hormones (Figure 1). hormones have been found in patients with HHS compared with
In DKA, the lack of insulin and corresponding excess of glucagon those with DKA.
promotes gluconeogenesis, glycogenolysis, and ketone body
CAUSES
formation in the liver. The combination of insulin deficiency and
hyperglycaemia reduces hepatic levels of fructose 2,6-biphosphate, Infections, especially pneumonia and urinary tract infection,
which alters the activity of phosphofructokinase and fructose remain the most common precipitating factor in the
1,6-bisphosphate. Glucagon excess decreases the activity of development of DKA and HHS. DKA may also be the first
pyruvate kinase, whereas insulin deficiency increases the activity presentation in patients with type 1 diabetes. Young patients
with recurrent episodes of DKA may have an underlying eating
disorder, or may be using insufficient insulin for fear that it will
cause weight gain. In around 5% of cases, no cause for the DKA
is found. Any illness that predisposes to dehydration may lead
to HHS. Various other precipitating factors for HHS are silent
myocardial infarction, cerebrovascular accident, mesenteric
ischaemia, acute pancreatitis and use of various medications,
such as steroids, thiazides, diuretics, calcium channel blockers,
propranolol, and phenytoin.

CLINICAL FEATURES
DKA usually develops in younger, lean type 1 diabetes patients
and develops within a day or so while HHS is usually occurs in
older and obese type 2 diabetic patient and develop over days
or weeks and is often preceded by illness, e.g. vomiting or
chronic co-morbidity, e.g. dementia, immobility that results in
several days of increasing dehydration. Predominant symptoms
in DKA are nausea and vomiting, pronounced thirst, excessive
urine production, and abdominal pain that may be severe. In
severe DKA, breathing becomes laboured and of a deep,
gasping character known as ‘Kussmaul respiration’. The
abdomen may be tender to the point that an acute abdomen
may be suspected, such as acute pancreatitis, appendicitis or
gastrointestinal perforation.
On physical examination there is usually clinical evidence of
dehydration, such as a dry mouth and decreased skin turgor. If
the dehydration is profound enough to cause a decrease in the
circulating blood volume, tachycardia and low blood pressure
Figure 1: Pathophysiology of DKA and HHS.
may be observed. In DKA a ‘ketotic’ odour is present, which is 359
 often described as ‘fruity’. If Kussmaul respiration is present, While diagnostic features of HHS include plasma glucose level
this is reflected in an increased respiratory rate. The patient of of 600 mg/dL or greater, total serum osmolality of 330 mOsm/kg
HHS may present with focal or global neurologic changes like or greater and absence of severe ketoacidosis. Since pH
drowsiness, lethargy, delirium, coma, focal or generalised on a venous blood gas level is 0.03 lower than pH on an
seizures, hemiparesis, and sensory deficits. arterial blood gas (ABG) analysis, venous pH may be used for
repeat pH measurements. Because this difference is relatively
DIAGNOSIS AND LABORATORY INVESTIGATIONS reliable and not of clinical significance, there is almost no
Laboratory features differentiating between DKA and HHS are reason to perform the more painful ABG. The Acetest and
summarised in Table 1. DKA is characterised by hyperglycaemia, Ketostix products measure blood and urine acetone and
ketosis and increased anion gap metabolic acidosis. American acetoacetic acid. They do not measure the more common
Diabetes Association categorises DKA into one of the three ketone body, β-hydroxybutyrate, so the patient may have
stages of severity: paradoxical worsening of ketosis as the latter is converted into
Mild: Blood pH mildly decreased to between 7.25 and 7.30 the former during the treatment. However, this should not be a
(normal 7.35 to 7.45); serum bicarbonate decreased to 15 to matter of concern when patient is improving as suggested
18 mmol/L (normal above 20); the patient is alert by change in pH and bicarbonate levels. Serum or capillary
β-hydroxybutyrate can be used to follow response to
Moderate: pH 7.00 to 7.25, bicarbonate 10 to 15, mild drowsiness
treatment. Levels greater than 0.5 mmol/L are considered
may be present
abnormal, and levels of 3 mmol/L correlate with the need
Severe: pH below 7.00, bicarbonate below 10, stupor or coma for DKA treatment. Patients with DKA who are in a coma
may occur. typically have effective osmolalities >320 mOsm/kg H2O. If the
osmolality is less than this in a patient who is comatose, search
Table 1: Differences Between DKA and HHS for another cause of obtundation such as cerebrovascular
DKA HHS accident, head injury, hyponatremia, meningitis and or
rhinocerebral mucormycosis. Hyperamylasemia may be
Plasma glucose (mg/dL) >250 >600 seen, even in the absence of pancreatitis. BUN level is
Arterial pH <7.3 >7.3 increased due to dehydration. Other relevant investigations
Sodium bicarbonate (mEq/L) <15 >15 include measurement of serum potassium, blood culture,
Serum and/or urinary ketones Positive (>1:2 Negative urinalysis and urine culture, chest radiography and electro-
dilution)
cardiography.
Effective serum osmolality Variable >320
(mOsm/kg)* DIFFERENTIAL DIAGNOSIS
Anion gap** >12 <12
Ketoacidosis is not always the result of diabetes. It may also
Mental status Variable (depends Usually
result from alcohol excess and from starvation; in both states
on severity) stupor or
coma
the glucose level is normal or low. Metabolic acidosis may occur
in diabetics for other reasons, such as chronic renal failure, shock
Total water deficit (mL/kg) 100 100 to 200
due to any cause and poisoning with ethylene glycol or
Sodium (mEq/kg) 7 to 10 5 to 13
paraldehyde (Tables 2 and 3).
Chloride (mEq/kg) 3 to 5 5 to 15
Potassium (mEq/kg) 3 to 5 4 to 6 MANAGEMENT
*Total and effective serum osmolality: Volume contraction is hallmark of DKA and HHS. I t
Total serum osmolality (mOsm/kg): 2[measured serum sodium contributes to hyperglycaemia by decreasing renal clearance
(mEq/L) + glucose (mg/dL)/18] + BUN (mg/dL)/2.8] (normal 290 ± 5) of glucose, causes insulin resistance by decreasing insulin
Effective serum osmolality (mOsm/kg): 2[measured serum sodium delivery to the site of insulin-mediated glucose disposal and
(mEq/L) + glucose (mg/dL)/18] (normal 285 ± 5)
through stimulation of catecholamine and glucocorticoids.
** Anion gap: Na+-Cl– + HCO3– (normal 12 ± 2)
If severe enough to cause hypotension, it contributes to

Table 2: Differential Diagnosis of Acidosis and Coma

Diabetic Lactic Uraemic Alcoholic Starvation Methanol or Rhabdomyolysis
Ketoacidosis Acidosis Acidosis Ketosis Ketosis Ethylene Glycol
Toxicity
Plasma glucose ↑ N N ↓ N or ↓ N N
Glucosuria ++ – – – – – –
Plasma ketones ↑↑ N N ↑ ↑ N N
pH ↓ ↓ ↓ N or ↓ N ↓↑ ↑
Anion gap ↑ ↑ ↑ ↑ ↑ ↑ ↑
Osmolality ↑ N ↑ N N ↑↑ N or ↑
Others Serum lactate ↑ Urea and Serum levels Myoglobinuria
>5 mmol/L creatinine positive Haemoglobinuria
360
 Diabetic Ketoacidosis, Hyperosmolar Hyperglycaemic State and Lactic Acidosis
acidosis through lactic acid production as well as decreased levels have dropped to 250 mg/dL in DKA and 300 mg/dL in
renal clearance of organic as well as inorganic acids. HHS, intravenous fluids should be switched to D5/1/2 NS to
Therefore, fluid resuscitation is a critical part of treating DKA prevent hypoglycaemia, recognising that insulin is still needed
and HHS and it should be started even before insulin therapy. to treat ketonaemia and rate of insulin infusion should be
Intravenous solutions replace extravascular and intravascular reduced to 1 to 2 U per hour. The glucose should be checked
fluids and electrolyte losses. They also dilute both the glucose every 2 hours initially and at least every 4 hours subsequently
levels and the levels of circulating counter-regulatory until a stable insulin regimen is determined. After resolution
hormones. of DKA (i.e. HCO3– >18, anion gap ≤12, and pH >7.3) or HHS (i.e.
serum osmolality < 315 mOsm/kg and patient is alert)
Administer high volumes of isotonic saline (1 to 3 L) in 2 hours.
patient should be switched to subcutaneous insulin. In DKA
Further isotonic saline should be administered at a rate
insulin drip should be discontinued 30 minutes after giving
appropriate to maintain adequate blood pressure and pulse,
subcutaneous insulin. In newly diagnosed diabetic patients,
urinary output, and mental status. After initial stabilisation
the initial dose of insulin should be 0.6 U/kg per day divided
with isotonic saline, switch to half-normal saline at 200 to
into a mixed regimen including both short- and long-acting
500 mL per hour (half-normal saline matches losses due to
insulin, until an optimal dose is established.
osmotic diuresis).
Potassium Replacement
Table 3: Clinical Pearls in Diagnosis and Management
Potassium replacement should be started with initial fluid
Pseudohyponatraemia: Osmotic effect of hyperglycaemia moves replacement if potassium levels are normal or low. Add 20 to
intravascular water to the extravascular space and causes 40 mEq/L of potassium chloride (KCl) to each litre of fluid once
pseudohyponatraemia. Correct serum sodium by approximately
K+ is under 5.5 mEq/L. Potassium should ideally be given as two-
1.6 mEq/L for 100 mg/dL of glucose over 100 mg/dL.
thirds as KCl, one-third as potassium phosphate. If patient is
Potassium: May be normal despite depletion of body stores due to
oliguric do not administer potassium unless serum concentration
metabolic acidosis.
is less than 4 mEq/L or there are ECG changes of hypokalaemia
Serum creatinine: May be falsely elevated due to elevated
(U waves).
acetoacetate (ketone body).
Captopril (ACE-Inhibitor): May cause false positive reaction for Bicarbonate typically is not replaced in DKA since acidosis will
ketone by nitroprusside test/ketostix. improve with the above treatments alone. Administration of
Total leucocytes: Raised with DKA per se and does not suggest bicarbonate has been correlated with cerebral oedema in
presence of infection until more than 15 × 109/L or marked left shift children. Bicarbonate should be given only if pH is less than
is present. 6.9 or if pH is less than 7.1 along with hypotension or if
Body temperature cannot be used as a guide to the presence of hyperkalaemia is present. When indicated it should be given at
infection: vasodilation causes warm feeling while core body the rate of 1 mEq/kg of bicarbonate as rapid infusion over 10 to
temperature is reduced. 15 minutes with further therapy based on repeated ABG
Hyperamylasaemia: Seen in DKA and is of salivary origin. Cannot be measurement done every 30 to 120 minutes. Additional
used as a marker for the diagnosis of pancreatitis. potassium should be given with bicarbonate therapy as
Hypertriglycridaemia: Seen in DKA due to enhanced lipolysis and transient hypokalaemia is not uncommon during alkali
decreased uptake by liver. It can cause pseudohyponatraemia and administration.
when marked, precipitates pancreatitis.
Ketosis may worsen paradoxically with treatment due to conversion Phosphate and magnesium replacements are not typically
of β-hydroxybutyrate to acetoacetate. needed, since levels correct when the patient resumes eating.
Bicarbonate should be given only if pH is less than 6.9 or if pH is less COMPLICATIONS
than 7.1 along with hypotension or if hyperkalaemia is present.
Most patients with DKA recover when treated properly and
Euglycaemic DKA: Plasma glucose may be normal in patient with
decreased oral intake and in pregnancy. majority of deaths result from late complications rather than
from DKA itself (Table 4). Patients with HHS are predisposed to
Insulin is needed to help switch from a catabolic state to an develop thromboembolic complications including cerebro-
anabolic state, with uptake of glucose in tissues and the vascular accident, myocardial infarction, mesenteric thrombosis,
reduction of gluconeogenesis as well as free fatty acid and pulmonary embolism and disseminated intravascular
ketone production. It should be started about an hour after coagulation. Various other complications seen in patients with
intravenous fluid replacement. It is stared at a dose of 0.2 U/ HHS are cerebral oedema, adult respiratory distress syndrome
kg, intravenous, bolus followed by 0.1 U/kg per hour as and rhabdomyolysis.
continuous infusion. The rationale to give bolus dose is to
PROGNOSIS
saturate insulin receptors fully before beginning insulin
infusion and to avoid lag time necessary to achieve steady- DKA accounts for 14% of all hospital admissions among
state insulin levels. There is no need to add albumin to prevent diabetics and 16% of all diabetes-related fatalities. In children
insulin absorption to the infusion set. However, intravenous younger than 10 years, DKA causes 70% of diabetes-related
tubing should be flushed with insulin infusate before use. In fatalities. When managed appropriately the overall mortality is
case glucose does not decrease by at least 10% or 50 mg/dL less than 5%. The overall mortality rate in HHS is between 10%
in an hour, insulin infusion rate should be doubled and a and 20% and is dependent on co-existing conditions and
second bolus of insulin should be administered. When glucose complications. 361
 Table 4: Complications in DKA
Complication Clues Treatment
Hypoglycaemia Rebound ketosis, adrenergic or neurologic sign Shift to DNS once plasma glucose falls to < 250 mg/dL
and reduce insulin infusion to 2 to 3 U per hour
Hypokalaemia Cardiac arrhythmia Potassium replacement
Infection Fever, WBC >15 × 109/L or marked left shift Appropriate antibiotics
Myocardial infarction Chest pain, new onset heart failure, hypotension Thrombolysis and other adjunctive measures
despite adequate fluid therapy, ECG
Cerebral oedema Drowsiness, coma with or without neurological signs, Intravenous mannitol 1 mg/kg, forced hyperventilation
especially if occurring after initial improvement with aim to keep PCO2 around 28 mm Hg
Acute gastric dilatation Vomiting of blood or coffee ground material Proton pump inhibitors
or erosive gastritis
Mucormycosis Facial pain, bloody nasal discharge, blackened nasal Intravenous amphotericin
turbinates, blurred vision, proptosis
Respiratory distress Hypoxemia in the absence of pneumonia, chronic Ventilatory support
syndrome pulmonary disease or heart failure
Acute pulmonary oedema Bilateral basal crepts with raised pulmonary capillary Judicious fluid replacement, especially in those with
wedge pressure co-morbidities such as renal failure or congestive heart
failure. Diuretics, if needed
Vascular thrombosis Stroke like picture or signs of ischaemia in non- Anti-fibrinolytic and anti-coagulant therapy
nervous tissue

PATIENT EDUCATION AND SICK DAY GUIDELINES Pyruvate is normally aerobically metabolised to CO2 and H2O in
All patients with diabetes should be educated about the the mitochondrion in the process of gluconeogenesis. In the
importance of monitoring plasma glucose levels during infection, setting of decreased tissue oxygenation, lactic acid is produced
trauma, and other periods of stress and not to stop insulin therapy as the anaerobic cycle is utilised for energy production. Lactate
in presence of any intercurrent illness (Table 5). is cleared from blood, primarily by the liver (80% to 90%)
and kidneys (10% to 20%). The lactate exits the cells and is
Table 5: Sick Day Guidelines transported to the liver where it is oxidised back to glucose.
With a persistent oxygen debt and overwhelming of the body’s
Never stop insulin and check for ketones
buffering abilities (whether from chronic dysfunction or
Measure plasma glucose four times a day
excessive production), lactic acidosis ensues. Lactic acidosis was
If RBG <200 mg/dL continue normal insulin
described and classified into 2 types:
If RBG 200 to 250 mg/dL add extra 4 U with meals
If RBG >250 mg/dL add extra 6 U with meals, drink milk, fruit juice, 1. Type A lactic acidosis
plenty of fluids Occurs with decreased tissue ATP production due to poor tissue
If nausea, vomiting and RBG >250 mg/dL, consult your physician perfusion or oxygenation. It can further be sub-classified into
immediately two types:
(a) Overproduction: Circulatory, pulmonary, or haemoglobin
LACTIC ACIDOSIS
transfer disorders are commonly responsible.
Definition and Epidemiology
(b) Underutilisation: Liver disease, gluconeogenesis inhibition,
Lactic acidosis is a condition of increased anion gap metabolic
thiamine deficiency, and uncoupled oxidative phosphory-
acidosis characterised by an excess of serum lactate due to
lation.
lactate production that exceeds its systemic consumption.
The normal blood lactate concentration in unstressed 2. Type B lactic acidosis
patients is 0.5 to 1 mmol/L. Patients with critical illness can be Occurs when evidence of poor tissue perfusion or oxygenation
considered to have normal lactate concentrations of less than is absent. It is further divided into 3 subtypes based on under-
2 mmol/L. Hyperlactataemia is defined as a mild-to-moderate lying aetiology.
persistent increase in blood lactate concentration (2 to 5 (a) Type B1: Seen in association with systemic disease, as such
mmol/L) without metabolic acidosis, whereas lactic acidosis diabetes mellitus, bowel ischaemia, severe iron-deficiency
is characterised by persistently increased blood lactate levels, anaemia, liver disease, alcoholic ketoacidosis, pancreatitis,
i.e. >5 mmol/L in association with metabolic acidosis. The malignancy (leukaemia, lymphoma, lung cancer), infection,
overall incidence of lactic acidosis in critically-ill patients is renal failure, seizures, heat stroke, pheochromocytoma,
unknown; however, increasing acid-base evaluations of thiamine deficiency, short gut syndrome, and other
critically-ill patients indicate that its presence is associated carbohydrate malabsorption syndromes.
with increased morbidity and mortality.
(b) Type B2: Several classes of drugs and toxins are implicated
Pathophysiology and Aetiology including biguanides (phenformin, metformin), acetami-
Lactate is a product of anaerobic glycolysis and is generated nophen, alcohols, iron, isoniazid, nucleoside analogues
from pyruvate with lactate dehydrogenase as a catalyst. (zidovudine, didanosine, lamivudine), β-adrenergic agents
362
 Diabetic Ketoacidosis, Hyperosmolar Hyperglycaemic State and Lactic Acidosis
(epinephrine, ritodrine, terbutaline), sodium nitroprusside, of tissue oxygen delivery, thereby causing cessation of acid
5-flourouracil, sugars and sugar alcohols (fructose, sorbitol production, remains the primary therapeutic focus. Early goal-
and xylitol), salicylates, sulphasalazine, strychnine and directed therapy for sepsis is well described and is associated
valproic acid. with improved outcomes. Appropriate measures include
(c) Type B3: Is due to inborn errors of metabolism. These treatment of shock, restoration of circulating fluid volume,
include glucose-6-phosphatase deficiency (von Gierke improved cardiac function, identification of sepsis source and
disease), fructose-1,6-diphosphatase deficiency, pyruvate appropriate therapy, and resection of any potential ischaemic
carboxylase deficiency, pyruvate dehydrogenase regions. Vital signs and cardiac rhythms must be monitored
deficiency, oxidative phosphorylation deficiency, and closely because acidosis predisposes to arrhythmias including
methylmalonic aciduria. tachyarrhythmias and fibrillation. Specific medications for the
treatment of lactic acidosis include sodium bicarbonate, tris-
Clinical Features (hydroxymethyl) aminomethane, carbicarb, and dichloroacetate.
No single clinical feature itself is indicative of the presence of Toxic aetiologies of lactic acidosis such as methanol, ethylene
lactic acidosis, as symptoms are dependent on the underlying glycol, and cyanide poisoning are unique circumstances that
aetiology. Nevertheless, a careful history is vital to determine require bicarbonate therapy to facilitate the detoxification
the underlying pathology. The onset of acidosis may be rapid processes.
(i.e. within minutes to hours) or progressive (i.e. over a period Prognosis
of several days). The physical examination also depends on the
The duration and degree of increased serum lactic acid appear
underlying cause of lactic acidosis. Signs of cardiovascular
to predict morbidity and mortality. Normalisation of serum
compromise frequently include cyanosis, cold extremities,
lactate concentration (<2 mmol/L) within the first 24 hours is
tachycardia, hypotension, dry mucous membranes, dyspnoea,
associated with 100% survival, 78% survival if normalisation
confusion, lethargy, stupor, or coma. Hyperventilation is
occurred in 24 to 48 hours, and only 14% survival if after 48
common as a compensatory mechanism causing respiratory
hours. The lactate level should be used only as a single tool in
alkalosis.
combination with clinical findings and other measures of
Laboratory Work-Up circulatory failure rather than as a decisive indicator of disease
No significant differences in serum lactate levels are noted in severity.
arterial and venous blood samples. The concentration of serum
RECOMMENDED READINGS
lactate must be measured as quickly as possible (within
4 hours of collection) in a sample transported on ice. The 1. Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA, Malone
JI et al. Hyperglycaemic crises in diabetes. Diabetes Care 2004; 27 (suppl. 1):
normal serum lactate level is approximately 1 mmol/L with a S94-102.
range up to 2 mmol/L. Values above 5 mmol/L in the setting of 2. Kitabchi AE, Nyenwe EA. Hyperglycaemic crises in diabetes mellitus:
acidaemia are indicative of lactic acidosis. Additional laboratory diabetic ketoacidosis and hyperglycaemic hyperosmolar state. Endocrinol
tests may be selected on the basis of the suspected underlying Metab Clin North Am 2006; 35: 725-51.
aetiology of lactic acidosis. 3. Nugent BW. Hyperosmolar hyperglycaemic state. Emerg Med Clin North
Am 2005; 23 (3): 629-48.
Treatment
4. Uribarri J, Oh MS, Carroll HJ. D-lactic acidosis: a review of clinical
Treatment of lactic acidosis requires identification of the presentation, biochemical features, and pathophysiologic mechanisms.
primary illness and appropriately directed therapy. Restoration Medicine (Baltimore) 1998; 77: 73-82.

363
 9.12 Infections in Diabetes Mellitus

Samar Banerjee

INTRODUCTION  Frequent minor/major surgery

Infection in diabetes mellitus (DM) is very common and  Chronic renal failure requiring dialysis and blood transfusion.
important complication. DM predisposes to infection and Infections commonly seen in diabetics are presented in Table 1.
infection in turn overwhelms the metabolic control. Effective Out of all these chronic infections, which are most important
control of each affects the control of the other condition. are diabetic foot, cholecystitis, pyelonephritis, candidiasis,
Diabetes is considered as a secondary immune deficiency rhinocerebral mucormycosis, Hepatitis C and HIV, etc.
disorder by World Health Organization (WHO).
Chronic hyperglycaemia impairs host defence. Some infections Table 1: Common Infections in Diabetes
occur more in diabetics, whereas some other infections occurs Bacterial
both in diabetics and non-diabetics. The different types of Tuberculosis, bacterial pneumonia
immune alterations that occur in diabetes are described below. Malignant otitis externa
Pyelonephritis
IMMUNE ALTERATIONS IN DIABETES
Necrotising fasciitis
1. Diminished chemotaxis, phagocytosis, and killing activity, Staphylococcal infections
of lymphocyte function (especially CD4 cells) Erythrasma
2. Lower levels of immunoglobulins and complement level Perinephric abscess
(C4, C4A, C1q and C3) Non-clostridial gas gangrene
Cholecystitis
Beyond these immune factors, local factors also predispose to
infections as follows: Periodontal infection

(a) Hyperglycaemia alters the endothelial function and Fungal

increase the oxidative stress Candidiasis
(b) Angiopathy both micro and macro, produces anoxia and Mucormycosis
results in microbial proliferation, impairment of oxygen Viral
dependent polymorphonuclear function, and perfusion of Viral hepatitis, particularly C
antibiotics, etc. HIV infections
(c) Sensory motor neuropathy produces pressure sores, ulcers,
abnormal pressure points in the foot due to small joint HEPATITIS C AND DIABETES
arthropathy and small muscle myopathy of foot and Hepatitis C virus (HCV) infection and diabetes both are slowly
microangiopathy predisposing to diabetic foot. and silently developing, diagnosed very late and often with
(d) Autonomic neuropathy is a predisposing cause of chronic complications at diagnosis. Patients with chronic HCV infection
urinary tract infection because of retention of urine in can lead to the development of type 2 diabetes. Allison et al, in
bladder. It also impairs the microvascular circulation. 1994 reported in a study of 100 patients, with cirrhosis, 50% of
Microvascular impairment also leads to reduced renal blood cases related to hepatitis had diabetes whereas hepatitis C
flow and frequent renal infection and papillary necrosis is negative cirrhosis group had diabetes in 9% of cases. Similarly,
the consequence. higher incidence of HCV infection is noted amongst diabetics
than non-diabetics.
OTHER CONTRIBUTORY FACTORS
Amarapurkar et al, in 2002, from India compared the aetiology
As part of disease management and the disease process, factors
of chronic liver diseases with and without DM, and found higher
which make a diabetic more vulnerable to infection are as
evidence of HCV than hepatitis B virus (HBV) in diabetics than
follows:
non-diabetics.
 Frequent hospitalisations
 Diabetic ketoacidosis
DM may also be significantly associated with hepato-
carcinogenesis in chronic HCV patients. Incidence of DM
 Administrations of drug/fluid/blood intramuscularly or
amongst HCV chronic infection are much higher than those
intravenously
with chronic HBV infection, alcoholic liver disease, and biliary
 Inappropriate antibiotic usage
cirrhosis. Older age, obesity, severe liver fibrosis and family
 Peripheral vascular diseases history of DM are related to potential risk or developing DM in
 Neuropathy HCV infected patients. In patients with cirrhosis planned for
 Gastroparesis, reflux and pulmonary aspiration hepatic transplantation, development of type 2 DM is 5 times
364  Indwelling catheterisation higher than of HCV origin.
 Infections in Diabetes Mellitus
Though finger prick for blood sugar examination and insulin Table 3: Various Causes of Higher Prevalence of Diabetes
injection is a mode of transmission, different studies have ruled Mellitus (DM) and Tuberculosis (TB)
out the possibility.
Reciprocal worsening by one of the other
Pathogenesis of Diabetes in HCV Infection Malnutrition and low body mass index
Multiple patho-mechanisms have been suggested but none Pancreatic tuberculosis in rare cases
is definitely confirmed. These are presented in Table 2. HCV Stress induced DM due to TB
infection is reported to induce insulin resistance due to Pituitary and adrenocortical hyper-reactivity
liberation of different cytokines like TNFα, which inhibits Vitamin D deficiency
tyrosine kinase phosphorylase pathway.
DM does not alter the symptomatology, drug response,
Table 2: Pathogenesis of Diabetes Mellitus in Hepatitis C Virus resistance or localisation of the lung lesion. But in persons above
Infection 40 years and in females genders, lower lung field involvement
is significantly high. Smear positive cases and radiologically
Hyperinsulinaemia, insulin resistance
reticulo-nodular appearance were less in TB with DM than
Insulin deficiency or poor insulin secretion
opacity, cavitation, and pleural involvement. Cavitary lesions
Pancreatic infection by hepatitis C virus
were higher in type 1 DM than type 2 DM.
Autoimmune β-cell damage
Non-alcoholic fatty liver disease Cavitary lesions though maintain high bacterial population, less
Increased iron stores smear positivity are noted in diabetes because this may be
related to muscle weakness due to uncontrolled glycaemia and
Effect of DM on HCV Positive Chronic Liver Disease less effective expectoration. Higher frequency of lower lobe
The three way interaction between the stages of chronic liver disease in elderly may be due to immunological alteration or
disease, diabetes and enzymatic cholestasis suggests that higher frequency of primary TB, increased alveolar oxygen
diabetes is a risk factor for the progression of viral liver disease pressure in lower lobes.
at least in part by induction of cholestasis. High blood glucose
Management strategy in TB and DM requires some special
in HCV infected persons leads to advanced and higher fibrosis.
attention.
DIABETES MELLITUS AND TUBERCULOSIS 1. Requirement of high calorie and high protein diet (2,000-
Tuberculosis (TB) in diabetes is 2 to 5 times higher, diagnosed 2,400 cal per day)
late, asymptomatic, and is usually due to reactivation of an old 2. Problems with anti-tuberculosis drugs in DM
focus than fresh infection. In a large cohort of 8793 patients from (a) Rifampicin
India, Patel reported TB to be the most common associated illness
Accentuates destruction of sulphonylurea by drug
(5.9%) with DM in India. Swai et al, in a prospective 7-year follow-
interaction through P450 cytochrome oxidase enzyme
up of 1250 diabetes patients, found that 5.4% cases developed
pulmonary TB and 0.2% spinal TB. In 25.7% cases, TB was detected Augments intestinal glucose absorption
before DM, in 45.7% after DM and in 20.6% simultaneously. (b) Isoniazid
Though chances of TB are higher in diabetics, infection rate by Antagonises sulphonylurea action
Mycobacterium tuberculosis and tuberculin sensitivity are not
Rarely causes pancreatitis
higher compared to non-diabetics. Higher sputum positivity,
more incidences of lung involvement particularly cavitations than (c) Biguanides
other lung changes are noted. Though lower lobe involvement Loss of appetite and weight
was claimed to be more in diabetes in earlier reports, recent Malabsorption of glucose
observations are in consensus that distribution of lung affection
are same as in non-diabetics (involving upper zone pre- Choice of anti-diabetic agents: sulphonylurea and biguanides
dominantly). Anorexia, weakness, sweating, and weight loss are have its real problems in TB. Moreover to combat higher calorie
common both to TB and DM. So appearance of any one illness intake and rare cases of pancreatic TB, pancreatic stimulant oral
over the other is detected very late. hypoglycaemic should be avoided. Insulin is the only mode of
treatment for lowering any degree of blood sugar within
Additional causes of increased susceptibility to TB in diabetes minimum time as few days of hyperglycaemia may affect the
are: (a) thickened alveolar epithelium and pulmonary basal anti-TB drug response. Insulin also helps in inflammatory
lamina leading to reduction of lung diffusion capacity, lung response and healing process.
capacity and elastic recoil; and (b) reduced bronchial reactivity
and dilation due to diabetic autonomic neuropathy. Peculiarities of TB in DM
In DM, TB has got the following characteristics:
Bacteriological conversion, relapse rate are same with diabetics
and non-diabetics. But relapse in diabetes are mostly with 1. Relative paucity of physical signs and diagnosis made at
resistant strain and with poor prognosis. far advanced stage.
2. Extensive caseation of lung tissue and cavitary lesions
Probable causes of higher prevalence of DM in TB are shown in
(bilateral or unilateral) are more in number.
Table 3. Diabetic state usually improves with anti-TB drugs. But
rifampicin can produce alimentary glycosuria and early phase 3. Little pleural involvement.
hyperglycaemia. 4. Greater tendency of haemoptysis.
365
 5. Less chance of extra-pulmonary involvement and Table 4: Common Causes of Insulin Resistance in HIV Infection
endobronchial TB.
Protease inhibitor therapy
6. More cases of sputum positive disease
Lipodystrophy
The intensity of TB depends upon the duration of DM in Increased local or systemic inflammatory mediators
uncontrolled stage and if controlled judiciously, response of TB Hepatic lipid accumulation
is same as in non-diabetic groups. Muscle lipid accumulation
Hepatitis C infection
Preventive management
Reduced systemic adiponectin, leptin and increased resistin
1. Persons who were Monteaux test negative and have Low testosterone
recent conversion to tuberculin test should have isoniazid
prophylaxis, if they are in close contact with an infective Protease Inhibitor Therapy
person. Protease inhibitor therapy directly affects blood glucose
2. All diabetics at the initial diagnosis and every year must metabolism than due to alteration of body fat gain or loss.
have a chest radiograph done.
Among the protease inhibitors (PIs), indinavir is strongly related
3. All diabetics with abnormal weight loss, unexplained cough to glucose intolerance and insulin resistance has been detected
or sudden increase of insulin requirement should have within 2 to 8 weeks of treatment even in HIV-negative persons.
sputum examination and chest radiograph. Regarding other proteases inhibitor, atazanavir has lowest effect
and amprenavir (after 48 weeks of therapy) and saquinavir have
PERIODONTAL DISEASE AND DIABETES MELLITUS
got moderate effect on insulin glucose axis.
Periodontitis or infection of the anchoring tissues surrounding
the teeth due to anaerobic Gram-negative organisms has been Diagnosis and Monitoring of DM in HIV Positive Cases
claimed as sixth complication of DM. Poorly controlled diabetics International acquired immunodeficiency syndrome (AIDS)
are likely to develop this chronic infection as periodontal Society recommends (2002 guidelines) fasting blood glucose
disease (PD) and in turn, this has the potential to alter blood before HAART, 3 to 6 months after drugs and at least annually
sugar control also. or protease inhibitor therapy. For person’s high-risk for insulin
resistance, OGTT may be performed. Substitution of protease
It has been postulated that sub-gingival bacterial content are
inhibitor by other antiretroviral drugs if possible (e.g. nevirapine
higher in DM, leading to more severe disease. This is equally for
or efavirenz or abacavir) may be practiced.
type 1 and type 2 diseases but is dependent upon glycaemic
control. Severe degree PD is also considered to be associated Diabetic patients are at higher risk for acquiring HIV infection
with higher risk of diabetic complications like proteinuria, stroke, because of multiple needle pricks. Diabetics can also contract
angina, myocardial infarction, and heart failure than in diabetic HIV from multiple surgical interventions or dialysis and blood
patients with mild PD. transfusion when chronic renal failure develops.
Treatment of PD shows significant reduction of HbA1c. Finally Whether HIV infections alone like HCV infection can produce
these can be accepted that, periodontopathic bacteria increase DM or IGT is not yet clear but it is proved beyond doubt that
cytokine release, which may amplify advance glycation end HAART regimen particularly indinavir is definitely correlated.
products (AGE) mediated cytokine response and vice versa. Thus, The risk of acquiring DM in HIV positive cases are more with
PD either precipitates or aggravates the diabetic process and concomitant HCV infections, obesity, genetic background, etc.
its complications, and PD and DM enjoy a two-way relation. Screening for DM should be done with protease inhibitor
Proper dental health is another avenue to diabetes control. therapy and more frequently in high-risk cases. Lifestyle
modification is of choice, metformin or glitazones can be added
HIV INFECTION AND DIABETES subsequently.
The prevalence of frank DM in people with HIV is low with
study reports from 0.5% to 15%. But IGT is much higher as RHINOCEREBRAL MUCORMYCOSIS
estimated to be 15% to 25%. Some degree of insulin resistance 50% cases of these occurs in a diabetic person and is a life-
is also noted up to 50% cases on protease inhibitor therapy. threatening flare in a person chronically infected with the
Co-infection with HCV is found in 40% cases of HIV positive organism, Rhizopus oryzae. During diabetic ketoacidosis the
persons and is more likely to develop DM or insulin resistance. inhibitory effect of serum passes away and the disease flares.
If HCV infection occurs in HIV positive cases, the risk of But this inhibitory effect is restored after correcting acidosis.
developing hyperglycaemia becomes five times. Elevated Early manifestations are facial, ocular or nasal pain with nasal
levels of ALT liver enzyme is an indicator for liver inflammations stuffiness and discharge. Subsequent manifestations are
and predicts insulin resistance in HIV cases with lipodystrophy proptosis, chemosis, necrotic black lesions on palate or nasal
in the presence or absence of hepatitis B and C. HIV-related mucosa, fever, headache, ophthalmoplegia, and visual loss from
hyperglycaemia, whether will have the negative health cavernous sinus thrombosis. Haemiparesis may be seen due to
sequences like complications of DM are not yet settled but thrombosis of carotid artery or jugular vein.
probably will have the same fate as in HIV negative cases with
Diagnosis is confirmed by demonstration of non-septate,
hyperglycaemia.
haphazardly branching hyphae from biopsy of necrotic tissue.
Common causes of insulin resistance in HIV infection are shown Magnetic resonance imaging is essential to identify the extent
in Table 4. of involvement. Surgical debridement of infected tissue,
366
 Infections in Diabetes Mellitus
drainage of the sinuses with amphotericin B injection is the FUNGAL INFECTIONS IN DIABETES
treatment of choice. These are very common but most neglected situation
presenting as oropharyngeal candidiasis, candidial vulvo-
CHOLECYSTITIS
vaginitis a common mode of presentation in type 2 DM,
Chronic cholecystitis with or without cholelithiasis is very inter-triginous candidiasis leading to gangrene of foot and
common in diabetes, probably because of supersaturation of paronychia.
bile, chronic infection, impaired gall bladder motility, decreased
cholecystokinin release and hepatic impairment. Emphy- Prevention of infections in diabetes can be adopted as
sematous cholecystitis, an uncommon gas producing virulent follows:
infection is similar to acute cholecystitis, but more frequent in Maintenance of good hygiene
males, with higher mortality due to gangrene or perforation. Standard immunisation
35% of cases occur in diabetes and 50% contain gallstone. Frequent check-ups
Crepitus on abdominal palpation, demonstration of gas in
Foot care
radiograph or computed tomography (CT) helps in diagnosis.
Prompt cholecystectomy with broad-spectrum antibiotics like Antibiotics usage
ampicillin-sulbactam 3g intravenously every 6 hours are the Catheterisation, IV lines with proper care
choice of treatment. Autonomic nervous dysfunction, BMI, LDL
CONCLUSIONS
cholesterol, and advancing eye have been shown to have
adverse impact on function of gall bladder. DM produces immune alterations of both cellular and humoral
immunity and often complicated by acute or chronic infections.
CHRONIC PYELONEPHRITIS AND CYSTITIS Common infections in DM are TB, pyelonephritis, Staphylococcal
Chronic urinary tract infection is 2 to 4 times common in infections, cholecystitis, candidiasis, viral hepatitis, etc. Hepatitis
diabetics, particularly in women and in the presence of C may be an aetiological agent for DM. TB in DM is 2 to 5 times
autonomic neuropathy and retained bladder. Bilateral infection higher. Chances of recurrence with multidrug resistant bacteria
is also more frequently seen with diabetes. Acute manifestations are common. More cavitary lesions, less sputum positivity and
as emphysematous pyelonephritis presenting with fever, loin with relative paucity of symptoms and signs are the features.
pain, haematuria, pneumaturia, is a life-threatening situation Treatment for DM should be done with insulin. Periodontitis is a
and in 90% cases occurs in diabetes only. It is produced by gas complication of DM and DM may worsen from periodontitis also.
forming organisms, Escherichia coli in 50% to 70% cases and is Proper dental care should be a part of diabetic control. Protease
complicated by papillary necrosis in 21% of cases. inhibitor therapy in HIV infection can lead to development of
Failure of remission of fever with therapy for urinary tract insulin resistance.But whether HIV produces β-cell damage is not
infection after 3 to 4 days in diabetics, possibility of known. HIV and DM may be complicated by HCV infections.
emphysematous pyelonephritis and perinephric abscess Rhinocerebral mucormycosis, cholecystitis, chronic urinary tract
should be thought of. Abdominal CT is better than other infection, and candidiasis are other common chronic infections
radiological methods for the diagnosis. Vigorous hydration and in DM.
intravenous antibiotics with percutaneous CT guided drainage
or nephrectomy are the modalities of treatment. Chronic fungal RECOMMENDED READINGS
urinary tract infection particularly due to candidiasis is also 1. Amarapurkar D, Das HS. Chronic liver disease in diabetes mellitus. Trop
common in diabetes. It can involve both upper and lower Gastroenterol 2002; 23: 3-5.
urinary tracts. Affection localised to the bladder may be also 2. Banerjee S. Chronic infections and diabetes mellitus. In:Tripathy BB, editor.
RSSDI Text Book of Diabetes Mellitus; 2nd Ed. Hyderabad: RSSDI; 2008; 2:pp
due to colonisation than infection but pyuria supports the later.
849-62.
Indwelling catheter if any should be removed. Bladder irrigation
3. Mehta S et al. The effect of HAART and HCV infection on the development
with amphotericin B, single dose of amphotericin B or oral of hyperglycaemia among HIV-infected persons. J Acquired Immune
fluconazole for 4 days is the treatment of choice. Deficiency Syndromes 2003; 33: 577-84.
4. Patel JC. Complications in 8793 cases of diabetes mellitus 14 years
CHRONIC INFECTIONS IN DIABETIC FOOT
study in Bombay Hospital, Bombay, India. Indian J Med Sci 1989; 43:
This is a frequent complication and most neglected issue by 177-83.
both the patient and the treating physician. This is discussed in 5. Pucher J, Stewart J. Periodontal disease and diabetes mellitus. Current
a separate chapter (Chapter 19 of this section). Diabetes Report 2004; 4: 46-50.

367
 9.13 Macrovascular Complications of Diabetes

Murlidhar S Rao

Diabetes mellitus (DM) directly and indirectly affects on human often associated with high-risk, unstable and vulnerable plaque
vascular tree and these constitute major source of morbidity with a large lipid core covered by thin fibrous cap which can
and mortality in both type 1 and type 2 diabetes. Generally, easily rupture and result in acute coronary syndrome and death
injurious effects of hyperglycaemia are divided into: (a) than in those without the diabetes. Diabetes, therefore, has
macrovascular complications, viz. coronary artery disease (CAD), definite accelerating impact on the pathogenesis of athero-
peripheral artery disease (PAD), and cerebrovascular stroke; and sclerosis which, in fact, is not qualitatively different from that
(b) microvascular complications, viz. diabetic nephropathy, occurring in non-diabetic individuals.
neuropathy, and retinopathy.
EFFECTS OF DIABETES ON PATHOGENESIS OF
MACROVASCULAR DISEASE IN DIABETES ATHEROSCLEROSIS
Unlike the microvascular disease which gets clicked with the 1. Endothelial Dysfunction
onset of diabetes, the macrovascular disease antedates Endothelium which is the innermost layer of the blood
the development of diabetes by several years. Around 75% to vessels and in fact the largest organ of the body is the initial
80% of all diabetic patients will die, many prematurely of and common target of all cardiovascular risk factors. The
cardiovascular (macrovascular) disease (CVD), particularly functional impairment of the vascular endothelium in
coronary heart disease (CHD). Diabetic foot problems (gangrene, response to injury occurs long before the development of
large non-healing infected ulcers) are the commonest cause of visible atherosclerosis. The endothelial cell behaves as a
non-traumatic lower limb amputation. In one Indian study done receptor-effective structure which senses different physical
at Chennai, the prevalence of CHD was 21.4% among diabetic or chemical stimuli that occur inside the vessel and, therefore,
patients, 14.9% among IGT subjects and 11% among non-diabetic modifies the vessel shape or releases the necessary products
patients.The prevalence of PAD in the same population was 6.3%. to counteract the effect of the stimulus and maintain
There is a close relationship existing between pre-diabetes, homeostasis. The endothelium is capable of producing a
diabetes and macrovascular (cardiovascular) disease throughout large variety of different molecules including the vasodilators
life; and the substantial body of evidence supports the concept (nitric oxide [NO] and prostacyclin) and vasoconstrictors
that increased risk of morbidity and mortality due to CVD is (endothelin-1 and angiotensin II) and nicely balancing their
associated with abnormalities in glucose metabolism across the effects. When this delicate balance is lost, the conditions are
entire continuum of glucose tolerance ranging from normal to given for the endothelium to be invaded by lipids and
clinical diabetes. leucocytes (monocytes and T-lymphocytes). The
inflammatory response is incited and fatty streaks appear –
Aetiopathogenesis
the first step in the formation of the atheromatous plaque
The central mechanism in macrovascular disease is the process which may later rupture and set the conditions for
of atherosclerosis which leads to narrowing of the arteries thrombogenesis and vascular occlusion. Therefore,
throughout the body. Atherosclerosis is a progressive disease of endothelial dysfunction which is universal in diabetes is the
the arterial wall involving the components of inflammation, starter in the process of atherosclerosis and many other
vascular lipid deposition and remodelling, fibrosis, and factors are the chasers. As a result of this, vascular NO
thrombosis. Diabetes is a major independent risk factor for CHD synthesis and stability are reduced and there is an
resulting from accelerated atherosclerosis of the coronary arteries impairment of endothelium-dependent NO-mediated
occurring at a much earlier age and advancing more rapidly to vasodilatation in diabetes. In the presence of endothelial
clinical cardiovascular events in persons with diabetes than in dysfunction the powerful vasoconstrictors like endothelin-I
those without it. This was shown in the very early studies like and angiotensin-II replace the vasodilators, NO and
‘Framingham study’ and more recent studies have shown that prostacyclin.
the risk of myocardial infarction (MI) in people with diabetes is
2. Oxidative Stress
equivalent to the risk in non-diabetic patients with a history of
previous MI. American Diabetes Association (ADA) and American Oxidative products are produced as a consequence of
Heart Association (AHA) have declared that diabetes is a coronary normal aerobic metabolism. These molecules are highly
artery disease equivalent rather than a risk factor. Multivariate reactive with other biological molecules and are referred
analyses of a number of large prospective studies with a follow- to as reactive oxygen species (ROS). Under normal
up of 12 to 20 years have shown that diabetes is associated with physiological conditions, ROS production is balanced by an
efficient system of antioxidants, molecules that are capable
2- to 5-fold increase in CHD and premature cardiovascular-related
of neutralising them and, thereby, preventing oxidant
deaths in both type 1 and type 2 diabetes.
damage. In pathological states, ROS may be present in
Atherosclerosis in diabetes is typically more diffuse, hetero- relative excess. This shift of balance in favour of oxidation
368 geneous and extensive, occurring earlier and faster and more termed ‘oxidative stress’ may have detrimental effects on
 Macrovascular Complications of Diabetes
cellular and tissue function and the cardiovascular risk Table 1: Cardiovascular Risk Factors Associated with Diabetes
factors generate oxidative stress. and IR
Both type 1 and type 2 diabetic patients are under Metabolic Factors
enhanced oxidative stress. Hyperglycaemia causes non- Hyperglycaemia
enzymatic glycosylation of proteins and phospholipids, Insulin resistance
thus increasing the intracellular oxidative stress. Therefore, Visceral obesity
advanced glycosylation end products (AGEs) formed later Hyperinsulinaemia
in this process are stable and virtually irreversible and Hypertriglycerdaemia
generate ROS with consequent increased vessel oxidative Reduced HDL cholesterol
damage and atherogenesis. Small dense LDL
Hyperhomocysteinaemia
3. Activation Increased lipoprotein (a)
Activation of polyol pathway and diacylglycerol (DAG), Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic
protein kinase C (PKC) cascade are the other consequences steatohepatitis (NASH)
of persistent hyperglycaemia (uncontrolled diabetes). Excess Coagulation and Inflammatory Factors
of intracellular glucose is metabolised by sorbitol pathway; Increased PAI-1 (plasminogen activator inhibitor-1)
and there is also rise in DAG, PKC levels intracellularly Increased platelet activation
consequent to persistent hyperglycaemia. This occurs in Increased fibrinogen
many tissues including heart, aorta, glomeruli and retina. Increased adhesion molecules (VCAM1 and ICAM1)
Increased tissue factor and factor 7
4. Other Factors
Decreased NO bioavailability
There are many cardiovascular risk factors in diabetes and Increased C-reactive protein
insulin resistance (IR). These are metabolic and lipid-related Infections: Cytomegalovirus, Chlamydia pneumoniae, Helicobacter
factors, coagulation and inflammatory factors and vascular- pylori, Bacteroides gingivalis
related factors (Table 1). Some of them are primarily related Vascular-Related Factors
to diabetes while others may be found in diabetic as well Hypertension
as non-diabetic individuals. Impaired endothelium-dependent vasorelaxation
Chronic smoking
Type 2 diabetes and IR typically occur in the setting of
Microalbuminuria
metabolic syndrome which also includes visceral
Increased arterial calcification
(abdominal) obesity, hypertension, dyslipidaemia, and Decreased arterial compliance
increased coagulability all of which lead to atherosclerosis
(Figure 1). Even in this setting of multiple risk factors, type 2
diabetes acts as an independent risk factor for the
development of ischaemic heart disease (IHD), stroke, and
death. Among people with type 2 diabetes women may
be at a higher risk for CHD than men. The prevalence of
microvascular disease in itself is also a predictor of CHD.

Diabetes is a strong independent predictor of risk for stroke

and cerebrovascular disease. Patients with type 2 diabetes
have a much higher risk of stroke nearing 150% to 400%.
Stroke-related dementia, cognitive disturbances, recurrence
as well as stroke-related mortality are elevated in patients
with diabetes.The impressive correlation between CAD and
alteration in glucose metabolism has raised the hypothesis
that atherosclerosis and diabetes may share common
antecedents. Large vessel atherosclerosis can precede the
development of diabetes suggesting that rather than
atherosclerosis being a complication of diabetes both
conditions may share common genetic and environmental
antecedents, a ‘common soil’.
Important steps in the initiation and growth of atherosclerotic
plaque are: Figure 1: Diabetes to atherosclerosis

1. Endothelial dysfunction and injury SMC = Smooth muscle cell

2. Sub-endothelial monocyte/macrophage accumulation

3. Lipoprotein infiltration CLINICAL MANIFESTATIONS OF MACROVASCULAR DISEASE
4. Smooth muscle cell proliferation Cardiovascular Disease
5. Influence of T lymphocytes and other inflammatory cells Cardiovascular syndromes in patients with diabetes present in
and protein lipid accumulation in foam cells finally leading similar ways to those in non-diabetic population, although
to plaque formation and adhesion thrombosis. many patients are younger, outcomes are worse, and ischaemic 369
 events are more likely to be ‘painless’ (or rather silent) due 3. Heart failure
to associated cardiac autonomic neuropathy. A cluster of Heart failure (HF) is 2 to 5 times more common in diabetic
cardiovascular risk factors clinically relevant are associated with population than in non-diabetic population. HF can occur
diabetes, pre-diabetes, and IR and have to be looked into while even in the absence of obvious CAD. Aetiology of HF in
evaluating the diabetic patients. These are: diabetes is complex; factors include the systolic and
1. Abdominal obesity with increased waist circumference (> diastolic performance of the LV affected by diabetic
90 cm in men and >80 cm in women) acanthosis nigricans, cardiomyopathy (diabetic heart muscle disease), the
‘hump’-like fatty bulge nape of the neck superimposed deleterious consequences of hypertension
2. Hypertension (>140/90 mmHg) and further loss of functioning myocardium following
acute coronary artery occlusion. The contractility of the
3. Dyslipidaemia
non-infarcted myocardium in diabetes is much reduced
Increased triglycerides which adds further to HF.
Decreased HDL cholesterol
4. Cardiac dysrhythmias
Small dense atherogenic LDL particles
Post-prandial lipaemia They are related to ischaemia, left ventricular hypertrophy
or CAN and frequently occur in diabetic subjects following
4. Microalbuminuria MI and may result in sudden death. Decreased heart rate
5. Increased levels of PAI-1 activity and fibrinogen variability and subtle changes in CV reflexes due to CAN in
The clinical syndromes of myocardial ischaemia due to occlusive the diabetic patients result in lethal cardiac dysrhythmias.
CAD are: 5. Diagnosis of ischaemic heart disease
1. Angina ECG, stress testing either treadmill (TMT) or pharmacologic
Angina may be relatively painless and can present atypically (Dobutamine), ambulatory ECG (Holter) monitoring,
in long-standing type 2 diabetic patients, particularly the echocardiography and ultimately coronary angiography
older ones with autonomic (sensory) neuropathy. Diabetic should be done at appropriate times in the diabetic patients
patients are more likely to remain asymptomatic while with IHD with or without symptoms. Coronary revascula-
showing the ECG changes during exercise testing or risation can be very beneficial in the diabetic patients with
ambulatory (Holter) ECG monitoring. Such diabetic patients CAD.
of angina show reversible ischaemia on myocardial isotope Cerebrovascular Disease
perfusion scanning in the absence of obvious angina. Silent
Transient ischaemic attack and stroke are more frequent among
myocardial ischaemia carries a more ominous prognosis in
diabetic patients, than in the non-diabetic patients particularly
diabetic patients than in the non-diabetic people.
those who had acute coronary ischaemic event earlier. Lacunar
2. Acute coronary syndromes infarcts, large infarcts and multi-infarct disease occur more
Unstable angina, non-ST elevation MI, and ST elevation often among the diabetic population than in the non-diabetic
MI represent a major cause of death in the diabetic population. Haemorrhagic strokes occur less commonly. The
population. These may also be painless or present with prognosis of stroke is also worse in the diabetic patients.
other symptoms like acute dyspnoea (left ventricular Hypertension often coexists and worsens the situation. Coma,
failure, LVF), a variety of cardiac arrhythmias often lethal, convulsions and dense hemiplegias are often present. Carotid
cardiogenic shock, or sudden death. Malaise, nausea and artery Doppler and B-Mode ultrasound imaging to measure the
vomiting, profuse sweating or collapse are the accom- carotid intima-media thickness (IMT, abnormal if more than 1.1
panying features. Because of loss of normal circadian mm) is an extremely simple and yet accurate indication of the
pattern of autonomic cardiovascular regulation, most diffuse atherosclerosis occurring in coronary and other arteries.
acute ischaemic events occur during the evening and at The obstructive athero-plaques may be found in the carotid
night among diabetic patients. Diabetic patients who arteries by ultrasound and colour Doppler. CT or MRI brain and
suffer an MI have a higher mortality than non-diabetic MR angiography of the brain are extremely useful in diagnosis
patients both in acute phase and on long-term follow-up. as well as in prognosticating the stroke. Stroke-related dementia
Infarct expansion or/and extension and recurrence of and recurrence of stroke are more frequent in diabetic patients.
infarction, acute LVF, and congestive heart failure (CHF) Cerebrovascular mortality rate is higher in both type 1 and type 2
all occur more commonly in the diabetic population than diabetic patients.
the non-diabetic population. Peripheral Arterial Disease
Serial determinations of CK-MB and quantitative estimation PAD is 2 to 3 times more frequent in diabetic males and 5 to 6
of troponins are more useful in assessing the infarct size times more common in diabetic females. Diabetes is the
and recurrence. All modes of echocardiography (2-D, commonest cause of non-traumatic limb amputation. Smoking,
Doppler and myocardial contrast echo) are extremely useful hypertension and dyslipidaemia and associated peripheral
in assessing the LV size and function, myocardial viability, neuropathy contribute to the increased prevalence of PAD in
presence of any thrombus in the LV or its walls and other diabetic patients. Clinical presentation of ischaemic limb disease
mechanical complications like mitral regurgitation, extends over a wide spectrum of intermittent claudication,
ventricular septal rupture or ventricular aneurysm. A major critical limb ischaemia, and gangrene resulting from total
cause of adverse outcomes is the five-fold higher frequency peripheral artery occlusion. Limb pain either at rest or on
370 of cardiac failure. walking is suggestive of occlusive PAD. Acute limb ischaemia
 Macrovascular Complications of Diabetes
characterised by pain, paraesthesia, pallor, pulselessness and disease presents special problems in treating ischaemia in the
perishingly cold limb may also occasionally occur. Chronic diabetic leg and foot. The outcomes tend to be worse and
lower limb ischaemia involving popliteal and tibial arteries mortality rates higher. Cilostazol 100 to 200 mg/day and anti-
results from atherosclerosis in the diabetic individuals. The platelet drugs along with exercise programme are useful in
combination of ischaemic PAD, peripheral neuropathy, injury improving limb ischaemia. Percutaneous transluminal
and infection results in diabetic foot disease. angioplasty with stenting is performed for claudication. The
role of bypass grafts for longer arterial occlusions remains
MANAGEMENT OF CARDIOVASCULAR DISEASE IN DIABETES poorly defined. Acute limb ischaemia should be treated with
The principles of management are the same as in normal thrombolysis.
population and are dealt with in detail in respective chapters.
The difference is that diabetic patients require high degree of RECOMMENDED READINGS
suspicion and aggressive treatment plan because of their poor 1. Annual Review of Diabetes 2009: American Diabetes Association.
prognosis as compared to non-diabetic patients. 2. Clinical Practice Recommendations 2010: American Diabetes Association;
Diabetes Care Jan 2010.
HEART FAILURE AND DIABETIC CARDIOMYOPATHY 3. Joslin’s Diabetes Mellitus. Eds. C Ronald Kahn, Gordon C Weir, George L
King, Allan M Jacobson, Allan C Moses and Robert J Smith; Lipincott Williams
Please see chapter on Heart Failure and Cardiomyopathy in
and Wilkins Publications; 14th edition.
Cardiology Section 12, Chapter 10.
4. Michael Fowler: Macrovascular and Microvascular Complications of
Diabetes; Clinical Diabetes, ADA Publication 2008; 26: 77-82.
MANAGEMENT OF CEREBROVASCULAR DISEASE AND
5. Mohan V, Gundu H Rao, editors. Epidemiology, risk factors and prevention.
PERIPHERAL ARTERIAL DISEASE IN DIABETES
Type 2 Diabetes in South Asians. New Delhi: Jaypee Brothers Medical Publishers
This is broadly similar for diabetic and non-diabetic patients 6. Murlidhar S Rao, Milind Y Nadkar. API Publications. Medicine Update Jan
although additional impact of neuropathy and microvascular 2010; Vol 20.

371
 9.14 Microvascular Diseases—Pathogenesis
of Chronic Complications
Suman Kirti

INTRODUCTION studies but resulted in occurrence of ANCA positive vasculitis

Chronic microvascular complications of diabetes mellitus are and is not approved for clinical use.
retinopathy, sensory motor, and autonomic neuropathy and Sorbitol Pathway (Polyol Pathway)
nephropathy. Three-fourth of diabetics develops retinopathy
Intra-cellular glucose is pre-dominantly metabolised by
after more than 15 years of diabetes, half of the diabetics
phosphorylation and subsequent glycolysis, but when
have neuropathy, and one-third have nephropathy in large
increased some glucose is converted to sorbitol by the enzyme
population studies in the US.The prevalence rates of retinopathy
aldose reductase. Increased sorbitol concentration alters redox
and overt nephropathy are reportedly lower while that of
potential, increases cellular osmolality, generates reactive
microalbuminuria is comparable with that reported in other
oxygen species and increases AGEs formation, and likely leads
ethnic groups in a study from South India. Risk factors for overt
to other types of cellular dysfunction. Cataract formation and
nephropathy in this study were poor glycaemic control, long
neuropathy and retinopathy to some extent have been linked
duration of diabetes and systolic blood pressure, while for
to this pathway. However, testing this theory in humans, using
microalbuminuria smoking, and diastolic blood pressure were
aldose reductase inhibitors, has not demonstrated significant
additional risk factors.
benefit on clinical endpoints of retinopathy or nephropathy,
Risk of chronic complications in type-1 and type-2 diabetes and marginal benefits in neuropathy. Newer aldose reductase
result from chronic hyperglycaemia. Large randomised clinical inhibitors like fidarestat are undergoing clinical trials; epelrestat
trials of individuals with type-1 or type-2 diabetes have has been approved for use.
conclusively demonstrated that a reduction in chronic hyper-
glycaemia prevents or delays retinopathy, neuropathy, and Protein Kinase C Pathway
nephropathy. Other incompletely defined factors may Hyperglycaemia increases formation of diacylglycerol, leading
moderate development of complications. For example, despite to activation of protein kinase C (PKC). PKC is a family of serine-
longstanding diabetes, some individuals never develop threonine kinases that alter the transcription of genes for
nephropathy or retinopathy though they may have similar fibronectin, type IV collagen, contractile proteins and extra-
glycaemic control to patients with microvascular complications cellular matrix protein in endothelial cells and neurons. Thereby
suggesting genetic susceptibility for developing particular PKCs regulates diverse vascular functions like contractility, blood
complications. flow, cellular proliferation, and vascular permeability. PKC
mediates TGF-β1, angiotensin-II and vascular endothelial
MECHANISM growth factor (VEGF) and modulates mitogen activated protein
Though hyperglycaemia is an important factor, the mechanism kinase (MAPK), which mediates sclerosis. Inhibitors of PKC-b like
of such diverse cellular and organ dysfunction is unknown. Four ruboxistaurin mesylate that reduce the direct cellular actions
prominent theories have been proposed. of AGEs, VEGF, Endothelin-1, reduce oxidised lipids and oxidant
production, are being studied in clinical trials in diabetes
AGEs Theory
mellitus (DM) for retinopathy and neuropathy.
Increased intra-cellular glucose causes nonenzymatic
glycosylation of intra- and extra-cellular proteins by interaction Hexosamine Pathway
of glucose with amino acid groups on proteins, resulting in Hyperglycaemia increases flux through the hexosamine
formation of advanced glycosylation end products (AGEs). Early pathway, which generates fructose-6-phosphate, a substrate
non-enzymatic glycation products are reversible. As hyper- for O-linked glycosylation and proteoglycan production.
glycaemia continues, intermediate poorly reversible products Hexosamine pathway may alter function by glycosylation of
are formed and later irreversible AGEs are formed. Serum levels proteins, such as endothelial nitric oxide synthase, or by changes
of AGEs correlates with the level of glycaemia and these in gene expression of transforming growth factor β (TGF-β) or
products accumulate as glomerular filtration rate declines. AGEs plasminogen activator inhibitor-1 (PAI-1).
have been shown to crosslink proteins (e.g. collagen, extra-
cellular matrix protein), accelerate atherosclerosis, promote Growth Factors
glomerular dysfunction, reduce nitric oxide (NO) synthesis, Growth factors appear to play an important role in DM related
induce endothelial dysfunction, and alter extra-cellular matrix complications and their production is increased by most
composition and structure. AGEs bind to specific receptors in of these proposed pathways. VEGF-A is increased locally in
endothelial cells, macrophages, and cultured mesangial cells. diabetic proliferative retinopathy and decreases after laser
Interaction of AGEs with the receptors in mesangial cells leads photocoagulation. Inhibition of angiotensin-II also reduces VEGF,
to increased transforming growth factor-β (TGF-β) expression which could explain one of the beneficial effects of angiotensin-
and extra-cellular matrix synthesis. Aminoguanidine, a II receptor blockers on microangiopathic diseases. Monoclonal
372 compound that inhibits AGEs, was useful in experimental antibodies to VEGF like ranibizumab in experimental studies have
 Microvascular Diseases—Pathogenesis of Chronic Complications
shown improvement in proliferative diabetic retinopathy. TGF-β prevent many early complications of type 1 DM. This large
is increased in diabetic nephropathy and stimulates basement multicentre clinical trial randomised 1,400 type 1 diabetics to
membrane production of collagen and fibronectin by mesangial either intensive or conventional diabetes management and
cells. Other growth factors, such as platelet derived growth factor, prospectively evaluated the development of retinopathy,
epidermal growth factor, insulin like growth factor, growth nephropathy, and neuropathy. The intensive group achieved a
hormone, basic fibroblast growth factor, connective tissue growth substantially lower HbA1c (7.3%) than the conventionally
factor and even insulin, have been suggested to play a role in managed group (9.1%).
DM related complications. Figure 1 shows the pathways and their
DCCT showed that improvement of glycaemic control reduced
interaction in the pathogenesis of microvascular disease.
non-proliferative and proliferative retinopathy by 47%,
Angiotensin-II microalbuminuria by 39%, and clinical nephropathy by 54% and
The renin-angiotensin system (RAS) in the kidney is abnormally neuropathy by 60%. Improved glycaemic control also slowed
activated in diabetes. Angiotensin-II directly binds to receptors the progression of early diabetic complications. A non-
in renal cells and induces matrix deposition in mesangial and significant trend in reduction of macrovascular events was
tubular cells through TGF-β1. Angiotensin-II stimulates VEGF observed during the trial (most individuals were young, with a
production in mesangial cells and impairs glomerular structure low risk of cardiovascular disease). Results of DCCT predicted
and function. Similar effects are observed in the retina. that type-1 diabetics with intensive management gain 7.7
additional years of vision, 5.8 additional years free from ESRD
Glycaemic Control and Complications and 5.6 additional years free from lower limb amputations. If all
The diabetes control and complications trial (DCCT) provided the complications were combined, intensively managed group
definitive proof that reduction in chronic hyperglycaemia can would experience 15.3 more years of life without significant

Figure 1: Pathways leading to microvascular diseases in diabetes mellitus.

AGE = Advanced glycation end products; PKC = Protein kinase C; NO = Nitric oxide; DAG = Diacylglycerol; TGF = Transforming growth factor; VEGF = Vascular endothelial
derived growth factor, Ang-II-Angiotensin-II, ET1, endothelin1; MAPK = Mitogen activated protein kinase; CTGF = Connective tissue growth factor; PECAM = Platelet/
endothelial cell adhesion molecules; ICAM = Inter-cellular cell adhesion molecules; PAI-1 = Plasminogen activator inhibitor; COX = Cycloxygenase; TNF = Tumour necrosis
factor; RAS = Renin-angiotensin system; NADPH = Nicotinamide adenine dinucleotide phosphate
373
 microvascular or neurological complications of diabetes as control (HbA1c 6.5%) versus standard glycaemic control (HbA1c
compared to diabetics receiving standard therapy. This 7.3%). These two large trials also confirm the importance of
translates into an additional 5.1 years of life expectancy for the glycaemic control in prevention of microvascular disease.
intensively treated diabetic. Intensive control for a mean of
Other Risk Factors
6.5 years resulted in 42% to 57% reduction in cardiovascular
events (nonfatal myocardial infarction, stroke or death from Hypertension is a major determinant of microangiopathy and
cardiovascular event) when followed-up for a mean of 17 years macroangiopathy in diabetes. It causes endothelial dysfunction,
even though their subsequent control was same as the impaired NO availability, renal vasoconstriction and decreased
conventionally treated group. Thus, the benefit of improved glomerular filtration, impaired tubuloglomerular feedback,
glycaemic control during the DCCT persisted even after the decreased medullary flow and impaired pressure natriuresis,
study concluded and the glycaemic control worsened. There is and progressive proteinuria. Intraglomerular pressure rise and
a benefit of improved glycaemia over an entire range of HbA1c stretch set off series of matrix changes. Strict blood pressure
values. The goal of therapy is to achieve HbA1c levels as close lowering with ACE-inhibitors (ACE-I) or angiotensin receptor
to normal as possible without excessive risk of hypoglycaemia. blockers (ARBs) that reduce intraglomerular pressure and block
the RAS, along with glycaemic control has been shown to
The United Kingdom Prospective Diabetes Study (UKPDS) reduce nephropathy. Large trials like microalbuminuria,
studied the course of more than 5,000 newly diagnosed cardiovascular and renal outcomes-heart outcomes prevention
type-2 diabetics randomised to: intensive management using evaluation (MICRO-HOPE), showed that adding ramipril, an
various combinations of insulin, a sulphonylurea or metformin ACE-I, slowed the progress and reduced the occurrence of
or; conventional therapy using dietary modification and nephropathy in diabetics by 24%. ARBs are more effective
pharmacotherapy with goal of symptom prevention. Individuals blockers of the RAS and also target the angiotensin-II, VEGF and
were also randomly assigned to different antihypertensive endothelial dysfunction, as well as acting favourably through
regimens. Intensively managed group achieved an HbA1c of the peroxisome proliferator-activated receptor (PPAR) in case
7.0% compared to HbA1c of 7.9% in the standard treatment of newer ARBs.
group. UKPDS demonstrated that each percent point reduction
in HbA1c was associated with 35% reduction in microvascular Dyslipidaemia has been implicated in increase in urinary
complications. As in the DCCT, there is a continuous relationship albumin excretion in diabetics and causes endothelial damage
between glycaemic control and development of complications. by oxidative stress. Treatment of dyslipidemia with fenofibrate
Improved glycaemic control was associated with improvement [fenofibrate intervention in event lowering in diabetes (FIELD)]
in lipoprotein risk profiles such as reduced triglycerides and and atorvastatin [collaborative atorvastatin diabetes study
increased HDL, though conclusive evidence of any change in (CARDS)] in large multicentric trials has shown improvement
cardiovascular risk was not seen. An important finding of the in retinopathy and maculopathy. Fibrates acting through
UKPDS was that strict blood pressure control significantly PPAR suppress endothelial proliferation and inhibit VEGF
reduced both microvascular and macrovascular complications, production.
and the beneficial effects of blood pressure control were greater Obesity contributes to microangiopathy by multiple factors
than those of glycaemic control. Lowering the blood pressure including mediators, directly secreted by adipocytes, such as
to moderate goals (144/82 mm Hg) reduced the risk of death, non-esterified fatty acids (NEFAs), tumour necrosis factor-α
stroke, microvascular endpoints, retinopathy, and heart failure ( TNF-α), leptin and adiponectin, which modulate micro-
(risk reduction between 32% and 56%). Deterioration in vascular changes, endothelial function, NO production and
maculopathy and visual acuity was also reduced. Post-trial inflammation. Smoking aggravates microangiopathy by
follow-up of 10 years of these patients showed that the inducing endothelial damage, oxidative stress, and vaso-
beneficial effect of BP control during the trial did not persist as constriction. Diets containing excess of saturated and trans fats
did the glycaemic control effects and the outcomes depended result in oxidative stress. Definitive benefit is demonstrated in
on the subsequent control of blood pressure. clinical studies by targeting hyperglycaemia, hypertension,
Action to control cardiovascular risk in diabetes eye subgroup obesity, smoking, dyslipidemia and modifying diet and lifestyle
(ACCORD-Eye) trial on 4065 type 2 diabetics from 77 centres in microangiopathic disease.
over US and Canada also showed 40% reduction in retinopathy
with intensive glycaemic control, and lipid control especially RECOMMENDED READINGS
with fenofibrate within a short period of 4 years. 1. Mohan V, Rao GHR. Type 2 Diabetes in South Asians: Epidemiology, risk
factors and prevention, 1st edition. New Delhi, India: Jaypee Brothers
The Action in Diabetes and Vascular Disease Medical Publishers (P) Ltd; 2006.
Preterax and diamicron modified release-controlled evaluation 2. Patel AS, MacMohan J, Chalmers B et al. Intensive blood glucose control
and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;
(ADVANCE) randomised-controlled trial at 215 centres in 20 358: 2560-72.
countries in Asia, Australia, Europe, and US involving 11140 type 3. Pickup J, Williams G. Textbook of Diabetes, 2nd edition. London: Blackwell
2 diabetics, studied over 5 years showed 21% reduction in Science Publishers; 2003.
development of new or worsening nephropathy and reduction 4. Silva PS, Cavallerano JD, Sun JK et al. Diabetic retinopathy: effect of
in new onset microalbuminuria with intensive glycaemic medications on onset and progression. Nat Rev Endocrinol 2010; 7 (7).

374
 9.15 Diabetes and Kidney Disease

Jamal Ahmad

DEFINITION AND EPIDEMIOLOGY spot collection (preferred method), as 24 hours or timed

Diabetic kidney disease (DKD) is characterised by excessive collections are more burdensome and add little to prediction
urinary albumin excretion (UAE) followed by loss of kidney or accuracy. Because of variability in UAE , two of the three
function. Proteinuria is a hallmark of diabetic kidney disease specimens collected within a 3 to 6 months period should be
(DKD). DKD has been classically defined by the presence of abnormal. Exercise within 24 hours, infection, fever, congestive
proteinuria ≥0.5 gm/24 hours or persistent albuminuria (≥ 300 heart failure (CHF), marked hyperglycaemia, and marked hyper-
mg/24 hours or ≥200 µg/min) if one of the following additional tension may elevate UAE over baseline values. Serum creatinine
criteria are fulfilled: presence of diabetic retinopathy and the should be measured at least annually in all adults with diabetes,
absence of clinical or laboratory evidence of the other kidney regardless of the degree of UAE.Estimated GFR (eGFR) is commonly
and renal tract disease. Persistent albuminuria in the range of co-reported by laboratories or can be estimated using formulae
30 to 299 mg/24 hours (microalbuminuria) has been shown to such as the modifications of diet in renal disease (MDRD) study
be the earliest stage of diabetic nephropathy (DN) in type 1 equation. Based on GFR the chronic kidney disease may be
diabetes and marker for development of nephropathy as well graded into five grades (Table 2). These have prognostic
as cardio vascular disease (CVD) risk in type 2 diabetes. importance. DM screening must be performed at diagnosis in
patients with T2DM and fifth year onwards in T1DM patients.
STAGES OF DIABETIC NEPHROPATHY
Table 2: Chronic Kidney Disease Stages
According to UAE values, DKD has been didactically categorised
into stages. The cut-off values used to characterise these stages Stages Description GFR (mL/
are described in Table 1. Recent studies suggest that only 30 to min/1.73 m2)
45% of microalbuminuria patients will progress to proteinuria over 1 Renal damage with GFR* normal increased ≥90
10 years of follow-up and some might regress to normoalbuminuria. 2 Renal damage with GFR* slightly decreased 60 to 89
3 GFR moderately decreased 30 to 59
Table 1: Diabetic Nephropathy Stages Based on Urinary Albumin
4 GFR severely decreased 15 to 29
Excretion
5 End-stage chronic renal failure <15 or
Stages Urine with 24 hours Random Urine Sample dialysis
Marked Urine
Time (mg/24 h)* Albumin Albumin * Renal damage is defined by abnormalities in urine and below tests, imaging
(µg/min)* Concentr- Concentr- exams or in pathology, GFR= glomerular filtration rate.
ation ation
(mg/Lit)** Ratio (mg/g)* MANAGEMENT OF DIABETIC KIDNEY DISEASE
Normoalbuminuria <20 <30 <17 <30 The best treatment for DKD is multiple risk factor interventional
Microalbuminuria 20 to 199 30 to 299 17 to 173 30 to 299 approach. The goal to be pursued is retarding the development
Macroalbuminuria ≥200 ≥300 ≥174 ≥300 or progression of DKD and to decrease cardiovascular risk and
mortality.
* Values according to the American Diabetic Association.
** Gross et al, Diabetes Care 2005. Hyperglycaemia
AETIOPATHOGENESIS Hyperglycaemia is a significant risk factor for the development
of microalbuminuria; both in type 1 and in type 2 DM. A
The important mechanism of proteinuria cited for excessive reduction of 1% in haemoglobin A1c is associated with a 37%
protein excretion in general are increased filtration, inadequate decrease in microvascular endpoints.
tubular absorption, overflow, and increased glomerular
filtration, inadequate tubular absorption, and increased tubular Clinical trials have demonstrated that intensive treatment of
secretion with the dominant mechanism being glomerular. hyperglycaemia is associated with a decreased risk for the
Angiotensin exerts complex haemodynamic and non- development of DKD in type 1 and type 2 diabetic patients. In
haemodynamic actions that includes induction of systemic the Intensive Blood Glucose Control and Vascular Outcomes in
vasoconstriction, increased glomerular arteriolar resistance, patients with type 2 Diabetes (ADVANCE) trial, the group in the
glomerular capillary pressure and glomerular capillary intensive arm for an average of 5 years showed a small reduction
permeability, reduction in the filtration surface area, stimulation in the number of cases with new onset microalbuminuria
of extracellular matrix proteins, and stimulation of renal compared to the standard therapy group.
proliferation and fibrogenic chemokinase.
Arterial Hypertension
SCREENING AND DIAGNOSIS Arterial hypertension is a main risk factor for the development
Screenings for microalbuminuria (MA) can be performed by of DKD and probably the best known relevant factor related to
measurement of the albumin-to-creatinine ratio in a random its progression. Analysis of UK prospective diabetes study (UKPDS) 375
 showed that every 10 mm Hg reduction in systolic BP is of renal disease, protein restriction in the diet has shown to
associated with a 13% reduction in the risk of microvascular reduce the decline of renal function and albuminuria.
complications, with the smallest risk among those patients with
Dyslipidaemia
systolic BP <120 mm Hg. In order to reach the BP goal of 130/80
mm Hg diabetic patients in general or 125/75 mm Hg in patients The desired target of low density lipoprotein (LDL) is <100 mg/
with proteinuria >1.0 g/24 hours, three to four antihypertensive dL for patients with DM in general, and <70 mg/dL when
agents are usually necessary. Due to the known renoprotective cardiovascular disease is present. No data based on a large
effect of ACE-inhibitors and ARB, these agents should be used clinical trial is available showing that the treatment of
dyslipidaemia is able to prevent the development or
initially along with a diuretic.
progression of DKD. In the Heart Protection Study (HPS),
Renin-Angiotensin System Blockade simvastatin, 40 mg, reduced vascular event rates and GFR
Angiotensin-converting enzyme (ACE) inhibitors could be decline in patients with DM by 25%, independent of baseline
used in normotensive subjects to prevent or postpone the cholesterol levels. Collaborative atorvastatin diabetes study
development of microalbuminuria. The aim of ACE inhibitors (CARDS) showed a modest beneficial effect of atorvastatin on
and ARBs use is not only to diminish the risk for the development eGFR, particularly in those with albuminuria.
of microalbuminuria and macro-albuminuria but also to Renal Replacement Therapy
decrease the occurrence of cardiovascular events. Diabetic patients with advance renal disease may require renal
An acute increase in serum creatinine up to 30% to 35% that replacement therapy to restore their body homeostasis and
stabilises within 2 months is expected. Increase in serum reduce symptoms of renal failure. Renal replacement can be
creatinine above these values should raise the possibility of renal provided by continuous ambulatory peritoneal dialysis (CAPD,
artery stenosis. Acute hyperkalaemia (>5.5 mEq/L) is an indication or haemodialysis). In some patients, where a kidney is available,
to stop these medications. Therefore, albuminuria, serum renal transplant may be considered. The indications and
creatinine and potassium should be checked monthly in the first contraindications are the same as for any other patient requiring
2 to 3 months after starting treatment with ACE inhibitors or ARB. RRT. It is advisable to start therapy early rather than delaying it
for terminal stages. These modalities are discussed in details in
Dual RAS blockade has been suggested to have an additive section 19, chapter 11 and 12.
effect on renoprotection. A recent large trial (ONTARGET) in
diabetic and non-diabetic subjects showed that the RECOMMENDED READINGS
association of the two classes of drugs had a major effect on 1. Ahmad J, Siddiqui MA, Habeeb A. Effective post-ponement of diabetic
nephropathy with enalapril in normotensive type 2 diabetic patients with
decreasing proteinuria but not on GFR decline or mortality. microalbuminuria. Diabetes Care 1997; 20 (10): 576-81.
More recently, the dual blockage of the renin-angiotensin- 2. Ahmad J, Shafique S, Abidi SMA, et al. Effect of 5 years enalapril therapy on
aldosterone system with Aliskiren, a direct renin inhibitor, and progression of microalbuminuria and glomerular structure changes in
losartan at maximal recommended dose (100 mg daily) type1 diabetic subjects. Diab Res and Clin Pract 2003; 60: 131-8.
showed a greater reduction in proteinuria (20%) compared 3. Dalla Vestra M, Simio ni N, Masiero A. Aliskiren: A new inhibitor of renin-
angiotensin aldosterone system activity. Minerva Endocrinol 2009; 34 (4):
to Losartan and placebo.
333-8. Review.
Dietary Intervention 4. Romero-Aroca P, Mendez-Marin I, Baget-Bernaldiz M, et al. Review of the
relationship between renal and retinal microangiopathy in diabetes
There are several modalities for a dietary intervention in DKD, mellitus patients. Curr Diabetes Rev 2010; 6 (2): 88-101. Review.
whether changing protein content or through the manipulation 5. Zelmanovitz T, Gerchman F, Balthazar AP, et al. Diabetic nephropathy.
of lipid content. In patients with type 1 DM, in different stages Diabetol Metab Syndr 2009; 1 (1): 10.

376
 9.16 Diabetic Retinopathy

Amod Gupta, Reema Bansal

DEFINITION AND EPIDEMIOLOGY

Diabetic retinopathy (DR) is a retinal microvasculopathy
resulting from prolonged hyperglycaemia. The prevalence of
DR increases with the duration of diabetes and nearly all with
type 1 and 60% with type 2 diabetes mellitus (DM) may develop
some retinopathy after 20 years. The major risk factors for the
onset and progression of DR are duration of diabetes, degree
of glycaemic control, hypertension, and hyperlipidaemia.
Prevalence rate of DR in the Indian subcontinent is reported
from 12% to 37% in type 2 DM.

AETIOPATHOGENESIS
Diabetic retinopathy (DR) starts from hyperglycaemia-induced
vascular injury. The earliest histological lesion is loss of pericytes
and thickening of the basement membrane of the retinal
capillaries. These changes result from various biochemical,
haemodynamic and endocrine factors, and eventually lead to
closure/incompetence of the capillaries.

SPECTRUM OF DIABETIC RETINOPATHY

Non-Proliferative Diabetic Retinopathy
Mild
Microaneurysms are out pouching of the retinal capillary walls
and are the first clinically detectable lesions on ophthalmoscopy.
The microaneurysms tend to cluster around small areas of
capillary non-perfusion (Figure 1). Hard exudates, located in the
outer plexiform layer of the retina, are extracellular accumulation
of lipids derived from leakage of serum from microaneurysms.
These are small white or yellowish white deposits with sharp
margins and glistening appearance (Figure 2). Dot and blot-
retinal haemorrhages are also seen.
Moderate
Soft exudates or cotton wool spots reflect an increasing
sign of ischaemia secondary to pre-capillary arteriolar
occlusion. In the area of retinal ischaemia the axoplasmic
flow is impaired resulting in accumulation of the axonal
Figures 1A and B: Fundus photograph of (A) the left eye with non-proliferative
intracellular fluid or organelles which is clinically seen as diabetic retinopathy showing dot and blot haemorrhages with hard exudates,
swelling of the retinal nerve fiber layer or cotton wool spots and (B) leaking microaneurysms on fundus fluorescein angiography.
(Figure 3).
Severe Proliferative Diabetic Retinopathy
Venous beading and loops, intra-retinal microvascular It is defined as the presence of newly formed blood vessels and/
abnormalities (IRMA), and widespread areas of capillary non- or fibrous tissue arising from the retina or optic disc, extending
perfusion develop as parts of the retina are deprived of blood along the posterior hyaloid surface. Ischaemia of the inner
and nourishment. Venous loops are hairpin or semi-circular retinal layers stimulates the production of angiogenic factors,
deviations of the vein from its normal course. The IRMAs are namely vascular endothelial growth factor (VEGF) which act
narrow, tortuous, intra-retinal vascular segment representing locally, diffuse through the vitreous to other areas of the retina,
either dilated retinal capillaries and/or intra-retinal new to the optic disc and also into the anterior chamber. The new
vessels (Figure 4). These may represent intra-retinal vessels may be found on the optic disc (neovascularisation on
neovascularisation. These serve as warning signs of future the disc or NVD) or elsewhere (neovascularisation elsewhere
proliferative DR (PDR). or NVE) on the retina (Figures 5 and 6).
377
 Figure 2: Fundus photograph of the left eye showing hard exudates.

Figures 4A and B: Fundus photograph of the right eye with severe non-
proliferative diabetic retinopathy showing superficial haemorrhages in all
Figure 3: Fundus photograph of the left eye showing soft exudates as cotton quadrants of retina (A) with venous beading and intra-retinal microvascular
wool spots. abnormalities on fundus fluorescein angiography (B).

Advanced Disease Diabetic macular oedema (DME) develops insidiously and

is the most common cause of moderate visual loss in patientsB
Complications of PDR include vitreous haemorrhage (Figure 7)
with DR. It is caused primarily by a breakdown of the inner
or subhyaloid haemorrhage (Figure 8), tractional/combined
blood retinal barrier resulting in leakage of fluid and plasma
retinal detachment (Figure 9), and neovascular glaucoma that
constituents from abnormally permeable microaneurysms,
lead to severe visual loss and blindness if left untreated.
IRMAs and dilated retinal capillaries. It may be focal or
Role of Statins diffuse.
In case of high basal serum cholesterol levels, it has been The early treatment of diabetic retinopathy study Table 1
established that statins enhance the efficacy of macular gril in (ETDRS) defined clinically significant macular oedema (CSME)
exudative maclupathy but definitive evidence is lacking that as follows (Figure 10):
statins benefit patient’s exudative maculopathy.
1. Retinal thickening at or within 500 µm of the centre of the
CLINICAL COURSE OF DIABETIC RETINOPATHY macula, and/or
In the initial stages, DR is asymptomatic, and hence, it is 2. Hard exudates at or within 500 µm of the centre of the
recommended that patients with type 1 DM undergo annual macula, if associated with thickening of the adjacent retina,
dilated fundus examination till they develop signs of and/or
retinopathy. Since in patients with type 2 DM, the onset and
3. Zone(s) of retinal thickening at least one disc area in size
duration of the disease is unknown, they should undergo
part of which is within one disc diameter of the centre.
fundus examination at the time of diagnosis of DM. Frequency
of the fundus examination thereafter will depend on the Patients may present with acute onset cobwebs/floaters
378 severity of the DR. or complete obscuration of vision caused by vitreous
 Diabetic Retinopathy
Figure 5: Fundus photograph of the right eye showing neovascularisation on Figure 8: Fundus photograph of the left eye showing extensive subhyaloid
the optic disc. haemorrhage over the macula.

Figure 6: Fundus photograph of the left eye showing neovascularisation Figure 9: Fundus photograph of the left eye showing extensive fibrovascular
elsewhere on the retina. proliferation around the optic disc causing tractional retinal detachment.

Figure 7: Fundus photograph of the left eye showing vitreous haemorrhage. Figure 10: Fundus photograph of the right eye showing clinically significant
macular oedema. 379
 haemorrhage from new vessels growing on the retina or optic and optical coherence tomography to plan treatment and
disc. The vitreous haemorrhage may absorb spontaneously over monitor the response to treatment. In patients with obscure
the next few days/weeks but is often complicated by recurrent media, ultrasonography is helpful in surgical planning.
attacks of fresh haemorrhage. The accompanying scar tissue
may contract leading to tractional retinal detachment. In severe TREATMENT
cases constant traction on retina may lead to retinal tearing Since DM has multifactorial origin, an optimal metabolic control
resulting in combined rhegmatogenous retinal detachment. of hyperglycaemia, HbA1c levels, hypertension, dyslipidaemia,
Patients with extensive retinal ischaemia tend to develop anaemia and nephropathy should be an important treatment
neovascularisation of the iris and angle of the anterior chamber goal. Medical management of diabetic macular oedema (DME)
leading to intractable neovascular glaucoma. includes systemic control of risk factors combined with local
Correlation Between Pathogenesis of Retinopathy and treatment that includes laser photocoagulation.
HbA1c Laser Photocoagulation
It is well established that good control of diabetes leads to Laser photocoagulation for CSME is currently the standard of
reduction in the microvascular complications including DR by as care. The goal of macular laser photocoagulation for diabetic
much as 37% by 1% reduction in HbA1c (UKPDS) other studies macular oedema is to limit vascular leakage through focal laser
also prove this point. burns of leaking microaneurysms or grid laser burns in areas of
diffuse breakdown of the blood-retinal barrier. The green
DIAGNOSIS AND MANAGEMENT (TABLE 1)
wavelength (Argon green, Frequency doubled Nd:YAG) is better
The diagnosis of DR is essentially clinical by using a direct absorbed by the haemoglobin and hence ideal for laser
ophthalmoscope. The ophthalmologists may, however, use photocoagulation.
stereoscopic biomicroscopic fundus examination besides several
ancillary investigations such as fundus fluorescein angiography, In recalcitrant cases pharmacological agents including
intravitreal corticosteroids and anti-VEGF agents are being
Table 1: Early Treatment Diabetic Retinopathy Study
(ETDRS) Levels of Diabetic Retinopathy, Non-Proliferative
Diabetic Retinopathy (NPDR)
Non-Proliferative Diabetic Retinopathy (NDPR)
Mild NPDR
At least one microaneurysm
Moderate NPDR
Haemorrhages or microaneurysms (H/Ma)
Soft exudates, venous beading (VB), and intraretinal
microvascular abnormalities (IRMAs) definitely present
Severe NPDR
H/Ma in all 4 quadrants
VB in 2 or more quardrants
Intra-retinal microvascular abnormalities (IRMA) in at least
1 quadrant
Very Severe NPDR
Any two or more of severe NPDR levels
Proliferative Diabetic Retinopathy (PDR)
Early PDR
New vessels on the retina
Definition not met for high-risk PDR
High-Risk PDR
New vessels on the disc of 1/4 to 1/3 or more of the disc
area or
Any new vessel and vitreous or preretinal or vitreous
haemorrhage
Clinically Significant Macular Oedema (any one of the
following):
Thickening of the retina located 500 μm or less from the
centre of the macula
Hard exudates at 500 μm or less from the centre of the
macula with thickening of the adjacent retina
A zone of retinal thickening, one disc area or larger in size, Figures 11A and B: Fundus photograph of the left eye showing (A) vitreous
any portion of which is one disc diameter or less from the haemorrhage with fibrovascular proliferation, and (B) same eye following pars
centre of the macula plana vitreous surgery.
380
 Diabetic Retinopathy
increasingly used as adjuvant to the standard laser photoco- PROGNOSIS AND PREVENTION
agulation therapy. All people with DM (type 1 as well as type 2) are at risk. The
Pan retinal photocoagulation (also called scatter laser photo- longer a person has diabetes, the higher the risk of developing
coagulation) is indicated in patients with severe NPDR and PDR. DR. Early detection, education, and research are the key to
This involves applying 1,500 to 2,000 spots of 500 µ size laser prevent visual impairment/blindness from DR. Ophthalmoscopy
burns of moderate intensity to ablate the peripheral ischaemic is the most commonly used technique to screen for DR. It is
retina. This leads to significant reduction in the release of VEGF critical to identify patients who are in immediate need of
from the hypoxic retinal tissues. Full scatter treatment for PDR treatment with laser photocoagulation.
results in partial or complete regression of retinal and optic disc
neovascularisation. RECOMMENDED READINGS
Pars Plana Vitreous Surgery 1. Ahmadi MA, Lim JI. Update on laser treatment of diabetic macular oedema.
Int Ophthal Clin 2009; 49:87-94.
The major indications are non-clearing vitreous haemorrhage,
2. Gupta A, Gupta V, Thapar S, et al. Lipid-lowering drug atorvastatin as an
macula-threatening traction retinal detachment and combined
adjunct in the management of diabetic macular oedema. Am J Ophthalmol
traction-rhegmatogenous detachment. The surgical objective 2004; 137:675-82.
includes clearing the media, relieving all anterior-posterior 3. Gupta V, Gupta A, Dogra MR, et al. Diabetic Retinopathy: An Atlas and Text.
and tangential traction using delamination, segmentation or Jaypee Brothers: Medical Publishers (Pvt. Ltd.), New Delhi; 2006.
en-bloc techniques and performing adequate platelet-rich 4. Singh R, Abhiramurthy V, Gupta V, et al. Effect of multifactorial intervention
plasma (PRP) to prevent development of subsequent immune on diabetic macular oedema. Diabetes Care 2006; 29:463-4.
reconstitution inflamm-atory syndrome (IRIS) neovascularisation 5. Williams R, Airey M, Baxter H, et al. Epidemiology of diabetic retinopathy
(Figures 11 A and B). and macular oedema: a systematic review. Eye 2004; 18:963-83.

381
 9.17 Diabetic Neuropathy

Manish Modi

DEFINITION AND EPIDEMIOLOGY Table 1: Classification of Diabetic Neuropathies

Diabetic neuropathy (DN) is defined as the presence of Symmetrical Polyneuropathies
symptoms and/or signs of peripheral nerve dysfunction in Distal sensory or sensorimotor polyneuropathy
people with diabetes after the exclusion of other causes. The Large-fibre neuropathy
importance of excluding nondiabetic causes was emphasised Small-fibre neuropathy
in the Rochester diabetic neuropathy study, in which up to 10% Autonomic neuropathy
of peripheral neuropathy in diabetic patients was deemed to
Asymmetrical Neuropathies
be of nondiabetic causes.
Cranial neuropathy (single or multiple)
There is a higher prevalence of DM in India (4.3%) compared Truncal neuropathy (thoracic radiculopathy)
with the West (1% to 2%). Probably Asian Indians are more Lumbosacral radiculopathy (asymmetrical proximal motor
prone for insulin resistance and cardiovascular mortality. neuropathy)
The prevalence of neuropathy increases with the duration of Limb mononeuropathy (single or multiple)
diabetes mellitus. The incidence of DN in India is not well known Entrapment neuropathy
but in a study from South India 19.1% type 2 diabetic patients Combinations
had peripheral neuropathy. According to an estimate, two-thirds Polyradiculoneuropathy
of the diabetic patients have clinical or subclinical neuropathy. Diabetic neuropathic cachexia
AETIOPATHOGENESIS Symmetrical polyneuropathies

The most important aetiological factors that have been Distal Symmetrical Polyneuropathy
associated with DN are poor glycaemic control, diabetes
Distal symmetrical polyneuropathy DSPN is the commonest
duration, visceral obesity and height, with possible roles for
type of DN and probably accounts for 75% of the DNs. It may
hypertension, age, smoking, alcohol consumption, hypo-
be sensory and/or motor and may involve small or large fibres,
insulinaemia, and dyslipidaemia. The pathogenesis of diabetic
or both. Sensory impairment occurs in glove and stocking
neuropathy involves an interaction between metabolic and
distribution and motor signs are not prominent. Large fibre
microvascular injury to nerve.
involvement causes painless paraesthesias with impairment of
1. Vascular Injury vibration, joint position, touch and pressure sensations, and loss
Endoneural ischaemia occurs by several mechanisms. of ankle reflex. In advanced stage, sensory ataxia may occur.
Vasodilatory signalling pathways including prostacyclins are Small fibre neuropathy on the other hand is associated with
inhibited and there is occlusion of vessels due to thickening of pain, burning, and paraesthesias.
endothelial basal lamina and fibrin and platelet deposition. Diabetic Autonomic Neuropathy
2. Direct Metabolic Injury Diabetic autonomic neuropathy affects various organs of the
Increased polyol production by overexpression of aldose body resulting in cardiovascular, gastrointestinal, urinary,
reductase induces neuropathy in animal models. Advanced sweating, pupils, and metabolic disturbances. It ranges from
glycation endproducts (AGEs) are directly neurotoxic by subclinical functional impairment of cardiovascular reflexes and
promoting inappropriate crosslinks among proteins, which is sudomotor functions to severe cardiovascular, gastrointestinal,
further accelerated in response to hyperglycaemia and greater or genitourinary dysfunction. Orthostatic hypotension, resting
polyol pathway flux. tachycardia, and heart rate unresponsiveness to respiration are
a hallmark of diabetic autonomic neuropathy.
Reactive oxygen species (ROS) are induced by AGEs, hypergly-
caemia and ischaemia. Reactive oxygen species damage Asymmetric Neuropathies
proteins, and inhibit mitochondrial electron transport. Cranial neuropathy
Mitochondrial dysfunction may serve as a final common Cranial neuropathy in diabetic patients most commonly involves
pathway for neuronal damage mediated by polyol, AGEs, and the oculomotor nerve, followed by trochlear and facial nerve in
ROS. Mitochondrial dysfunction might account for persistent order of frequency. Third nerve palsy with pupillary sparing is
injury that occurs during periods of relative normoglycaemia the hallmark of diabetic oculomotor palsy and is attributed to
and contributes to genetic differences in susceptibility to nerve infarction.The pupillary fibres are peripherally located and,
hyperglycaemic complications. therefore, escape in diabetic oculomotor palsy.
CLINICAL FEATURES Truncal neuropathy
Table 1 gives the classification of DN which are discussed in Diabetic truncal neuropathy is associated with pain and
382 the following paragraphs. paraesthesias in T4-T12 distribution in chest or abdominal
 Diabetic Neuropathy
distribution. Bulging of abdominal wall may occur because of touch, vibration and temperature in the hands and feet; and
muscle weakness. It usually occurs in older patients with NIDDM. tendon reflexes. Electrodiagnostic tests like nerve conduction
The onset may be abrupt or gradual and the patient may be studies typically show low amplitude sensory response with
confused with an intra-abdominal/thoracic disease, or herpes prolonged distal latency. Compound muscle action potential
zoster. (CMAP) amplitudes are initially normal, but decline with disease
progression.
Asymmetrical Proximal Diabetic Neuropathy
Nerve biopsy is useful only in situations, when other causes of
It is also referred to as diabetic amyotrophy. The patients
neuropathy need to be ruled out. Skin biopsy has been used in
complain of pain in the lower back, hip, anterior thigh, typically
diagnosis of small fibre neuropathy. Recently, confocal corneal
unilateral but may be bilateral. Within days or weeks, the
microscopy in the assessment of diabetic polyneuropathy has
weakness and wasting of thigh and leg muscles follows. Knee
been reported. In confocal microscopy, the cornea is scanned
reflex is reduced or absent. Numbness or paraesthesias are a and images of Bowman’s layer, which contains a rich nerve
minor phenomena. Nerve biopsy shows multifocal nerve fibre plexus, are examined for nerve fibre density, length and branch
loss suggesting ischaemic injury, and perivascular infiltrates density, which is significantly reduced in DN and correlates with
suggesting an immune mechanism. This has prompted the severity of neuropathy.
intravenous immunoglobulins (IVIg) and cyclophosphamide
therapy, which have resulted in rapid recovery. TREATMENT
Currently, no medication has been shown to reverse neuropathy.
Limb Neuropathies
The treatment is aimed at preventing the progression of
There are two major mechanisms of limb neuropathies in neuropathy and providing symptomatic relief. Aggressive
diabetics, viz. nerve infarction and entrapment. Nerve infarctions control of blood glucose is central to the treatment of diabetes
are associated with abrupt onset pain followed by variable and remains the only treatment shown to delay the onset and
weakness and atrophy. The recovery is slow over a period of slow progression of neuropathy.
months, as the primary pathology is axonal degeneration.
Agents that have been shown to slow and reverse nerve injury in
Median, ulnar, and peroneal nerves are most commonly
animal models include aldose reductase inhibitors (ARIs) that
affected. In diabetic patients, nerve entrapment is commoner
reduce shunting of glucose into polyol pathway; drugs that
than nerve infarction. The entrapment neuropathies have decrease ROS (alpha lipoic acid,glutathione, dimethylthiourea and
insidious onset, have characteristic electrodiagnostic features vitamin E), lipid lowering agents, and transition metal chelators
such as conduction block or segmental nerve conduction (desferrioxamine and α lipoic acid). Although ARI have been shown
slowing in the entrapped segment of the nerve. Carpal tunnel to improve nerve conduction velocity and the density of small
syndrome is three times more common in diabetic patients than fibres on sural nerve biopsy and α lipoic acid showed improvement
the normal population. The other entrapment neuropathies in in pain following intravenous therapy, no agent has resulted in
diabetic patients are ulnar, radial, lateral femoral cutaneous clinically meaningful improvement in human trials.
nerve of thigh, peroneal, and medial and lateral planter nerves.
Immunosuppressing therapies have been used in diabetic
DIAGNOSIS lumbosacral radiculoneuropathy, based on the evidence that it
The American Academy of Neurology recommends that DN is may have an autoimmune basis. Therapies tried include
diagnosed in the presence of somatic or autonomic neuropathy corticosteroids, immunoglobulins and plasma exchange.
when other causes of neuropathy have been excluded. At least Symptomatic Treatment
two of the five criteria are needed: Symptoms, signs, electro-
Neuropathic pain relief is one of the most challenging issues in
diagnostic test, quantitative sensory and autonomic testing.
DN.The mainstays of therapy are anticonvulsant agents, tricyclic
For diagnosis of DN, bedside examination should include antidepressants, selective serotonin reuptake inhibitors (SSRIs)
assessment of muscle pain; sensation of pin prick, joint position, and opiates (Table 2). Each of these classes of medication has

Table 2: Therapeutic Agents for Neuropathic Pain

Class of Drugs Compounds Mechanism of Action Dose Per Day Adverse Effects
Tricyclic Amitriptyline Na-channel inhibition, 10 to 150 mg Sedation, dry mouth, blurred vision, weight
Antidepressants 5-HT/noradrenaline gain, urinary retention, cardiac effects
inhibition
Imipramine 25 to 150 mg
Nortriptyline 25 to 150 mg
Serotonin/ Venlafaxine 5-HT/Noradrenaline 75 to 225 mg Nausea, sedation, hypertension
reuptake inhibitor Duloxetine reuptake inhibition 20 to 120 mg
Anticonvulsants Carbamazepine Sodium channel blocking 200 to 800 mg Hyponatraemia, ataxia, hepatic dysfunction
Oxcarbamazepine Sodium channel blocking 600 to 2400 mg Hyponatraemia, sedation
Gabapentin Calcium channel agonist 900 to 3600 mg Sedation, dizziness
Pregabalin Calcium channel agonist 150 to 600 mg Sedation, peripheral oedema
Ion channel blockers Mexiletine Sodium channel blocking 300 to 750 mg Arrhythmia
Opioids Tramadol Opioid receptor agonist 50 to 400 mg Nausea, vomiting, constipation, orthostatic
Oxycodone Add on hypotension, dizziness somnolence
383
 drug interaction and side-effects that may be more profound PROGNOSIS
in the elderly. Transcutaneous nerve stimulation (TNS), magnetic There is accumulating evidence suggesting that not only
field therapy, infrared high therapy and spinal cord stimulation surrogate markers of microangiopathy such as albuminuria, but
has also been tried in a small number of patients with painful also those used for polyneuropathy, such as nerve conduction
DN. velocity and vibration perception threshold, may predict
COMPLICATIONS mortality in diabetic patients. Autonomic neuropathy may be
associated with early mortality from cardiac involvement.
Foot Ulcers
The late sequelae of diabetic neuropathy are recognised to be RECOMMENDED READINGS
foot ulceration, which may occasionally result in amputation 1. Asbury AK. Approach to the patient with peripheral neuropathy. In: Kasper
and Charcot (neuropathic) arthropathy. Foot ulcers occur in 15% DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, editors.
Harrison’s Principles of Internal Medicine; 16th Ed. McGraw Hill Co; 2005: pp.
of the diabetic patients and are responsible for 20% of the 2500-09.
hospitalisation among diabetic patients. Peripheral neuropathy 2. Boulton AJM, Mallik RA, Arrezo JC, et al. Diabetic somatic neuropathies.
causes loss of protective sensation. The intrinsic foot weakness Diabetic Care 2004; 27(6):1458-86.
and atrophy associated with moderate and advanced 3. Harati Y, Bosch EP. Disorders of peripheral nerves. In: Bradley WG, Daroff RB,
neuropathy alter the anatomy of the foot and potentiate friction Fenichel GM, Jankovic J, editor. Neurology in Clinical Practice; 5th Ed.
Butterworth Heinemann, Philadelphia, 2008: pp. 2249-356.
injury. Autonomic neuropathy reduces foot sweating and
4. Smith AG, Singleton JR. Diabetic neuropathy. In: Bromberg MB, Smith AG,
increases foot oedema. On top of this, small and large vessel
editors. Handbook of Peripheral Neuropathy. Taylor and Francis, FL; 2005:
stenosis and loss of vasodilatory regulation result in distal limb pp. 179-204.
ischaemia promoting tissue fragility and impaired wound 5. Zeigler D. Treatment of diabetic neuropathy and neuropathic pain. Diabetes
healing. Care 2008; 31(2):S255-61.

384
 9.18 Sexual Dysfunction in Diabetes

Shashank R Joshi

BACKGROUND AND INTRODUCTION MANAGEMENT

Sexual and urologic complications of diabetes frequently Investigations
occur in diabetes but are often under reported. Men may The patients with ED are often evaluated with the erectile
have difficulty with erections or ejaculation. Women may have function (EF) domain of the 15 item international index of
problems with sexual response and vaginal lubrication. erectile function (IIEF), two diary questions regarding the
Urinary tract infections and bladder problems occur more patient’s ability to penetrate (SEP2) and have successful
often in people with diabetes. Diabetes mellitus (DM) may lead intercourse (SEP3), and a global assessment question (GAQ). The
to abnormalities of normal sexual function in both men and work-up includes fasting and prandial glucose, HbA1c, lipids
women via diabetic induced vascular and neuropathic profile, kidney function and prostate specific antigen (PSA). It
damage. Also, poorly-controlled diabetes may increase also includes sometimes gonadal evaluation of testosterone,
the morbidity associated with the treatment of erectile
follicle-stimulating hormone (FSH), luteinising hormone (LH),
dysfunction (ED) in men. Erectile dysfunction is a common
prolactin and thyroid-stimulating hormone (TSH). It is useful to
clinical problem and it seriously hampers quality of life for men
do an ultrasound of abdomen and pelvis for gonadal as well as
and their spouse. It is well known that the incidence of ED
bladder function/residual urine estimation. In few cases, semen
increases with age and usually is often associated with co-
and scrotal sonography and Doppler may also be done.
morbid conditions like smoking, cardio vascular disease,
hypertension, dyslipidemia and diabetes. The incidence of ED TREATMENT
in men with diabetes is approximately 3 to 7 folds higher than Role of Phosphodiesterase Type-5 (PDE5) Inhibitors
in the general population. ED may also be the presenting
symptom for DM and can predict both vascular or neurologic The treatment of ED, in general, was revolutionised by the
sequelae, which may occur later. Often ED is a marker of availability of sildenafil, followed by tadalafil and vardenafil. All
endothelial dysfunction. Fifty per cent of the Indian diabetic the three medications work by inhibiting the enzyme PDE5 in
men in their lifetime will have the risk of developing ED if the penile tissue. Sexual stimulation provokes the release of
glycaemic control is not well controlled. As 50% of the diabetic nitric oxide (NO), leading to increased cellular concentrations
men suffer from erectile dysfunction, the onset of ED in of cyclic guanosine monophosphate (cGMP) and subsequent
diabetics is associated with increasing age, duration of the penile smooth muscle relaxation. This process is reversed
diabetes, development of microangiopathy, neuropathy, by the conversion of cGMP to guanosine monophosphate,
alcohol intake and anti-hypertensive medication. which is mediated by phosphodiesterase type-5 (PDE5),
the predominant functional PDE type found in the penis.
MECHANISMS OF ERECTILE DYSFUNCTION IN DIABETES Phosphodiesterase type-5 inhibitors (PDE5i) act at this step to
The pathophysiology of ED in diabetes is multifactorial with maintain elevated levels of cGMP and continued smooth muscle
endothelial, vascular, autonomic, endocrine and neurologic relaxation. Since the release of NO is a neurologically-mediated
factors either in isolation or in harmony. The neurogenic event, neuropathy (as may occur with diabetes) may blunt the
factors involve loss of unmyelinated C fibres in the early stage efficacy of PDE5i. This is indeed borne out clinically, as diabetics
and large myelinated fibres in the late stage. The vascular have a poorer response overall to PDE5i than men with ED of
factors implicated are atherosclerosis and microangiopathy, other causes. Therefore, diabetics need a higher dose as well as
stenosis of internal pudendal artery, small penile vessels show have a non-responder group.
changes like endothelial proliferation, subintimal fibrosis,
Other Therapy Options
endarteritis obliterans. Diabetes mellitus associated with
hypercholesterolaemia and hypercoagulability which also The other therapy options are intracavernosal alprostadil
additionally impair vascular function. There is impaired injection, vacuum erection devices (VED) penile prosthesis.
relaxation of the corpus cavernosal smooth muscle in diabetics Intracavernosal injections and penile prosthesis are useful in
in response to neuronal- and endothelial-derived nitric oxide, diabetics while VED are not very useful in diabetics.
which may be due to the advanced glycosylation and its end Unlike the other modalities, prosthesis surgery is irreversible.
products. It is now well known that adult male hypogonadism In that the corporal tissue is permanently altered such that
is seen with at least 10% of men who have ED with diabetes. physiologic erections are no longer possible. If the prosthesis
Usually, the hypogonadism is central, viz. hypothal- has to be removed, there will be complete erectile failure.
amopituitary in origin. It is well known that the low levels of
testosterone, lead to a decline in sexual desire as well as Treatment of Hypogonadism
erectile dysfunction. Psychogenic factors are supplementary There are now few studies of sexual function in hypogonadal,
to the organic component and contribute to 30% of the ED in diabetic men treated with testosterone. It is now well known that
diabetes. testosterone improves sexual function (particularly sexual desire 385
 and response to PDE5i in cases of initial failure to respond) in some sexual dysfunction is not routine and these results should be
selected patients. Additional testosterone replacement therapy interpreted with caution. Usually, a gynaecological and urological
also has beneficial effects on lean body mass and insulin sensitivity test should be done.
in diabetic men with hypogonadism. A number of different
testosterone formulations are available which are discussed THE IMPORTANCE OF MANAGING LIFESTYLE FACTORS IN
elsewhere (see Section 10 Chapter 11 Disorders of Gonads). TREATING SEXUAL PROBLEMS IN DIABETES
As with most aspects of diabetes care, routine exercise, careful
EJACULATORY DYSFUNCTION monitoring of glucose levels and usage of appropriate therapies
Most men with diabetes may have sexual disorders other to prevent hyperglycaemia are the keys to prevent progression
than erectile dysfunction like diminished sexual desire, lack of of diabetes-induced sexual problems. Weight management and
ejaculation with sexual climax (an ejaculation or retrograde dietary prudence are also critical in the management of
ejaculation) and premature ejaculation. Successful antegrade diabetes. There is an evidence to suggest the weight loss may
ejaculation depends on the co-ordination of three neurologic reverse erectile dysfunction in some men. In a study of 65 obese
events: seminal emission, bladder neck closure and contraction men with ED and the metabolic syndrome (MetS, obesity with
of the muscles of the pelvic floor (e.g. bulbocavernosus, associated abnormalities of blood pressure, abnormal glucose
ischiocavernous, etc.). In diabetes, neuropathy disrupts the level/diabetes and abnormal cholesterol levels), eating a
ischiocavernosus nerve signals which control the closure of the ‘Mediterranean diet’ (emphasising fresh fruit and vegetables)
connection between the bladder and urethra which, in turn, for 2 years led to normalisation of erectile function (as
causes abnormal ejaculation. In this situation ejaculate is determined by an International Index of erectile function score
deposited in the innermost portion of the urethra but the greater than 22) in men as compared to men in the group that
connection between the bladder and urethra does not close. did not have dietary manipulation. A similar study in women
Since the bladder neck is open, some or all of the ejaculate may with sexual dysfunction and metabolic syndrome showed a
leak backwards into the bladder during the muscle contractions significant improvement in mean sexual function (mean
that normally expel the semen from the penis. In the most increase on the female sexual function index from 19.7 to 26.1
severe cases there may be total lack of seminal emission. Either in the treatment group versus no change from baseline in the
of these conditions will impact fertility. It may also be a source control group). Also noted in both these studies were was
of psychological disturbance to the man; indeed, some men improvements in serum insulin and glucose level in men and
report that they are not able to fully enjoy orgasm in the women who ate the Mediterranean diet. So, lifestyle plays a key
absence of ejaculation. From a fertility standpoint, sperm may role in sexual health in both sexes in a diabetic.
be retrieved from post-ejaculate urine and then used for
artificial insemination. Alternative strategies to overcome CONCLUSION
retrograde ejaculation generally focus on attempts to help the Sexual dysfunctions are common in people with diabetes but
bladder neck close. A variety of pharmacologic agents have also neglected and may arise from a variety of vascular, neurologic
been used including anticholinergics, antihistamines and alpha- and hormonal causes. While PDE5i do not work as well in
adrenergics. diabetics as in other populations, they still represent a good
first-line treatment. If their use is unsatisfactory, intracorporal
FEMALE SEXUAL DYSFUNCTION IN DIABETICS
injections and implantable prosthesis are excellent alternatives.
This is a poorly understood and studied subject in diabetics. Vacuum devices represent another viable alternative, although
The best studied class of female sexual dysfunctions is arousal satisfaction is generally not as high. Beyond erectile difficulties,
disorder; physiologically, this is accompanied by vasodilatation men may complain of ejaculatory symptoms which arise from
and engorgement of the female external genitalia. Given that neuropathy of sympathetic nerves. Female sexual dysfunctions
the processes involved in female genital engorgement are is mostly under reported in diabetics but further clinical
governed by many of the same molecular processes that occur advances may lead to increased hope and more efficacious
during male genital engorgement. Caruso et al, undertook a treatments for these disorders.
randomised controlled double-blinded (RCDB) trial of 100 mg
sildenafil in type 1 diabetic women with sexual dysfunction. RECOMMENDED READINGS
Of the 28 women, who have completed the trial, significant
1. Dandona P, et al. Hypogonadotrophic hypogonadism in type 2 diabetes.
improvement was seen in both subjective and objective Aging Male 2008; 11 (3): 107-17.
parameters. Subjectively, arousal, orgasm and dyspareunia were 2. Grandjean C, Moran B. The impact of diabetes mellitus on female sexual
all improved in those taking sildenafil in comparison to baseline well-being. Nurs Clin North Am 2007; 42 (4): 581-92.
and those taking placebo. Colour Doppler ultrasonography 3. Hatzichristou D, et al. Efficacy of tadalafil once daily in men with diabetes
was performed on the clitoral arteries, revealing an increase in mellitus and erectile dysfunction. Diabet Med 2008; 25 (2): 138-46.
blood flow in these women. However, it should be noted that 4. Perimenis P, et al. Long-term treatment with intracavernosal injections in
the use of ultrasonography in the evaluation of women with diabetic men with erectile dysfunction. Asian J Androl 2006; 8 (2): 219-24.

386
 9.19 The Diabetic Foot

Pendsey Sharad Purushottam

INTRODUCTION
Diabetic foot is one of the commonest chronic complications
of diabetes. It is the leading indication for hospital admissions
and prolonged stay.
A classical triad of neuropathy, ischaemia and infection
characterises the diabetic foot.
The presence of infection rapidly worsens the clinical picture
often requiring limb amputation. Diabetic foot ulcers are
common and estimated to affect 15% of all diabetics. In India,
it is estimated that approximately 40,000 legs are being
amputated every year, of which 75% are neuropathic feet which
are potentially preventable.

CLASSIFICATION
Diabetic foot is mainly classified into two types: neuropathic
foot, in which neuropathy dominates; and neuroischaemic foot, Figure 2: Neuroischaemic foot.
in which occlusive vascular disease dominates although
neuropathy is present. Neuropathy leads to fissures, dry skin, Table 1: Wagner’s Classification
deformities, callus formation at plantar pressure points and
Grade 0 No ulceration in a high-risk foot
plantar ulcerations (Figure 1), bullae and neuropathic (Charcot)
Grade 1 Superficial ulceration
joint. Ischaemia leads to pain at rest, ulceration on foot margins
Grade 2 Deep ulceration that penetrates up to tendon, bone or
(Figure 2), digital necrosis and gangrene. Differentiating between
joint
these entities is essential because their complications are
Grade 3 Osteomyelitis or deep abscess
different and require different therapeutic strategies.
Grade 4 Localised gangrene
Wagner’s (Table 1) and University of Texas wound classification Grade 5 Extensive gangrene requiring amputation
(Table 2) are the most acceptable classifications. Wagner classi-
fication accounts only for wound depth and does not consider Table 2: The University of Texas Wound Classification System
presence of ischaemia or infection. In Texas system, one needs to Stages Description
mention both the grade and the stage of the wound. Stage A No infection or ischaemia
Stage B Infection present
Stage C Ischaemia present
Stage D Infection and ischaemia present
Grading Description
Grade 0 Epithelialised wound
Grade 1 Superficial wound
Grade 2 Wound penetrates to tendon or capsule
Grade 3 Wound penetrates to bone or joint

AETIOPATHOGENESIS
Neuropathic Foot
Chronic symmetrical progressive sensorimotor neuropathy
leads to loss of protective sensation. The majority of foot ulcers
are a consequence of mechanical trauma unnoticed by the
patient. Commonest sites of ulcerations are in the forefoot. Ulcers
occur at sites of high pressure on either plantar or dorsal surfaces
and are caused by bony prominences, ill-fitting footwear and toe
deformities. Chronic hyperglycaemia leads non-enzymatic
glycosylation of proteins causing limited joint mobility. Foot
deformities occur as a result of atrophy of intrinsic muscles of
Figure 1: Neuropathic plantar ulcer.
the foot which alter the architecture of the foot.The combination 387
 of these risk factors increase the plantar pressures significantly of bones, fractures, subluxation and dislocation of the joints.
in the forefoot and the risk of foot ulceration (Table 3). Osteolysis of bones leads to ‘sucked candy’ appearance of
metatarsals or ‘pencil-like’ appearance of phalanges.
Table 3: Factors Contributing to Foot Ulceration
Goal of management is to convert destructive stage into phase
Extrinsic Factors Intrinsic Factors of stabilisation. Strict rest, off loading by total contact cast and,
Inappropriate footwear Bony prominences finally, rehabilitation by using custom-made indepth shoes.
Walking barefoot Limited joint mobility Those with extensive destruction of ankle joint, may require
Falls and accidents Joint deformity surgical fixation.
Objects inside shoes Callus
Foot Infection
Sharp injuries Fissures
Thermal trauma Previous foot surgery Infection in diabetic foot is a limb threatening condition
Activity level Neuro-osteoarthropathic joint because the consequences of deep infection in a diabetic foot
are more disastrous than elsewhere mainly because of certain
Charcot Foot anatomical peculiarities. Foot has several compartments which
A Charcot joint or neuroarthropathy is defined as a relatively are inter-communicating and the infection can spread from
painless progressive arthropathy of single or multiple joints. The one into another, lack of pain allows the patient to continue
most frequent location of the neuropathic joint is the tarsal- ambulation further facilitating the spread. The foot also has soft
metatarsal region, followed by the metatarsophalangeal joints, tissues, which cannot resist infection, like plantar aponeurosis,
and then the ankle and subtalar joints. The initial presentation tendons, muscle sheaths and fascia.
is often a hot swollen foot (acute stage), the precipitating event Osteomyelitis generally results from contiguous spread of deep
usually being a minor trauma. soft tissue infection through the cortex to the bone marrow.
The process of destruction takes place over a few months (chronic Majority of the deep longstanding foot infections are associated
stage, Figure 3) and leads to classic rocker bottom deformity. with osteomyelitis (Figure 4).
Multiple factors appear to contribute to the development of the
Charcot foot. A peripheral neuropathy with loss of protective
sensations, an autonomic neuropathy with increased blood flow
to the bone, and mechanical trauma, have emerged as the most
important determinants. Diagnosis is usually made on clinical
grounds and typical radiological features such as fragmentation

Figure 4: Radiograph showing osteomyelitis of great toe phalanges.

The diagnosis of osteomyelitis can be made by plain

radiography which usually shows focal osteopaenia, cortical
erosions or periosteal reaction in early stage and sequestration
in the late stage. A simple clinical test is probing to bone. A sterile
metal probe is inserted into the ulcer, if it penetrates to the
bone it almost confirms the diagnosis of osteomyelitis. Chronic
discharging sinus and sausage-like appearance of the toe are
the clinical markers of osteomyelitis. Definitive diagnosis
requires obtaining bone biopsy for histopathology.
Newer imaging techniques are like nuclear bone scan,
computerised tomography scan (CT), positron emission
tomography (PET), magnetic resonance imaging (MRI). Of these,
MRI is more sensitive and specific.

EXAMINATION AND DIAGNOSIS

Examination of feet is an integral part of physical examination of
every patient, more so a diabetic patient. Look for changes like dry
skin, fissures, interdigital mycoses, deformities, callus, abnormal
Figure 3: Radiograph showing Charcot Foot destruction of tarsal bones.
388 shape of foot, ulceration, prominent veins and nail lesions.
 The Diabetic Foot
Feel peripheral pulsations. Chronic sensorimotor neuropathy  Treatment can be modified based on the clinical response,
can be assessed by detecting sensation to pinprick and cotton as determined by the diabetes specialist, podiatrist’s clinical
wool and vibration using 128 Hz tuning fork. Hand-held bio- assessment. Microbiology results (cultures and sensitivities)
thesiometer can assess vibration perception threshold. 10 gm can then be used to modify antibiotic usage, depending
monofilament can detect the loss of protective pain sensation. on clinical response.
The filament is applied perpendicular to the foot over metatarsal  Continue antibiotic therapy until there is an evidence that
heads till it buckles. Buckling of the filament occurs at 10 g the infection has resolved, but not necessarily until a wound
equivalent of linear pressure. Measuring ankle/brachial pressure has healed.
index (ABI) using hand-held Doppler helps in assessment of
vascular supply. Normal ABI is >0.9, in ischaemia it is <0.9. PREVENTION
MANAGEMENT Early detection and surveillance of potential risk factors for
ulceration can decrease the frequency of wound development
Diabetic foot should be managed using a multidisciplinary team
(Table 4). Patients should be educated regarding the importance
approach. Off-loading and debridement are considered vital to
of maintaining good glycaemic control, wearing appropriate
the healing process for diabetic foot wounds. The goal of off-
footwear, avoiding trauma and performing frequent self-
loading is to redistribute force from ulcers sites and pressure
examinations.
points at risk to a wider area of contact. There are multiple
methods of pressure relief, including total contact casting, half Table 4: Risk Categorisation System
shoes, removable cast walkers, wheelchairs and crutches. The
open diabetic foot ulcer may require debridement if necrotic Category Risk Profile Check-up Frequency
or unhealthy tissue is present. The debridement of the wound 0 No sensory neuropathy Once a year
will include the removal of surrounding callus and aid in 1 Sensory neuropathy Once every 6 months
decreasing pressure points at callused sites on the foot. 2 Sensory neuropathy Once every 3 months
Additionally, the removal of unhealthy tissue can aid in with signs of peripheral
removing colonising bacteria in the wound. It will also facilitate vascular disease
the collection of appropriate specimens for culture and permit 3 Previous ulcer/amputation Once every 1 to 3 months
examination for the involvement of deep tissues.
Prevention of Diabetic Foot Includes
Infection in a diabetic foot is limb-threatening and at times life-
threatening and must be treated aggressively. Superficial  Primary prevention: screening of high-risk feet and proper
infections should be treated with debridement, oral antibiotics. advice on preventive footwear.
All patients with deep infections should be hospitalised and  Secondary prevention: management of trivial foot lesions
started on broad-spectrum antibiotics. The choice of antibiotics such as callus removal, treatment of nail pathologies, and
initially should be empirical but once the culture reports are deroofing blisters, etc.
known, it should be specific. Surgical debridement should be  Tertiary prevention: prompt referral to specialist for
carried out which should include all the devitalised tissues, advanced foot lesions.
sloughed tendons and infected bones.
Majority of patients with neuropathic feet require preventive
Dressing Material footwear such as sandals or shoes. They should be strictly
The selection of wound dressings is also an important instructed to avoid slippers and ‘chappals’. Therapeutic
component of diabetic wound care management. Saline- footwear are required for minority of patients who have
soaked gauze dressings are inexpensive, variety of new dressing partial foot amputation, Charcot foot, or grossly deformed
materials have been developed, such as film and foam dressings, feet.
hydrogels, hydrocolloids and alginates.
Understanding the diabetic foot, proper examination of
Vaccum assisted closure (VAC), sterile maggots therapy have feet, investigations to classify the foot ulcers and proper
been shown to promote wound healing in diabetic ulcers. management techniques using team approach along with
A recombinant platelet-derived growth factor (PDGF) is also preventive steps, would go a long way in limb salvage
currently in use and has been shown to stimulate wound and prevention of limb amputation in people with diabetes.
healing in non-infected neuropathic ulcers.
RECOMMENDED READINGS
Empiric Antibiotic Management of Patients
1. Andrew JM Boulton, Peter R Cavanagh and Gerry Rayman, editors.
Antibiotic therapy is necessary for all infected wounds; all The Foot in Diabetes; 4th Ed. West Sussex: John Wiley and Sons,
Grade 2 and Grade 3 ulcers; superficial ischaemic ulcers that Chichester; 2006. For recent advances in the management of diabetic
are deteriorating, as ischaemia can mask signs of infection. foot.
2. Levin ME. Pathogenesis and management of diabetic foot lesions.
 Antibiotic therapy is insufficient without appropriate In: Levin ME, O’Neal LW and Bowker JH, editors. The Diabetic Foot; 6th Ed.
wound care. Proper wound cleansing, debridement of any New Delhi: (India) Private Limited Harcourt; 2002. For aetiopathogenesis
and epidemiological aspects of the diabetic foot.
callus and necrotic tissue and, especially, off-loading of
pressure has to be done completely and early. 3. Michael E. Edmonds and Alethea VM Foster, editors. Managing the Diabetic
Foot; Oxford, London: Blackwell Science Ltd; 2000. For management
 Take into consideration any recent antibiotic therapy and, principles of diabetic foot.
if concerns about resistant organisms exist (e.g. MRSA), 4. Pendsey Sharad. Diabetic Foot: A Clinical Atlas. Jaypee Brothers, New Delhi;
treatment has to be modified accordingly. 2003. 389
 9.20 Diabetes and Pregnancy

V Seshiah

INTRODUCTION PATHOGENESIS OF GLUCOSE INTOLERANCE DEVELOPING

A new structure develops de novo during pregnancy and DURING PREGNANCY
matures till it is expelled at the completion of the gestational During pregnancy, there is an increased elaboration of placental
period. The metabolic adaptations that occur during pregnancy chorionic somatomammotrophin (human placental lactogen
are to accommodate a rapidly growing tissue transplant, the or hPL), prolactin and cortisol. The surge of counter hormones
conceptus (placenta and foetus). For its own normal growth results in the insulin resistance and stress the carbohydrate
and development, the conceptus brings about alterations in metabolism (diabetogenic stress). Normally a pregnant woman
maternal fuel metabolism and hormones. The placenta increases her endogenous insulin production by more than 30%
facilitates embryogenesis, growth, maturation and survival of from her non-pregnant insulin level. A pregnant woman, who
the foetus. It has the capacity to synthesise steroid and peptide is unable to secrete adequate insulin to compensate for the
hormones and to modulate and transport maternal fuel to the insulin resistance of pregnancy, develops gestational diabetes.
foetus, ‘an exquisite hormono-metabolic adaptation’. Women with GDM are insulin resistant and have impaired β-
cell function.
CLASSIFICATION OF DIABETES IN PREGNANCY
Pregestational Diabetes CONSEQUENCES OF THE CHANGES IN FUEL METABOLISM
This term denotes pregnancy occurring in women who already DURING PREGNANCY ON THE FOETAL DEVELOPMENT
have established type 1 or type 2 diabetes. They have to be Effect of Maternal Fuels on Foetal Development
followed-up taking into consideration the age of onset, duration The clinical hyperglycaemia-hyperinsulinism hypothesis of
of diabetes, mode of therapy and the existing complications. Pedersen (Figure 1) has been modified to include contributions
Gestational Diabetes Mellitus of other maternal fuels besides glucose that are also responsive
Gestational diabetes mellitus (GDM) is defined as any degree to maternal insulin. All of these can influence the growth of
of glucose intolerance with onset or first recognition during the foetus and the maturation of the foetal β-cell and increase
pregnancy. Abnormal glucose tolerance during pregnancy is in insulin secretion. Within this formulation, growth will be
not only associated with increasing pregnancy morbidity but disparately greater in insulin-sensitive tissues (excessive
also increases the likelihood of subsequent diabetes in the abdominal fat deposition, organomegaly of liver, spleen and
mother. Maternal hyperglycaemia has a direct effect on the heart and accelerated skeletal maturation) than in insulin-
development of foetal β-cell mass and is associated with insensitive tissues in the foetus.
increased susceptibility to the development of obesity and Consequences of Maternal Hyperglycaemia on Foetus and
diabetes in the offspring (Figure 1). This effect on the offspring Neonates
is independent of other genetic factors. As such GDM has
Prevention of foetal morbidity necessarily starts before
implications beyond the index pregnancy, identifying two
conception, reflecting the importance of pre-pregnancy
generations (mother and her offspring) at risk of future
counselling in obtaining good glycaemic control and
diabetes. The recognition of glucose intolerance during
advising folic acid 400 µg per day to prevent neural defects.
pregnancy is more relevant in the Indian context as Indian
Consequences of maternal hyperglycaemia are described in
women have 11-fold increased risk of developing GDM
Table 1.
compared to white women. It is important to detect these GDM
cases because, if unrecognised, pregnancy may end in perinatal Table 1: Consequences of Maternal Hyperglycaemia on Foetus
death and foetal wastage. and Neonates
First Trimester Second Trimester Third Trimester
Foetal Problems Foetal Problems Foetal and Neonatal
Problems
Malformations Hypertrophic Hypoglycaemia
Growth retardation Cardiomyopathy Hypocalcaemia
Foetal wastage Polyhydramnios Hyperbilirubinaemia
Erythraemia Respiratory distress
Placental syndrome
insufficiency Macrosomia
Pre-eclampsia Hypomagnesaemia
Foetal loss Intrauterine death
Figure 1: Pedersen/Freinkel hypothesis.
Low IQ
390
 Diabetes and Pregnancy
Consequences of Diabetes on the Pregnant Mother the time for obesity correction but permitted weight gain is up
Complications of diabetes in pregnancy occur almost exclusively to 9 kg. Underweight subjects are those not gaining weight as
in pre GDM. expected, particularly in the third trimester, require admission
to ensure adequate nutrition to prevent low birth weight infants.
 Hypoglycaemia
 Diabetic ketoacidosis Insulin Therapy
 Retinopathy Gestational diabetes mellitus
 Nephropathy Fasting or postprandial plasma glucose exceeding 90 mg/dL or
 Hypertension 120 mg/dL respectively after 2 weeks of medical nutrition
 Diabetic gastropathy
therapy (MNT), on more than two occasions is an indication for
insulin therapy. Human insulin is recommended. The patient
DIAGNOSIS may require a small dose of intermittent acting insulin about 4
World Health Organization Criteria to 6 units as initial dose given before breakfast. The dose has to
be titrated on follow-up. A few of them may require combination
World Health Organization (WHO) recommends using a 2-hour of soluble and intermittent acting insulins. Usually, they may
75 g oral glucose tolerance test (OGTT) with a threshold plasma not require more than 20 units of insulin per day (the total dose
glucose concentration of more than 7.8 mmol/L (140 mg/dL)
is divided 2/3 in the morning and 1/3 in the evening). Recently
at 2 hours similar to that of impaired glucose tolerance (IGT)
short-acting analogues have been found to be safe and
outside pregnancy. This criterion is widely followed in much of
approved for use during pregnancy.
the world including India; most suitable for universal screening
in high-risk population for diabetes. It will be advantageous to Pregestational type 1 diabetes mellitus: Maintenance of
estimate fasting plasma glucose also as this will help in planning normoglycaemia before conception is essential to prevent
treatment strategy. foetopathy, since the organogenesis is completed by the sixth
week after conception, at a time when most of the women
National Institute for Health and Clinical Excellence (NICE)
are not even aware of their pregnancy. It has been proved in
Guidelines
experimental animals and from observations in human
World Health Organization criteria of 2 hours plasma glucose pregnancies that glucose has to be normal before conception
>140 mg/dL with 75 gm oral glucose load for diagnosing GDM. to avoid congenital malformation.
Do not screen using fasting plasma glucose, random blood
glucose or glucose challenge test. Two special diagnostic procedures in the first half of the
pregnancy are relevant to detect any malformation in the foetus
International Association of Diabetes in Pregnancy Study in a pregnant woman who attends the antenatal clinic after
Group conception. Ultrasonography is performed to diagnose
The International Association of Diabetes in Pregnancy Study anomalies like anencephaly, cardiac and spinal abnormalities.
group (IADPSG) suggest 75 gm glucose load for an OGTT in all Elevated serum alpha-foetoprotein at 14 to 16 weeks of
clinical settings in or outside of pregnancy. The diagnosis of gestation indicates neural tube defect.
GDM is made if any one or two glucose value F >92 mg/dL/1
In a pregestational type 1 diabetic woman, the requirement of
hour >180 mg/dL/2 hours >153 mg/dL, which is almost similar
insulin may fall during the early part of first trimester and
to the existing Carpenter and Couston criteria American
diabetes association (ADA) criteria of FPG >95 mg/dL, 1 hour increase as the pregnancy advances and plateaus during third
>180 mg/dL and 2 hours >155 mg/dL. trimester. They may require morning and evening ‘split and
mixed’ dose of insulin, i.e. both short and intermittent acting
MANAGEMENT insulins in the morning and evening. A few pregnant women
may require less insulin in the last week of pregnancy attributed
The important predictor of foetal outcome either in pre-
gestational or gestational diabetes is the glycaemic control to foetal handling of maternal glucose. Sudden decrease in
attained immediately before and during pregnancy. The plasma requirement of insulin in the third trimester of pregnancy
glucose level of normal pregnant women is less than 90 mg/dL indicates foetal jeopardy.
and 120 mg/dL, respectively during fasting and post-prandial Type 2 diabetes mellitus in women: Pre-gestational type 2 diabetic
states. Hence, the best foetal outcome can be expected by women, desiring to become pregnant, should also undergo pre-
maintaining the mean plasma glucose level around 105 mg/dL pregnancy counselling. Pre-pregnancy control of diabetes with
in a pregnant diabetic woman. insulin is ideal. Sometimes a hitherto undiagnosed type 2
diabetic woman may progress through the early weeks of
Medical Nutrition Therapy
gestation at the risk of malformation in her offspring or a known
The expected weight gain during pregnancy is 300 to 400 gm type 2 diabetic woman who is already on oral hypoglycaemic
per week and a total weight gain of 10 to 12 kg by term. Hence, agent (OHA) may present to antenatal clinic after conception
the meal plan aims to maintain euglycaemia and to provide and at times in second or third trimester of pregnancy. The best
sufficient calories to sustain adequate nutrition for the mother course at this juncture is to withdraw OHA and introduce insulin
and foetus and to avoid excess weight gain and post-prandial besides monitoring foetal well-being.
hyperglycaemia. Calorie requirement depends on age, activity,
pre-pregnancy weight and stage of pregnancy. Approximately Insulin requirement
30 to 40 kcal/kg ideal body weight, or an increment of 300 kcal/ The insulin requirement varies from person to person, both in
day above the basal requirement, is needed. Pregnancy is not type 1 and type 2 diabetic pregnant women. The aim should 391
 be to maintain plasma glucose at an acceptable level and A randomised controlled study found that in women with GDM,
not to unduly worry about the amount of insulin being metformin (alone or with supplemental insulin) was not associated
administered. A few type 2 diabetic women may require very with increased perinatal complications as compared with insulin.
high dose of insulin, even more than 200 units/day compared Metformin has been found to be useful in women with polycystic
with pregnant mothers with gestational diabetes. One should ovarian disease (PCOD) who failed to conceive.Continuing this drug
not be unduly concerned about the dose of insulin, as the aim after conception is still a controversy, but there are a few studies
during pregnancy is to have optimal glucose control for good favouring continuation of metformin throughout pregnancy
foetal outcome. in these women. More studies are required before routinely
recommending OHAs during pregnancy.
Insulin Treatment During Delivery
The goal is to maintain the glucose level of 90 to 108 mg/dL to GESTATIONAL DIABETES MELLITUS LIKELY TO DEVELOP
avoid the risk of neonatal hypoglycaemia. Insulin requirement DIABETES
declines after delivery to approximately 60% of the dose prior The future risk of developing diabetes for a gestational
to pregnancy. Insulin dose has to be adjusted on follow-up. diabetic is 2-fold, if she becomes overweight, but maintaining
the ideal body weight approximately halves the risk. The
Role of Oral Hypoglycaemic Agents
requirement of insulin in addition to diet to maintain
Normally, OHAs are not recommended during pregnancy. euglycaemia during the index pregnancy is also predictive of
However, there are instances of women treated with OHAs future diabetes.
completing their gestation successfully. A randomised unblended
clinical trial compared the use of insulin and glibenclamide in RECOMMENDED READINGS
women with GDM who were not able to meet glycaemic goals 1. John C Pickup, Gareth Williams. Textbook of Diabetes; 3rd Ed. Blackwell
on meal plan. Treatment with either agent resulted in similar Publishing; 2003.
pregnancy outcomes. All these patients were beyond the first 2. Ronald C Kahn, et al. Joslin’s Diabetes Mellitus; 14th Ed. Lippincott Williams
trimester of pregnancy at the initiation of therapy. and Wilkins; 2005.

392
 9.21 Prevention of Diabetes Mellitus

Yash Pal Munjal

INTRODUCTION STRATEGIES FOR PREVENTION OF DIABETES

Diabetes mellitus has reached pandemic proportions. It is Two major strategies have been evaluated for reducing the
estimated that 285 million people corresponding to 6.4% of incidence of type 2 diabetes, i.e. lifestyle interventions and
the adult population in the world were afflicted with diabetes drugs. Surgery (metabolic surgery) is emerging as the third arm
in the year 2010. This figure is growing at a fast pace and it is of prevention. The first two steps aim at modifying the risk
expected to touch 438 million by the year 2030 and that will profile for diabetes. The risk factors of diabetes can be classified
constitute 7.8% of the adult population globally. About 70% of into modifiable risk factors and non-modifiable risk factors
this diabetic population will happen to be living in low and (Table 1). The modifiable risk factors are the subject matter of
middle income group countries. In India it is estimated that intervention.
there are 50.8 million patients of diabetes, followed by China
which has 43.2 million. Most of these cases occur between the Table 1: Risk Factors for Type 2 DM
age group of 40 to 59 years which is a decade earlier than the Modifiable Non-Modifiable
western world. A large pool of diabetics remains undetected,
Overweight and obesity Ethnicity
ranging from 70% to 80% in different parts of the world. It is a Sedentary lifestyle Family history
matter of concern all over the world. Besides this there is a large Previously identified impaired glucose Age
population with impaired fasting glucose (IFG) and/or impaired tolerance (IGT) and impaired fasting Gender
glucose tolerance (IGT). The prevalence of this group in our glucose (IFG) History of gestational
country is around 14%. It is estimated that approximately 40% Metabolic syndrome diabetes mellitus
of the patients with IGT shall progress to diabetes in the next 5 Elevated TG, reduced HDL Polycystic ovarian
years to 10 years. The cost of medicare for managing these Hypertension disease
patients will be quite staggering for the economy of any country, Dietary factors
Intra-uterine environment
particularly the developing countries. The progression and
Inflammation
onset of diabetes takes 10 years to 15 years, and therefore, Use of drugs like corticosteroids, diuretics
provides a good opportunity for prevention of diabetes and
thus prevent morbidity. Based on the demographic profile of Lifestyle Interventions
this disease, prevention can be primary, secondary and tertiary
Lifestyle interventions include medical nutrition therapy (MNT)
as outlined in Figure 1. These preventive measures are based
and physical activity (PA). They serve to address the issue of
on the correction of the two major pathogenetic mechanisms,
overweight and obesity, improve insulin sensitivity and prevent
i.e. insulin resistance and insulin deficiency. The issue of lifestyle
the progression from IFG and/or IGT and to overt diabetes and
changes and pharmacological interventions are the hallmark
control inflammation, an important aspect in prevention of
in all stages of preventive strategy. In this chapter lifestyle
micro- and macrovascular complications.
measure and comparative value of pharmacological prevention
are discussed in high-risk and IGT/diabetic patients. Obesity or overweight
The present epidemic of diabetes is very significantly fuelled
by the growing problem of overweight and morbid obesity.
Obesity is again a global problem increasing progressively.
Excessive truncal adiposity is very well correlated with the risk
for diabetes, hypertension and cardiovascular disease. The
changing lifestyle, lack of physical activity and increasing stress
are some of the important contributory factors. To sum up, the
marked increase in the intake of energy dense food with very
little or no physical activity and high level of stress contributes
significantly to the progression of the epidemic. The question
arises: how and at what level of natural history diabetes can be
prevented especially by modifying lifestyle factors? To answer
this, a prospective Nurses Health Study of 84,941 female nurses
was conducted. They were followed for 16 years and a series of
risk factors related to dietary behaviour, physical activity, weight
and cigarette smoking were identified and targeted. This was
associated with a remarkable 91% reduction in the risk of
developing diabetes. Even with a family history of diabetes the
Figure 1: Stages of prevention of diabetes.
risk reduction was 88%. In theory, therefore, diabetes can be 393
 prevented, largely by lifestyle changes despite genetic Nutrition
background. In most of the trials reduction in weight predicts Diet: Recommendations for individuals should consider the
a decrease in incidence of diabetes. It is estimated that each following maintain calorific intake. The calories are to be
kilogram of weight loss is associated with approximately 16% distributed in various forms of food constituents.
reduction in the occurrence of overt diabetes. Similar results
were observed in the Finnish diabetes prevention programme Distribution of food/calories: This is dealt in Chapter 5 of this
(FDPP) in which weight loss averaging 3 to 4 kg over 4 years section.
in overweight subjects with IGT led to a 58% decline in the Physical activity
occurrence of overt diabetes. A similar result was observed
Physical activity is an important element in the prevention and
by the diabetes prevention programme (DPP) in the United
management of type 2 diabetes in all its stages. Large and
States in which lifestyle interventions involving exercise and
well planned studies have established the importance of
dietary changes in subjects with IGT reduced the occurrence
exercise. One has to do 30 to 45 minutes of aerobic exercise
of diabetes by 58%. The results of studies involving lifestyle
and resistance exercises for 6 days a week and preferably all
modifications are shown in Table 2.
the 7 days. The beneficial effects of physical activity are due to
Table 2: Results of Lifestyle Modifications the mechanisms given in Table 3.

Study Duration Relative Risk Table 3: Benefits of Physical Activity

(Years) Reduction (%)
Decreases insulin resistance/improve insulin sensitivity
Malmo 6 63 Decreases overall adiposity
Da Qing 6 42 Reduces central adiposity
Finnish DPP 3 58 Improves blood glucose levels (glucose tolerance), lipid levels and
DPP (USA) 3 58 blood pressure
DPP (Japan) 4 67 Desirable changes in muscle mass
DPP (India) 3 28
Though there are difficulties in implementing lifestyle measures,
The results of these lifestyle intervention programmes are some of the tips that may help to achieve the goal are given in
quite impressive in the prevention of diabetes but practically Table 4.
lifestyle management is replete with problems. These
Pharmacotherapy for Prevention
interventions are labour intensive (one study needed 16 one
to one sessions delivered by case managers to achieve target Considerable emphasis has been focused on the prevention of
weight reduction and exercise levels). Although lifestyle diabetes with the drugs which are used for the treatment of
interventions produced successful results, in research diabetes as well. Table 5 gives the important drug trials and their
settings they are difficult to replicate even in well funded results. The diabetes prevention programme research group
healthcare systems. After completion of DPP all the study found a 31% reduction in the incidence of diabetes with
participants were offered an intensive lifestyle programme metformin (at 2.8 years). Acarbose showed 25% risk reduction
in a group sessions format. Those subjects who opted were over 3 years in STOP NIDDM study. However, sustained effects
enrolled in DPP outcome study (DPPOS). This study was with acarbose have not been studied. Troglitazone proved to
conducted to evaluate whether the effects of diabetes be effective in controlling blood sugar levels but was removed
prevention were sustained over a period of time. During the from the market because of serious liver toxicity. In the DREAM
trial phase the training in group session format and follow-
Table 4: Practical Tips for Nutrition and Physical Activity
up was aggressive during the additional follow-up averaging
over 6.8 years in DPPOS. Its results were published in the Calculate Calorie Intake Based on Weight and Activity Profile
year 2009 thus giving a mean follow-up of approximately Fats – Restrict 20% to 25% of total calories
10 years. In the intensive lifestyle modification (ILS) group, Increase fibre content (20 to 30 gm per day)
as compared to the other group, a 34% risk reduction was Small frequent meals
noted. The Japanese and Indian studies have shown similar Encourage intake of whole grains, beans, fruits, vegetables and
results. (Though of shorter duration). nuts
In case of over-weight individuals, reduction of weight Emphasise on portion size/slow eating
by restricting calories and increasing exercise is of vital Physical Activity
importance. However, it has been observed that it is not Set goal – 45 minutes exercise of moderate intensity aerobic and
necessary to reduce the weight to the level of ideal body resistance exercise every day
weight, but a reduction of about 5% to 10% in the body weight Individual-based exercise programme is useful
gives substantial reduction. In severely overweight subjects May use small gadgets like pedometer
with IGT, gastric bypass surgery led to a weight loss of 22.5 kg Start slowly and build up gradually
(and 28 kg in the Swedish SOS Intervention Study), the Others
incidence of diabetes reduced 30-fold compared with normal Provide family help and support
patients. Weight loss associated with improvement of Failures be circumvented
gastrointestinal hormones is considered to, contribute in
Close follow-up
394
reducing the incidence of diabetes.
 Prevention of Diabetes Mellitus
trial rosiglitazone showed risk reduction of 60% over 3 years PREVENTION OF DIABETES IN THE INDIAN CONTEXT
study period, but due to its cardiovascular side effects the drug The Indian Diabetes Prevention Programme 1 (IDPPI) was the
has been withdrawn from the market. In case of obese people, first study to show that lifestyle modification was effective in
orlistat has been shown to reduce the risk of diabetes by 37% preventing diabetes in native Asian Indians. IDPPI was a
as compared with placebo. Pravastatin when given to non- multicentre randomised, controlled and 3-year prospective
diabetics for cardiac or cholesterol lowering reasons reduced study in subjects with IGT. The study groups were as follows:
the number of new cases of diabetes. ACE-Inhibitors (ramipril, Group 1: control group with no intervention (n = 133)
perindopril) and angiotensin receptor blockers (telmisartan and
olmesartan) have shown improvement in glucose tolerance Group 2: subjects advised lifestyle modification (n = 120)
when given to non-diabetics. But these are not substantiated Group 3: subjects treated with 500 mg of metformin (n = 128)
in subsequent well planned trials. Group 4: subjects treated with both lifestyle modification and
metformin (n = 121)
Table 5: Review of Drug Intervention Trials
The median follow-up period was 30 months and the 3 years
Study Drug Study Duration Relative Risk decrease in cumulative incidence of DM was 55%, 39.3%, 40.5%
(Years) Reduction (%) and 39.5% in groups 1 to 4 respectively.The relative risk reduction
DPP Metformin 3 31 in lifestyle modification (28.5%; P = 0.018), metformin (26.4; P =
India (IDPPI) Metformin 3 26 0.029), lifestyle modification and metformin (28.2%; P = 0.022)
compared with the control group was very similar. The study
TRI POd Troglitazone 1 75
showed that progression from IGT to diabetes was high in Indians.
STOP NIDDM Acarbose 3 25
Both lifestyle modification and metformin were equally effective
XEN DOS Orlistat 4 37 and there was no added benefit in combining them.
DREAM Rosiglitazone 3 60
The study thus showed that primary prevention of DM was
Lifestyle measures as compared with pharmacological possible in a comparatively lean but highly insulin resistant
intervention have shown better results and that is intensive indian population by moderate changes in physical activity and
lifestyle changes are two times better than pharmacotherapy. diet. Family history of DM in first degree relatives of Indian
diabetics was 45% to 54% compared to 38% in Europeans
In a cost benefit analysis discussed in American Diabetes suggests a strong ethnic genetic susceptibility. Prevalence of
Association Annual Scientific Sessions 2011 it was also overweight among Indian urban children (17.8% boys and
demonstrated that though lifestyle measures are more effective 15.8% girls aged 14 to 19 years) with lack of physical activity
in prevention of diabetes, the cost benefit ratio is better in and high carbohydrate, high fat and high calorie diet would be
patients being managed on metformin. a forerunner of DM. Intrauterine malnutrition or overnutrition
and poor control of gestational DM also increase the chance of
BARIATRIC SURGERY future DM. Urbanisation and migration seem to increase the
The basic clinical outcome of bariatric surgery is to reduce incidence of DM. Screening for glucose intolerance for
weight and this in turn has proved to be useful in the prevention preventive measures at an early age is a requisite in Indians as
of diabetes. It is also postulated that there is a change in the they develop hyperglycaemia at a younger age. It is ideal to
intestinal hormones (incretins) which are known to control achieve primary prevention of type 2 diabetes by non-
diabetes. In one of the prospective Studies of over 2000 patients pharmacological intervention in the relatively lean Asians as
who underwent various forms of bariatric surgery (the compared with western population.
commonest being vertical banded gastroplasty) and compared
Role of Vitamin D in Prevention
with a standard-care group, it was demonstrated that the
patients who underwent bariatric surgery, the risk of diabetes Recent studies (Women health study: nurses health study)
was reduced by 86% at 2 years and 75% at 10 years follow-up. It have drawn attention to the role of vitamin D and calcium
was also found out in the sub-group where there was 12% or homeostasis in the metabolic syndrome. It was observed that
more of weight loss from the baseline people did not develop low levels of vitamin D are contributory to insulin resistance,
diabetes at all. reduced calcium mediated insulin secretion and higher
incidence of diabetes. Vitamin D along with calcium supple-
Bariatric surgery is also reported to induce a remission in ments has shown improvement in insulin resistance and insulin
diabetic patients. Similarly another randomised control secretion. Asians have high prevalence of vitamin D deficiency
prospective trial of gastric banding versus conventional and vitamin D with calcium supplements is likely to improve
therapy there was remission in 73% as compared to 13% of β-cell function.
control procedures. Gastric banding procedures improve
glycaemic control in diabetic patients. The patient selection POPULATION BASED-PREVENTION STRATEGIES
has to be careful and as compared to morbid obese patients World health organisation and other member countries who are
bariatric surgery has to be considered in patients with a body seized with the problem of chronic diseases especially diabetes
mass index (BMI) of more than 35 kg/m2 as compared to have formulated a series of guidelines for implementation at the
obese people with BMI of more than 40 kg/m 2. Large scale community level for the control and prevention of diabetes.
trials are underway to establish the long-term benefits of international diabetes federation (IDF) has also given its
the various procedures for control and prevention of guidelines. Based on the recommendations of WHO and IDF, the
diabetes. following strategies provide an insight in preventing DM at
395
 community level. The approach with each country and sub- first degree relatives of type 1 diabetics and offspring of auto-
population will vary from place to place. However the basic plan antibody positive, gestational diabetic parents, children born to
of prevention will remain the same globally. older mothers especially in first born children of mothers over
40 years of age and high parental age. The groups more prone
The prevention strategies can be grouped in three steps:
to develop type 1 diabetes have been tabulated in Table 7. In
Identification of People at High-Risk patients with new onset of diabetes, treatment with Anti CD3
Large population based surveys for diabetes detection may be monoclonal antibodies (teplizumab) have recently been shown
an expensive exercise and is not feasible. It is therefore, prudent to slow the decline in C-Peptide levels.
to identify people at high-risk and screen them. This is more
Table 7: Risk Factors in Various Groups
cost effective and beneficial exercise. The people at high-risk
can be identified by so called opportunistic screening, by Group Level of Risk
various questionnaire and diabetes risk tests which have been General population 0.7% to 1.5%
devised by several countries. These risk scores are based on the
following: Offspring of diabetic parents (mother/father) 2% to 5%

 High BMI (cut-off values vary from continent to continent)

Siblings 5% to 6%

 IGT/IFG
Monozygotic twins 33% to 50%

 Gender From the Table above it is quite apparent that first degree
 Family history of diabetes relatives of diabetic patients, siblings and children born to older
 Waist measurement
mothers have a higher propensity to develop diabetes.
 Dyslipidaemia Various studies to see the effect of interventional trials in type I
diabetes like DPPTI (diabetic prevention trial of north America
India has also formulated its own diabetes risk score. These and European nicotinamide diabetes intervention trial (ENDIT)
parameters contribute to one another but are not mutually have been completed and have shown negative results.
exclusive. Table 6 gives the details of the Indian population at risk.
Interventions in animal models have shown success in
Table 6: Measurement of Risk in Indian Population preventing or delaying type 1 DM. Interventions that target the
Plasma glucose – fasting blood glucose followed by oral glucose immune system directly are immunosuppression, selective T cell
tolerance test, if necessary subset deletion and induction of immunologic tolerance to islet
HbA1C > 6% proteins. Another approach is to prevent cell death by blocking
cytotoxic cytokines or increasing islet cell resistance to the
Waist circumference (85 cm for female and 90 cm for male)
destructive process. However, these interventions have not
Cardiovascular disease risk factors been successful in preventing type 1 diabetes in humans. The
Family history diabetes prevention trial type 1 also concluded that insulin (IV
Body mass index (BMI) more than 23 kg/m2 and SC or PO) did not prevent type 1 DM. Therefore, the focus is
shifting to develop a vaccine for prevention of type 1 diabetes,
Interventions and this is being followed vigorously.
Based on these parameters the people at risk have been graded
CONCLUSION
into high, medium and low-risk areas. According to the level of
their risk grading the interventions can be planned based on their The evidence base for prevention of type 2 diabetes is quite
relative risk category. The interventions have to be aggressive robust. The cost involved and the benefits accruing may be
especially in high and medium risk population. The possible role considered acceptable at government and community level.
of various inventions medical nutrition therapy (MNT), physician Every doctor practicing curative medicine should also focus on
assistant (PA), Bariatric Surgery) has been discussed above and the preventive aspects of DM. Relatives of patients with overt
need not be repeated. The interventions suggested by IDF and diabetes, children born to mothers with gestational DM, family
WHO provide the blue print but the exact programme has to be history of DM in patients visiting for other ailments and over-
designed on geographical and ethnic basis in each country. weight individuals need to be screened and to be suggested
lifestyle measures.
Prevention of Type 1 Diabetes
Exercise and nutrition counselling will go a long way in
Type 1 diabetes is a T helper cell mediated autoimmune disease
preventing diabetes. Provide healthy food alternatives and
in a genetically susceptible individual. The susceptibility and
encourage physical activity. Use metformin and bariatric surgery
protection loci are in the short arm of chromosome 6 in the major
wherever appropriate.
histocompatibilty complex. Environmental factors like infections
including viruses especially coxsackie and rubella, ingestion of RECOMMENDED READINGS
bovine milk proteins and nitrosourea compounds during
1. Global strategy on diet, physical activity and health, Geneva, World Health
childhood, malnutrition and infection during pregnancy have Organisation; 2004.
been attributed as environmental triggers. For an effective
2. The Diabetes Prevention Programme Research Group 2002. Reduction in
prevention strategy there is need for an efficient prediction the incidence of diabetes type 2 with lifestyle intervention or metformin.
strategy using genetic and immune markers (Islet cell antibodies, N Engl J Med 2002; 346: 393-403.
GAD antibodies). First phase insulin response in intravenous 3. Type 2 Diabetes Prevention: A Review
396 glucose tolerance test is also an early marker. Risk groups include Http:/www.worlddiabetesfoundation.org/composite-35.htm
Section 10
Endocrinology
Section Editor: Nikhil Tandon
10.1 Basic Considerations of Endocrinology 398
Ashok Kumar Das
10.2 Endocrine Disorders—A Clinical Approach 403
M.S. Seshadri
10.3 Disorders of Hypothalamus and Pineal Gland 407
Abdul Hamid Zargar, Bashir Ahmad Laway
10.4. Disorders of Anterior Pituitary 410
R.V. Jayakumar
10.5. Disorders of Posterior Pituitary 417
G.R. Sridhar
10.6. Disorders of Thyroid Glands 419
Nikhil Tandon, Gunjan Garg
10.7. Disorders of Parathyroid Glands 430
Ambrish Mithal, Beena Bansal
10.8. Disorders of Adrenal Glands 433
Eesh Bhatia, Vijayalakshmi Bhatia
10.9. Disorders of Puberty 442
A.C. Ammini
10.10 Disorders of Growth and Development 446
Nalini S. Shah
10.11 Disorders of Gonads 452
Shashank R. Joshi
 10.1 Basic Considerations of Endocrinology

Ashok Kumar Das

INTRODUCTION DEFINITION OF HORMONES

The endocrine system consists of ductless glands which, by Hormones (endocrine signals) are chemical messengers that
releasing chemical signals (hormones) in the blood stream, are secreted by ductless glands of the endocrine system and
regulate function in distant organs. The endocrine system act on distant target organs via specific cell receptors resulting
works closely with the nervous system to maintain in the upregulation of specific second messengers which, in
homeostasis. The major endocrine glands are pituitary, turn, brings about the changes in the cell structure/function.
hypothalamus, thyroid, parathyroid, islets of Langerhans
Hormones secreted by various endocrine organs have been
(pancreas), adrenals and gonads (testes and ovaries).
listed in Table 1.
Hormones act on multiple cell types by interacting with cell
surface (protein hormones) or nuclear (steroid hormones) CLASSIFICATION
receptors. The effects of the hormones are both, short-term, due Hormones can be classified based on the location of the target
to enzymatic catalytic reactions within the cell and long- term, cell.
due to changes in the expression and upregulation of genes.
Autocrine Signals
In addition to dedicated endocrine glands, there are endocrine These are chemical messengers secreted by cells into the
cells within the organs whose primary function is not extracellular fluid and affect the function of the same cell.
endocrine. These include cells within the heart that produce
atrial natriuretic peptide (ANP), liver cells that produce Paracrine Signals
insulin like growth factor type 1 (IGF-1), cells within the kidney These are chemical messengers secreted by cells which affect
that produce erythropoietin (EPO) and numerous cell types neighbouring cells of a different type. For example, glucagon
within the gastrointestinal tract that produce gastrointestinal produced by the alpha-cells of the Islets of Langerhans act on
hormones. the adjacent insulin secreting beta cells.

Table 1: Hormones and Their Sites of Production Juxtacrine

Gland Hormone
Dedicated endocrine glands
Hypothalamus Anti-diuretic hormone (ADH), oxytocin, corticotrophin-releasing hormone (CRH), thyrotrophin-
releasing hormone (TRH), gonadotrophin-releasing hormone (GnRH), growth hormone
regulating hormone (GHRH), somatostatin, dopamine
Pituitary gland Growth hormone (GH), adrenocorticotrophic hormone (ACTH), thyroid stimulating hormone
(TSH), follicle stimulating hormone (FSH), luteinising hormone (LH), prolactin
Thyroid gland T3, T4, calcitonin
Parathyroid gland Parathyroid hormone (PTH)
Islets of Langerhans Insulin, glucagon, somatostatin
Adrenal gland (cortex) Cortisol, aldosterone, dehydroepiandrosterone (DHEA)
Adrenal gland (medulla) Epinephrine, norepinephrine
Ovary Oestradiol, progesterone, inhibin
Testis Testosterone, inhibin, anti-müllerian hormone
Organs with primary function
other than endocrine
Brain (pineal gland) Melatonin
Heart Atrial natriuretic peptide (ANP)
Kidney Erythropoietin
Adipose tissue Leptin, adiponectin
Stomach Gastrin, somatostatin, ghrelin
Intestines Secretin, cholecystokinin, GLP-1, GLP-2, gastrin inhibitory peptide, motilin
Liver Insulin-like growth factor (IGF)
Hormones produced to a significant
degree by peripheral conversion
Lungs Angiotensin II
Kidney 1, 25(OH)2 Vitamin D
Adipose, mammary glands Oestradiol-17β
Liver Testosterone
398 Genital skin, prostate 5-Dihydrotestosterone
 Basic Considerations of Endocrinology
Peptide hormone can remain bound on the membrane of
one cell and interact with a receptor on juxtaposed cell. For
example, sex steroids in the ovary, angiotensin II (AT II) in kidney
and platelet derived growth factor (PDGF) in the vascular wall.
Intracrine
Figure 2: Chemical structure of thyroxine, tyrosine and epinephrine.
Hormones can act inside the cell without being released, e.g.
insulin and somatostatin that can inhibit their own release from
Peptide hormones
pancreatic β and δ cells, respectively.
Peptide hormones are most prevalent and consist of chains of
Neurocrine amino acids. Larger peptides are usually referred to as proteins,
These are the hormones secreted by neural cells and they while complex protein hormones with carbohydrate side
consist of neurotransmitters and neurotrophins. Neurotrophins chains are called glycoprotein hormones. A summary of the
foster the production of proteins associated with neuronal classification based on the chemical structure is given in Table 2.
growth, differentiation and development. Neurotrophins
include nerve growth factor, brain derived neurotrophic factor Peptide hormones can be classified into various families as
(BDNF), neurotrophin-3, neurotrophin 4/5. listed in Table 3.

Classification on the Basis of Chemical Structures Table 2: Classification of Hormones Based on the Chemical
Hormones can also be classified based on their chemical Structure
structures and on their mechanisms of action. There are three Precursor Type of compound Examples
general classes of hormones classified by chemical structure.
Protein Protein Growth hormone
Steroid hormones Peptide ACTH
These hormones are derived from cholesterol and have the Cleavage of peptide Thyroxine → Triiodothyronine
basic backbone of the cholesterol molecule, with variations in Cleavage of amino acid Phenylalanine → Catecholamine
side chains providing functional specificity. The basic structure Cholesterol Steroid Cortisol
1,25(OH)2 D3
of steroid hormones is illustrated in Figure 1.
Amino Modified amino acid Epinephrine
acid Tripeptide Thyrotropin-releasing hormone
Fatty acid Retinoids Retinoic acid
Eicosanoids Prostaglandin E

Table 3: Classification of Peptide Hormones

Growth hormone Growth hormone (GH)
family Prolactin (PRL)
Human placental lactogen (hPL)
Glycoprotein hormone Gonadotrophins (LH, FSH, CG)
family Thyroid stimulating hormone (TSH)
Gastrointestinal Gastrin family: gastrin, cholecystokinin (CCK)
hormones Secretin family: glucagon, secretin, glicentin,
and peptides vasoactive intestinal peptide (VIP), gastric
inhibitory polypeptide
Proopiomelanocortin β Endorphins
(a prohormone)

MECHANISM OF ACTION OF HORMONES

Peptide Hormones
Figure 1: Chemical structure of steroid hormone. A peptide hormone binds to a cell-surface receptor, resulting
in activation of an enzyme that catalyses the synthesis of cyclic
The adrenal cortex and the gonads are the main sources of AMP (cAMP) from ATP. Cyclic AMP then serves as a second
steroid hormones. The major steroid hormones are gluco- messenger for perpetuation of hormone action. Other second
corticoids (cortisol), mineralocorticoids (aldosterone), messengers have been discovered.
androgens (testosterone), oestrogens (including oestradiol and
Steroid Hormones
oestrone), progestogens (e.g. progesterone).
Steroid hormones enter the cell and bind to cytoplasmic
Amino acid derivatives receptors. The hormone-receptor complex enters the nucleus
Amine-derived hormones are derivatives of the amino acids and activates specific genes, initiating transcription of the
tyrosine and tryptophan. Examples are thyroxine, message followed by protein translation. Steroid hormones act
catecholamines such as dopamine, epinephrine and more slowly than peptide hormones because of the time
norepinephrine. The chemical structure of the amino acid required to produce new proteins as opposed to activating
derivatives is illustrated in Figure 2. proteins that are already present. 399
 Hormone Receptors Table 4: Hormones Utilising Second Messengers
As mentioned earlier, the two main sites of hormone receptors Second Examples of hormones which
are: cell surface and nuclear. messenger utilise this system
Cell surface receptors Cyclic AMP TSH, FSH, LH, antidiuretic hormone,
Cell surface receptors have ligand recognition domains that epinephrine, norepinephrine, glucagon,
are exposed on the outer surface of the cell membrane. Cell calcitonin, parathyroid hormone
surface receptors are of four types: Protein kinase Insulin, growth hormone, prolactin, oxytocin,
activity erythropoietin, several growth factors
1. G protein linked receptors (have seven transmembrane
Calcium and/or Angiotensin II, antidiuretic hormone,
domains): A common way to translate a signal to a biologic
phosphoinositides gonadotrophin- releasing hormone,
effect inside cells is by way of nucleotide regulatory thyrotrophin-releasing hormone
proteins (G proteins). These are also called serpentine
Cyclic GMP Atrial natriuretic peptide, nitric oxide
receptors, as the proteins span the cell membrane seven
times. Hormones whose action is mediated by these Hormones secreted from various principal endocrine organs
receptors include catecholamines, prostaglandins, and their salient effects have been listed in Tables 5 to 7.
adrenocorticotropic hormone (ACTH), glucagon, para- Detailed description of each one of them is given in the
thyroid hormone (PTH), thyroid stimulating hormone (TSH) respective chapters.
and luteinising hormone (LH).
2. Receptors with intrinsic ligand regulated enzymatic activities: Table 5: Hormones Secreted by the Hypothalamus
These receptors have an intrinsic tyrosine kinase domain. Effect on hormone Hormones
When the ligand binds to the receptor, the tyrosine kinase secretion affected
domain undergoes autophosphorylation. This leads to Thyrotrophin-releasing Stimulates TSH
production of transcription factors in the nucleus that alter hormone (TRH) Stimulates Prolactin (PRL)
gene expression. Hormones whose action is mediated by Gonadotrophin-releasing Stimulates LH
these receptors include growth factors, atrial natriuretic hormone (GnRH) Stimulates FSH
peptide (ANP), epidermal growth factor (EGF) and platelet- Dopamine Inhibits Prolactin
derived growth factor (PDGF). Inhibits LH
3. Cytokine and colony stimulating factor receptors: These Corticotrophin-releasing Stimulates ACTH
receptors contain a surface exposed amino terminal hormone (CRH)
domain that binds the ligand (i.e. hormone), a single Growth hormone-releasing Stimulates GH
membrane spanning domain and a carboxy terminal hormone (GHRH)
effector domain. They initiate tyrosine kinase activity in Growth hormone-inhibiting Inhibits GH
the cytoplasm. In particular, they activate the so called hormone (somatostatin) Inhibits TSH
Janus tyrosine kinases (JAKs) in the cytoplasm. These in Inhibits Insulin
turn phosphorylate signal transducer and activator of
transcription (STAT) proteins. The phosphorylated STATs Table 6: Hormones Secreted by Pituitary and Their
move to the nucleus where they act as transcription factors. Physiological Effects
Hormones whose action is mediated by these receptors Hormones Organs Major functions
include growth hormone (GH) and leptin.
Anterior pituitary gland
4. Receptors having serine-threonine kinase activity: Their Growth hormone (GH) Liver, adipose Promotes growth
effects are mediated by SMADs, intracellular proteins which tissue (indirectly), control
when phosphorylated move to the nucleus, bind to DNA of protein, lipid and
carbohydrate
and initiate transcription of various genes. metabolism
Nuclear receptors Thyroid stimulating Thyroid gland Stimulates secretion
These receptors mediate the actions of hormones such as hormone (TSH) hormones of thyroid
steroid hormones and thyroid hormones. In particular, oestrogen Adrenocorticotrophic Adrenal gland Stimulates secretion
and triiodothyronine (T3) receptors bind hormones in the hormone (ACTH) (cortex) of glucocorticoids
nucleus. The T3 receptors also bind thyroxine (T4), but with Prolactin (PRL) Mammary gland Milk production
lesser affinity. The glucocorticoid receptor is located mainly in Luteinising hormone (LH) Ovary and testis Control of
the cytoplasm but migrates promptly to the nucleus as soon reproductive function
as it binds to its ligand. Nuclear receptors also include two Follicle stimulating Ovary and Control of
families of retinoic acid receptors, RAR and RAX. These receptors hormone (FSH) testis reproductive
function
have an extensive role to play in foetal development.
Posterior pituitary gland
Second Messengers Antidiuretic hormone Kidney Conservation of
Second messengers are intracellular molecules which link the (ADH) body water
hormone receptors with the effector pathways in the target Oxytocin Ovary and testis Stimulates milk
ejection and uterine
cells. Examples of second messengers and the respective
contractions
400 hormones have been listed in Table 4.
 Basic Considerations of Endocrinology
Table 7: Hormones Secreted by Other Glands and Their Actions Effects of Hypo- and Hyperfunctioning of Various
Endocrine Glands
Gland Hormones Major functions
The various endocrine dysfunctions due to hypo- and
Thyroid Thyroxine (T4) Increases the rate of hyperfunctioning are depicted in Table 8.
Triiodothyronine (T3) chemical reaction
and basal metabolic rate
LABORATORY DIAGNOSIS OF HORMONAL DISORDERS
Calcitonin Promotes calcium
deposition in bone The diagnosis of endocrine disorders is based on clinical
Adrenal Cortisol Glucose homeostasis, examination and focused investigations. The basic approach
cortex anti-inflammatory in the diagnosis involves:
effects and many others  Proving hypo- or hyperfunction of the glands by
Aldosterone Na+, K+ and water
DHEA, homeostasis measurement of serum or urine hormone levels as
Androstenedione Androgenic action compared to normal age and sex-matched individuals
Adrenal Epinephrine Same effects as  Establishing aetiologic basis by radiological investigations
medulla Norepinephrine sympathetic stimulation and ancillary tests like FNAC and biopsy in some cases.
Pancreas Insulin and glucagon Carbohydrate metabolism The laboratory evaluation is discussed in detail in the chapter
Parathyroid Parathyroid hormone Controls serum calcium ion on ‘Endocrine Disorders: A Clinical Approach’, in great detail.
(PTH) concentration by increasing
calcium absorption TREATMENT
Testis Testosterone Development of male Treatment of endocrine diseases depends on the functional
reproductive system
status of the endocrine glands, degree of disability, age and
and male secondary
sexual characters coexistent morbidities. In general, hypofunctioning glands
Ovaries Oestrogens Development of female are treated by replacement of the appropriate hormones in
Progesterone reproductive system, female adequate physiological doses with regular follow-up and dose
breasts and female secondary adjustment for stressful conditions. Hyperfunctioning glands
sexual characters need careful evaluation to determine the cause of the excess
Placenta Human chorionic Promotes growth of function. Medical therapy is attempted whenever feasible,
gonadotrophin corpus luteum using hormone antagonists and receptor blockers. In case of
Human somato- Promotes development
tumours that are not responsive to medical therapy, surgical
mammotropin of some foetal tissues
removal of the glands can achieve cure, however, at the risk of
Kidney Renin Conversion of angiotensinogen
causing iatrogenic hypofunctioning.
to angiotensin
Erythropoietin Increases erythrocyte Deficiency Disorders
production
Almost all the hormones are available, either as chemically
Stomach Gastrin Stimulates the
synthesised entities or as recombinant molecules. Some are
gastric acid secretion
oral preparations (T3, T4, steroids) while others are given
Small Secretin Stimulate pancreatic acinar
intestine cells to release bicarbonate parenterally (GH, testosterone). Novel systems of delivery are
Cholecystokinin Stimulate gallbladder being used like testosterone patches, insulin analogues.
contraction
The hormones are usually started in physiological doses and
Adipocytes Leptin Inhibits appetite adjusted according to the response. Details of hormone
Heart Atrial natriuretic Increases sodium replacement are provided in the relevant chapters discussing
peptide excretion by kidneys individual hormone deficient states.
CONTROL OF ENDOCRINE ACTIVITY Hormone Excess States
Hypothalamic anterior pituitary hormones, and those The treatment of such diseases can be either medical or surgical.
produced by target organs under their influence, are regulated Medical
by a classical feedback loops which involve hormonal, neural
and direct feedback mechanisms (Figure 3). Another category Medical therapy for hyperfunctioning states includes agents
of hormones, such as insulin and PTH, are directly regulated which, either function as antagonists (e.g. somatostatin
by circulating levels of glucose and calcium. analogues for GH excess), agonists for endogenous inhibitors
(bromocriptine, dopamine analogue for prolactin excess) or
The concentration of hormone as seen by target cells is enzyme inhibitors (carbimazole and propylthiouracil for
determined by three factors: hyperthyroidism; metyrapone, ketoconazole for Cushing’s
 Rate of production syndrome).
 Rate of delivery: dependent of blood flow
 Rate of degradation and elimination Surgical
In addition to medical therapy, hyperthyroid states can also
MECHANISMS OF ENDOCRINE DISEASES be treated with surgery (thyroidectomy) or radioactive iodine
Based on the physiological functions, endocrine diseases are ablation. Primary hyperparathyroidism due to parathyroid
classified into three subtypes: hormone excess, hormone adenoma or parathyroid hyperplasia are cured by surgically
deficiency and hormone resistance. removing the parathyroid glands. Pituitary micro- and macro- 401
 Figure 3: Classic feedback loops for control of hormone secretion.

Table 8: Showing Effects of Hypo- and Hyperfunctioning of Various Endocrine Glands

Hormones Hyperfunction Hypofunction
Anterior pituitary Growth hormone Acromegaly and gigantism Impaired growth and short stature
Adrenocorticotropic hormone Cushing’s disease Secondary hypoadrenalism
Prolactin Galactorrhoea amenorrhoea syndrome
in women; reduced libido and
hypogonadal features in men
Luteinising hormone Hypogonadotrophic hypogonadism
Follicle stimulating hormone
Posterior pituitary Anti-diuretic hormone Diabetes insipidus
Thyroid Thyroxine (T4) Hyperthyroidism Hypothyroidism
Triiodothyronine (T3)
Adrenal cortex Cortisol Cushing’s syndrome Addison’s disease
Aldosterone Conn’s syndrome
Adrenal medulla Epinephrine Hypertension
Norepinephrine (Pheochromocytoma)
Pancreas Insulin Insulinoma Diabetes mellitus
Glucagon Glucagonoma
Parathyroid Parathyroid hormone (PTH) Primary hyperparathyroidism Hypoparathyroidism: hypocalcaemia
Testis Testosterone Hypogonadism
Ovary Oestrogens Hypogonadism
Progesterone

adenomas can be surgically resected by various surgical 2. David G Gardner, Dolores Shoback. Greenspan’s Basic and Clinical
approaches in case of compressive symptoms and mass effect Endocrinology; 8th Ed. Churchill Livingstone: McGraw Hill Publication; 2008.
or treated with radiation delivered either by conventional 3. Guyton, Hall. Textbook of Physiology; 11th Ed. Philadelphia: WB Saunders;
2006.
means or through a stereotactic approach.
4. Henry M Kronenberg, Shlomo Melmed, Kenneth S Polonsky, Reed P Larien.
RECOMMENDED READINGS Williams Textbook of Endocrinology; 11th Ed. Philadelphia: WB Saunders; 2008.
1. Besser GM, Thorner MO. Comprehensive Clinical Endocrinology; 3rd Ed. 5. Larsen PR, Kronenberg HM, Melmed S, et al. William’s Textbook of
402 Philadelphia: Mosby, Elsevier Science; 2002. Endocrinology; 10th Ed. Philadelphia: WB Saunders; 2003.
 10.2 Endocrine Disorders—A Clinical Approach

MS Seshadri

INTRODUCTION some disorders. For example, in pseudohypoparathyroidism,

Endocrinology is a discipline that deals with hormonal disorders. there is a defect in the G protein coupled to PTH receptor
The term ‘hormone’ traditionally means a chemical signal which precludes PTH action on target tissues, resulting in
produced by a discrete gland which reaches distant target hypocalcaemia despite inappropriately normal or elevated PTH
organs and tissues through the blood stream and regulates their levels. Constitutive activation of the hormonal receptor in spite
function. Glands producing hormones constitute the endocrine of normal circulating levels of the hormone can lead to endocrine
system. In addition, cells may also produce other chemical disorders with clinical features of hormonal over-activity.
signals, which may either exert an effect on the cell which For example, in McCune Albright syndrome focal activation
produces them (autocrine) on adjacent cells (paracrine). of the G protein coupled to skeletal PTH receptors leads to
lytic bone lesions indicative of excessive PTH action on the
Endocrine glands may be a single discrete gland, e.g. skeleton, even though circulating PTH levels are not elevated.
adenohypophysis (anterior pituitary), or multiple discrete
glands, e.g. parathyroid glands or could even be scattered SYNTHESIS OF HORMONES
throughout an organ, e.g. islets of Langerhans in the pancreas. Synthesis of hormones is an orderly and sequential process
Further, the same endocrine gland may produce more than one and involves the action of a series of enzymes on a defined
hormone, e.g. production of glucocorticoid, mineralocorticoid substrate. Polypeptide hormones are initially produced as
and adrenal androgens from the adrenal cortex. preprohormones which are cleaved to prohormones which in
turn are converted to the hormone by sequential removal of
There may be different receptors through which a single
short peptide fragments. If there is a deficiency of any of the
hormone exerts its effect such as the receptors for epinephrine
enzymes involved in intracellular hormone synthesis, the
and the response of the target tissue may depend on the nature
concerned hormone will not be produced and a precursor may
of the receptor that it expresses.
accumulate, giving rise to clinical symptoms, e.g. in congenital
CHEMICAL NATURE OF HORMONES adrenal hyperplasia (CAH), a deficiency of the 21 hydroxylase
Hormones may be derived from a single amino acid such as enzyme leads to decreased production of cortisol leading to
thyroxine or serotonin, from cell membrane lipids as in hypoadrenalism, while adrenal androgens accumulate and
prostaglandins or from cholesterol, e.g. steroid hormones. They produce virilisation of a female infant. A number of hormones
can be polypeptides, e.g. parathyroid hormone (PTH) or exert their cellular effects by stimulating or suppressing
glycopeptides, e.g. thyroid stimulating hormone (TSH). intracellular enzymes.

FUNCTIONS OF THE ENDOCRINE SYSTEM GENES AND HORMONES

The role of this complex system is to maintain the consistency The production of hormones, receptors and enzymes are
of the internal environment (milieu interior) of all the cells regulated by genes in the endocrine cell or in the target cell.
in the intact organism. Hormones also mediate growth, Therefore, it is not surprising that several endocrine disorders
differentiation, sexual maturation and reproduction. Together are genetically determined. The clinician therefore needs to
with the nervous system, the endocrine system helps the elicit a detailed family history in patients with endocrine
organism to cope with changes in the external environment disorders. The genetic abnormality may involve an entire
chromosome as in Turner’s or Klinefelter’s syndrome or may just
also. At different times in the life of the organism, the same
involve single gene mutations as in some patients with growth
hormone may play different roles, e.g. during intrauterine life,
hormone deficiency.
insulin promotes growth but in the extrauterine life it is a
powerful regulator of plasma glucose. INTERACTIONS BETWEEN ENDOCRINE AND IMMUNE
SYSTEMS
MECHANISM OF ACTION OF HORMONES
There is a close interaction between the endocrine system and
Hormones act on target cells through receptors which are
the immune system. There may be a primary alteration in the
located on the cytoplasmic membrane, e.g. PTH receptor or in
immune system that leads to endocrine gland dysfunction, or
the nucleus, e.g. steroid hormone receptors. A hormonal
a primary alteration in endocrine function that leads to altered
disorder may be due to abnormal production of the hormone,
immune responses. Further, biochemical changes in the
e.g. overproduction of thyroxine by the thyroid gland in
extracellular fluid due to primary endocrine disease may lead
hyperthyroidism. Sometimes, the endocrine disorder is due to
to decreased ability to tackle infections.
abnormalities in the signal transduction through the receptor,
e.g. complete androgen insensitivity syndrome where a Several endocrine disorders such as primary thyrotoxicosis,
genotypic male with 46 XY (male) karyotype with normal autoimmune hypothyroidism and autoimmune adrenal
testosterone production presents phenotypically as a female. insufficiency (Addison’s disease) are clearly immunologically
The biochemical nature of hormonal resistance is defined in mediated. The altered hormonal mileau in endocrine disorders 403
 may significantly impair immunity, e.g. hypercortisolism in clinical symptoms and signs, e.g. in chronic liver disease there
Cushing’s disease suppresses humoral and cell-mediated are clinical features of hyperoestrogenism, like gynaecomastia
immune responses and leads to opportunistic infections. In and testicular atrophy in men. Similarly, there may be a sharp
endocrine disorders such as diabetes mellitus the alteration in decline in insulin requirements in patients with diabetes
plasma glucose levels as a consequence of the endocrine who develop chronic kidney disease, resulting in frequent
disease may alter neutrophil function and predispose to hypoglycaemic events unless insulin dose is reduced. Some
recurrent bacterial infections and non-enzymatic glycosylation drugs used in treating endocrine disorders are inactivated
of collagen may interfere with proper wound healing. or excreted by the liver or kidney. Hence, in the presence of
renal or hepatic insufficiency, these agents need to be either
Some patients with systemic autoimmune disorders such as
withdrawn or their doses reduced. For example, metformin must
Sjögren’s syndrome or systemic lupus erythematosus may have
not be used in people with even mild elevations of serum
associated autoimmune endocrine disease leading to
creatinine (>1.5 mg/dL).
hypothyroidism or hypoadrenalism.
RHYTHMIC NATURE OF HORMONE SECRETION
Most autoimmune endocrine disorders are caused by organ-
specific autoimmune responses, e.g. Type 1 diabetes mellitus Several circulating hormones exhibit characteristic biological
and autoimmune thyroiditis. The tendency for familial rhythms. ACTH and cortisol show diurnal variation with peak
aggregation of endocrine disorders may therefore be due to levels in the early morning while oestrogen and progesterone
heritable abnormalities of the immune system. When show cyclical variations during different phases of the menstrual
autoimmunity is the basis for the development of an endocrine cycle over a period of about one month. Altered rhythmicity of
disorder more than one endocrine gland may malfunction, e.g. hormone production may be the earliest sign of disease and
association of autoimmune thyroid disease with adrenal can be used as a diagnostic test, e.g. loss of diurnal variation in
deficiency or hypoparathyroidism. Other non-endocrine tissues serum cortisol levels is an early abnormality in Cushing’s
may be affected by the autoimmune process in a patient with syndrome.
autoimmune endocrine disease, e.g. association of atrophic
CLINICAL FEATURES OF ENDOCRINE DISORDERS
gastritis and B12 malabsorption with autoimmune thyroid
disease. Therefore, when a patient presents with one endocrine The clinical features in endocrine disorders can be very common
problem, the clinician may have to look for other associated such as weight-gain or very unusual such as hypokalaemic
endocrine and other immunologically mediated non-endocrine periodic paralysis in thyrotoxicosis. Since, hormones circulate
disorders. A detailed evaluation of other organ systems may be to all parts of the body, symptoms and signs may reflect
necessary if the patient has additional symptoms. For instance, involvement of a range of organ systems. For example, in a
in a patient with autoimmune thyroiditis with some symptoms patient with thyroid hormone excess, there may be weight loss,
of peripheral neuropathy, a detailed neurologic examination palpitations, dyspnoea, fatiguability, increased appetite,
may reveal features of subacute combined degeneration of the diarrhoea and nervousness suggesting involvement of the
cord due to B12 deficiency. cardiovascular, respiratory, musculoskeletal, alimentary
and nervous systems. Hence, a detailed general physical
TRANSPORT OF HORMONES IN CIRCULATION examination (e.g. height, weight, heart rate, blood pressure) and
Hormones are carried in the circulation usually bound to plasma evaluation of all major organ systems is mandatory for any
proteins and the bound fraction constitutes the major portion patient with suspected endocrine disease. In children height
of the measured hormone level, e.g. thyroxine bound to should be recorded at each visit and the height velocity in cm/
thyroxine binding proteins constitutes more than 99% of year calculated annually so that early disorders of growth can
circulating total thyroxine. However, it is only the free fraction, be identified, evaluated and treated. In adolescents, the extent
which is not bound to circulating proteins, that is physiologically of pubertal development (Tanner staging) should be recorded
active. The concentration of the free hormone is so low that accurately.
accurate measurement may be very difficult, e.g. free T4 or free
cortisol. Therefore, a calculated value for the free hormone level The unusual nature of symptoms in endocrine diseases may
such as free thyroxine index or a free testosterone index is lead to wrong referrals to a number of different specialists
often used. There are many disorders where the concentration including psychiatrists. Symptoms in a patient with
of the hormone in serum is altered due to alterations in the pheochromocytoma may be mistaken for a panic attack or a
concentration of the binding protein. For example, during patient with insulinoma and recurrent hypoglycaemia may land
pregnancy hepatic production of thyroxine binding proteins up with a neurologist for ‘seizure disorder’ or with a psychiatrist
like thyroxine binding globulin (TBG) increases in response to for a behavioural disorder. Several endocrine disorders such
oestrogen, accounting for increase in Total T4 levels seen in as primary hypothyroidism and Cushing’s syndrome may
pregnancy. In nephrotic syndrome, the serum albumin is very have psychosis or altered behaviour as a major component
low because of massive proteinuria and this may lead to low of the symptom complex. On the other hand drugs used in
levels of measured Total T4, without affecting free hormone psychiatric practice often cause endocrine dysfunction, e.g.
levels. hyperprolactinaemia, amenorrhoea and galactorrhoea in
patients who are on phenothiazines.
METABOLIC INACTIVATION OF HORMONES
Hormones are degraded at different sites such as the liver Iatrogenic Endocrine Disorders
and kidney and major dysfunction of these organs may cause Drugs used in endocrine practice are often misused and
abnormal levels of certain hormones. This in turn may lead to may result in clinical manifestations of endocrine disease.
404
 Endocrine Disorders—A Clinical Approach
Glucocorticoid misuse is the most common cause for Cushing’s highly purified hormone and a standard curve is constructed.
syndrome in clinical practice. Supraphysiological doses of The reading of the unknown sample can be read off the standard
thyroxine are often erroneously prescribed to obese patients curve. The label can be a radionuclide (radioimmunoassay) or an
and may result in thyrotoxicosis with osteoporosis or atrial enzyme (ELISA) or a fluorescent probe or a chemiluminescent
fibrillation. Amiodarone induced thyrotoxicosis, anticonvulsant probe (chemiluminescence assay).
induced osteomalacia, ketoconazole induced adrenal and
All assays of hormones should include appropriate quality
androgen deficiency and antipsychotic drug-induced hyper-
controls at low, normal and high levels of the analyte in question
prolactinaemia are other common examples of iatrogenic
so that the reproducibility and accuracy of the test from day-
endocrine disease. It is, therefore, mandatory to elicit a detailed
to-day and from assay-to-assay is ensured. It is necessary that
drug history in patients presenting with endocrine disorders
the clinician knows whether the laboratory is adhering to these
so as to avoid expensive investigations and unnecessary
standards and it is better to get the tests done by an accredited
procedures.
laboratory [(The national accreditation board for testing and
When Should a Physician Suspect an Endocrine Disorder? calibration laboratories (NABL) is the agency responsible for
The basis for suspecting an underlying endocrine disorder is accreditation)]. In the event of a laboratory report not consistent
given in Table 1. with the clinical picture, the clinician should alert the laboratory
about a potential error in measurement so that issues can be
Table 1: Basis of Clinical Suspicion of Endocrine Disorder sorted out. Similarly, the laboratory should alert the clinician if
Suspect an endocrine disorder in the event of the report is very abnormal, since an early therapeutic response
Rapid changes in body-weight
may be mandated. It is this cross-talk between the clinician and
Unpredictable changes in blood pressure
laboratory that ensures that the patient gets the maximum
Hypotension on trivial insults benefit out of the test carried out.
Unexplained hypertensive response to drugs The concentrations of hormones in blood are tightly regulated
Inappropriate responses of body temperature by trophic hormones secreted by the pituitary or by serum levels
No fever in the presence of an infection of chemicals such as glucose or calcium. If T4 levels are low due
High fever in the absence of an infection
to a thyroid problem, TSH, which is the corresponding trophic
Unusual reactions to drugs
hormone, would be high. On the other hand if T4 is low and
Hypertension during anaesthesia in unrecognised-
pheochromocytoma TSH also is low, it implies that the gland secreting the trophic
Failure to recover from anaesthesia in unrecognised- hormone, i.e. pituitary is hypofunctioning. Similarly, in a patient
hypothyroidism with hypercalcaemia, elevated PTH levels imply that the normal
Recent changes in skin pigmentation
Hyperpigmentation in adrenal insufficiency and ACTH Table 2: Laboratory Tests in Hormonal Disorders
producing tumours
Hypopigmentation of usually pigmented areas in Suspected hypothyroidism: Free T4 and TSH
hypopituitarism Suspected hyperthyroidism: Free T4 and TSH
Disorders of growth and sexual maturation Primary amenorrhoea: FSH and LH
Disorders of sexual differentiation in an infant Secondary amenorrhoea: FSH, LH, prolactin and TSH
Disorders of menstrual function and reproduction Suspected metabolic bone disease: Ca, phosphorus, albumin,
Inappropriate secondary sexual characters globulin, alkaline phosphatase, PTH and 25-OH vitamin D if indicated
Gynaecomastia in a male Tetany: Ca, phosphorous, albumin, creatinine, Na+, K+, HCO3–, chloride,
Hirsutism in a female PTH and 25-OH vitamin D if indicated
Inappropriate biochemical changes Spontanoeus hypoglycaemia: Fasting plasma glucose and fasting
Hyponatraemia in the presence of a high urine spot sodium insulin
(SIADH)
Suspected Cushing’s syndrome: Screening plasma cortisol at 8 am
Kaliuresis despite hypokalaemia (Conn’s syndrome)
after 1 mg dexamethasone administered at 11 pm previous night.
If cortisol in more than 1.8 µg % do a formal low and high dose
LABORATORY TESTS AND THEIR INTERPRETATION Dexamthasone suppression test
Circulating levels of hormones are usually present in minute Suspected primary hyperaldosteronism: Na, K, HCO3 and chloride,
serum aldosterone and plasma renin activity
concentrations. The methods used for assaying hormones follow
some general principles. A fixed concentration of a specific Suspected endocrine hypertension: Na+, K+, HCO 3–, chloride, Ca,
phosphorous, creatinine, albumin/globulin, alk phosphatase, 24
antibody against the hormone is incubated with the serum
hours urine metanephrine and normetanephrine, aldosterone and
sample for a defined period of time. Subsequently,a fixed quantity plasma rennin activity
of a labelled hormone is added and incubated for a defined time
Suspected Sheehan’s syndrome/hypopituitarism: FSH, LH, Free T4,
period. Finally, the antibody-bound and unbound fractions of the TSH, 8 am cortisol
hormone are separated by a chemical agent or a second antibody.
Virilised female: Testosterone and DHEAS
The concentration of the label is measured in the bound and
Suspected polycystic ovary syndrome: Plasma glucose fasting and
in the free fraction by a detector. The proportion of labelled
post-prandial, fasting lipid profile, testosterone, prolactin, TSH
hormone bound to antibody is inversely proportional to the
Child with ambiguous external genitalia: 17-OH progesterone, Na+,
quantity of the unlabelled hormone present in the clinical sample.
K+, HCO3–
This same process is carried out with known concentrations of
405
 regulatory process is not in place and that there is unregulated STIMULATION AND SUPPRESSION TESTS
overproduction of PTH. In contrast, if a hypocalcaemic patient These are used in ambiguous situations when the basal level of
has elevated PTH this is expected and would be interpreted as the hormone has yielded a borderline low or high value
secondary hyperparathyroidism. Therefore, when tests are indicating that the hormonal abnormality is subtle. By and far
ordered both trophic and target hormone should be measured these tests need to be validated in each institution as the
together for proper interpretation. published ‘normal’ responses vary.
The clinician ordering the test should know details of In general, stimulation tests are used in target organ hypofunction
collection, e.g. PTH samples and ACTH samples which are and suppression tests in target gland hyperfunction. For example,
thermolabile, should be collected in test tubes placed in a in a patient with endogenous overproduction of cortisol from
beaker of crushed ice and the serum separated using a an adrenal adenoma, exogenous administration of high doses
refrigerated centrifuge. When FSH and LH are checked in of a synthetic glucocorticoid like dexamethasone fails to suppress
menstruating women it is appropriate to collect the sample cortisol levels. This is one of the most common suppression tests
on the second or third day of the menstrual cycle, i.e. follicular used in endocrine practice. Conversely, in patients with symptoms
phase enabling appropriate interpretation in the clinical suggestive of adrenal insufficiency, the basal serum cortisol levels
context. A mid-cycle sample on the other hand may have a are not adequate to discriminate a normal from a deficiency state.
very high LH value, and unless the clinician is informed the Serum cortisol levels <20 µg/dL with dynamic testing using
result may be misinterpreted. In women when tests are intravenous synthetic ACTH 1-24 (Synacthen), are diagnostic of
ordered one should verify the last menstrual date and if adrenal insufficiency. Individual situations and the appropriate
pregnancy is suspected or confirmed, be aware that the serum tests will be discussed in each individual chapter in this section.
level of several hormones such as total T4, prolactin and
cortisol are higher in pregnancy than in the non-pregnant RECOMMENDED READINGS
state. 1. Anthony C Fauci, Eugene Braunwald, Dennis l Kasper et al, Harrison’s
Principles of Internal Medicine; 17th Ed. McGraw Hill.
The common set of tests ordered in typical clinical situations is 2. Leslie J DeGroot, J Harry Jameson. Endocrinology; 5th Ed. Saunders; 2008.
shown in Table 2. These will be the initial tests. Further testing 3. Shlomo Melmed,Henry Kronenberg. William’s Textbook of Endocrinology; 11th
may be needed in individual situations. Ed. Saunders; 2007.

406
 10.3 Disorders of Hypothalamus and Pineal Gland

Abdul Hamid Zargar, Bashir Ahmad Laway

HYPOTHALAMUS Langerhans cell histiocytosis, vascular accidents and neuro-

Hypothalamus is the ultimate brain structure that allows surgical trauma. Patients present with polyuria, polydipsia with
maintenance of homeostasis.This neuroendocrine gland, weighing dilute urine in presence of increased serum osmolality and good
approximately 4 grams, is situated between thalamus above and response to administration of ADH.
pituitary gland below. The key functions of hypothalamus are: Syndrome of inappropriate ADH secretion (SIADH)
1. Reception of sensory inputs like light, pain and temperature Manifests with hyponatremia. Clinical features depend upon the
from external environment. severity of hyponatremia. Normal serum sodium is 136 to 145
2. Receiving information regarding internal environment like mEq/L. Mild hyponatremia (plasma sodium 125 to 135 mEq/L)
blood pressure, osmolality and glucose. presents with nonspecific symptoms in the form of weakness,
3. Other inputs like feedback, both positive and negative, from lethargy, and headache. Severe hyponatremia (plasma sodium
hormones such as glucocorticoids, sex hormones and <125 mEq/L) presents with confusion, seizures and coma.
thyroid hormones. Diagnosis of SIADH requires presence of hyponatremia with
plasma osmolality <270 mosmol/kg (normal plasma osmolality
Functionally, hypothalamus and pituitary act in concert as a being 285 to 295 mosmol/kg); urinary osmolality of >100 mOsm/
unit and pituitary could be considered as an extension of kg with elevated urinary sodium (>40 mEq/L) and presence of
hypothalamus. The unit is supplied by a rich network of portal normal thyroid and adrenal function without any volume
vessels. Hypothalamic neuronal cells synthesise and release overload state.
specific stimulatory and inhibitory factors directly into the
portal system of vessels. This allows reliable transmission of Disorders of Appetite
hypothalamic peptides into the pituitary, without any systemic Hypothalamic obesity
dilution. Almost one fourth of patients with hypothalamic disorders
The hypothalamic nuclei along with afferent and efferent nerve manifest with obesity. Obesity results from involvement of
fibres connect the hypothalamus to various portions of brain ventromedial nucleus (satiety centre). Common causes include
and brainstem. The hypothalamus is divided into four regions craniopharyngioma, granulomatous disorders, head trauma and
from anterior to posterior including preoptic, supraoptic, tuberal infiltrations. Syndrome also presents with headache, visual
and mammary regions and three zones namely, periventricular, disturbances, hypogonadism, diabetes insipidus and increased
medial and lateral. sleep.

The hypothalamus is responsible for important body functions Anorexia nervosa

including water metabolism, temperature regulation, appetite Common disorder affecting women of less than 25 years. These
control, sleep-wake cycle, circadian rhythms and control of women have distorted body image, exercise excessively and
sympathetic and parasympathetic functions. The neuro- induce vomiting.There is a functional hypothalamic disturbance
endocrine control of anterior pituitary is the most important and many endocrine abnormalities are associated with it.
function of hypothalamus. These include amenorrhoea, low serum thyroxine (T4) and
adrenocorticotrophic hormone (ACTH). Growth hormone (GH)
CLINICAL FEATURES OF HYPOTHALAMIC DISORDERS and prolactin levels are elevated. The manifestations completely
Disorders of varied aetiologies affecting hypothalamus may reverse with weight gain.
give rise to similar clinical features because of small size of the
Abnormalities of Sleep-Wake Cycle and Circadian Rhythm
hypothalamus. Common manifestations are headache,
vomiting, visual disturbances, signs of pyramidal and Suprachiasmatic nuclei are responsible for the maintenance of
extrapyramidal tract involvement and cerebellar signs. Other circadian rhythms resulting in sleep-wake cycle, temperature
manifestations include disturbances of puberty, water control and cognitive function. Hypersomnolence with or
metabolism and caloric imbalance. without obesity occur in around 30% of patients with
hypothalamic syndrome. Day time sleepiness and night time
MANIFESTATIONS OF HYPOTHALAMIC DISORDERS hyperactivity is common.
Disorders of Water Metabolism Abnormalities of Emotion and Behaviour
Central diabetes insipidus Agitation, destructive behaviour with activation of sympathetic
Destruction of anti-diuretic hormone (ADH) producing nervous system during the episodes is more common in lesions
magnocellular neurons in supraoptic and paraventricular nuclei of ventromedial nucleus. Gelastic or laughing seizures are
or defects in the transport of ADH to posterior pituitary results common in hamartoma of tuber cinereum. Abnormalities in EEG
in central diabetes insipidus. Common causes are idiopathic, are present during the seizures.
407
 Disordered Control of Pituitary disorder is more common in boys causing undescended testes
Precocious puberty and hypogonadism. Nerve deafness, colour blindness, cleft
palate, exostosis and renal abnormalities may also be associated.
Premature activation of hypothalamo-gonadal axis results in
precocious puberty in girls (<8 years of age) and boys (<9 years Growth Hormone Deficiency
of age). Activation of the axis in girls is mostly idiopathic, but in Many congenital defects involving hypothalamus like septo-
boys around 50% have hypothalamic lesion, hamartoma being optic dysplasia, anencephaly may result in GHD. Affected
the most common (Figures 1A and B).Precocious puberty in these children have normal height and weight at birth with delay in
patients is gonadotrophin releasing hormone (GnRH) dependent height and bone age at one year of age associated with
confirmed by predominant LH rise after GnRH injection. increased subcutaneous fat and hypoglycaemia.
Congenital ACTH Deficiency
Specific Hypothalamic Syndromes
It can occur in septo-optic dysplasia. Children present with
Clinical features of common hypothalamic syndromes are
vomiting, hypoglycaemia without pigmentation and electrolyte
summarised in Table 1.
abnormalities.
Table 1: Clinical Features of Common Hypothalamic Syndromes
System Prader-Willi Laurence–Moon-Biedl Cohen Carpenter Alstorm
Facial Narrow forehead, olive shaped Squint High nasal bridge, open Flat nasal bridge, —
eyes, squint, V shaped mouth, mouth, short philtrum, acrocephaly, high
high arched palate dysplastic ears arched palate
Skeletal Short stature, syndactyly, Short stature, polydactyly, Short or tall stature Polydactyly, syndactyly, Short stature
scoliosis, dislocated hips clinodactyly genu valgum
Neuro- Decreased IQ, hypotonia Decreased IQ, retinitis Mild mental retardation Mild mental Normal IQ
muscular pigmentosa retardation
Endocrine Hypogonadism, diabetes Hypogonadism, diabetes Hypogonadism, delayed Obesity Hypogonadism
mellitus, obesity insipidus, obesity puberty, obesity in males, obesity
Others Hyperphagia Renal abnormalities — — —

Figures 1A and B: (A) Sagittal view T1-weighted pre-contrast MRI in 6-year old boy with central precocious puberty showing hypothalamic hamartoma (arrow);
(B) Sagittal view T1-weighted contrast enhanced MRI in a 20-year boy presented with hypogonadism and delayed puberty showing nodular soft tissue component
and cyst wall enhancement suggestive of craniopharyngioma (arrow).

HYPOTHALAMIC HYPOFUNCTION SYNDROMES HYPOTHALAMIC TUMOURS

Kallmann’s Syndrome Craniopharyngioma
KAL gene normally directs migration of GnRH neurons from the It constitutes 3% to 5% of all intracranial neoplasms. These arise
olfactory placode to hypothalamus. Defective gene causes from Rathke’s pouch, are cystic or partially cystic, and are usually
408
agenesis of olfactory bulb (and subsequent hypo/anosmia).The located in suprasellar area. Most cases present in childhood with
 Disorders of Hypothalamus and Pineal Gland
features of raised intracranial tension, visual disturbances, short that the pineal gland conveys information concerning light-dark
stature, delayed puberty and diabetes insipidus. Most of the cycles for the organisation of seasonal and circadian rhythms
adults present with visual symptoms; suprasellar calcification in humans. Circadian rhythm disturbance is associated with shift
in curvilinear, flocculent or granular pattern may be present on work, jet lag, blindness, insomnia and old age.
skull X-ray. Computed tomography or MRI is the preferred
imaging modality (Figures 1A and B). Treatment usually Pathology of Pineal Gland
involves surgery and radiotherapy. Psychiatry
Hypothalamic Hamartoma Abnormalities of circadian function have been postulated in
depression and mania. There is evidence to suggest a decrease
A rare benign brain tumour located near the hypothalamus. It
in the amplitude of melatonin in depression and increase in
consists of mass of neurosecretory neurons, fibre bundles and
mania. Most pharmacological anti-depressant treatment
glial cells and secretes LHRH. It presents as true isosexual
stimulates melatonin secretion, acting through increased
precocious puberty more so in boys before the age of 3 years,
availability of the precursors (tryptophan and serotonin), or by
and can be associated with laughing seizures if the size is larger
direct action on serotonin and catecholamine receptors.
than 10 mm. MRI is the preferred imaging and appears as
isodense prepontine mass without any enhancement after Pineal tumours
giving contrast (Figures 1A and B). Mass usually does not
Pineal tumours are rare and constitute less than 1% of
increase in size on long-term follow up and does not need
intracranial space-occupying lesions. These tumours originate
surgical intervention. Puberty is LHRH dependent and is treated
from three different cell lines: parenchymal cells (pineo-
with LHRH agonists.
blastomas and pineocytomas); germ cells (teratomas,
PINEAL GLAND germinomas and mixed germ cell tumours); and supporting
The pineal gland is a small central structure and weighs around stroma (gliomas). The most common symptoms are secondary
100 to 150 mg in humans. The main cellular component is the to hydrocephalus (headache, vomiting and drowsiness)
pinealocyte and it is richly vascularised. Its predominant together with visual disturbances, diabetes insipidus and
innervation is sympathetic, arising from the superior cervical reproductive abnormalities. Germinomas and teratomas occur
ganglion. In humans it gets calcified after puberty. The main predominantly in males. There is no consistent information on
function of this gland is to synthesise melatonin. Most synthetic overproduction or underproduction of melatonin with specific
activity occurs during the dark phase, with a major increase in types of tumour.
the activity of serotonin-N-acetyltransferase. Melatonin has Clinical Uses of Melatonin
been traditionally considered to be derived principally from the
pineal gland. However, several investigations have now The established role of melatonin in humans is that of phase
demonstrated that melatonin synthesis occurs also in the retina shifting and resetting of circadian rhythms and melatonin has
of several vertebrate classes, including mammals. As in the been used to treat jet lag and disorders of circadian-based sleep
pineal gland, melatonin synthesis in the retina is elevated at disorders. Melatonin has also been shown to regulate sleep in
night and reduced during the day. humans. It also has been shown to have a hypnotic effect. It
also is believed to be effective in seasonal affective disorders.
Physiology of Pineal Gland Scientific evidence in favour of melatonin in sleep disorders is
Shortly after birth very little melatonin is detectable in body not strong, but the drug is safe if given for less than three
fluids. The melatonin rhythm appears around 6 to 8 weeks of months. It is available as an over-the-counter drug.
life. The plasma concentration of melatonin increases rapidly
thereafter and reaches a life-time peak on an average at 3 to 5 RECOMMENDED READINGS
years age. Subsequently steady decline occurs reaching mean 1. Braunstein GD. Hypothalamic syndromes. In: Degroot LJ, Jameson JL, editors.
Endocrinology; 14th Ed. Philadelphia: WB Saunders; 2001: pp 269-81.
adult concentrations in mid to late teens with a major decline
prior to puberty. Melatonin is synthesised and secreted during 2. Low MJ. Neuroendocrinology. In: Kronenberg HM, Melmed S, Polonsky KS,
Larsen PR, editors. Williams Textbook of Endocrinology; 11th Ed. Philadelphia:
the dark phase of the day. The duration of secretion of melatonin WB Saunders; 2008: pp 85-154.
correlates with duration of darkness (night). Even a brief 3. Raine JH, Donaldson MDC, Savage MO, Hintz RL, editors. Obesity. Practical
exposure to light of sufficient intensity at night rapidly Endocrinology and Diabetes in Children; 2nd Ed. Oxford: Blackwell Publishing
suppresses melatonin production. It is reasonable to assume Ltd; 2006: pp 173-182.

409
 10.4 Disorders of Anterior Pituitary

RV Jayakumar

The pituitary gland consists of the anterior pituitary (adeno- ADRENOCORTICOTROPHIC HORMONE (ACTH)
hypophysis), posterior pituitary (neurohypophysis) and the This is a 39 amino acid polypeptide derived from a precursor
intermediate lobe. It is located inside the sella turcica, a molecule proopiomelanocortin (POMC). The secretion of POMC
depression in the sphenoid bone in the base of the skull. It is is stimulated by CRH, arginine, vasopressin and stress. It is
related superiorly to the optic chiasma, hypothalamus and the inhibited by glucocorticoids. ACTH stimulates synthesis and
third ventricle from which, it is separated by the diaphragma secretion of glucocorticoids and androgens from the adrenal
sellae, antero-inferiorly to the sphenoid sinus and laterally to cortex.The release of ACTH has a diurnal rhythm, with the highest
the cavernous sinuses on either side. Histologically, anterior levels recorded at around 4 am and lowest in the evening. Plasma
pituitary has five different hormone secreting cells. The cortisol release also responds to this rhythm accordingly. In
somatotrophs (secrete growth hormone, GH), lactotrophs addition to pituitary secretion, ACTH can be produced ectopically
(secrete prolactin, PRL), thyrotrophs (secrete thyroid stimulating from other sources, e.g. small cell carcinoma of lung, medullary
hormone, TSH), corticotrophs (secrete adrenocorticotropic carcinoma of thyroid and carcinoid tumours.
hormone, ACTH) and gonadotrophs (secrete follicle stimulating
Increased production of ACTH from a pituitary adenoma results
hormone, FSH; and luteinising hormone, LH). The release of
in Cushing’s disease and is the commonest cause of Cushing’s
anterior pituitary hormones is under control of hypothalamic
syndrome (detailed in the chapter on Adrenal). Such adenomas
releasing hormones, which have either stimulatory or inhibitory
are usually microadenomas (<10 mm) and are treated by
action (Table 1). These hypothalamic hormones are carried to
surgical removal. Those not responding to surgery may require
adenohypophysis through the portal venous plexus located on
radiotherapy. Medical treatment with cabergoline and
the median eminence. The release of hypothalamic hormones
somatostatin analogues are sometimes beneficial for ACTH
is modulated partly by neuronal and chemical inputs and partly
secreting pituitary adenomas
by input from higher centres.
Defective production of ACTH results in secondary adrenal
Table 1: Hypothalamic Control of Anterior Pituitary Hormones insufficiency with predominantly glucocorticoid deficiency in
Hypothalamic Action Anterior pituitary the face of normal mineralocorticoid production, because the
factor hormone latter is under the dominant control of the renin angiotensin
Growth hormone Stimulatory Growth hormone system. So classic features of Addison’s disease like salt wasting,
releasing hormone (GHRH) hyperkalaemia and hyperpigmentation are absent. Treatment
Growth hormone releasing Inhibitory Growth hormone involves replacement with glucocorticoids.
inhibiting hormone
THYROID STIMULATING HORMONE (TSH)
(GHRIH)/somatotrophin
release inhibitory This is a glycoprotein hormone having an alpha and a beta subunit
factor (SRIF) similar to other glycoprotein hormones such as FSH, LH and hCG.
Thyrotrophin releasing Stimulatory Thyroid stimulating While the alpha subunit is common for all these hormones, the beta
hormone (TRH) hormone (TSH), subunit is responsible for specific biological activity. TSH regulates
Prolactin thyroid hormone and release by the thyroid gland. Plasma level of
Gonadotrophin releasing Stimulatory Luteinising thyroid hormone and TRH regulate the TSH release. It is so finely
hormone (GnRH) hormone (LH) adjusted that even a slight decrease in circulating thyroid hormone
Follicle stimulating increases pituitary TSH release; hence measurement of plasma TSH
hormone (FSH) is the single most sensitive test to assess primary hypothyroidism.
Prolactin inhibiting Inhibitory Prolactin
factor/dopamine The tumours of anterior pituitary involving TSH producing cell
are extremely rare. They present with hyperthyroidism by chronically
Corticotrophin releasing Stimulatory Adrenocorticotropic
hormone (CRH) hormone (ACTH) stimulating the thyroid gland (central hyperthyroidism). Serum T4
levels are high while TSH levels are inappropriately normal or
Vasopressin Stimulatory ACTH
marginally elevated. The characteristic feature of TSH secreting
adenoma is the elevation of alpha subunit in blood. Deficiency
Anterior pituitary develops from the ectoderm of Rathke’s pouch, of TSH is usually part of a plurihormonal deficiency secondary
an upward invagination from the roof of the embryonic to neoplasia or vascular conditions.
stomodaeum. Many pituitary transcription factors have now been
identified which temporally regulate the development of anterior GONADOTROPHINS
pituitary cell lineages.The main factors include LHX 3, HESX 1, Prop The gonadotrophic hormones, FSH and LH are secreted from the
1 and Pit 1. Deficiency of these transcription factors can lead to anterior pituitary under the stimulation of pulsatile secretion of
410 congenital, isolated or combined, pituitary hormone deficiencies. GnRH. In males, LH acts on Leydig cells to increase synthesis and
 Disorders of Anterior Pitutary
secretion of testosterone, while in females LH activates production Table 3: Causes of Tall Stature
of oestrogens, androgens and progesterone from interstitial cells
of ovary. Gametogenesis in both sexes is controlled by FSH. Both Gigantism
LH and FSH are under stimulatory control of hypothalamic GnRH Marfan’s syndrome
(LHRH). In pre-pubertal period, FSH response to LHRH is greater Hyperthyroidism in childhood
than LH while with onset of puberty, LH response exceeds that of Homocystinuria
FSH.A decrease in testosterone in males and oestrogens in females Cerebral gigantism
increases LH secretion whereas damage to germ cells increase the
Sexual precocity
FSH, contributed by loss of inhibin production from Sertoli cells in
males. Functioning gonadotrophic adenomas producing LH and
FSH are rare. In adults they usually present with features of a non-
functioning pituitary mass lesion.
Patients with isolated gonadotrophin deficiency usually have
hypothalamic pathology coming under the group of Kallmann’s
syndrome with anosmia. Isolated LH deficiency in men is a rare
syndrome (fertile eunuch syndrome), in which patients lack
secondary sexual characters but have normal sized testes with
arrested spermatogenesis.

GROWTH HORMONE
Human growth hormone is a linear polypeptide with 191 amino
acids. A significant proportion of it in the serum is bound
with GH binding protein. The main biological effect of GH is
promotion of linear growth in postnatal life until completion
of puberty. In addition, GH, both directly and through release
of IGF-1 (Insulin growth factor-1) from the liver, has anabolic
effects on protein, lipid and carbohydrate metabolism. The
release of GH occurs in a pulsatile fashion. Hypothalamic GHRH
stimulates whereas GHIH/SRIF inhibits its release from the
pituitary (Table 2). Circulating GH, IGF-1 and glucocorticoids also
decrease its secretion. GH deficiency in children results in short
stature, while that in adults has been correlated to general asthenia.

Table 2: Factors Affecting GH Release

Augment GH release Suppress GH release
Stages III and IV NREM sleep REM sleep
Exercise Obesity
Figure 1: Clinical features of acromegaly.
Stress Emotional deprivation
GHRH Glucocorticoids
Insulin-hypoglycaemia Somatostatin
Arginine Hyperglycaemia
L-Dopa IGF-1
Clonidine Hypothyroidism
Oestrogen Cyproheptadine
Glucagon

Gigantism and Acromegaly

Excess production of GH prior to closure of skeletal epiphysis
leads to gigantism while in adults it causes acromegaly. In nearly
98% of such patients, excess GH release is from a pituitary
somatotroph adenoma. In exceptional cases, it may be
secondary to excess release of GHRH from a hypothalamic
tumour or due to ectopic secretion of GHRH from a bronchial
carcinoid, pancreatic islet cell tumour or phaeochromocytoma.
Clinical Features
Patients with gigantism have abnormally tall stature (Table 3).
Figure 2: Broad hands in acromegaly.
In acromegaly (Figures 1 and 2), there is acral (hand and feet) 411
 and soft tissue enlargement leading to facial disfigurement
(bulbous nose, prominent supra-orbital ridge, prognathism,
thick lips, malocclusion and splaying of teeth causing difficulty
in biting food and macroglossia). There may be cutaneous
gyratus on the scalp and thick heel pad.
O ther cutaneous manifestations include thick skin,
prominent palmar creases, forehead furrows, increase in skin
tags, acanthosis nigricans, hirsutism, acne, increased
sweating and malodourous sebum secretion. Patients may
notice increase in size of ring, shoes and hat. Enlargement of
visceral organs like liver, spleen, heart and thyroid are
common, but this may not always be clinically apparent.
Enlargement of larynx and paranasal sinuses lead to thick
sonorous voice. Cardiovascular diseases like cardiomyopathy,
hypertension and congestive heart failure are the major
cause for excess mortality in these patients. Respiratory
disturbances including central and obstructive sleep apnoea
are common. Synovial oedema often leads to entrapment
neuropathies like carpal/tarsal tunnel syndrome. Arthralgia,
degenerative arthritis and hyperextensibility of joints are
common and are directly related to the severity and duration
of GH excess. An excess cancer risk, putatively mediated Figure 3: MRI scan showing pituitary GH secreting microadenoma.
through IGF-1 excess, has been suggested, but the issue is
far from settled. In view of this, close follow-up including part of familial syndromes like MEN 1 (parathyroid adenoma
surveillance for colonic polyps is indicated in patients with and pancreatic tumours) or Carney’s complex or McCune
acromegaly. Rarely, some patients may have galactorrhoea Albright syndrome.
with or without associated hyperprolactinaemia. Enlarging
Prognosis
pituitary macroadenoma may cause bitemporal headache,
visual field defect (bitemporal hemianopia) and signs of raised The mortality in acromegaly is about four times greater than in
intracranial tension. In 15% to 25% of patients there may be general population. The high mortality is due to cardiovascular,
impaired glucose tolerance or frank diabetes mellitus. cerebrovascular, pulmonary and neoplastic disorders. The post
treatment GH level is the significant determinant of mortality
Diagnosis in patients with acromegaly.
The diagnosis of acromegaly can be made on the basis of the Treatment
characteristic clinical appearance. However, as the changes Treatment of acromegaly should aim to normalise GH and IGF-1
may be subtle and slowly progressive, diagnosis is often delayed levels, remove tumour mass effect and preserve normal
for more than 10 years from onset of the disease and serial pituitary function. The general consensus about the criteria for
photographs provide a good evidence for clinical diagnosis. cure is to achieve a mean growth hormone level of less than
For GH secretory status, failure of GH suppression after an oral 2.5 ng/mL and a glucose suppressed GH <1 ng/mL, with a normal
glucose load is considered diagnostic. In normal subjects, GH IGF-1 which is associated with survival rates equal to those of
levels after glucose load fall to <1 ng/mL, whereas in acromegaly, general population.Trans-sphenoidal surgery, pharmacological
GH levels remain unsuppressed. Serum IGF-1 levels are also therapy and various forms of radiation therapy are used to treat
elevated and can be used in the diagnosis, but more importantly GH secreting adenomas.
in the follow-up of acromegaly. Nearly 30% of patients may have Surgery
associated hyperprolactinaemia, while secretion of other
pituitary hormones such as gonadotrophins, TSH and ACTH may Trans-sphenoidal surgery for the pituitary adenoma is the accepted
be decreased. first line therapy in patients with a somatotroph adenoma. Surgery
alleviates acromegalic symptoms, removes the tumour mass,
MRI, with gadolinium enhancement, is the gold standard for relieves optic tract pressure effects and regularises GH level in about
detecting a pituitary somatotroph adenoma (Figure 3); 70% of patients. The most important determinant of a successful
imaging of chest and abdomen for ectopic production of surgical outcome is the experience of the surgeon. Better results
GHRH or GH is rarely required. Radiological studies of skull are obtained in microadenomas (90%) while less than 50% of
reveals thickness of calvarium, enlarged air sinuses and macroadenomas respond to surgery alone.
mastoid air cells, sellar enlargement (deep and wide sella,
occasionally having double floor) and nuchal ligament Radiotherapy
calcification. X-ray hand shows tufting of terminal phalanx Pituitary irradiation is a mode of therapy for pituitary adenomas
with soft tissue swelling whereas X-ray foot reveals heel paid but the slow biochemical response rate of 20% cure in 10 years
thickness (>20 mm). X-ray spine may show scoliosis with time, qualifies it as a follow-up therapy after inadequate surgical
calcification of spinal ligament. Rarely acromegaly occurs as removal rather than as a primary form of treatment. External
412
 Disorders of Anterior Pitutary
radiotherapy aims to give 4500-5000 rads to the pituitary gland, Hyperprolactinaemia and Prolactinomas
Proton beam therapy, giving heavy particle pituitary radiation, Persistent elevation of serum prolactin level in the absence of
achieves higher cure rates. Stereotactic ablation of GH secreting pregnancy and lactation indicates hypothalamo-pituitary
adenoma by gamma knife radiosurgery or linear accelerator are dysfunction. The elevation of prolactin may be physiological,
newer forms of treatment for acromegaly. However, these are pathological or secondary to drug therapy (Table 4).
available only in few centres and the initial long-term results
are favourable. The hyperprolactinaemic syndrome is commoner in women,
which may be explained by their exposure to oestrogen.
Treatment Prolactinomas are a frequent cause of organic hyper-
Somatostatin analogues constitute the main medical modality prolactinaemia, and they form about 40% to 50% of all pituitary
of treatment for acromegaly. They mainly bind to somatostatin adenomas. About 65% to 70% of prolactinomas are micro-
receptor subtypes 2 and 5 (SSTR2 and 5) expressed on adenomas (<10 mm in size) which are frequently present in
somatotrophs and inhibit secretion of GH 45 times more females whereas macroadenomas (>10 mm in size) are seen
potently than endogenous somatostatin. Previously, octreotide with equal frequency in both the sexes.
a synthetic analogue of somatostatin used to be given as
subcutaneous injection in doses of 50 to 200 mcg, eight hourly Table 4: Causes of Hyperprolactinaemia
to normalise GH; GH is normalised in more than 70% of patients Physiological Pathological
by this drug. Presently, several long acting preparations of Sleep, stress, pregnancy and Hypothalamo-pituitary
somatostatin analogues are available for treatment and their nursing tumours, inflammatory and
long-term efficacy is also well established. The commonly used Pharmacological granulomatous diseases
drugs are octreotide LAR and lanreotide. A monthly injection Dopamine receptor blockers, Pituitary stalk lesions
of 20 mg octreotide LAR or a fortnightly injection of 30 mg phenothiazines, haloperidol, prolactinomas
Lanreotide will effect persistent suppression of GH in more than metoclopramide, Plurihormonal adenomas
60% to 70% of acromegalic patients. These agents are relatively domperidone empty sella
safe, side effects being transient gastrointestinal symptoms Dopamine synthesis inhibitor Primary hypothyroidism
and increased incidence of gall stones. Recently, the new methyl dopa Polycystic ovarian syndrome
somatostatin analogue SOM 230 (Pasreotide) which acts on Catecholamine depletors, Chronic kidney disease Liver
more types of somatostatin receptors has been found to reserpine cirrhosis Idiopathic
be useful in tumours unresponsive to the conventional Ranitidine,cimetidine,
somatostatins. Because of their cost, in the Indian scenario, fluoxetine, amitriptyline,
these somatostatin analogues are used while waiting for the oestrogens
radiotherapy to be effective or after insufficient surgical removal
of pituitary adenoma, even though primary medical treatment Clinical Manifestations
with these agents are becoming common in the West.
The frequent clinical presentations of hyperprolactinaemia in
Dopamine agonists like bromocriptine have been used for
women are amenorrhoea, galactorrhoea and infertility. The
several years to reduce GH levels. However, GH normalisation
alteration of menstrual cycle may vary from oligomenorrhoea
occurred in less than 15% patients on a dose of 10 to 30 mg per
to amenorrhoea, and rarely no menstrual dysfunction may be
day in divided doses. Cabergoline, a long acting dopamine
seen. Galactorrhoea, occurs in about 60% to 80% of hyper-
agonist, is also used at a dose of 0.5 mg daily but the long-term
prolactinaemic women and may be the only finding in a patient
efficacy is the same as that of bromocriptine.
presenting with infertility. Seborrhoea and moderate hirsutism
Another form of medical treatment of acromegaly is the use of may be present due to increased adrenal androgen production.
growth hormone receptor antagonist called pegvisomant In men with hyperprolactinaemia, the common presenting
which antagonises the action of GH on GH receptor complaints are progressive loss of libido and sexual potency.
and decrease the IGF-1 levels. This agent has no effect on Galactorrhoea or gynaecomastia are present in 15% to 25% of
tumour size, and may even be associated with an increase patients. Fluid retention with increase in body weight is seen in
in size. both sexes. Headache is present in patients with both micro-
and macroadenomas and has no correlation with the size of
PROLACTIN
adenoma. Defects in visual fields and hypopituitarism can occur
Prolactin is a single chain 198 amino acid polypeptide, which is in macroadenomas.
essential for production of milk from the mammary gland in
lactation and pregnancy. It is mainly under the inhibitory control Diagnosis
of PIF, which is dopamine. The major stimulus for prolactin Diagnosis of hyperprolactinaemia is confirmed by measuring
secretion is suckling, but its level can go up with stress, sleep and basal levels of prolactin from multiple pooled samples.
hypoglycaemia. Administration of oestrogens, phenothiazines Sometimes, a high prolactin level may be revealed only by doing
and TRH increases its serum levels. Excess circulating prolactin in the test in dilution (Hook effect) and conversely prolactin levels
females results in amenorrhoea-galactorrhoea syndrome, while may be falsely elevated by the presence of biologically inactive
in men it manifests as loss of libido and sexual dysfunction. Its prolactin called macroprolactin. Thyroid function tests should
deficiency is not symptomatic in males and non-lactating women, be done in all cases of hyperprolactinaemia as primary
whereas in post-partum period and in lactating women its hypothyroidism can cause elevation of PRL, mediated by the
deficiency produces absence of lactation. high TRH levels. In all cases of macroprolactinomas other
413
 pituitary hormones should be carefully evaluated to assess Table 5: Aetiology of Hypopituitarism
accompanying deficits. A prolactin of >100 ng/mL in a non-
pregnant woman is generally due to a pituitary adenoma. Pituitary and para-pituitary tumours; craniopharyngioma and
chromophobe adenoma
Imaging of the hypothalmo-pituitary area is very important in
Radiotherapy
such situations, with contrast enhanced dynamic MRI being the
Surgery
preferred method. Using high resolution scans, microadenomas
as small as 2 to 3 mm can be detected. Trauma: Skull fracture and perinatal
Vascular: Apoplexy, Sheehan’s syndrome, post-snake bite, sickle cell
Treatment disease
The aim of treating hyperprolactinaemia is to normalise Infiltration: Sarcoidosis, histiocytosis, haemochromatosis
prolactin level, relieve symptoms and shrink the tumour. In this Lymphocytic hypophysitis
regard, the efficacy of dopaminergic drugs is well established Infection: Basal meningitis and encephalitis
and it is accepted as the first-line therapy with prolactinomas. Congenital and genetic disorders: Pit 1, Prop1, HESX 1, LHX 3 mutations
Other treatment modalities available are pituitary surgery and idiopathic
radiation. Pituitary surgery is indicated mainly for those who
are intolerant and resistant to dopamine-agonists, and for Clinical Features
those macroprolactinomas that do not shrink adequately with Clinical features of hypopituitarism depend on the type (single
medical therapy. or plurihormonal) and extent of hormone deficiency, speed
of onset and local pressure effects of the pituitary lesion. The
The most extensively used dopamine agonists are ergot clinical features of pituitary mass lesions include bi-temporal
derivatives bromocriptine and cabergoline. These drugs should headache, visual field defect (bi-temporal hemianopia), features
be started in low doses (e.g. 1.25 mg at night for bromocriptine of raised intracranial pressure, rarely cranial nerve palsies, CSF
and 0.5 mg cabergoline once a week) and slowly increased in rhinorrhoea (when the mass erodes the sellar floor), temporal
step-wise manner. The usual dose of bromocriptine is 2.5 mg to lobe epilepsy and hypothalamic features. In slowly progressive
20 mg per day in two or more divided doses. It causes reduction pituitary lesions like that following radiation or vascular insult,
of prolactin level to normal in 60% to 100% cases. Clinical e.g. Sheehan’s syndrome or post-snake bite hypopituitarism, a
symptoms are relieved in 1 to 3 months, and tumour shrinkage characteristic pattern is present. Secretion of growth hormone
occurs in 70% to 90% cases. Cabergoline is a long acting ergot fails first, followed by gonadotropins, TSH and lastly, ACTH.
derivative and at a dose of 0.5 mg to 1 mg, prolactin levels are Prolactin deficiency is rare, except in Sheehan’s syndrome.
suppressed for 7 to 14 days; hence weekly dose is sufficient. Generally, hyperprolactinaemia is the rule. This may be due to
Once prolactin levels are normalised and sexual functions have release of lactotrophs from the tonic inhibition of dopamine or
improved and tumour has reduced in size, the dose of dopamine due to secretion from a prolactinoma. Diabetes insipidus is not
agonists can be reduced and a supervised trial off therapy can a feature of anterior pituitary disease; its presence denotes
be given especially in microprolactinomas. hypothalamic or stalk lesion. The clinical features of individual
The common adverse effects of dopamine agonists are nausea hormone deficiencies are given in Table 6.
and postural hypotension which can be circumvented by
starting the drug at a smaller dose given at night after meals. Table 6: Clinical Features of Hormone Deficiency
It can also exacerbate underlying psychosis. Other rare but Hormone Age group Manifestations
serious side effects are hepatic dysfunction, CSF rhinorrhoea,
Growth hormone In children Short stature
cardiac arrhythmias and valvular stenosis. During pregnancy,
In adults Abnormal body composition,
prolactinomas can enlarge and cause visual impairment. This is
reduced sense of well being
more common in macro- than microprolactinomas. Hence, and performance,low
dopamine agonists are discontinued when a lady with bone mass
microprolactinoma conceives, and they are closely monitored Gonadotropins In males Poor libido, impotence,
for headache and signs of visual field defects. Macro- reduced facial hair,
prolactinomas may need treatment during pregnancy. atrophic testes, infertility
Bromocriptine has been the most widely used dopamine In females Amenorrhoea, infertility,
agonist in pregnancy with no reported adverse effects on breast atrophy
the mother and baby; cabergoline also appears safe in TSH In children Growth retardation,
pregnancy even though experience with its use in pregnancy dry skin, constipation
is limited. In adults Myxoedema, slow relaxation
of deep tendon reflexes
PITUITARY INSUFFICIENCY (HYPOPITUITARISM) ACTH Weakness, tiredness, postural
This is a clinical condition characterised by deficiency of one or hypotension and giddiness,
more of the pituitary hormones. While selective deficiency of pallor and hypoglycaemia
one or two hormones is either congenital or idiopathic, multiple Prolactin Lactation failure
hormone deficiencies usually result from tumours or destructive
lesions. Causes of hypopituitarism are varied (Table 5). Common For diagnosis of pituitary failure, clinical examination is
causes include non-hormone secreting pituitary tumours, important. In children, documentation of height, weight and
pituitary surgery and cranial iradiation. pubertal status are necessary. Blood pressure should be checked
414
 Disorders of Anterior Pitutary
for postural drop and visual fields documented by perimetry. It every effort should be made to prevent its occurrence by
is a good guide to suspect pituitary deficiency in the following avoiding unnecessary and extensive radiation or surgical
situations: post-partum failure of lactation, hyperinvolution of therapy.
uterus, and involution of breast; sparse pubic and axillary hair,
NELSON’S SYNDROME
in patients with unexplained amenorrhoea, features of ACTH
or TSH deficiency and raised intracranial pressure; women with This entity results from an aggressive ACTH producing adenoma
unexplained anaemia and asthenia; males with decreased libido in a patient who has undergone bilateral adrenalectomy for
and sexual potency. Cushing’s syndrome. These patients present with headache,
visual field defects and external ophthalmoplegia, all suggestive
Diagnosis of pituitary mass lesion. The high circulating ACTH levels
The diagnosis of hypopituitarism is based on endocrine tests produce hyperpigmentation due to its MSH-like action. This
ranging from measuring basal levels of all hormones, to condition represents enhancement of tumour growth, by
stimulatory tests of individual hormones. Insulin tolerance test removal of negative feedback of high cortisol secretion from
is the gold standard to assess the pituitary GH and ACTH reserve. adrenal gland. This is shown to be preventable by external
LHRH and TRH tests are done to assess the reserve of gonado- pituitary irradiation in some patients. Once established, trans-
tropins and TSH, respectively. MRI of the hypothalamo-pituitary sphenoidal decompression and radiotherapy are the modalities
area should be done to look for structural lesions. Congenital of treatment. In order to identify Nelson’s syndrome early,
mutations in pituitary transcription factors can be associated periodic pituitary imaging is recommended in all patients
with small anterior pituitary, absent stalk and an ectopic who have undergone bilateral adrenalectomy for Cushing’s
posterior pituitary bright spot. syndrome.
Treatment PITUITARY APOPLEXY
The treatment of hypopituitarism includes therapies directed This is a life-threatening clinical situation arising from acute
at the underlying disease process and hormone replacement infarction of the pituitary gland. A haemorrhagic infarction
therapy (Table 7) which should aim at improving symptoms, usually arises in the presence of pituitary tumour, while
while avoiding over-treatment and should mimic the ischaemic infarction can occur in normal gland following
normal hormonal milieu as far as possible. Replacement is obstetric haemorrhage or anticoagulant therapy. This usually
usually given with the target hormones rather than pituitary causes anterior pituitary hypofunction, which can be
hormones. permanent or transient. The degree of hypopituitarism
depends on the extent of pituitary destruction. Clinically,
Table 7: Endocrine Replacement Therapy for Hypopituitarism
pituitary apoplexy presents with severe headache, sudden
Hormone Replacement Dose change of sensorium, ophthalmoplegia, visual loss and
deficiency prostration. Once suspected, it should be treated immediately
Growth hormone Growth hormone 0.25 to 0.7 mg/d S/C with glucocorticoid supplementation and other supportive
Gonadotrophin Women measures to reduce pressure effects. Deterioration in
Oestradiol valerate 1 to 2 mg/d sensorium and visual impairment are indications for surgical
Conjugated oestrogens/ 0.625 to 1.2 mg/day decompression.
Ethinyl oestradiol 20 to 30 mcg/day
Progesterone Cyclical therapy CRANIOPHARYNGIOMAS
Men These tumours, which are often cystic, arise from the Rathke’s
Testosterone enanthate 250 mg every pouch remnants. They constitute 3% to 5% of intracranial
or propionate 3 weeks IM tumours and majority are diagnosed when children present
TSH L-thyroxine 50 to 200 µg/d oral with growth failure or sexual infantilism. There may be
ACTH Hydrocortisone 15 to 20 mg/d oral associated diabetes insipidus. The treatment of choice is surgery
Prolactin None None followed by radiation.

In combined deficiency of TSH and ACTH, steroid replacement EMPTY SELLA SYNDROME
should always precede thyroid replacement. In patients on This is a clinical condition similar to a pituitary tumour, and
steroid replacement therapy the importance of increasing the occurs when a defect in the diaphragma sellae results in
dose of steroid during stress should be emphasised. Acute subarachnoid space herniation into the sellar space. Pressure
adrenal crisis will require parenteral steroids. Replacement of on the bony walls of the sella causes subsequent remodeling,
growth hormone in AGHD (adult growth hormone deficiency) sellar enlargement and flattening of the pituitary gland.
is known to improve lean body mass and bone mass and Though the exact pathogenesis remains unclear, raised
improve cardiovascular risk. In hypogonadal patients desirous intracranial pressure in a subject with a diaphragmatic defect
of fertility, treatment with gonadotropins (recombinant is thought to predispose to the empty sella syndrome. This is
HCG and FSH) are indicated. There is now evidence that frequently detected when a patient with obesity and
hypopituitarism is associated with excessive mortality as headache is investigated by pituitary imaging (Figure 4).
compared to normal population. It is possible that with proper Though clinically uncommon, this is seen in 20% of women at
hormone replacement therapy, this mortality can be reduced. autopsy. It can cause diagnostic difficulty when it mimics the
Lastly, as hypopituitarism requires complex drug regimens, radiological appearance of a pituitary tumour. Treatment is
415
 symptomatic for primary empty sella, and those with a
secondary cause should receive appropriate therapy of the
underlying disease process.

LYMPHOCYTIC HYPOPHYSITIS
This occurs usually in the post-partum period and patients
present with headache, visual disturbance, hyperprolactinaemia,
diabetes insipidus or hypopituitarism. It is thought to be
autoimmune in origin and it is difficult to differentiate it from
pituitary adenoma. Patients may have antipituitary antibodies
and other organ and non-organ specific autoantibodies.
Treatment is with steroids and surgery is usually not necessary
except for a tissue diagnosis. It may remit spontaneously
also.

RECOMMENDED READINGS
1. DeGroot LJ, Jameson JL. Endocrinology; 5th Ed. Philadelphia: WB Saunders
Company; 2006: pp 291-57.
2. Kohler PO. Clinical Endocrinology; 2nd Ed. John Wiley and Sons; 1996:
pp 11-52.
3. Melmed S, Kleinberg DL. Anterior Pituitary Williams Textbook of
Figure 4: Sagittal view MRI showing empty sella (white arrow). Endocrinology; 10th Ed. Philadelphia:WB Saunders Company; 2003: pp 177-
281.

416
 10.5 Disorders of Posterior Pituitary

GR Sridhar

The posterior pituitary develops from neural ectoderm of the Table 1: Causes of Diabetes Insipidus (DI)
forebrain and secretes the hormones vasopressin and oxytocin.
Vasopressin or anti-diuretic hormone (ADH) is produced by Central DI
Tumours of hypothalamo-pituitary region
hypothalamic supraoptic nucleus and oxytocin by para-
Craniopharyngioma
ventricular nucleus. They traverse with neurophysins to Suprasellar extension of pituitary tumours
posterior pituitary, from where they directly enter systemic Germinoma
circulation. ADH regulates water balance in the kidney. It is Pinealoma
released in late sleep to prevent dehydration and enuresis. Metastasis
Oxytocin primarily affects uterine contraction and post-partum Infiltrative lesions
milk ejection, although it could influence cognition. Sarcoidosis
Histiocytosis X
DISORDERS OF POSTERIOR PITUITARY Tuberculosis
Leukaemias
ADH deficiency (impaired production or end organ resistance)
Pituitary or hypothalamic surgery
leads to diabetes insipidus. Inappropriate secretion causes
Severe head injury (stalk section)
SIADH (syndrome of inappropriate ADH). Ruptured cerebral aneurysm
Idiopathic
DIABETES INSIPIDUS (DI) Familial
Epidemiology and Clinical Features Nephrogenic DI
Diabetes insipidus is uncommon (3:100,000 general population) Congenital or familial
but, when it occurs, must be identified and promptly corrected. Acquired
Chronic renal diseases
It presents as polyuria (>3 litres of urine daily of dilute urine),
Acute tubular necrosis
leading to thirst that may disturb sleep. It can occur at any age Primary aldosteronism
and in both sexes. Its occurrence in adults depends on the Chronic hypercalcaemia
aetiology; it often occurs as a result of pathological insults to Drug-induced (lithium, demeclocycline)
the hypothalamic-pituitary axis. In children, organic central DI
should be suspected in children presenting after the age of five Modalities of Diagnosis
years, and with features of anterior pituitary insufficiency, such Firstly polyuria (>3 L/d) should be demonstrated by measuring
as growth retardation. 24 hours fluid intake and urine output. In diabetes insipidus
Urine specific gravity (SG) is <1.010 and serum sodium exceeds hypertonicity occurs if water loss cannot be corrected by
145 mEq/L. Polyuria may be less severe when ADH deficiency is fluid ingestion. In the presence of polyuria, hypertonicity and
partial or when other endocrine diseases coexist, such as the absence of other causes of polyuria, the diagnosis of
hypothyroidism or Addison’s disease. diabetes insipidus can be made. In the face of unambiguous
features, water deprivation may not be performed. Further
Aetiology investigations may be needed to differentiate DI from primary
DI may result from deficient ADH production from the polydipsia, identify partial forms of DI and to evaluate for the
hypothalamus-pituitary (central DI) or from renal end-organ cause of DI.
resistance to ADH action (nephrogenic DI) (Table 1).
Water deprivation test
Hereditary DI results from mutations of genes: arginine This test, done under supervision, is started early in daytime;
vasopressin gene, arginine vasopressin receptor gene, and the earlier the better. The subject is weighed, 97% baseline
vasopressin sensitive water channel gene. weight calculated and noted prominently, for termination if
Clinical Features this is reached during the test. In those who are already on
replacement with desmopressin, it must be stopped 24 hours
Polyuria, depends on the degree of ADH deficiency. Daily urine
earlier, while steroids (for other indications, e.g. hypopituitarism
volume may vary from a few litres to nearly 18 litres. Nocturia is
are not stopped).
invariable, unlike in primary polydipsia.
Fluid is withheld until one of the following occurs: orthostatic
If water is denied, hypertonia leads to irritability, fever, mental
hypotension and postural tachycardia appear, > 5% of the
dullness, prostration and death. If DI is due to primary pituitary
initial body weight has been lost, or the urinary concentration
lesion, neurological abnormalities coexist. Children may present
does not increase >0.001 SG or >30 mOsm/L. Serum osmolality
with poor feeding, failure to thrive and irritability.
is determined and 5 units of aqueous vasopressin injected SC.
Post pituitary-surgery DI is often transient. When permanent, Urine for SG or osmolality measurement is collected 60 min after
persistent polyuria begins about 10 to 14 days postoperatively. the injection before allowing fluids to be ingested. 417
 A normal response produces maximum urine osmolality after SYNDROME OF INAPPROPRIATE ADH SECRETION (SIADH)
dehydration (often >1.020 SG or >700 mOsm/L), exceeding the In SIADH, hyponatraemia occurs due to excess water relative to
plasma osmolality; osmolality does not increase more than an solute. There is no oedema. Causes are listed in Table 2. Clinical
additional 5% after injection of vasopressin. features are due to hyponatraemia: anorexia, nausea, vomiting,
Interpretation cramps, weakness and coma. SIADH is diagnosed by hypotonic
hyponatraemia, urine osmolality >100 to 150 mmol/kg, without
A plasma osmolality of more than 288 mOsmol/kg before
extracellular depletion. Systemic conditions such as dysfunction
vasopressin injection denotes sufficient dehydration. In a
of thyroid, adrenal, heart, liver and kidney, head injury,
normal person, vasopressin results in <9% rise of urine
malignancy or lung infection should be excluded.
osmolality, in contrast to central DI, where the rise is more than
9%. Nephrogenic DI shows little change in urine osmolality Table 2: Causes of SIADH
with dehydration and little further increase with vasopressin.
Psychogenic polydipsia requires prolonged fluid deprivation Pulmonary disorders
Pneumonia
before plasma osmolality reaches 288 mOsm/kg; though
Tuberculosis
vasopressin results in less than 9% increase.
Lung abscess
Differential Diagnosis Pneumothorax
In primary polydipsia, rather than nocturia, modest daytime Positive pressure ventilation
polyuria occurs; acquired nephrogenic DI has less polyuria Bronchogenic carcinoma
compared to primary nephrogenic DI or central DI. CNS disorders
Hypernatraemia with normal serum creatinine and low urine Encephalitis, meningitis, brain abscess
sodium with polyuria suggests water diuresis (e.g. DI) than Vascular injury
osmotic diuresis. On MRI a ‘bright spot’ is shown by normal Trauma
posterior pituitary; it is absent in central DI, although Guillain-Barré syndrome
some ‘normal individuals’, i.e. without diabetes insipidus Brain tumours
could also have absent bright spot. Coexistence of DI with Endocrine disorders
pituitary mass suggests the mass is likely malignant or Myxoedema
infiltrative. Adrenal insufficiency
Anterior pituitary insufficiency
Management, Course and Prognosis
Ectopic ADH production
Central DI is treated by desmopressin, a long acting vasopressin Drugs
analogue. Ambulatory replacement is started with intranasal Stimulation of ADH release (clofibrate, vincristine,
administration (5 to 10 μg) at bedtime, and the dose titrated by cyclophosphamide)
control of nocturia. Oral desmopressin preparations are Enhancement of ADH action (chlorpromazine)
available; although there is no single fixed dose, it can be started Unknown (morphine, carbimazine)
at one oral tablet of DDAVP (0.1 mg) per 8 hours. The antidiuretic
dose-equivalence ratio for intranasal to oral desmopressin is It is treated by correcting the cause and depends on the severity:
1: 18. restriction of free water by 500 to 1000 ml/d may only be needed.
Demeclocycline (600 to 1200 mg/d) is needed uncommonly.
An intact thirst mechanism is an important defense against
complications. When unconscious (e.g. postoperative period, OXYTOCIN
following head injury), 1 μg of DDAVP is injected; although
The other posterior pituitary hormone, oxytocin, has two
some if residual vasopressin exists, potentiators such as chlor-
actions: it contracts uterine myometrium, and stimulates breast
propamide (100 to 500 mg/d), clofibrate (500 mg 6 hourly) or
milk ejection. It also affects social and emotional bonding. There
carbamazepine (400 to 600 mg/d) are used. Carbamazepine and is no clinical condition of excess oxytocin.
vasopressin are best not used together.
Annual follow-up is necessary. DI should not be considered RECENT ADVANCES
idiopathic till four years later. Vasopressin is also used in treatment of cardiac arrest and in
vasodilatory shock. Newly developed vasopressin antagonists
Nephrogenic DI is treated with thiazide diuretics (hydro- are useful in treating hyponatraemia of heart failure. Oxytocin
chlorothiazide 25 to 50 mg/d) and low salt intake. Thiazide use may improve communication in autism. Potential roles for
diuretics impair sodium chloride co-transporter in renal distal oxytocin are being studied as a regulator of bone mass.
convoluted tubule. Increased renal sodium excretion causes
antidiuretic effect. Rarely, indomethacin or high dose RECOMMENDED READINGS
vasopressin may be needed. 1. Makarys AN, McFarlane SI. Diabetes insipidus: diagnosis and treatment of
a complex disease. Cleveland Clin J Med 2006; 73: 65-71.
Rarely when diabetes mellitus and diabetes insipidus coexist, 2. Rajaratnam S, Shailajah K, Seshadri MS. Aetiology and treatment response
the latter can be suspected by the low specific gravity in an in patients with spontaneous diabetes insipidus. J Assoc Physicians India
individual with diabetes mellitus. 2000; 48: 972-5.

418
 10.6 Disorders of Thyroid Glands

Nikhil Tandon, Gunjan Garg

STRUCTURAL EMBRYOLOGY atom against the downhill transport of two Na atoms. The NIS
Thyroid tissue is present in all vertebrates, and is first recognised also transports TcO4–, ClO4–, and SCN–, which has allowed these
in humans about 1 month after conception. The primordium agents to be used for thyroid scanning and blocking iodine
begins as thickening of epithelium in the pharyngeal floor. This uptake. The NIS is also present in non-thyroidal tissues e.g. breast,
forms a diverticulum which later is displaced caudad assuming salivary gland. Another protein involved in iodine transport is
a bi-lobate shape. It remains attached to pharyngeal floor by pendrin, which is a product of the PDS gene. Mutation in NIS and
the thyroglossal duct, the lower portion of which differentiates PDS genes are associated with congenital hypothyroidism.
into pyramidal lobe of the gland. Rest of the thyroglossal duct After uptake, iodine is oxidised by the enzyme thyroid
undergoes dissolution and fragmentation by about second peroxidase (TPO), followed by iodination of tyrosine molecules
month of conception, leaving behind a small depression at the in Tg, a process called organification. TPO is now recognised
junction of the middle and posterior thirds of the tongue to be the major component of what was previously called
(foramen caecum). Persistence of this duct can form thyroglossal thyroid microsomal antigen. Monoiodotyrosine (MIT) and
cyst. About 10% of the thyroid, the parafollicular or C cells, diiodotyrosine (DIT) are then coupled in varying proportion to
develops from the ultimobranchial bodies originating from 4th form T3 and T4, a reaction also catalysed by TPO. There are 3 to 4
and 5th pharyngeal pouches. A number of proteins are known T4 molecules on each molecule of Tg, while only 20% of Tg
to be crucial for normal thyroid gland development. These molecules contain T3. Tg is then processed in lysosomes to
include the thyroid-specific transcription factor PAX8, as well release T4 and T3 in circulation, while the uncoupled MIT and
as thyroid transcription factors 1 and 2 (TTF1 and 2). DIT are deiodinated by dehalogenase thereby recycling iodine.
The thyroid gland contains enough stored hormone to maintain
FUNCTIONAL ONTOGENY
a euthyroid state for at least 6 to 8 weeks.
Thyroid follicular cells acquire capacity to form thyroglobulin
(Tg) by 29th day of gestation, while the ability to concentrate REGULATION OF THYROID HORMONE SECRETION
iodine and initiation of hormonogenesis occurs by the 11th Thyroid stimulating hormone or thyrotrophin (TSH), released
week of gestation. Thyroxine-binding globulin ( TBG) is from the anterior pituitary, stimulates all steps in the formation
detectable in serum by 10th gestational week and increases and release of thyroid hormones, and the conversion of T4 to T3.
subsequently, enabling a progressive increase in circulating TSH itself is under the positive regulation of the hypothalamic
thyroid hormone levels to term. tripeptide, thyrotropin releasing hormone (TRH). Somatostatin,
glucocorticoids, cytokines such as IL-1 and TNF-α, phenytoin
ANATOMY AND HISTOLOGY and dopamine suppress TSH secretion. In turn, TSH and TRH
The thyroid is one of the largest of endocrine organs, weighing secretion is inhibited by T4, forming a negative feedback loop
about 15 to 20 gm in adults, with each lobe being approximately that keeps free T4 levels within a narrow range.
4 cm (height) × 2 cm (width) × 2 to 2.5 cm (thickness). The two
lobes are connected by the isthmus, which is approximately 2 While T4 is solely secreted directly by the thyroid, about
cm in height and width, and 0.5 cm in thickness. The gland is 80% of T3, which is the active hormone, is generated by 5’
supplied by the superior and inferior thyroid arteries. The gland monodeiodination of T4. T4 to T3 conversion is impaired by
is formed of follicles, which are filled with colloid. From the apex fasting, systemic illness or acute trauma, oral contrast agents
of follicular cells, numerous microvilli extend into colloid. It is at and variety of medications (e.g. propylthiouracil (PTU),
or near this surface of the cell that iodination, exocytosis and the propranolol, amiodarone, glucocorticoids).
initial phase of hormone secretion occur. Colloid contains Tg THYROID HORMONE TRANSPORT AND ACTION
molecules in which thyroid hormones are present. The lining
Thyroid hormone exists in circulation in both free and bound
cells of the follicle are cuboidal in the inactive phase and columnar
form. About 75% to 80% of thyroid hormone is bound to
in the active phase. About 20 to 40 follicles are grouped to form
thyroxine binding globulin (TBG). Other proteins to which
a lobule, which is demarcated by connective tissue septa and
thyroid hormone is bound are transthyretin (TTR), and albumin.
supplied by a single artery.The parafollicular cells (C cells) secrete
Only the free-fraction enters cells and produces biological effect
calcitonin, which participates in calcium metabolism.
by binding to a nuclear DNA bound thyroid hormone receptor
SYNTHESIS AND SECRETION OF THYROID HORMONES (TR), for which T3 has a 15-fold higher binding affinity than T4.
There are two TR genes, TRα and TRβ. The coded protein has
The thyroid secretes two iodine containing hormones,
three major functional domains, one to bind ligand, one to bind
tetraiodothyronine (T4) and triiodothyronine (T3). Active uptake
DNA, and the other for transcriptional activation.
of iodine by the follicular cell, against a concentration gradient,
is mediated by the NaI symporter (NIS), which is expressed at the Resistance to thyroid hormones (RTHs) occurs because of
basolateral margin of the cell. NIS enables the entry of one iodine mutation in TRβ gene. Patients with RTH may have features of 419
 hypothyroidism if resistance is severe and generalised, while in characterised by mental retardation, abnormal speech and
some instances they may have features of hyperthyroidism if hearing, diplegia, and strabismus; myxoedematous type,
resistance is predominantly in the hypothalamic-pituitary axis characterised by prominent features of hypothyroidism, mental
and not in peripheral tissues. Treatment is difficult and is retardation and short stature. Learning disability has been
directed towards suppression of TSH using thyroid hormone described even in euthyroid children living in endemic areas.
analogues such as TRIAC (3, 5, 3’ triiodo-thyroacetic acid). Exposure to iodine deficiency during pregnancy is also
associated with abortions, stillbirths, increased foetal anomalies
CLINICAL EVALUATION and perinatal mortality.
History and physical examination should be tailored to evaluate Magnitude of the Problem in India
for presence of a thyroidal enlargement: size, shape, symmetry,
nodularity, consistency, associated lymphadenopathy, fixity, Results of sample surveys conducted in 325 districts covering all
retrosternal extension, and auscultation for a bruit; presence the States/Union Territories revealed that 263 districts are
of the features of hypothyroidism or hyperthyroidism. In case endemic, where the prevalence of iodine deficiency disorders is
of Graves’ disease, associated features of thyroid associated more than 10%. It is estimated that more than 71 million persons
ophthalmopathy and infiltrative dermopathy must also be are sufferring from goitre and other iodine deficiency disorders.
sought. To address this public health problem, the Government of India,
During clinical examination the exact dimensions of the thyroid has implemented the National Iodine Deficiency Disorders
gland can be documented, while in epidemiological studies Control Programme (NIDDCP) formerly known as National Goiter
goitre can be graded as follows: Control Programme (NGCP). This is a 100% centrally assisted
programme with a focus on the provision of iodised salt, IDD
Grade 0: No visual or palpable goitre. survey/resurvey, laboratory monitoring of iodised salt and urinary
Grade 1: A goitre that is palpable, but not visible when the neck iodine excretion, health education and publicity. Government of
is in the normal position. Thyroid nodules in a thyroid which is India has banned the sale of non iodated salt in the entire country
otherwise not enlarged are included in grade 1. for direct human consumption under Prevention of Food
Grade 2: A swelling in the neck that is clearly visible when the Adulteration Act (1954), with effect from 17th May, 2006.
neck is in normal position and is consistent with an enlarged For effective implementation of the programme at the State
thyroid when the neck is palpated. level, the Ministry of Health is providing financial assistance to
Goitre is said to be present when each lateral lobe has a volume all the States/UTs for establishment of an IDD Control Cell, and
greater than the terminal phalanx of the thumb of the subject IDD Monitoring Laboratory, in addition to assistance for
being examined. conducting surveys and health education and publicity for
consumption of iodated salt by the population.
IODINE DEFICIENCY DISORDERS (IDDs)
HYPERTHYROIDISM
Iodine is the key trace element required for thyroid
Thyrotoxicosis is the hypermetabolic condition associated
hormonogenesis. The recommended dietary allowance (RDA)
with elevated levels of free thyroxine (FT4) and/or free triiodo-
for iodine in a non-pregnant adult is 150 mcg/day, while that in
thyronine (FT3). Hyperthyroidism includes diseases that are a
a pregnant female is 200 mcg/day. Iodine content in food and
subset of thyrotoxicosis, that are caused by excess synthesis and
water depends critically on the iodine content of the soil. Soil
secretion of thyroid hormone by the thyroid.
iodine content is increased by plants that concentrate iodine,
colloids that absorb iodine and by an acid pH, while it is The common causes of thyrotoxicosis are shown in Table 1. It is
decreased by repeated flooding and by an alkaline pH. Sea food important to remember that all causes of hyperthyroidism, except
and sea weed are rich sources of dietary iodine. iodine-induced hyperthyroidism, are associated with an increased
radioactive iodine uptake (RAIU). Thyrotoxicosis without
Iodide in the plasma is taken up via active transport into the
hyperthyroidism is not associated with an increased RAIU.
thyroid follicular cells, a process which becomes more efficient
in the iodine deficiency state. Iodine deficiency results in Table 1: Common Causes of Thyrotoxicosis
enlargement of the thyroid to enhance the ability of the glands
Conditions causing hyperthyroidism
to trap iodine. The term endemic goitre is used to describe Graves’ disease
goitre seen in a population with iodine deficiency. An area is Toxic multinodular goitre
defined to be endemic if more than 5% of children, between Toxic adenoma
6 to 12 years of age, are found to have goitre. The stages of Iodide-induced hyperthyroidism
goitre formation include an initial diffuse parenchymatous Trophoblastic tumour
goitre, followed by diffuse colloid goitre, hyperplastic nodular Increased TSH secretion: thyrotrophinoma
goitre, nodular parenchymatous goitre and nodular colloid Conditions causing thyrotoxicosis not associated with
goitre. The first two stages are most likely to disappear after hyperthyroidism*
Thyrotoxicosis factitia
making region iodine replete, while later stages are unlikely to
Subacute thyroiditis
involute. Post-partum thyroiditis
Other manifestations of iodine deficiency depend on the Chronic thyroiditis with transient toxicosis
severity and age at exposure. Endemic cretinism is a state of Ectopic thyroid tissue (struma ovarii, functioning metastasis of Ca
severe congenital hypothyroidism occurring in an endemic thyroid)
420 area. Two clinical types are recognised: neurological cretinism * These conditions are associated with decreased radioactive iodine uptake.
 Disorders of Thyroid Glands
Clinical Features
The common symptoms and signs of thyrotoxicosis can be
explained on the basis of an increased metabolic rate and
sympathetic activity (Table 2). The latter are observed despite
no change in circulating levels of catecholamines and could
result from a heightened sensitivity at the receptor level.
The symptom profile depends on the severity and duration of
thyrotoxicosis and the age of the patient. Patients commonly
complain of weight loss despite an increased appetite, irritability,
palpitation, tremors, increased sweating, hyperdefaecation,
weakness and fatiguability.

Table 2: Common Symptoms and Signs of Thyrotoxicosis

System Symptoms Signs

CVS Palpitation, dyspnoea Tachycardia, atrial

fibrillation, cardiac failure,
wide pulse pressure
CNS Restlessness, irritability, Tremors, proximal
tremors, insomnia muscle weakness,
periodic paralysis
GIT Increased appetite, Exaggerated bowel sounds,
hyperdefaecation pernicious anaemia
Eye Foreign body sensation,
Stare, lid lag, globe lag,
prominence of eyes*, proptosis*, extraocular
diplopia*, diminishedmuscle involvement*,
vision* exposure keratitis*,
lagophthalmos*
Figure 1: Thyrotoxic facies.
Reproductive Short menstrual cycles, Gynaecomastia
system loss of libido is seen in all patients with hyperthyroidism except those with
Thyroid Neck swelling Goitre, bruit iodide-induced hyperthyroidism. On a thyroid scan in a
General Weight loss, weakness, Weight loss, warm and hyperthyroid patient, uniform tracer distribution suggests
heat intolerance, moist skin, onycholysis, Graves’ disease, patchy distribution suggests toxic MNG and
hyperpigmentation palmar erythema unifocal activity corresponding to a nodule, with suppression
pruritus of the rest of the thyroid gland, suggests a toxic adenoma.
*Reported only in infiltrative ophthalmopathy in Graves’ disease (and not
GRAVES’ DISEASE
routinely, in other causes of thyrotoxicosis).
This is the most common cause of hyperthyroidism in iodine
On examination, the common signs are: goitre, tachycardia, replete parts of the world and is characterised by the triad of
rhythm disturbances like atrial fibrillation, widened pulse diffuse toxic goitre, infiltrative ophthalmopathy and infiltrative
pressure, warm and moist skin, bruit over thyroid, and eye signs. dermopathy. It is a part of the spectrum of autoimmune thyroid
Hair and nails may be soft and friable. Eye signs common to all disease which also includes Hashimoto’s thyroiditis and atrophic
thyrotoxic states include: lid retraction (retraction of the upper thyroiditis. Peak presentation occurs in the 3rd and 4th decades,
eyelid with a rim of sclera visible between lid and limbus); lid while the disease is rare in the first decade and in the elderly.
lag, globe lag, and fine tremors of lightly closed eyelids. A typical While data from the Western world suggests a female: male ratio
thyrotoxic face is depicted in Figure 1. Proximal muscle wasting of 7-10:1, most reports from India describe only a 2- to 3-fold
disproportionate to the weight loss, thyrotoxic myopathy, can excess of female disease. The immunopathogenesis of Graves’
be disabling. Untreated thyrotoxicosis can lead to osteoporosis. disease involves the formation of autoantibodies which stimulate
Menstrual disturbance, commonly hypo- or oligomenorrhoea the TSH-receptor and can activate adenylate cyclase as TSH
or even amenorrhoea, and loss of libido, erectile dysfunction agonists. Evidence for genetic susceptibility to Graves’ disease is
and gynaecomastia have been described. provided by a high concordance rate in monozygotic twins and
Older patients may present with ‘apathetic thyrotoxicosis’ where is possibly mediated through the HLA and CTLA-4 locus. It is
typical adrenergic features are lacking and they may present currently believed that immune response directed against an
instead with depression or apathy, weight loss, atrial fibrillation, antigen common to the thyroid and orbital tissue or skin can be
worsening angina pectoris or congestive heart failure. responsible for ophthalmopathy and dermopathy respectively.
Precipitation of autoimmunity may be caused by infection and
Diagnosis stress, though this has never been unequivocally proven.
Approach to the diagnosis of a patient with clinical suspicion
Clinical Features Specific to Graves’ Disease
of thyrotoxicosis is shown in Figure 2. Elevated serum total and
FT4 and suppressed TSH are seen in patients with thyrotoxicosis. In addition to those common to all causes of thyrotoxicosis,
Some patients may have normal T4 and an isolated elevation of certain clinical features are observed exclusively in Graves’
421
T3, a state called T3 toxicosis. As mentioned above, increased RAIU disease due to its autoimmune aetiology.
 Figure 2: Approach to a patient with clinical features suggestive of thyrotoxicosis.

Coeliac disease and gastric achlorhydria may coexist with Infiltrative dermopathy
Graves’ disease. Up to 3% patients may have pernicious anaemia. This occurs in 5% to 10% of white patients with Graves’ disease
Myasthenia gravis may occur in approximately 1% of patients and is invariably accompanied by severe ophthalmopathy. It is
with Graves’ disease, while 3% to 5% of patients with myasthenia rarely reported in Indian patients with Graves’ disease. Lesions
may have Graves’ disease. are non-pitting, indurated areas of skin on legs commonly on
Infiltrative ophthalmopathy shins (pretibial myxoedema), but can occur at other sites, often
as nodular lesions (Figure 3). Clubbing has been reported in
Extraocular and orbital adipose tissue are inflamed and swollen
long standing disease and is called thyroid acropachy. The
by the accumulation of glycosaminoglycans (GAGs) secreted
hypermetabolic state leads to axial bone destruction,
by fibroblasts under influence of cytokines. Smoking is
presumably secondary to enhanced osteoclast activity.
considered an important risk factor for development of
ophthalmopathy in Graves’ disease. Early symptoms include
foreign body sensation, conjunctival congestion and periorbital
swelling. Exophthalmos, which can be asymmetric, may prevent
eyelid closure during sleep, a condition called lagophthalmos.
Diplopia due to extraocular muscle involvement, corneal
ulceration due to exposure keratitis and loss of vision are
extreme manifestations. The American Thyroid Association has
classified thyroid-associated ophthalmopathy (Table 3), which
can be remembered by the mnemonic NOSPECS based on the
first letter of each category.

Table 3: The NOSPECS Classification of Thyroid Associated

Ophthalmopathy
Class Description

N No eye symptoms or signs

O Only signs, no symptoms (upper eye lid retraction, stare, lid
lag, proptosis <22 mm) Figure 3: Severe dermopathy.
S Soft tissue involvement (signs and symptoms)
P Proptosis >22 mm Laboratory investigations in Graves’ disease
E Extraocular muscle involvement Like all causes of thyrotoxicosis, Graves’ disease is associated
C Corneal involvement with elevated T4 and T3 and suppressed TSH. Elevation of T3 is
S Sight loss (optic nerve involvement) proportionately to a greater extent than T4. TPO antibodies are
present in 80% patients. Thyroid scan will show a diffusely
An overall activity score (0 to 7) is helpful in the follow-up of enlarged gland with uniformly increased radiotracer uptake. By
such patients and can be determined by assigning 1 point each definition, TSH-receptor autoantibody should be present in all
for the presence of spontaneous retrobulbar pain, pain on eye patients, though they are not recommended for routine clinical
movement, eyelid erythema, conjunctival injection, chemosis, use. CT or MRI of the orbits usually reveal thickening of extra-
422 swelling of the caruncle, or eyelid oedema or fullness. ocular muscles with sparing of tendons.
 Disorders of Thyroid Glands
Treatment Propranolol (20 to 40 mg qid) or atenolol (25 to 50 mg OD) are
Three main therapeutic modalities are available for the the preferred agents.
management of Graves’ disease: medical therapy with anti- Radioactive iodine ablation
thyroid drugs; radioactive iodine ablation; and surgery.
Pregnancy should be excluded immediately before RAI therapy
Medical therapy is planned in potentially fertile women. Thionamide therapy
Thionamides (methimazole, carbimazole and propylthiouracil) should be stopped at least 3 to 7 days prior to RAI therapy. In
are the preferred agents used for medical therapy.All these agents recent years, the trend is favouring a simple fixed dose regimen.
inhibit thyroid hormone synthesis, with the organification step Most patients with Graves’ disease are treated with 5 to 10 mCi.
being most sensitive to their action. In addition, propylthiouracil These doses are effective in 90% to 95% of patients. Even with
(PTU) also inhibits extrathyroidal conversion of T 4 to T 3 . small doses of radioiodine, permanent hypothyroidism will
Carbimazole is entirely converted to methimazole (half-life is 6 occur in about 40% patients within 10 years. Pregnancy should
hours), which is the active agent. The usual dose for carbimazole be deferred for at least 6 months after I131 ablation. In patients
is 30 to 45 mg/day, initially given in three divided doses. Once with moderate to severe Graves’ ophthalmopathy, RAI therapy
euthyroid state is achieved, the dose can be gradually reduced may worsen the eye disease and thus shall be avoided. If RAI
to a maintenance dose of approximately 10 mg, which can be therapy is used in such patients, they should stop smoking and
given as a single daily dose. PTU, due to a shorter duration of receive a course of oral corticosteroids immediately after the
action (half-life is 1.5 hours), is given as a dose of 50 to 100 mg at radioiodine treatment.
8 hourly intervals. If T4 levels do not fall after 4 to 8 weeks, the Surgery
dose should be increased. Later dose is adjusted to maintain T4
Surgery is usually preferred in patients with very large goitre
levels in normal range. There is no consensus about the duration
causing compressive symptoms or patients with significant eye
of treatment which is usually given for 12 to 18 months. In
involvement, or in those having severe adverse reaction to
addition to the titration regimen described above, an alternate
antithyroid drugs. Surgery is also indicated if there are
regimen is the block-replacement regimen, which is currently not
suspicious or proven malignant nodules. Patients should be
preferred because of a concern of increase in side effects.
euthyroid before surgery to decrease the risk of arrhythmias
The likelihood of long-term remission with a full course of during induction of anaesthesia and risk of post-operative
antithyroidal agents is about 50%. Once a patient relapses, there thyroid storm. The surgical procedure of choice is bilateral
is no advantage in repeating another full course of medical subtotal thyroidectomy taking care to avoid potential
therapy because the chance of a relapse is nearly 100% in this complications, hypoparathyroidism and recurrent laryngeal
situation. nerve injury and bleeding into the operative site.
Minor side effects including cutaneous reactions, arthralgia, and OTHER CAUSES OF THYROTOXICOSIS
gastrointestinal adverse events, occur in approximately 5% of
Two other important causes, in addition to Graves’ disease, are
patients and tend to be mild or transient. Agranulocytosis is
toxic MNG and toxic adenoma.
the most feared adverse effect requiring drug withdrawal.
Recently, serious hepatic adverse effects including acute liver Toxic Multinodular Goitre (MNG)
failure have been reported with propylthiouracil in children. Toxic MNG is usually reported in a person with a long-standing
Current guidelines recommend that methimazole be used MNG, in which one or more nodules become functionally
as the first line therapy in treatment of patients with autonomous. It usually occurs in older individuals, 4th-5th
hyperthyroidism and that the use of propylthiouracil should decade, and in addition to the usual features of thyrotoxicosis
be reserved for individuals in the first trimester of pregnancy, may also have obstructive symptoms due to a large goitre.
patients with life-threatening thyrotoxicosis or thyroid storm Further, cardiovascular manifestations may be prominent
and patients who have experienced adverse effects of because of the older age of patients. Patients with mild toxic
methimazole (except agranulocytosis). MNG are also at risk for developing iodine-induced thyro-
toxicosis (Jod-Basedow effect) after exposure to intravenous
Other agents occasionally used to treat hyperthyroidism include contrast or treatment with amiodarone.
lithium, which decreases thyroid hormones release.
Dexamethasone, in a dose of 2 mg 6 hourly, inhibits secretion Radioisotope scans show a combination of hyper- and hypo-
of hormone, T3 neogenesis and has immunosuppressive effects. functioning areas. Medical therapy should be used to attain
It has been used in patients with severe thyrotoxicosis or thyroid euthyroidism following which either radioiodine ablation (25
storm. Inorganic iodine (as in Lugol’s solution or SSKI) acutely to 30 mCi) or surgery should be performed as definitive therapy.
reduces the synthesis and release of T4 and T3, and also reduces Toxic Adenoma
the vascularity of thyroid gland. Iodine is used to prepare patient
The disorder is usually caused by a benign single adenoma that
rapidly for surgery or as an adjunctive measure in patient with
is palpable as a solitary nodule and hence is sometimes referred
thyroid storm. Typical doses are Lugol’s solution 3 to 5 drops tid
to as hyperfunctioning solitary nodule or toxic nodule. The basic
and SSKI one drop tid. Iodine containing medications like
pathogenesis of a large fraction of these tumours, is one of
sodium ipodate and iopanoic acid have also been used in those
several somatic point mutations in the TSHR gene, commonly
with side effects to thionamides.
in the third transmembrane loop. This condition occurs in a
Symptomatic therapy with beta-adrenergic antagonists is used younger age group than does toxic multinodular goitre,
to relieve symptoms like palpitations, tremors and anxiety. typically in patients in their 30s or 40s.
423
 Patients develop features of thyrotoxicosis only when the If patients are allergic to iodine, lithium carbonate (300 mg every
adenoma achieves a diameter of 2.5-3 cm. Radioisotope scan 6 hours, with twice daily lithium levels checked until a
shows a hyperfunctioning ‘hot’ nodule, with suppression of the therapeutic dose of 1 mmol/l is attained) can be used instead.
remainder of the gland. Radioiodine ablation of the adenoma Intravenous steroid will also block the conversion of T4 to T3 and
is the treatment of choice, since usually the remaining thyroid so dexamethasone 4 mg four times daily intravenous (or
tissue does not take up radioiodine. Larger adenomas may hydrocortisone 100 mg four times daily) is recommended. If
require surgery. there are no contraindications to beta-blockers, then the choice
is propranolol 80 mg three times daily (orally or via nasogastric
Figure 4 provides the approach to making an aetiological
tube), or 1mg/min intravenously. If beta-blockers are contra-
diagnosis in a patient with thyrotoxicosis.
indicated, the possible alternatives would include calcium
Thyroid Storm (Thyrotoxic Crisis) channel blockers or digoxin.
Thyroid storm is a life-threatening condition, with features of Supportive measures include correction of dehydration and
severe thyrotoxicosis, including fever (38.5°C), tachycardia out hypernatraemia, if present, and administration of glucose.
of proportion to the fever, confusion, agitation, nausea and Salicylates should be avoided and hyperpyrexia should be
vomiting, hypertension, congestive cardiac failure, increased managed with paracetamol, cold sponging, fans or ice packs.
transaminases, with biochemical evidence of thyrotoxicosis.
It is unusual for untreated hyperthyroidism to present as thyroid SUBCLINICAL HYPERTHYROIDISM
storm, as there are usually precipitating events such as surgery, Subclinical hyperthyroidism is a condition of chronically
sepsis, burns injury, cardiovascular accident, parturition, status suppressed serum TSH levels and normal levels of circulating
epilepticus, I131 treatment. free thyroid hormone. Subclinical hyperthyroidism may
accelerate bone loss in postmenopausal women and is
The treatment principles are to decrease the production and
associated with a higher incidence of atrial arrhythmia including
release of thyroid hormones, to block the effects of circulating
atrial fibrillation in elderly patients. It can occur either because
T4 and T3, to deal with the underlying precipitants, and to provide
of excessive supplementation with thyroxine or because of
general support.
evolving thyrotoxic state. Treatment by titrating thyroxine
Large doses of antithyroid drug (PTU 300 to 400 mg every 4 therapy should be done to ensure that serum TSH remains in
hourly) are given by mouth, by nasogastric tube, or if necessary, the mid-normal range. In endogenous causes of subclinical
per rectum. PTU is preferred to methimazole due to its hyperthyroidism, therapy should be planned if a resultant tissue
additional effect of inhibiting the peripheral conversion of T4 effect is evident, such as a low bone mineral density or
to T3. SSKI (5 drops every 6 hours), ipodate (500 mg twice daily) arrhythmias. In other situations, patients can be followed up to
or Lugol’s solution (3 to 5 drops tid) acutely retard the release assess disease evolution before committing to any definitive
of hormone from the thyroid gland. therapy.

Figure 4 : Approach to establish aetiology in a patient with thyrotoxicosis.

424
 Disorders of Thyroid Glands
HYPERTHYROIDISM IN PREGNANCY resistance causing diastolic hypertension and decrease in
If a subnormal serum TSH concentration is detected during exercise tolerance. Pericardial effusion may occur in severe
gestation, hyperthyroidism must be distinguished from both primary hypothyroidism, while a small heart size is common in
normal physiology during pregnancy and hyperemesis central hypothyroidism. ECG changes include sinus bradycardia
gravidarum, which may also be associated with suppressed TSH and low voltage complexes with ST-T wave abnormalities. Cold
with or without elevated serum FT4 levels. Differentiation of intolerance occurs due to diminished blood supply and
Graves’ disease from gestational thyrotoxicosis is supported vasoconstriction. Pleural effusion and obstructive sleep apnoea
by evidence of autoimmunity, a goitre, and presence of TSH may occur as well.
receptor antibodies.
Table 4: Causes of Hypothyroidism
Rise in TBG levels during pregnancy, results in increase in total
Primary hypothyroidism with goitre
T4 levels. Therefore either free T4 levels should be measured or
Acquired
one can use the normal (non-pregnant) range for the serum Hashimoto’s thyroiditis
total T4 concentration multiplied by 1.5. Iodine deficiency disorders
Goitrogen exposure
Medical therapy with antithyroid drugs (ATDs) is advocated at
Antithyroid drug treatment
the lowest possible dose to ensure a euthyroid state with FT4 Congenital
near the upper limit of normal. As methimazole may be Iodide transport or utilisation defect
associated with congenital anomalies propylthiouracil should Defects in thyroid hormonogenesis
be used as a first-line drug, especially during first-trimester Primary hypothyroidism with atrophic gland
organogenesis. TSH receptor-stimulating antibodies freely cross Acquired
the placenta and can stimulate the foetal thyroid. These Atrophic thyroiditis
antibodies should be measured before pregnancy or by the end Post-ablative hypothyroidism (radioiodine therapy, surgery)
of the second trimester in mothers with current Graves’ disease, Congenital
or with a history of Graves’ disease. Thyroid agenesis
Thyroid dysplasia
In women with elevated TRAb or in women treated with ATD, Transient primary hypothyroidism
foetal heart rate monitoring, and assessment of foetal thyroid After thyroiditis: silent, subacute or post-partum thyroiditis
size by ultrasound should be performed to assess foetal thyroid Central hypothyroidism
status. Surgery is best avoided, but if it becomes essential it Acquired
should be performed in the second trimester. Neither Pituitary or hypothalamic disease, e.g. tumour, haemorrhage,
radioactive iodine ablation nor iodine/iodine-containing agents granulomatous disease, hypophysitis
should be considered for therapy in pregnancy. Congenital
TSH deficiency or TSH receptor defects
HYPOTHYROIDISM
Resistance to thyroid hormone action
Reduced production of thyroid hormone is the central feature Generalised resistance to thyroid hormone action
of the clinical state termed hypothyroidism.
Primary hypothyroidism is due to disease of thyroid itself. Modest weight gain despite reduced appetite and constipation,
It accounts for approximately 99% of cases, with < 1% being due to reduced gut peristalsis, are common complaints.
due to TSH deficiency known as central or secondary hypo- Myxoedema megacolon and myxoedema ileus are uncommon.
thyroidism. Primary hypothyroidism can be further sub- Neuromuscular manifestation include slowed physical and
classified depending on whether it is associated with goitre or mental functions, lethargy, somnolence, agitation (‘myxoedema
an atrophic gland, and each of these entities can either be madness’) or depression, deafness, carpal tunnel syndrome and
congenital or acquired in aetiology (Table 4). ‘hung-up’ reflexes may also be present.

Clinical Features In adult women, hypothyroidism may be associated with

diminished libido, failure of ovulation, polymenorrhoea,
In adult hypothyroidism, clinical features can largely be
menorrhagia, and reduced fertility. In men, hypothyroidism may
explained by the reduced metabolic rate and deposition of
cause reduced libido, impotence and oligospermia. These
glycosaminoglycans (GAG) in different body compartments.
disturbances in the reproductive system are often associated
Symptoms of hypothyroidism develop gradually. The term
with hyperprolactinaemia (since prolactin is also under the
myxoedema refers to the boggy appearance of the skin and
control of TRH) and rarely can also be associated with pituitary
subcutaneous tissues in the patients in a severe hypothyroid
enlargement due to thyrotroph hyperplasia. Energy metabolism
state. Peripheral manifestations of hypothyroidism are less
is reduced leading to a decrease in appetite, cold intolerance,
manifest in patients with secondary hypothyroidism.
reduced protein synthesis and lipid accumulation (elevated TG
Skin is pale and cool, and reduction in sweat and sebaceous and LDL-cholesterol).
secretion causes dryness and coarseness. Capillary fragility
A child with congenital hypothyroidism is sluggish and may
causes easy bruisability. Scalp and body hair become dry and
present with prolonged physiological jaundice, meconium ileus,
brittle and tend to fall. GAG deposition in the pharynx and larynx
umbilical hernia, feeding difficulty, dry scaly skin and a large
contributes to hoarseness of voice.
tongue. Unless diagnosed and treated early, irreversible
Cardiovascular involvement includes decreased cardiac output, neurological impairment can occur. Severe hypothyroidism in
narrowing of pulse pressure and increased systemic vascular infancy is called cretinism. 425
 During infancy, in addition to constipation, hoarse cry, and thyroidectomy for cancer but can also occur with less complete
somnolence, there is delay in eruption of deciduous teeth and forms of thyroidectomy depending on the amount of tissue left
reaching physical and mental milestones. Persistence of behind. Hypothyroidism after destruction of thyroid tissue with
untreated hypothyroidism will cause impaired linear growth, radioiodine is common and is the one established disadvantage
resulting in dwarfism and delay in closure of fontanelles. X-ray of this form of treatment for hyperthyroidism in adults. Its
pelvis will reveal dysgenesis of femoral capital epiphysis, which frequency is determined, in large part, by the dose of radioiodine.
is pathognomonic for hypothyroidism in infancy and childhood. The incidence of post-radioiodine hypothyroidism increases
Clinical features of hypothyroidism beginning in childhood, with time. Even when doses are calculated to render a patient
juvenile hypothyroidism, are a combination of those seen in euthyroid, approximately 10% of patients are hypothyroid
infantile and adult hypothyroidism. Retarded linear growth, at the end of the first year and a further 2% to 3% become
delayed sexual maturation and poor intellectual performance hypothyroid every year, over the next decade.
are important. Drugs
Diagnosis Lithium and amiodarone are commonly used drugs which are
Plasma TSH is the best initial diagnostic test, and a normal value associated with hypothyroidism.
excludes primary hypothyroidism. Low T4 with elevated TSH CONGENITAL CAUSES OF PRIMARY HYPOTHYROIDISM
confirms the diagnosis of primary hypothyroidism, while normal
T 4 with isolated elevation of TSH leads to the diagnosis of In addition to thyroid agenesis or dysplasia, iodide transport
subclinical hypothyroidism. Individuals with subclinical defects (NIS or pendrin mutations) and defects in thyroid
hypothyroidism who have elevated anti-TPO antibodies are hormone genesis can cause goitrous primary hypothyroidism.
more likely to progress to overt hypothyroidism than antibody Pendred’s syndrome is characterised by sensorineural hearing loss.
negative individuals. Therapy
Central hypothyroidism is characterised by a low T4 and an Since primary hypothyroidism inevitably requires life long
inappropriately normal TSH. Evaluation for other pituitary replacement therapy, it is advisable to reconfirm the diagnosis
hormone deficiency is recommended to confirm the diagnosis by repeating thyroid function tests, if the clinical features are
and guide therapy. Imaging to look for pituitary-hypothalamic equivocal, before starting therapy.
disease using MRI should also be performed.
Adults
In severe non-thyroidal illness also, total plasma T4 and T3 are Levothyroxine is the drug of choice and most adult patients
low. These may revert to within normal range in 3 to 6 months require a daily dose of 75 to 150 µg (1.7 µg/kg/day). The initial
after recovery from illness. dose depends on the degree of hypothyroidism, age and
general health status of the patient. Therapy in young healthy
ACQUIRED CAUSES OF PRIMARY HYPOTHYROIDISM
subjects can be initiated with the full dose. In elderly patients,
Hashimoto’s Thyroiditis/Chronic Lymphocytic Thyroiditis average replacement dose is slightly lower and treatment
It is the most common cause of goitrous hypothyroidism in should be started with a small initial dose. The recommended
iodine sufficient parts of the world. It is more common in starting dose in the elderly is 25 µg/day, which is then increased
women. It is characterised by intrathyroidal lymphocytic by 12.5 to 25 µg at monthly intervals. In pregnancy, thyroxine
infiltration with germinal centre formation, follicular damage requirement increases by 25 to 50%. If any patient is requiring
or destruction and fibrosis. Goitre develops gradually, and is a dose >150 µg/day, compliance should be assessed. The dose
firm in consistency. Presence of anti-TPO antibodies and should be given as a single dose, on an empty stomach, in the
thyroglobulin autoantibodies favours the diagnosis. History morning. Absorption of thyroxine is hampered by iron
of autoimmune endocrinopathies and other autoimmune preparations and antacids containing aluminium and these
diseases like rheumatoid arthritis should be ascertained in preparations should not be given at the same time as thyroxine.
the individual and first degree relatives. Immunogenetic Aim of treatment is to keep TSH in the mid-normal range.
predisposition, exposure to excess iodine, therapy with Keeping in mind the time required by the pituitary-thyroid axis
interferon and pregnancy or post-partum state are known risk to reset, TSH should be measured no sooner than 6 to 8 weeks
factors for Hashimoto’s thyroiditis. after initiating therapy or making a dose change. Once an
Iodine Deficiency Disorders individual becomes euthyroid on a stable dose of thyroxine, an
annual TSH is adequate for monitoring. Over treatment, as
(Already Discussed)
indicated by suppressed TSH levels, should be avoided due to
Primary Idiopathic Hypothyroidism risk of osteoporosis and atrial fibrillation.
Several authors use the term autoimmune thyroiditis to include Subclinical hypothyroidism may be treated if any of the
the goitrous (Hashimoto’s thyroiditis) and non-goitrous variants following are present: goitre, high titres of anti-TPO antibodies
(primary idiopathic hypothyroidism/atrophic thyroiditis). The or pregnancy. In the absence of these findings, patients may be
lack of goitre in atrophic thyroiditis is attributed to antibodies kept under follow-up, with repeat thyroid function tests at 6
that block the action of TSH. Clinical manifestations are the same monthly intervals to look for progression to overt hypo-
as for Hashimoto’s thyroiditis except for the absence of goitre. thyroidism.
Post-ablative Hypothyroidism Infants and children
Hypothyroidism after thyroidectomy depends on the extent A dose of approximately 50 µg/day, is advocated in congenital
426 of the surgery. The incidence is 100% after total/near total hypothyroidism with the aim of maintaining T4 levels at about
 Disorders of Thyroid Glands
10 µg/dL.The pituitary feedback mechanism matures at 2 years can pass through a transient hypothyroid phase before
of age, and the target of therapy then can be normal TSH level. reverting to euthyroidism. Using propranolol 10 to 20 mg, orally
3 to 4 times daily, controls symptoms of thyrotoxicosis. NSAIDs
Secondary hypothyroidism: Since corticotroph failure may co-
can be used for pain relief, though severe cases may require
exist, glucocorticoid replacement must be initiated before
glucocorticoid therapy.
starting T4 therapy. Monitoring is with serum T4 levels.
Postpartum Thyroiditis
Myxoedema Coma
Postpartum thyroiditis is the occurrence of thyrotoxicosis,
Myxoedema coma is the ultimate stage of severe long-standing hypothyroidism, and/or thyrotoxicosis followed by hypo-
untreated hypothyroidism, most often in elderly subjects and thyroidism in the first postpartum year in women without overt
frequently in cold winter months. thyroid disease before pregnancy.
Myxoedema coma can be the first presentation of new It occurs in 8% to 10% of women in postpartum period and up
hypothyroidism, often precipitated by infection, stroke, to 30% of those who were anti-TPO antibody positive in
myocardial infarction, sedative drugs or exposure to cold. pregnancy. The thyroid gland does not show fibrosis as in
Treatment is initiated on the basis of clinical suspicion, especially Hashimoto‘s thyroiditis or giant cell infiltration as in subacute
in non-responsive patients with a history of hypothyroidism, thyroiditis. The condition is painless. These patients are very
although blood should be taken for thyroid function tests and likely to experience a recurrence following a subsequent
cortisol first. Initially, the precipitating illness needs to be pregnancy. Course of this disease in majority is self-limiting.
identified and treated and general supportive treatments The clinical manifestations can include an initial thyrotoxic phase
instituted. Functional adrenal insufficiency should also be (3 to 6 months after delivery) followed by a hypothyroid phase
treated with intravenous hydrocortisone. lasting for a few months before returning to euthyroid state.
The important clinical features are altered sensorium (or coma), Symptomatic treatment with beta-blockers is needed in the
subnormal temperature, bradycardia, manifestations of severe toxic phase and thyroxine replacement in the hypothyroid
myxoedema and hypotension. The core temperature must be phase. Reassessment of thyroid function tests should be
checked using a low reading thermometer, as the mortality of performed after stopping thyroxine therapy, one year after
this condition is related to the severity of the hypothermia. delivery to check for return to the euthyroid state.
If intravenous thyroxine is available, a single dose of 500 µg T4 Women with a history of postpartum thyroiditis have increased
can replete the hormone pool and can be followed by 100 µg risk of developing permanent primary hypothyroidism in the
IV daily. Alternatively, 500 µg thyroxine can be administered 5- to 10-year period following the episode of postpartum
through a nasogastric tube, followed by 100 to 200 µg/day. thyroiditis. An annual TSH level should be performed in these
Glucocorticoid replacement with IV hydrocortisone (5 to 10 mg/ women.
hour) should also be given. No hypotonic fluids should be given.
Respiratory support using ventilator may be required. No Since hypothyroidism is a potentially reversible cause of
external heating should be done because it may cause depression, women with postpartum depression should be
cutaneous vasodilatation and increase the strain on the heart. screened for hypothyroidism, even though there is limited
Despite aggressive intensive care, a high mortality rate of up to evidence supporting an association between postpartum
50% is reported. depression and postpartum thyroiditis.
Riedel’s Thyroiditis
THYROIDITIS
This rare cause of thyroiditis is characterised by fibrosis of the
The term thyroiditis indicates inflammation of the thyroid gland. thyroid and adjacent structures and occurs primarily in middle
Causes of thyroiditis include chronic autoimmune (Hashimoto’s) aged women. Patients usually present with a stony hard,
thyroiditis, subacute thyroiditis, postpartum thyroiditis, Riedel’s immobile goitre resulting in pressure symptoms due to
thyroiditis, amiodarone-induced thyroiditis (all of the above compression of trachea, oesophagus and recurrent laryngeal
conditions are painless) and also acute infectious thyroiditis, nerve. The presence of eosinophils on fine needle aspiration
radiation thyroiditis and traumatic (e.g. surgery, palpation, specimens has been demonstrated histologically, suggesting a
FNAB), thyroiditis (all of which are painful). unique autoimmune response to fibrous tissue.
Subacute Thyroiditis (de Quervain’s Thyroiditis, Viral One-third of the patients have hypothyroidism. When
Thyroiditis, Granulomatous Giant Cell Thyroiditis) symptoms of obstruction are present, surgical removal of
It is most likely viral in origin. It commonly presents with neck gland is indicated.
pain, which may radiate to ear or mandible. Hoarseness, Glucocorticoids have been used for treatment because they
dysphagia and signs of thyrotoxicosis may be present. reduce inflammation. Tamoxifen, 20 mg twice daily, has been
Patients may also complain systemic features like lassitude successful in some patients. The proposed mechanism of action
and weakness. Thyroid gland is very tender and firm. The is the induction of transforming growth factor beta (a potent
characteristic feature on histopathological examination is a well inhibitor of fibroblast proliferation).
developed follicular lesion that comprises of a central core of
colloid, surrounded by multinucleate giant cells. On evaluation, Non-Toxic Goitre
ESR is usually high and RAIU is suppressed to extremely low Simple, non-toxic or euthyroid goitre represents any thyroid
levels (0 to 5%). Serum TSH is suppressed and serum T4 and T3 gland enlargement that is not associated with either
levels are high. This condition is nearly always self-limiting, but hyperthyroidism or hypothyroidism and which does not occur 427
 due to inflammation or neoplasia. The diagnosis of euthyroid a diagnosis. Multiple sites should be aspirated to improve the
gland is based on palpation and imaging of thyroid gland or diagnostic yield. A satisfactory specimen contains at least five
on evaluation of thyroid functions. Thyroid enlargement may or six groups of 10 to 15 well-preserved cells.
be diffuse or multinodular or there may be a solitary nodule.
Thyroid function tests
Each nodule contains a collection of thyroid follicles. Larger
nodules may develop a fibrous capsule by compressing A suppressed TSH, with or without elevated T4 is suggestive of
surrounding parenchyma. an autonomously functioning nodule/s.

Most affected patients do not exhibit clinical symptoms and Radionuclide scan
signs of thyroid dysfunction and usually seek medical attention A pertechnetate scan is often used to make a functional
for thyroid enlargement. Large goitre may cause symptoms of diagnosis of a nodular goitre. Nodule showing no uptake of
dysphagia, dysphonia, or hoarseness by compressing local radioactivity is called a ‘cold’ nodule, while that with an uptake
structures like oesophagus, trachea, or the recurrent laryngeal similar to the rest of the thyroid is called a ‘warm’ nodule.
nerve. Nodules which take up increased amount of radioactivity
along with suppressed uptake in the rest of the gland are
Suspicion of malignancy is higher if the nodule occurs in the
called ‘hot’ nodules. Initially it was considered that only ‘cold’
very young or elderly, shows rapid progression in size, is hard
nodules harboured malignancy. However, current evidence
in consistency, has restricted mobility, associated lymph-
suggests that all types of functional nodules can contain
adenopathy or hoarseness.
malignancy.
The incidence of multinodular goitre (MNG) is more common
Ultrasound
in women and increases with age. Most patients are
asymptomatic and do not require any therapy. Intervention is This is a useful modality to differentiate solid from cystic
required if hyperthyroidism results (toxic MNG) or an enlarging nodules. A purely cystic nodule is unlikely to contain a neoplasm.
MNG causes pressure symptoms. Surgery is the best option for However, most nodules have both a solid and a cystic
these situations. A dominant nodule in a MNG has the same component. Ultrasound can be used to guide the FNAC from
biological behaviour and chance of harbouring a malignancy the solid component of such nodules.
as a solitary thyroid nodule. Management of a solitary thyroid nodule (Figure 5)
Investigations ‘Hot’ nodules with a suppressed TSH should be treated with
Fine needle aspiration cytology radioiodine ablation or with surgery if they are large in size.
Other emerging treatment alternatives are percutaneous
Fine needle aspiration cytology (FNAC) is the investigation of
ethanol and laser treatment.
choice in nodular goitre. In case of an inconclusive aspiration, a
repeat FNAC should be performed. If even that is inconclusive, If FNAC is suggestive of a malignancy or is suspicious, patient
an ultrasound-guided FNAC increases the likelihood of reaching should be managed surgically with appropriate follow-up. If the

Figure 5: Approach to a patient with a solitary thyroid nodule.

428
 Disorders of Thyroid Glands
FNAC suggests a benign disease, the patient can be followed If FNAC is non-diagnostic, even after an ultrasound-guided
up without any intervention. Suppressive regimens with aspirate, surgery is the preferred option.
levothyroxine have been tried with non-significant trend
Thyroid Neoplasia
towards 50% reduction in nodule size. The disadvantage with
this approach is the likelihood of causing subclinical Thyroid tumours are the most common endocrine neoplasm. Most
thyrotoxicosis and its attendant complications. of these are benign hyperplastic (or colloid) nodules or benign
follicular adenomas but approximately 5% to 10% of these are
Table 5: Classification of Thyroid Neoplasia carcinomas.The likelihood of malignancy is high if the lesion occurs
in the young (<20 years) or elderly (>70 years), male, history of
Primary epithelial tumours
external neck radiation in childhood/adolescence, recent onset of
Tumours of follicular cells
compressive features and a family history of thyroid cancer. FNAC
Benign tumours: Follicular adenoma
is the investigation of choice, as described in the section above. A
Malignant tumours: Papillary carcinoma, follicular carcinoma,
poorly differentiated cancer, undifferentiated cancer (anaplastic classification of thyroid neoplasia is provided in Table 5.
cancer)
RECOMMENDED READINGS
Tumours of C cells
1. Eng CY, Quraishi MS, Bradley PJ. Management of thyroid modules in adult
Medullary thyroid cancer patients. Head Neck Oncol 2010; 2:11.
Mixed tumours 2. Inoue M, Arata N, Koren G, Ito S. Hyperthyroidism during pregnancy. Can
Mixed medullary–follicular cancer Fam Physcian 2009; 55(7):701-3.
Non-epithelial tumours 3. Rastogi MV, LaFranchi SH. Congential hyperthyroidism. Orphanet J Rare Dis
2010; 5:17.
Lymphomas
4. Rivkees SA. Pediatric Grave’s Disease: Controversies in Management. Harm
Others
Res Paediatr 2010; 74(5):305-11.

429
 10.7 Disorders of Parathyroid Glands

Ambrish Mithal, Beena Bansal

There are four parathyroid glands located posteromedial to the PRIMARY HYPERPARATHYROIDISM
thyroid gland. The upper two glands develop from the fourth This is a disorder characterised by increased PTH secretion by
branchial arch, while the lower two develop from the third the gland. The causes are outlined in Table 1.
branchial arch, but migrate caudally with the thymus. Anomalies
in migration may result in glands in ectopic positions, like the Table 1: Causes of Primary Hyperparathyroidism
mediastinum. Adenomas
There are two types of cells in parathyroid glands—chief cells, Solitary
which secrete parathormone (PTH) and oxyphil cells, which are Multiple
considered non-secretory. Isolated
Part of hereditary syndromes
PARATHORMONE – MEN-1
PTH is a single chain polypeptide with 84 amino acids. The – MEN-2A
principal role of PTH is tight regulation of extracellular calcium – Hyperparathyroidism-jaw tumour syndrome (HPT-JT)
levels. Chief cell hyperplasia

Parathyroid glands have calcium sensing receptors (CaSRs) on Clinical Features

the cell membrane and vitamin D receptors in the nucleus. The
The effects of primary hyperparathyroidism are mainly seen on
parathyroid gland is exquisitely sensitive to calcium—it is said
bone and kidneys. Typically, in India, the disease very much
that that the chief cell can virtually ‘sniff’ calcium!
resembles the description by Fuller Albright in 1930s—a disease
Point mutations associated with loss of function cause a of ‘bones, stones and groans’. This is thought to be related to the
syndrome, familial hypocalciuric hypercalcaemia (FHH). On the widespread vitamin D deficiency in Indians. Some form of bone
other hand, gain-of-function mutations cause autosomal involvement is seen in 80% to 100% of cases in India. Patients
dominant hypocalcaemia hypercalciuria (ADHH). present with bone pains, skeletal deformities and pathologic
fractures. The distinctive bone manifestation othef primary
Low calcium and low vitamin D will stimulate PTH synthesis,
hyperparathyroidism seen in 50% to 90% of Indian patients is
secretion and also increase number of chief cells. Prolonged
brown tumours (on radiograph) or osteitis fibrosa cystica
hypocalcaemia and hypovitaminosis D can therefore lead to
(histologically). Clinically palpable bony swellings may be
secondary hyperparathyroidism and enlarged parathyroid glands.
present. On histopathology, the pathognomonic features are
PTH ACTIONS increase in giant multinucleated osteoclasts in scalloped areas
on the bone surface (Howship’s lacunae) and a replacement of
PTH acts through cell surface receptors PTH1R and PTH2R.
the normal cellular and marrow elements by fibrous tissue.
PTH1R is the classic PTH receptor expressed in bone and kidney.
Other radiological findings include subperiosteal resorption of
Bone phalanges and salt and pepper appearance of the skull.
(a) PTH releases calcium from bone and increases remodelling. Kidney involvement, due to deposition of calcium in renal
i. It acts directly on the osteoblasts through its receptors. parenchyma (nephrocalcinosis) is seen in 5% to 10% cases and
The action on osteoclasts is indirect (through cytokine recurrent nephrolithiasis in 10% to 40% of Indian patients.
release from osteoblasts which then stimulate
Proximal muscle weakness and atrophy of muscles may be so
osteoclasts).
striking as to suggest a primary neuromuscular disorder.
ii. Continuous exposure to PTH (as in hyper-parathyroidism)
increases osteoclast mediated bone resorption leading The patient who suffers a combination of severe bone disease
to osteoporosis. On the other hand, intermittent and profound myopathy can be rendered immobile and has
exposure to PTH increases net bone formation and been referred to as a ‘parathyroid cripple’.
therefore synthetic PTH (1-34) called teriparatide is Neuropsychiatric manifestations, mild gastrointestinal
given for treating osteoporosis. symptoms, pancreatitis, chondrocalcinosis, pseudogout,
Kidneys pancreatitis and hypertension are associated with primary
(a) PTH increases calcium reabsorption in renal tubules and hyperparathyroidism.
increases phosphorus excretion. Rarely, the patient may present in hypercalcaemic crisis. The
(b) It stimulates 1-α hydroxylase which converts 25(OH) symptoms are general malaise, anorexia, polyuria, thirst,
vitamin D to active 1,25(OH)2 vitamin D, which in turn vomiting, constipation, abdominal pain, depression, confusion,
stimulates calcium absorption from the gut. progressing to stupor and coma.
430
 Disorders of Parathyroid Glands
In the West (North America and Europe), the majority of patients Management of symptomatic primary hyperpara-
with hyperparathyroidism are asymptomatic and diagnosed thyroidism
during routine biochemical screening. Such cases are now Parathyroidectomy is the treatment of choice in all symptomatic
increasingly seen in India as well. cases after preoperative localisation by 99mTc-sestamibi
Diagnosis scintigraphy or ultrasonography.
In a patient with hypercalcaemia, the diagnosis is established Postoperative management: Serum calcium declines within 24
by demonstrating elevated PTH levels. With the exception of hours after successful surgery. Acute postoperative hypocalcaemia
lithium, thiazide use and familial hypocalciuric hypercalcaemia is seen if:
(FHH), virtually all other causes of hypercalcaemia are associated  Severe bone disease is present preoperatively
with suppressed PTH (Table 2).  The patient is vitamin D deficient
 There is associated hypomagnesaemia
Table 2: Differential Diagnosis of Hypercalcaemia
 There is injury to all the parathyroid glands or their blood
High PTH supply during surgery.
Primary hyperparathyroidism
Lithium therapy Parenteral calcium replacement is indicated if:
Familial hypocalciuric hypercalcaemia  There are signs of hypocalcaemia; or
Hypercalcaemia of malignancy  Serum calcium is less than 8 mg/dL
Local osteolytic hypercalcaemia An infusion of 0.5 to 2 mg/kg/h of 1 mg/mL solution of calcium
Multiple myeloma gluconate in dextrose (not saline) usually suffices to relieve
Breast cancer symptoms.
Humoral hypercalcaemia of malignancy
High vitamin D levels
Magnesium deficiency impairs the secretion of PTH, so
hypomagnesemia should be corrected whenever detected.
Vitamin D intoxication
Increased 1,25(OH) 2D: sarcoidosis and other granulomatous Management of asymptomatic primary hyperpara-
diseases thyroidism
Idiopathic hypercalcaemia of infancy The National Institutes of Health (NIH) sponsored Third
High bone turnover Workshop in 2009 recommends surgery only if significant
Hyperthyroidism hypercalcaemia, renal dysfunction or osteoporosis is present
Immobilisation (Table 3). It is also recommended in young individuals and in
Thiazides whom medical surveillance would be difficult. All other cases
Vitamin A intoxication should be appropriately monitored (Table 4).
Renal failure
Severe secondary hyperparathyroidism Table 3: Guidelines for Parathyroid Surgery in Asymptomatic
Aluminium intoxication Primary Hyperparathyroidism (PHPT)
Milk-alkali syndrome  Serum calcium 1 mg/dL above upper limit of normal
 Creatinine clearance <60 mL/min
Management  Bone mineral density T-score < -2.5 at any site and/or a previous
Management of hypercalcaemic crisis fragility fracture
If a patient presents with hypercalcaemic crisis, immediate  Age <50 years
management of hypercalcaemia followed by definitive  Patients in whom medical surveillance is neither desired nor
treatment of hyperparathyroidism is needed. possible

1. Hydration, increased salt intake, mild and forced diuresis:

Table 4: Asymptomatic Primary Hyperparathyroidism Patients
Many hypercalcaemic patients are dehydrated because of Who Do Not Undergo Parathyroid Surgery
vomiting, and/or hypercalcaemia induced polyuria. The first
Asymptomatic patients should be monitored regularly:
principle of treatment is to restore normal hydration.
Calcium levels start decreasing within hours.  Serum calcium biannually
 Serum creatinine annually
Under life-threatening circumstances, up to 6 litres of
 Bone density every 1 to 2 years (lumbar spine, hip, forearm)
isotonic saline plus frusemide in doses up to 100 mg
every 1 to 2 hours may be required. Careful monitoring of
central venous pressure and serum electrolytes should be Bisphosphonates can be given to individuals with PHPT for
done. whom skeletal protection is the primary reason for intervention
whereas the calcimimetic cinacalcet can be used to lower serum
2. Bisphosphonates: calcium and PTH levels during long-term therapy in PHPT.
IV pamidronate 30 to 90 mg or zolendronate 4 to 8 mg
reduces calcium levels over 24 to 48 hours. Flu like reactions HYPOPARATHYROIDISM
are common. Rarely, these drugs can precipitate renal Hereditary or acquired hypoparathyroidism presents
dysfunction, so proper hydration is essential. with chronic hypocalcaemia. The differential diagnosis of
431
 hypocalcaemia is given in Table 5. The so called ‘idiopathic lenticular cataracts can also be present. Alopaecia and
hypoparathyroidism’ is probably autoimmune in origin, and candidiasis are associated with autoimmune polyglandular
autoantibodies to the calcium sensing receptor have been failure.
demonstrated in patients, including Indians.
Treatment
Table 5: Causes of Hypocalcaemia Treatment involves replacement with vitamin D or 1,25(OH)2D3
(calcitriol) combined with calcium supplementation. For most
PTH absent
patients, 0.5 to 1 µg calcitriol combined with 1g elemental
 Hereditary hypoparathyroidism
calcium is satisfactory. The wide dosage range reflects the
Idiopathic hypoparathyroidism
variation encountered from patient-to-patient; precise
Syndromes associated with hypoparathyroidism
regulation of dose is required. Since the urinary calcium
– DiGeorge syndrome, Kenney Caffey syndrome, etc.
excretion is high in these patients, care must be taken to avoid
Polyglandular autoimmune type 1 deficiency
excessive urinary calcium excretion after calcium and vitamin
Autosomal dominant hypocalcaemia hypercalciuria (ADHH)
D therapy; otherwise, kidney stones can develop. A thiazide
 Acquired hypoparathyroidism diuretic especially along with a low sodium diet is beneficial in
Surgery mitigating hypercalciuria and easing the daily management of
Radiation these patients.
 Hypomagnesemia
PSEUDOHYPOPARATHYROIDISM
PTH ineffective
 Chronic renal failure Pseudohypoparathyroidism (PHP) is a hereditary disorder
characterised by symptoms and signs of hypoparathyroidism,
 Active vitamin D lacking
typically in association with distinctive skeletal and
Decreased dietary intake or sunlight exposure
developmental defects. The hypoparathyroidism is due to
Defective metabolism
– Anticonvulsant therapy
deficient end organ response to PTH. Hyperplasia of the
– Vitamin D dependent rickets type 1 parathyroids, a response to hormone resistance, causes
Active vitamin D ineffective elevation of PTH levels. Four types of PHP exist; PHP I, subdivided
– Intestinal malabsorption into a and b, PHP II and pseudoPHP (PPHP). PHP Ia, PHP Ib and
– Vitamin D dependent rickets type II PHP II have hypocalcaemia and hyperphosphataemia. Pseudo-
Pseudohypoparathyroidism pseudohypoparathyroidism (PPHP) has normal calcium and
phosphorus levels.
PTH overwhelmed
 Severe acute hyperphosphatemia Albright’s hereditary osteodystrophy (AHO) phenotype is
Tumour lysis present in PHP Ia and PPHP. AHO phenotype consists of short
Acute renal failure stature, round face, skeletal anomalies (brachydactyly - short
Rhabdomyolysis fourth and fifth metacarpals and metatarsals) and heterotopic
calcification. Basal ganglia calcification is seen in half of these
Osteitis fibrosa after parathyroidectomy
patients.
Clinical Features of Hypoparathyroidism Treatment of PHP is similar to that of hypoparathyroidism,
Symptoms include muscle spasms including the classic except that the doses of vitamin D and calcium are usually lower
carpopedal spasms, facial grimacing and in extreme cases, than those required in true hypoparathyroidism.
laryngeal spasm, convulsions and respiratory arrest. Increased
RECOMMENDED READINGS
intracranial pressure occurs in some patients with long standing
hypocalcaemia, often in association with papilloedema. Mental 1. Bilezikian JP, Khan AA, Potts JP. Guidelines for the Management of
Asymptomatic Primary Hyperparathyroidism: Summary Statement from
changes include irritability, depression and psychosis. The QT the Third International Workshop. J Bone Miner Res 2009; 94: 98-101.
interval on electrocardiogram may be prolonged. Arrhythmias 2. Goswami R, Brown EM, Kochupillai N, Gupta N, Rani R, Kifor O,
occur and effect of digitalis may be reduced. Intestinal cramps Chattopadhyay N. Prevalence of calcium sensing receptor autoantibodies
and chronic malabsorption may occur.Chvostek’s and Trousseau’s in patients with sporadic idiopathic hypoparathyroidism. European J
Endocrinol 2004; 150: 9-18.
signs may be positive. Trousseau’s sign is the development of
3. Mithal A, Bandiera F, Meng X, Silverberg SJ, Shi Y, Mishra SK, Griz L, Macedo
carpal spasm when sphygmomanometer cuff is kept inflated
G, Celdas G, Bandeira C, Bileziakian JP, Rao D. Clinical Presentation of Primary
at a pressure 30 mmHg above systolic blood pressure for 2 Hyperparathyroidism: India, Brazil and China. The Parathyroids; 2nd Ed.
minutes. Chvostek’s sign manifests as twitching of facial muscles California: Academic press;2001:pp375-86.
when the facial nerve is tapped anterior to the ear. 4. Mithal A, Wahl DA, Bonjour JP, Burckhardt P, Dawson-Hughes B, Eisman JA,
El-Hajj Fuleihan G, Josse RG, Lips P, Morales-Torres J. IOF Committee of
Basal ganglia calcification is common and extrapyramidal Scientific Advisors (CSA) Nutrition Working Group. Global vitamin D status
syndromes are seen occasionally. Brittle hair and nails and and determinants of hypovitaminosis D. Osteoporosis Int 2009; 20: 1807-20.

432
 10.8 Disorders of Adrenal Glands

Eesh Bhatia, Vijayalakshmi Bhatia

INTRODUCTION signals from the hypothalamus, ACTH (and hence cortisol) is

The adrenal glands are divided into two major parts: the cortex secreted with a circadian rhythm, being highest in the early
and medulla. In this chapter only function and disorders of the morning and lowest at midnight. Cortisol exerts a feedback
adrenal cortex will be considered. effect both at the level of the pituitary and the hypothalamus.
Thus, a deficiency of cortisol resulting from an enzyme block or
The adrenal cortex secretes three main sets of hormones: the destruction of the adrenal gland leads to an elevation of ACTH.
glucocorticoids (cortisol), mineralocorticoids (aldosterone) and
androgens (dehydroepiandrosterone, DHEA). The steroid Aldosterone
hormones are synthesised from cholesterol through a series of While aldosterone secretion is increased by ACTH in the short-
enzymatically catalysed steps. The enzymes are differentially term, its regulation is predominantly under the effect of the renin-
expressed in differing zones of the cortex. Thus, the outermost
zona glomerula secretes mineralocorticoids, while the
remaining zones (fasiculata and reticularis) secrete cortisol and
androgens. A simplified diagram showing the synthesis of the
adrenal hormones is shown in Figure 1. Cortisol is required for
an adequate stress response, intermediary metabolism and
immune functions. Aldosterone regulates plasma volume, blood
pressure and electrolytes. The adrenal androgens are important
for secondary sexual characteristics in females.
Glucocorticoids
The synthesis of cortisol is regulated by adrenocorticotrophin
hormone (ACTH), which is synthesised and stored in
corticotrophes of the anterior pituitary. The secretion of ACTH
is regulated by three influences: positive signals [from
hypothalamic hormones, corticotrophin releasing hormone
(CRH) and arginine vasopressin (AVP)], extrinsic signals (e.g.
Figure 2: Regulation of hypothalamic-pituitary-adrenal axis.
stress) and negative feedback by cortisol (Figure 2). Through

Figure 1: Adrenal steroid hormone synthetic pathways.

(*StAR: steroidogenic acute response protein; **3 βHSD: 3 β-hydroxysteroid dehydrogenase; ***17 βHSD: 17 β-hydroxysteroid dehydrogenase). 433
 angiotensin system (Figure 3). A decrease in plasma volume Table 1: Aetiology of Cushing’s Syndrome
stimulates the secretion of renin from the juxtaglomerulus
Aetiology Comment
apparatus cells surrounding the afferent arterioles in the kidney.
Renin cleaves angiotensinogen to angiotensin I, which is then ACTH-dependent 80%
converted by the angiotensin converting enzyme (ACE) to Pituitary adenoma Most common aetiology of endogenous
angiotensin II. The latter then stimulates aldosterone release, Cushing’s syndrome; mostly microadenomas
sodium retention and increase in plasma volume. In addition, (<10 mm diameter)
potassium ions directly stimulate the secretion of aldosterone. Ectopic ACTH Small cell carcinoma lung (most common),
bronchial adenoma, bronchial and thymic
carcinoids, medullary thyroid carcinoma,
pheochromocytoma
Ectopic CRH Rare
ACTH-independent 20%
Adrenal adenoma Small, homogeneous tumour
Adrenal carcinoma Large adrenal mass, rapid course, poor
prognosis
Primary adrenal May be micronodular or macronodular
hyperplasia
Oral or parenteral Most common aetiology of Cushing’s
steroids syndrome; cortisol and ACTH are unde-
tectable (in case of most synthetic steroids)
CRH = Corticotrophin releasing hormone; ACTH = Adrenocorticotrophin
Figure 3: Regulation of aldosterone secretion. hormone. The common aetiologies of endogenous Cushing’s syndrome are
pituitary adenoma, ectopic Cushing’s syndrome and adrenal tumours.
Adrenal Androgens
These include predominantly androstenedione and DHEA. They in the neck (buffalo hump). Protein catabolism results in reduced
are relatively weak androgens in comparison to the end muscle mass of the limbs, thinning of the skin, broad (>1cm) and
product, testosterone and consequently have minimal effects reddish-violet striae (Figure 4A), easy bruising without trauma
in males. In contrast, in females, over-secretion can lead to and proximal muscle weakness. These features are important in
virilisation. Adrenal androgens are regulated by ACTH. distinguishing CS from exogenous obesity. Growth retardation
is an important sign in children. Other frequent features, though
HYPERFUNCTION OF THE ADRENAL CORTEX
not specific for CS, include hypertension, glucose intolerance or
Cushing’s Syndrome diabetes, depression and other changes in mood, and hirsutism,
Cushing’s syndrome (CS) was named after Sir Harvey Cushing oligomenorrhoea or amenorrhoea in women. Fungal skin
who described the syndrome in 1912. Excessive production of infections are common. Osteoporosis, most severely affecting the
adrenal glucocorticoids results in a characteristic combination lumbar spine, is frequent and may result in pathological fractures.
of clinical features. Though CS is an uncommon illness, it has a Specific aetiologies of CS have characteristic clinical features.
high morbidity and mortality if untreated. This is mainly due to Cushing’s disease (CD) is more common in females of the age
an increased risk of cardiovascular disease as well as infections. groups 20 to 40 years and the course is often slowly progressive.
Therefore, early diagnosis and treatment is essential. Hyperpigmentation may be noted. Ectopic ACTH syndrome,
Aetiology due to a slow growing malignant tumours, such as small cell
carcinoma lung present with weight loss, marked hyper-
CS results from an excess of corticosteroids, either endogenous
pigmentation, hypokalaemia and muscle weakness. In contrast,
or exogenous. The various causes for CS are shown in Table 1. In
ectopic ACTH syndrome due to a slow growing tumours such
clinical practice, the excessive use of steroids with glucocorticoid
as bronchial carcinoid or cortisol-secreting adrenal adenoma
activity is the most common aetiology of CS (exogenous CS). In
may be indistinguishable from CD. In contrast,adrenal carcinomas
contrast, CS due to endogenous causes is relatively uncommon.
have a rapid course, palpable abdominal mass and, in case of
Certain medical conditions, such as depression, alcoholism, females, may lead to virilisation.
severe obesity and pregnancy may closely mimic clinical
Diagnostic evaluation
features of CS (‘pseudo-Cushing’s’). This occurs as a result of
activation of the hypothalamic-pituitary-adrenal axis and The diagnostic evaluation of CS is done in two parts. First, the
increased secretion of CRH. In such conditions, the levels of diagnosis is confirmed and then the aetiology determined
cortisol are elevated and other diagnostic tests may also be (Figure 5). To confirm the diagnosis of CS, cortisol levels in
falsely positive. The features of CS remit with the resolution of serum, urine or saliva are measured. Alternatively, testing for
the basic medical problem. the lack of suppression of serum or urine cortisol after supra-
physiological doses of dexamethasone is utilised. Unfortunately,
Clinical features no single test is more than 95% sensitive, and hence a battery
The clinical features of CS result from the effects of excessive levels of tests needs to be conducted. Screening tests include the
of glucocorticoids on the body. There is an increased body fat, overnight 1 mg dexamethasone suppression test, 24-hour urine
mainly in a truncal distribution: marked central obesity with cortisol and midnight salivary cortisol (not commonly available
434 abdominal fat, rounding of face (moon face) and fat deposition in India) (Figure 5). The 2-day low-dose dexamethasone
 Disorders of Adrenal Glands
Figures 4A to C: Clinical features of adrenocortical disorders. (A) Broad violaceous striae in a patient with Cushing’s disease; (B) Addison’s disease: hyperpigmentation
of the hands; (C) Addison’s disease: hyperpigmentation of gums and buccal mucosa).

suppression test (0.5 mg 6 hourly over 48 hours followed by performed. In case a pituitary adenoma is clearly visible no
serum cortisol measurement) is often used as a confirmatory further tests are required (Figure 6). However, if no tumour is
test. Recent guidelines suggest that at least 2 of the above 4 seen, the best option is to proceed to inferior petrosal sinus
tests need to be positive to diagnose CS. sampling to directly measure ACTH secretion from the pituitary,
preferably after injecting CRH intravenously. If ACTH is higher
To determine the aetiology of CS, plasma ACTH levels are in either petrosal sinus compared to a peripheral vein, this
measured. In case plasma ACTH is undetectable (<10 pg/mL) a suggests a pituitary aetiology. On the other hand, if there is no
CT scan of the adrenal glands is performed for an adrenal gradient it indicates an ectopic ACTH source. A CT of the chest
tumour (Figures 6A to C). If ACTH is elevated or normal, the and abdomen can then be performed to visualise any tumour.
most likely aetiologies are a pituitary adenoma or ectopic ACTH Alternatively, since petrosal sinus sampling can only be
syndrome. In this case, an MRI of the pituitary with contrast is performed in advanced referral centres, in many centres if a

Figure 5: Approach to a patient with Cushing’s syndrome.

*Screening tests: Overnight dexamethasone suppression test (8 am cortisol >1.8 μg/dL after 1 mg of dexamethasone at midnight); 24 hours urine cortisol >50 mg.
Confirmatory test: 48 hours dexamethasone suppression test (serum cortisol >1.8 μ g/dL after 0.5 mg dexamethasone 6 hourly for 2 days). **DHEA-S =
Dehydroepiandrostenedione; ***IPSS = Inferior petrosal sinus sampling (for ACTH).
435
 Figures 6A to C: Radiological features in adrenal disorders. (A) T1- weighted MRI image of microadenoma of the pituitary [arrows]; (B) Contrast CT scan of right
adrenal adenoma [arrow]; (C) Contrast enhanced CT scan of bilateral adrenal tuberculosis [asterix].

pituitary MRI does not show an adenoma, a CT scan of the chest/ Other Aetiologies
abdomen is directly performed. Detailed evaluation of CS is a The treatment for ectopic ACTH syndrome involves surgical
specialised task and is best carried out by an experienced removal of the neoplasm or, if not feasible, chemotherapy or
endocrinologist in a referral hospital. radiotherapy of the primary tumour. Adrenal adenomas are
cured after unilateral adrenalectomy. In contrast, the prognosis
Management of adrenal carcinoma is poor. Treatment involves resection of
Cushing’s disease the tumour and then treatment with mitotane (o,p’-DDD), an
Different modes of treatment include trans-sphenoidal adrenolytic agent.
resection of the tumour, bilateral adrenalectomy, focused
PRIMARY ALDOSTERONISM
radiotherapy and medical treatment with drugs which block
adrenal steroidogenesis. The primary treatment modality is Excessive aldosterone production by the adrenal cortex results
trans-sphenoidal surgery with an operating microscope using in a syndrome characterised by hypertension, hypokalaemia
a sub-labial or transnasal approach. This should always be and metabolic alkalosis, known as primary aldosteronism (PA).
performed by a neurosurgeon experienced in this technique This needs to be differentiated from the more common
so as to obtain optimum results. Since most patients harbour secondary aldosteronism, where the stimulus to aldosterone
microadenomas (size <10 mm), a complete resection is feasible production is an increased rennin secretion due to causes such
without damaging the normal pituitary. Immediate remission renal artery stenosis or malignant hypertension.
rates are close to 70% to 90% while long-term remission is 60% Prevalence
to 70% in most centres. Undetectable postoperative cortisol (< Earlier studies reported that less than 1% of patients with
1.8 µg/dL) shortly after surgery suggests greater chance of long- hypertension who were screened by presence of hypokalaemia
term remission. Patients need to be on life-long follow-up since had PA. More recently, studies in certain series of hypertensive
relapses of the disease (15% to 20% over 10 years), as well as patients, suggest that more than 10% are secondary to PA.
new pituitary hormone deficiencies, may occur at any time
point. In case of failure of initial surgery or relapse, a repeat trans- Aetiology
sphenoidal surgery is attempted or bilateral adrenalectomy or Causes of PA are shown in Table 2. An important treatable cause
pituitary radiotherapy can be utilised. of PA is a unilateral aldosterone-producing adenoma (Conn’s
Bilateral adrenalectomy is nearly always successful in Table 2: Aetiology of Aldosteronism
the treatment of CD. However, the morbidity and mortality Aetiology Comment
of the surgery is significant and life-long replacement with
glucocorticoids and mineralocorticoids is necessary. In addition, Primary
the pituitary tumour may increase in size after surgery and lead Adenoma Small homogeneous tumour
to elevated ACTH, hyperpigmentation and local tumour invasion Carcinoma Very uncommon
(Nelson’s syndrome) in nearly 15% to 20%. Fractionated external Hyperplasia Common; may be unilateral or bilateral
beam radiotherapy or stereotactic radiosurgery is effective in Familial hyperaldosteronism Autosomal dominant; type I is also
reducing ACTH levels but the effect is slow. Control can be (types I and II) known as glucocorticoid remediable
aldosteronism
achieved in approximately 50% to 60% within 5 years. Side effects
Miscellaneous Both aldosterone and PRA are low
such as hypopituitarism are frequent and occasionally damage
(ingestion of licorice)
to adjoining structures can occur. Finally, medical therapy with
drugs such as ketoconazole or metyrapone (not available in India) Secondary
can be utilised to block adrenal steroidogenesis. While the drugs Malignant hypertension, Both PRA and aldosterone elevated
renal artery stenosis
are effective, they have numerous side-effects and are frequently
used for only for short-term control, such a prior to surgery or PRA = Plasma rennin activity; aldosterone secreting adenoma and adrenal
436 hyperplasia are most frequent causes. All other aetiologies are rare.
awaiting the results of radiotherapy.
 Disorders of Adrenal Glands
syndrome). Such adenomas are commonly unilateral, benign years, family history of early-onset hypertension, associated
and less than 2 cm in diameter. Aldosterone secreting carcinomas hypokalaemia or association with early cardiovascular events.
are very rare. Cortical nodular hyperplasia of the adrenal gland is A flow chart for confirming the diagnosis is shown in Figure 7.
far more common than an adenoma. The hyperplasia may be The best screening test is the ratio of plasma aldosterone
unilateral or bilateral. Hereditary forms of hyperaldosteronism (in ng/mL)/plasma renin activity (in ng/mL/hour). Before
(familial aldosteronism types I and II) are autosomal dominant performing this test drugs such as diuretics, angiotensin
disorders. The former is also known as glucocorticoid- converting enzyme inhibitors and angiotensin receptor
remediable aldosteronism and can be ameliorated by small blockers should be stopped for four weeks. An elevated value
doses of glucocorticoids. (>30) is highly suggestive of PA. A high ratio should be followed
a confirmatory test for PA, which aims to assess non-suppression
Clinical Features
of aldosterone after salt loading and increasing plasma volume.
Patients present with sustained hypertension, which may be Once PA is confirmed, a CT scan of the adrenals is performed. In
severe. The hypertension may require two or more drugs for its case a single adenoma is visualised, and the patient is <40 years
control. Hypokalaemia and/or increased urine potassium of age, surgery can be advised. In all other cases (bilateral
excretion is found in one-third of patients with PA (more adenomas, hyperplasia) if surgery is desired, it is recommended
commonly in adenomas). Hypokalaemia may be associated with that bilateral adrenal venous sampling for aldosterone should
muscle weakness (and in severe cases can lead to periodic be performed to determine the side of aldosterone production.
paralysis), polyuria and mild hyperglycaemia. The frequency of This last test carries some risk of haemorrhage into the adrenal
cardiovascular accidents and hypertensive cardiomyopathy are gland and requires special expertise.
higher in PA when compared to essential hypertension,
Management
probably due to the adverse effects of high aldosterone on
target tissue. In case of adenoma or unilateral hyperplasia, a unilateral
adrenalectomy, performed laparoscopically, improves both
Diagnosis hypokalaemia and hypertension. However, hypertension which
The diagnosis should be suspected in patients with severe is long-standing, or requiring more than 2 drugs for control prior
hypertension, poor control with 2 or more drugs, onset <30 to surgery, may persist though control will improve. If medical

Figure 7: Approach to a patient with suspected primary aldosteronism.

*Screening test: Morning plasma aldosterone (measured in ng/mL) and plasma renin activity (measured in ng/mg/hour) ratio >30; **Confirmatory test: Infusion of 2 litres
of 0.9% saline over 4 hours; serum aldosterone >10 ng/dL. (not to be performed in uncontrolled hypertension or cardiac impairment).
437
 therapy (bilateral lesions, patient preference) is opted for, tumours can be followed up by CT scan and by functional assays
mineralocorticoids receptor blockers (spironolactone, after six months and then annually for 4 to 5 years for any change
eplerenone) and potassium-sparing diuretics (triamterene, in size. If their size increases they should undergo surgery.
amiloride) are effective.
ADRENAL INSUFFICIENCY
ASYMPTOMATIC ADRENAL MASSES
Adrenal insufficiency (AI) can result from either destruction of
In recent years, due to the easy availability of ultrasound and both adrenal cortices (primary AI) or from a deficiency of ACTH
CT imaging, adrenal masses are often detected incidentally (secondary AI). Patients with primary AI (Addison’s disease) may
(‘incidentaloma’). In autopsy studies, the frequency of adrenal present acutely in shock (adrenal crises) or more indolently, with
adenomas is 6%, with an increasing prevalence with age. The increased pigmentation, weakness and postural hypotension.
prevalence of adrenal carcinoma, however, is low. The Once diagnosed, the disease has an excellent prognosis with
management of such masses depends upon the evidence of appropriate replacement of steroids and most patients have a
malignancy at other sites, the functional activity of the tumours normal life-expectancy.
and their size and radiological characteristics (Figure 8).
Prevalence
For the evaluation of such masses, screening for functional
tumours (urine or plasma metanephrines, overnight 1 mg The overall prevalence of AI (primary, secondary due to
dexamethasone suppression test for cortisol) should be hypothalamic and pituitary tumours, and congenital adrenal
performed. In addition, in case the patient is hypertensive, the hyperplasia) is approximately 5 per 10,000. The prevalence
ratio of plasma aldosterone to plasma renin should be of Addison’s disease in Western countries, primarily of
measured. If the mass is found to be functionally active, it should autoimmune aetiology, is 125 to 280 per million. However, its
be undergo resection. In case it is non-functional, in subjects prevalence in India is not known.
with evidence of malignancy elsewhere, fine needle aspiration
Aetiology
cytology (FNAC) to rule out a metastatic lesion should be
performed. In addition, if an infective aetiology (tuberculosis, AI develops after approximately 90% of the adrenal cortex is
histoplasmosis) is suspected, FNAC and other relevant tests destroyed. In Western countries the most common aetiology is
should be undertaken. In other cases the radiological an autoimmune destruction of the adrenal cortex (Table 3).
characteristics of the mass should be considered. Masses >4 cm However, in developing countries such as India, infectious
in diameter, having an irregular margin, heterogeneity or non- disorders such as tuberculosis constitute nearly half the cases.
enhanced CT scan attenuation >10 Hounsfield units have a Less frequently encountered are fungal infections, mainly
greater chance of malignancy and should be removed. Other histoplasmosis.

Figure 8: Approach to a patient with incidentally detected adrenal mass.

438
 Disorders of Adrenal Glands
Table 3: Aetiology of Adrenal Insufficiency important for central tolerance. APS type 2 consists of AI,
autoimmune thyroid disease and/or type 1 diabetes. It is far
Aetiology Comment
more frequent than APS 1.
Primary
Clinical Features
Autoimmune Frequency 80-90% in industrialised
nations, approximately 50% in Indians Acute AI can result from overwhelming sepsis, most commonly
Infections due to Neisseria meningitides (Waterhouse-Friderichsen
Tuberculosis Frequency 50% in Indians syndrome), oral anti-coagulants, bilateral thrombosis of the
Fungal Histoplasmosis adrenal veins or the phospholipid syndrome. Patients present
Viral (HIV-AIDS) Cytomegalovirus with abdominal pain and unexplained shock which is
Adrenomyeloleucodystrophy X-linked, males involved, associated unresponsive to fluids or vasoconstrictors, hyperkalaemia,
and adrenoleukodystrophy neurological degeneration, accumu- hyponatraemia and metabolic acidosis.
lation of very long chain fatty acids
Malignancy Lymphoma, metastases Chronic AI is far more common than acute adrenal failure.
Infiltration Haemochromatosis, amyloidosis,
Patients present with lassitude, weakness, weight loss and
sarcoidosis postural hypotension of variable duration. Abdominal
Haemorrhage Septicaemia, antiphospholipid complaints (vomiting, pain) may be prominent. Hyper-
syndrome pigmentation of the skin (palm creases, nipples, and nails) and
Secondary
oral mucosa (gums, buccal mucosa, and tongue) is characteristic
Pituitary and hypothalamic –
(Figures 4B and C). In patients with an autoimmune aetiology,
tumours, infiltration, surgery, skin pigmentation and vitiligo may coexist. Evidence of other
radiation, haemorrhage autoimmune disorders (hypothyroidism, Graves’ disease,
Steroid withdrawal Common after prolonged supra- premature ovarian failure, coeliac disease) may be present or
physiological steroids usage develop subsequently. Androgen deficiency may be apparent
in females leading to loss of pubic and axillary hair and decrease
Autoimmune and tubercular aetiologies are equally common in Indians; all
other aetiologies of primary adrenal insufficiency are uncommon. in libido. Some patients may present in acute adrenal crises after
a predisposing illness or stress.
Autoimmune AI may occur independently or be associated with Diagnosis
other disorders of organ-specific autoimmunity, (known as Routine tests reveal hyponatraemia, hyperkalaemia and mild
autoimmune polyglandular syndromes, APS). APS type 1 metabolic acidosis. The diagnosis is confirmed by the
consists of mucocutaneous candidiasis, hypoparathyroidism measurement of serum cortisol after stimulation with 250 ug
and AI. Multiple other autoimmune disorders are frequent. APS of intramuscular synthetic aqueous 1 to 24 ACTH (Synacthen®)
type 1 results from recessive mutations in the autoimmune (Figure 9). A serum cortisol <18 µg/dL, measured 30 or 60
regulator gene (AIRE) which codes for a transcription factor minutes after ACTH injection, indicates inadequate adrenal

Figure 9: Approach to a patient with adrenal insufficiency.

* Other causes: see Table 3
439
 function. A simultaneous plasma ACTH sample is elevated, Stress doses: Stress doses should be emphasised in all patients
usually >100 pg/mL. To determine the aetiology of Addison’s with AI. In less severe forms of stress (fever, infections and
disease, a CT scan or MRI of the adrenal glands is performed. surgery under local anaesthesia) the dose of the glucocorticoid
In the case of infections such as tuberculosis and should be increased to 2 to 3 times of daily dose for the duration
histoplasmosis, one or both adrenal glands are usually of the stress. In case of severe stress (e.g. surgery under general
enlarged, heterogeneous and with calcifications. In case of anaesthesia, severe infections, major accident) higher doses
normal or atrophic glands, adrenal antibodies may be of glucocorticoids should be provided parenterally. A dose
measured, but this test is not available in India. Thyroid of hydrocortisone 150 to 200 mg/day in four equal doses
function should be tested at onset in patients suspected to intramuscular or intravenous should be given initially, and
have an autoimmune aetiology. gradually tapered when the stress subsides. All patients should
be provided an identification card to keep, which provides
Management information on their disease and emergency measures in case
Acute AI of crises. Their family members should be taught to inject
If strongly suspected, it is not necessary to confirm the diagnosis hydrocortisone or dexamethasone if required.
of the illness prior to starting treatment when the patient is Glucocorticoid-Induced Adrenocortical Deficiency
critically ill. A random sample for cortisol can be obtained and Prolonged glucocorticoid use, whether for therapeutic
parenteral fluids and steroids are immediately started. reasons, intention abuse, or inadvertently due to spurious
Replacement with normal saline or dextrose-saline should be admixture with other drugs, leads to suppression of the
started at a fast rate, and monitored closely. Parenteral hypothalamo-pituitary-adrenal (HPA) axis and adrenal
hydrocortisone 100 mg intravenously and should be followed cortex. This is most likely to occur with use of more potent
by 8 to 10 mg/hour hydrocortisone by continuous intravenous glucocorticoids which have longer duration of action, e.g.
infusion. In case it is not feasible to give intravenous steroids by dexamethasone, high doses, prolonged use and oral/
infusion, intravenous or intramuscular hydrocortisone should parenteral administration. It is unlikely after inhalational or
be given in a dose of 50 mg 6 hourly. The precipitating cause topical steroids, though rare instances of adrenal insufficiency
must be sought and appropriate treatment, e.g. antibiotics have been noted. The use of prednisolone in doses of more
should be instituted. Once the patient is recovering the dose thant 20 to 30 mg/day for more thant 1 week, or in lower
of hydrocortisone can be gradually tapered and oral doses for less thant 1 month, is likely to lead to significant
hydrocortisone or prednisolone can be substituted. Once the suppression. However, glucocorticoids in physiological
dose of hydrocortisone is <50 mg/day, fludrocortisone in a daily amounts (prednisolone <5 mg/day, hydro-cortisone 15 to 20
dose of 0.1 mg should be added. mg/day), especially if given early morning, are unlikely to lead
Chronic AI to adrenal cortical suppression.
Patients with long-standing AI require replacement with both A small proportion of patients who receive prolonged high
glucocorticoids and mineralocorticoids. The glucocorticoids doses of glucocorticoids may develop clinically apparent
commonly used are hydrocortisone (12 to 15 mg/m2 in two or secondary AI if the steroids are withdrawn abruptly. This is
three divided doses) or prednisolone (2.5 to 5 mg/day in two most likely to occur in the setting of acute stress such as
divided doses). The larger portion of the steroid is taken as early infection, serious injury or major surgery. The AI occurs due to
in the morning as feasible and second dose at 2 to 4 pm. suppressed levels of ACTH, as well as due to an inability of the
Hydrocortisone tablets may be difficult to procure in some cities. atrophied adrenal gland to respond to ACTH (Figure 2). Such
The dose of steroids should be adjusted depending upon patients, despite having certain physical features of CS due to
features of under-replacement (weight loss, lack of energy and chronic steroid excess, present with many of the signs and
increasing pigmentation) or over-treatment (weight gain, striae, symptoms seen in primary AI. However, they are not
and hypertension). The dose of fludrocortisone is 0.05 to 2.5 hyperpigmented. Serum cortisol is low or undetectable
mg/day taken as a single morning dose. The dose can be (except if the patient is ingesting hydrocortisone or
adjusted depending upon blood pressure, oedema and prednisolone) and plasma ACTH is also suppressed. The
electrolytes. A normal salt intake is advised, but salt and response of serum cortisol after injecting 250 ug soluble 1 to
fludrocortisone dose may need to be increased in summer 24 ACTH (rapid ACTH stimulation test), or after insulin
months. Replacement with adrenal androgen, DHEA, may be hypoglycaemia, is subnormal. The former test can be used to
useful in some women with features of androgen deficiency monitor the recovery of the HPA axis.
such as dry itchy skin and loss of libido.
As a general principle, the smallest dose of glucocorticoids
The aetiology of AI should be sought and treated. While there should be used for the shortest period of time to obtain a
is no specific treatment known to reverse features in patients required therapeutic effect. The steroid should be given as a
with an autoimmune (idiopathic) aetiology, these patients single dose in the morning or on alternate days, if feasible. It
need to be tested at onset and subsequently at yearly intervals should be tapered to physiological doses (<5 mg/day
for development of autoimmune thyroid disorders (hypo- prednisolone or 10 to 12.5 mg/m2 hydrocortisone/day) as
thyroidism or Graves’ disease). Other organ-specific auto- soon as feasible to allow the HPA axis to recover and then
immune disorders develop less frequently, but should be kept stopped. The problems which may arise on tapering
in mind. Infectious causes (tuberculosis, histoplasmosis) should glucocorticoids include flare up of the original illness and
be appropriately treated, though recovery of adrenal function adrenal insufficiency. Overall recovery of the HPA axis may
440
after treatment is unlikely. take weeks to >1 year and is longer with a higher dose and
 Disorders of Adrenal Glands
longer duration of treatment. For higher doses given for vomiting, lethargy and hypotension and may be mistaken
prolonged periods, it is recommended that glucocorticoid for ordinary diarrhoeal episodes. The typical electrolyte
be withdrawn over weeks or months. The dose can be pattern of hyponatraemia, hyperkalaemia and metabolic
reduced weekly or two weekly by 10 mg if the daily dose of acidosis should alert the physician. Untreated, salt-wasting
prednisolone is >30 mg, and 5 mg once the daily dose is <30 CAH is associated with morbidity and mortality. Further, in
mg. After a dose of <20 mg/day is reached slower reduction, childhood, the effects of postnatal adrenal androgen
e.g. by 2.5 mg every 2 to 4 weeks, can be done. After reaching production result in peripheral precocious puberty in boys
physiological doses, the glucocorticoid can be given on and heterosexual precocity or virilisation in a girl. Certain
alternate days, thus allowing the HPA axis to recover faster. mutations of the CYP 21A gene give rise to a mild variety of
At this time, the adrenal recovery should be studied by disease called late onset congenital adrenal hyperplasia
measuring the basal cortisol or more accurately by using the (LOCAH). This presents in the peripuberted age with
short ACTH stimulation test (described earlier). An 8 am hirsutism, menstrual irregularity, anovulation and, less
serum cortisol or stimulated cortisol of >20 ug/dL, suggests commonly, male pattern scalp hair loss, muscular habitus and
normal adrenal function and glucocorticoids can be clitoromegaly.
discontinued. Testing may have to be done on more than one
occasion until recovery is documented. Diagnosis
The diagnosis of classic 21 hydroxylase deficiency is made by
CONGENITAL ADRENAL HYPERPLASIA measurement of serum 17 OHP or its urinary metabolite
As discussed earlier, the production of adrenal steroids pregnanetriol. Serum 17 OHP is >10,000 ng/dL and plasma renin
requires numerous enzymes, several belonging to the activity is elevated. Supportive tests include electrolytes and
cytochrome P450 family (see Figure 1). When any of these blood gas analysis. LOCAH on the after hand, has lower levels
enzymes is deficient (e.g. due to a genetic mutation), cortisol of 17 OHP, necessitating stimulation by ACTH to establish a firm
production is decreased and there is release of the negative diagnosis. Basal 17 OHP (done at 8 to 9 AM) is usually > 200 ng/
feedback on the corticotrophs of the pituitary. The resulting dL and stimulated 17 OHP ranges from 1500 to 2000 ng/dL.
elevated ACTH drives growth of the adrenal glands (causing
Treatment
hyperplasia) as well as hyperfunction of several enzymes in
steroid synthesis. Biochemical precursors proximal to the This is aimed at replacing cortisol, with hydrocortisone or
enzymatic block are massively elevated and shunted prednisolone, which will also bring about the suppression of
into the pathways which may have a block, such as the precursors and thereby androgen formation. Simultaneously,
mineralocorticoid or androgen pathways. This gives rise to fludrocortisone is administered. Added salt must be provided
typical clinical characteristics as well as a diagnostic steroid in the first year of life, till the baby starts getting salt from table
profiles in serum and urine. foods.
21-Hydroxylase Deficiency Treatment of LOCAH includes glucocorticoids for suppressing
Deletions or mutations in the CYP 21A gene encoding the androgen and bringing about ovulation. Spironolactone may
21 hydroxylase enzyme are responsible for 95% of congenital be added to give better relief of hirsutism and estrogen –
adrenal hyperplasia (CAH). It is a relatively common genetic progesterone pills may be needed for regularisation of
disorder, with a worldwide prevalence of approximately menstrual cycles.
1:15,000 births. It is characterised by deficiency of cortisol. Other CAH
Proximal to the block, the elevated serum precursor 17
P450 oxido-reductase deficiency is the latest in the list of
hydroxyprogesterone (17 OHP), is shunted into the androgen
P450 enzyme mutations that can cause a disorder of sexual
pathway to produce excess of dehydroepiandrosterone,
differentiation. Other enzyme deficiencies include 3 β hydro-
androstenedione and testosterone. The latter brings about
xysteroid dehydrogenase, 11 hydroxylase and 17 hydroxylase.
virilisation of the female foetus in utero, and virilisation in The last two may cause hypertension as well cortisol
both genders postnatally. Thus, the labia in a female newborn deficiency.
may resemble a scrotum, the clitoris may resemble a small
penis, and the perineum may be partially or completely RECOMMENDED READINGS
fused, obliterating the external vaginal opening. In the most 1. Arlt W. The approach to the adult with newly diagnosed adrenal
severe degree of masculinisation, the genitalia will resemble insufficiency. J Clin Endocrinol Metab 2009; 94: 1059-67.
those of a completely normal male baby but with apparent 2. Bhatia E, Jain SK, Gupta RK, Pandey R. Tuberculous Addison’s disease: lack
bilateral cryptorchidism. Pigmentation can be appreciated of normalization of adrenocortical function after antituberculous
on the genitalia and nipples in addition to the skin. If the chemotherapy. Clin Endocrinol 1998; 48: 355-9.
enzymatic block is severe, features of mineralocorticoid 3. Biller BMK, Grossman AB, Stewart PM, Melmed S, Bertagna X, et al.Treatment
of adrenocorticotrophin-dependent Cushing’s syndrome: a consensus
deficiency will also be present (salt-wasting variety). In statement. J Clin Endcorinol Metab 2008; 93: 2454-62.
contrast, the simple virilising type does not affect mineralo- 4. Case detection, diagnosis, and treatment of patients with primary
corticoid production much. aldosteronism: an Endocrine Society Clinical Practice Guideline. J Clin
Endocrinol Metab 2008; 93: 3266-81.
Newborn female babies can be diagnosed at birth, due to
5. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice
the abnormal genitalia. However, male babies will only come Guideline. J Clin Endocrinol Metab 2008; 93: 1526-40.
to light during salt wasting episodes which may start from 6. Young WF. The incidentally discovered adrenal mass. N Engl J Med 2007;
about 1 week of age. These are characterised by diarrhoea, 356: 601-10.
441
 10.9 Disorders of Puberty

AC Ammini

INTRODUCTION
Puberty is the transitional period between childhood and
adulthood when rapid linear growth, sexual maturation and
reproduction capacity are attained. It is an extremely important
phase in the physical and psychosocial development for both
girls and boys. Initiation of puberty is brought about by a
complex series of inter-related endocrine events leading
to activation of the hypothalamo-pituitary-gonadal axis
(Figures 1 and 2).
There has been a positive secular trend in adult height since
mid 19th century in most European countries. Adult height is
increased by 1.5 to 2 cm per decade during this period up to
1960. This was believed to be due to improvements in nutrition,
hygiene and health care. During this period, age at menarche
decreased from 17 years to 13 years.
Energy balance exerts a critical influence on puberty and
reproductive functions. The neuroendocrine mechanisms
involved in the coupling between energy homeostasis and
puberty onset are not clear. This possibly involves several
metabolic hormones and neuropeptides, which involve/
interact at the brain/hypothalamic centres regulating
reproduction. Some of the metabolic hormones could be
insulin, leptin and ghrelin. These may act as links between
energy store, like adipose tissue and reproductive system,
indicating if adequate energy stores are present for normal Figure 2: Midcycle positive feedback effect of oestradiol on hypothalamic-
anterior pituitary axis.
reproductive functions.
Kisspeptin (product of Kiss 1 gene) acting through its receptor (G
protein coupled receptor 54) has been shown to have an
important role in the regulation of the gonadotrophic axis and
reproduction. Mutations (in human) and deletions (genetically
targeted mutations in mice) of either Kiss 1 or Kiss 1 receptor
(GPR54) cause hypogonadotrophic hypogonadism. Neurones that
express Kiss 1/Kisspeptin are found in discrete nuclei in the
hypothalamus and other brain areas. Kisspeptin neurones stimulate
gonadotrophin-releasing hormone (GnRH) neurones, the final
common pathway, through which brain regulates reproduction.
Kisspeptin neurones express both oestrogen and androgen
receptors, and these neurones are believed to be direct targets for
the action of gonadal steroids. This may be involved in triggering
and guiding tempo of sexual maturation at puberty, preovulatory
GnRH/LH surge, seasonal control of reproduction, etc. It also has
functions outside the realm of reproductive endocrinology like
in vascular dynamics, metastasis, placental physiology, etc.

PINEAL GLAND
The status of the pineal gland has evolved from ‘the seat of
human soul’ (Descartes, 17th century) to that of a neuroendo-
crine transducer with isolation of melatonin. It transforms the
Figure 1: LH, FSH feedback mechanism.
information about light received from retina to an endocrine
E2 = Oestradiol; Te = Testosterone; LH = Luteinising hormone; FSH = Follicle response by synthesis and release of melatonin. Melatonin is a
stimulating hormone; GN = Gonadotrophin.
442 powerful neurotransmitter which makes the pineal gland, a
 Disorders of Puberty
‘biological clock’. Melatonin also has an antigonadotrophic effect
in most animals. The seasonal changes in the number of hours
per day that melatonin is secreted, mediate the temporal coupling
of reproductive activity to seasonal changes in day length.
Increase in GnRH pulse frequency and amplitude triggers a
cascade of events starting from increase in luteinising hormone
(LH), follicle stimulating hormone (FSH) and sex steroids and
this brings about the manifestations of puberty, both external
(breast development, genital enlargement) and internal (uterus,
ovaries, testes). Pubic hair develops largely through the effects
of androgens secreted by the adrenal glands.
Sexual maturity scoring is used to describe different phases of
puberty. The most widely used description of pubertal events
in boys and girls is that of Marshall and Tanner who examined
groups of English girls and boys as they went through puberty.
The different phases of external pubertal development in girls
are designated as Tanner stages, B1 through B5 for breast
development (Figures 3A and B) and PH1 through PH6 for
pubic hair growth (Figures 4A to E). It takes about 4 years
from B2 (palpable breast bud under the nipple) to adult breast
development. Breast development before the age of 8 years is
considered precocious while no breast development till 13
years of age is considered delayed.

Figures 4A to E: Stages of normal pubic hair development in female.

Pubertal development in boys begins with increase in testicular

size (Figures 5A to E). Later pubic hair appears, penile size
increases and voice breaks. Spermatozoa first become
detectable around 13 to 14 years of age.
TIMING OF PUBERTY
Signs of puberty before the age of 8 years in girls and 9 years
in boys are considered early or premature; while no signs of
puberty till the age of 13 in girls and 14 in boys are defined as
delayed puberty. Diagnostic evaluation is aimed at differentiat-
ing pathological conditions from normal variants. The normal
variants include constitutional delay or acceleration of growth
and development, premature thelarche, premature pubarche
and pubertal gynaecomastia.
In constitutional delay of growth and development, there is
spontaneous pubertal development, more than 2 SD, later than
the mean age at onset of puberty. Growth is slower, but final
adult height is often in the target range.
Premature Thelarche
Breast tissue develops early, sometimes during the first 2 years
of life, occasionally in neonatal period and then persists till the
time of puberty. It is an isolated event without signs of
accelerated growth or skeletal maturation.
Premature Pubarche
It is the development of pubic or axillary hair (before age 8 in
Figures 3A and B: Stages in normal breast development in female [front (A) girls and 9 in boys). The adrenal androgen levels are normal,
and lateral view (A)].
there is no increase in growth and skeletal age is comparable 443
 estimated to be 1 in 5000 to 1:10,000. It follows the normal
sequence of events in pubertal development. The cause
remains unidentified in 40% to 60% of cases, more so in girls.
Lesions in pituitary hypothalamic area (hypothalamic
hamartoma, glioma, astrocytoma, germinoma), internal
hydrocephalus, earlier episodes of meningitis, radiotherapy,
traumatic brain injury, etc. can cause true precocious puberty.
The magnetic resonance imaging of brain is indicated in all
cases of true precocious puberty.

GONADOTROPHIN INDEPENDENT PRECOCIOUS PUBERTY

(PRECOCIOUS PSEUDOPUBERTY)
It starts before and independently of the HPG axis maturation.
Appearance of secondary sexual characteristics is due to the
increased production of sex steroids. HPG axis is suppressed
due to the abnormally elevated sex steroids. Oestrogens
produce isosexual puberty in girls and heterosexual puberty
in boys. Similarly, androgens produce isosexual puberty in boys
and heterosexual puberty in girls. There are several causes for
precocious pseudopuberty including hormone secreting
tumours of the central nervous system, adrenal gland, gonads
and liver; testotoxicosis; McCune Albright syndrome; steroid
biosynthetic disorders, like congenital adrenal hyperplasia.
Germ cell tumours secrete human chorionic gonadotrophin
(hCG) which in turn stimulate LH receptors in testes which
produce testosterone. These tumours can arise from the CNS
(pituitary, pineal), liver, retroperitoneal or posterior mediasti-
num. Gonadal and adrenal tumours produce testosterone.
Familial Testotoxicosis
There is early Leydig cell maturation and testosterone
production due to an activating mutation of the LH receptor.
It is an autosomal dominant disorder, affecting only boys.
Figures 5A to E: Stages in normal genital and pubic hair growth development
in male.
McCune Albright Syndrome
This syndrome manifests with café-au-lait spots, fibrous
dysplasia and follicular cysts with precocious pseudopuberty.
to chronological age or slightly advanced. Premature pubarche The cause is a somatic mutation in the alpha subunit of the G
is to be differentiated from premature adrenarche where protein resulting in pathological over secretion of a variety of
adrenal androgens are elevated, like in congenital adrenal hormones. In addition to precocious pseudopuberty, patients
hyperplasia or androgen secreting tumour. may manifest with hyperthyroidism, Cushing’s syndrome or
Pubertal Gynaecomastia increased growth hormone secretion.
Some degree of gynaecomastia can be observed in over Congenital adrenal hyperplasia is the most common cause for
50% of boys. In most cases, it is only a small induration under premature adrenarche. These patients may develop precocious
the nipple which regresses in 6 to 18 months. In some cases, true puberty after starting glucocorticoid therapy.
it is more pronounced and persists longer. In such cases, Absence of puberty could be due to disturbances in hypo-
medical/surgical intervention may be required. Rarely thalamus, pituitary or gonads (Tables 1 and 2). Plasma LH and
pubertal gynaecomastia can be due to increased oestrogen FSH are low when it is pituitary or hypothalamus (hypogonado-
production or other conditions like Klinefelter’s syndrome, trophic hypogonadism), while these are high when there is
partial androgen insensitivity syndrome, true hermaphroditism, primary gonadal failure called hypergonadotrophic hypogona-
etc. dism (Table 3). Sex steroids are low and follicular maturation
Pathological conditions, which lead to early puberty, can be or sperm production does not occur in both situations.
divided into gonadotrophin dependent (true precocious
puberty) or gonadotrophin independent (precocious pseudo- Table 1: Hypothalamic Causes for Absent Puberty
puberty) disorders. Migration disorder of the GnRH neurone (Kallman syndrome)
Disturbances of GnRH secretion
GONADOTROPHIN DEPENDENT EARLY PUBERTY
Mutations of GnRH receptor gene
(TRUE PRECOCIOUS PUBERTY)
Mutations in leptin/leptin receptor gene
It is initiated by premature activation of hypothalamo-pituitary-
Mutations in Kiss 1/GPR54 gene
444 gonadal (HPG) axis and is more common in girls. Prevalence is
 Disorders of Puberty
Table 2: Pituitary Causes for Hypogonadism (Congenital or Primary amenorrhoea in a girl with normal secondary sexual
Acquired) development should raise the possibility of congenital
malformation of the genital tract (Müllerian duct). Cases of
Congenital
complete androgen insensitivity also present with primary
Mutations in pituitary transcription factors
amenorrhoea with normal breast development. Absence of
Mutations of the gene for LH or FSH subunit
pubic and axillary hair, and the presence of gonads in the labia
Mutations of LH or FSH receptor gene
are clues to diagnosis of this syndrome.
Congenital midline defects
Acquired Children with disorders of sexual development also have
Tumours of the hypothalamic pituitary region problems of pubertal development. Congenital adrenal
Pituitary surgery/radiation hyperplasia (CAH) is the most common cause for disordered
Hypophysitis and infiltrative disorders sexual development in girls. Appropriately treated children
Post-traumatic enter puberty normally. However, some girls, especially those
with simple virilising forms of CAH who did not receive medical
attention during neonatal period, may present at puberty with
Table 3: Causes of Hypergonadotrophic Hypogonadism
masculinisation and primary amenorrhoea. 46 XY disorder of
Girls Boys sexual differentiation (DSD), e.g. partial androgen insensitivity
Turner’s syndrome and variants Klinefelter’s syndrome syndrome, disorders of testosterone biosynthesis, gonadal
Pure gonadal dysgenesis Disorders of testosterone dysgenesis, etc. will also require appropriate treatment for
biosynthesis proper pubertal development. It is a bigger challenge in our
Damage to ovaries Testicular damage country as many of these may not have been diagnosed or
– Oophoritis – Radiation treated during childhood.
– Radiation – Chemotherapy
– Chemotherapy – Torsion RECOMMENDED READINGS
– Surgical ablation – Trauma 1. Blakemore SJ, Burnett S, Dahl RE. The role of puberty in the developing
adolescent brain. Hum Brain Mapp 2010;31:926-33.
Absence of signs of puberty (breast development in girls or 2. Lehman MN, Merkley CM, Coolen LM, et al. Anatomy of kisspeptin neural
testicular volume less than 3 mL in boys) by 15 years requires network in mammals. Brain Res 2010; 1364:90-102.
evaluation. The major cause still will be constitutional delay in 3. Stukenborg JB, Colo’n E, Soder O. Ontogenesis of testes development
growth and development. and function in humans. Sex Dev 2010;4:199-212.
4. Topaloglu AK, Kotan LD. Molecular causes of hypogonadotropic
Functional hypothalamic hypogonadism refers to a reversible hypogonadism. Curr Opin Obstet Gynecol 2010;4:264-70.
dysfunction usually associated with anorexia nervosa, severe 5. Walvoord EC. The timing of puberty: Is it changing? Does it matter? J
emotional stress or participation in intense physical training. Adolesc Health 2010; 47(5):433-9.

445
 10.10 Disorders of Growth and Development

Nalini S Shah

Growth is a unique and complex process that is affected by one hand with gentle pressure over the knees.With the other hand,
multiple factors. However, children normally grow in a remarkably foot piece is slided to rest firmly against the soles of the feet which
predictable manner. Deviation from a normal growth pattern can are flexed perpendicular against the foot piece (Figure 1B). After
be the first manifestation of a wide variety of disease processes, 2 to 3 years of age, height should be measured on a wall-mounted,
including endocrine and non-endocrine disorders. well-calibrated ruler with an attached horizontal measuring bar
fixed at 90 degrees [e.g. a stadiometer (Figure 1C)]. The child should
Clinical assessment using parameters like height measurement,
stand erect with the back of the head, back, buttocks area and heels
growth velocity, use of appropriate growth charts, mid-parental
touching the vertical bar of the stadiometer; the horizontal
height, body proportions and stage of puberty can generate
measuring bar is lowered to the child’s head to obtain the
valuable clues for differential diagnosis of growth disorders.
measurement (Figure 1D).The height can be expressed as standard
MEASUREMENT OF HEIGHT deviation scores (SDS or Z scores). Z score is calculated using the
formula: (Child’s height – mean height for age from a reference
Accurate serial height measurements documented over time
chart) ÷ 1 SD of height for that age and sex in the reference chart.
on a growth chart are important for the diagnosis of growth
The Growth Monitoring Guidelines Consensus Meeting of the
abnormalities. During first 2 to 3 years of life, length should be
Indian Academy of Paediatrics recommends the use of Agarwal
measured with an infantometer (Figure 1A). It contains a firm
et al, growth charts as reference charts for Indian children.
horizontal platform, an attached yardstick, a fixed head plate, and
a movable foot plate. During measurement, one person supports In addition to height, weight measurement will provide clues
the child’s head and ensures that the head is positioned in the towards the aetiology of short stature. Normal or elevated
Frankfort horizontal plane (lower margin of the bony orbit and weight SDS points towards endocrine disorders like Cushing’s
upper margin of the external auditory meatus in the same syndrome or pseudohypoparathyroidism while low weight SDS
horizontal line).A second person can align the child’s legs by placing points towards systemic illnesses.

Figures 1A to D: (A) Infantometer; (B) Method of measuring length with an infantometer; (C) Stadiometer; (D) Method of measuring height with a stadiometer.
446
 Disorders of Growth and Development
HEIGHT VELOCITY AND GROWTH PATTERN characterised by moving up or down on the growth chart
Assessment of height velocity is an essential part of evaluation which depends on the height of parents so that most children
of a short child. Length of an average Indian child at birth is 50 achieve their genetically determined height percentiles by 2
cm. During infancy, the average height gain is 25 cm reaching years of age. Thereafter, growth typically proceeds along the
75 cm by first birthday. During second year, the growth rate is same percentile until the onset of puberty. Children with
12.5 cm followed by 6 to 7 cm during third and fourth years. constitutional delay of growth and puberty (CDGP) grow at a
After that, the growth rate is approximately 5 cm per year till rate parallel to but below the 3rd percentile, whereas children
pubertal spurt. A growth spurt is observed during pubertal with conditions such as growth hormone deficiency or systemic
period which may be up to 11 cm/year in girls and 12 cm/year illnesses have a growth pattern that progressively falls further
in boys. Average total height gain during the pubertal period is below the 3rd percentile or crosses percentiles. Growth patterns
24 to 25 cm and 27 to 29 cm in girls and boys respectively. The of few common disorders causing short stature are shown in
majority of mean height difference between adult men and Figure 2.
women results partly from the height difference at the age of GENETIC POTENTIAL
pubertal onset, with boys being taller at their later age of takeoff
Most commonly used but a crude method to assess the genetic
than girls and partly from greater gain in height of boys during
potential is to calculate the midparental height (Target height).
the pubertal growth spurt.
The midparental height is a child’s expected adult height based
The growth pattern of a child should be recorded on a growth on the heights of the parents. It is calculated by the formula:
chart to have a longitudinal assessment of growth. Intrauterine average of mother’s height and father’s height plus or minus
environment affects the size of a baby at birth. During first 18 6.5 cm for boys and girls respectively. It is important to measure
to 24 months of life, children pass through an important phase the parents’ heights in the office, rather than use their reported
of growth, often called catch-up or catch-down growth. It is height to avoid over-or underestimation of midparental height.
A rough estimate of the child’s projected height, without taking
skeletal maturation or pubertal tempo into account, can be
determined by extrapolating the child’s growth along his or her
own height percentile to the corresponding 18-year point. If
the estimated final height is within 8 to 10 cm of the midparental
height, the child’s current height is appropriate for the family.
However, if the projected height differs from the midparental
height by more than 8 to 10 cm, a variant growth pattern or a
pathologic cause should be considered.
BODY PROPORTIONS
The evaluation of upper-to-lower body segment ratios in short
children helps to differentiate causes of disproportionate short
stature like skeletal dysplasia from causes of proportionate short
stature. Lower segment is determined by measuring the
distance from the top of symphysis pubis to the floor in a child
standing in erect position. The lower body segment is
subtracted from the child’s height to obtain the upper body
segment value. The upper-to-lower body segment ratio (US:LS
ratio) is then derived by dividing the upper body segment value
by the lower segment value. Body proportions vary with age of
a child. The average US:LS ratio is 1.7 at birth and decreases to
1.3 at 3 years, 1.1 at 6 years and 1.0 at 10 years of age. Children
with achondroplasia have a normal sized trunk with short limbs,
while children with spondyloepiphyseal dysplasias will have
short trunk with normal limbs.
Measuring the arm span is also crucial in the evaluation of body
proportions. The arm span is the distance between the tips of
the left and right middle fingers when a child is standing against
a flat wall with arms outstretched as far as possible, creating a
90 degree angle with the torso. Arm span is shorter than height
by 2.5 cm at birth and equals height by 10 years of age. Children
Figure 2: It Illustrates charting of height and weight of an 8½ years old short with long limbs like Klinefelter’s syndrome and short trunk like
girl (height below 5th percentile line and weight at 25th percentile) marked by
arrows. It also illustrates extension of height percentile parallel to 5th percentile scoliosis may have a disproportionately higher arm span than
line till 18 years of age (black circles) and compares it with mean parental height height.
(MPH) and target height range which helps to differentiate familial short stature
(black circles) from pathological short stature (blue diamonds). The figure also PUBERTAL ASSESSMENT
shows typical growth patterns of a child with constitutional delay in growth Pubertal assessment has an important role in the diagnosis of
and puberty (green circles).
short stature. Onset of puberty is followed by height spurt which 447
 is seen during adolescence. Hence, onset and progression of SHORT STATURE
puberty will affect the stature in the peri- and post pubertal Short stature is defined as height that is two standard deviations
periods. The stage of puberty is assessed by the Tanner’s below the mean height for age and sex (less than the 3rd
method of sexual maturity rating. Orchidometer is used for percentile) or more than two standard deviations below the
accurate measurement of testicular volume. midparental height. A growth velocity disorder is defined as an
abnormally slow growth rate, which may manifest as height
BONE AGE ASSESSMENT
deceleration across two major percentile lines on the growth
Bone age estimation is an important investigation in the chart. Many children with height SDS less than 2 SD may not
evaluation of short child. This is conventionally done from X- be pathological and hence, evaluation for short stature may be
rays of wrist and hand. The bone age is estimated from the limited to children with following features:
appearance of epiphysis, size and shape of bones using
1. Severe short stature [height (Ht) SDS < -3SD)]
Greulich-Pyle atlas or Tanner-Whitehouse method. A child with
2. Severe growth deceleration [height velocity (HV) SDS < -2
delayed bone age has a better prognosis for future height gain
SD over 12 months]
than those with appropriate or advanced bone age. Children
3. Ht SDS < -2 SD and HV SDS < -1SD over 12 months
with familial genetic short stature have bone age appropriate
4. Ht SDS < -1.5 SD and HV SDS < -1.5 SD over 2 years.
for chronologic age whereas CDGP children have slightly
delayed bone age. Children with endocrine causes such as Causes of short stature are listed in Table 1. Table 2 summarises
growth hormone deficiency or hypothyroidism are likely to the points to be focused during history-taking physical
have markedly delayed bone age. Adult height can be predicted examination of a short child. Figure 3 represents an algorithm for
with the help of Bayley-Pinneau charts by using chronologic the evaluation of a short stature. Figures 4A to H shows few children
age and bone age. suffering from one of the common disorders leading to short stature.

Table 1: Causes of Short Stature According to the ESPE Classification

A. Primary Growth Disorders Head trauma
1. Clinically defined syndromes Central nervous system infections
Turner syndrome Granulomatous disease, e.g. histiocytosis
Cornelia de Lange syndrome 4. Other disorders of the growth hormone-IGF axis
DiDeorge syndrome (velocardiofacial syndrome) (primary IGF-I deficiency and resistance)
Down’s syndrome Bio-inactive growth hormone
Noonan’s syndrome Abnormalities of the growth hormone receptor
Prader-Willi-Labhart syndrome (growth hormone insensitivity syndrome)
Neurofibromatosis type 1 Abnormalities of GH signal transduction, e.g. STAT5B defect
Silver-Russell syndrome
ALS (acid-labile subunit) deficiency
2. Small for gestational age with failure of catch-up growth IGF-I deficiency
IGF-I deficiency, IGF resistance IGF resistance (IGF1R defects, postreceptor defects)
Due to known cause, e.g. prenatal infections, drugs, smoking, alcohol
5. Other endocrine disorders
Idiopathic
Cushing syndrome
3. Skeletal dysplasias
Hypothyroidism
Achondroplasia
Leprechaunism
Hypochondroplasia
Diabetes mellitus (poorly controlled)
Dyschondrosteosis (Leri-Weil and other defects in the SHOX gene)
Short adult stature caused by accelerated bone
Osteogenesis imperfecta I-VI
Mucopolysaccharidosis (type IH, IS, II-VII) maturation, e.g. precocious puberty, hyperthyroidism,
Mucolipidosis (type II and III) CAH, exogenous oestrogens or androgens
4. Dysplasias with defective mineralisation 6. Metabolic disorders
Hypophosphatasia Disorders of calcium and phosphorus metabolism
X-linked hypophosphataemic rickets Disorders of carbohydrate metabolism
B. Secondary Growth Disorders Disorders of lipid metabolism
1. Insufficient nutrient intake (malnutrition) Disorders of protein metabolism
2. Disorders in organ systems 7. Psychosocial
Cardiac disorders Emotional deprivation
Pulmonary disorders, e.g. cystic fibrosis Anorexia nervosa
Liver disorders Depression
Intestinal disorders, e.g. Crohn’s disease, malabsorption syndromes 8. Iatrogenic
Short bowel syndrome Systemic glucocorticoid therapy
Renal disorders, e.g. Fanconi syndrome, renal acidosis chronic Local glucocorticoid therapy (inhalation, intestinal, others)
anaemia, e.g. thalassaemia Other medication
3. Growth hormone deficiency (Secondary IGF-1 deficiency) Treatment of childhood malignancy
Idiopathic Total body irradiation
Genetic (HESX1, PROP1, POU1F1, LHX3, LHX4, GHRHR, GH) Chemotherapy
Associated with syndromes of cerebral or facial malformations, e.g. Other specified iatrogenic causes
septo-optic dysplasia, empty sella syndrome
Associated with perinatal conditions, e.g. Rubella C. Idiopathic Short Stature
Acquired (craniopharyngioma, other pituitary tumours, 1. Familial (idiopathic) short stature
448 e.g. germinoma, hamartoma) 2. Non-familial (idiopathic) short stature
 Disorders of Growth and Development
Table 2: Points to be Focused during History-taking and Evaluation of a Short Child
History Comments
Birth size (length, weight, head circumference) To identify small for gestational age
and gestational age (symmetric vs asymmetric)
Birth history (breech delivery, asphyxia, jaundice, hypoglycaemia) Associated with pituitary dysfunction
Previous growth information May provide clues about the aetiology
Onset and progression of puberty Has significant impact on stature
Current and previous medical history Identify organic or iatrogenic causes
Cardiac: dyspnoea, anasarca, cyanosis Cardiac failure, cyanotic heart disease
Pulmonary: chronic cough, dyspnoea Cystic fibrosis, bronchial asthma, tuberculosis
Intestinal: abdominal distension, diarrhoea Malabsorption syndromes like coeliac disease
Renal: polyuria, vomiting, fatigue Chronic kidney disease, RTA
Neurological: headache, vomiting, focal neurological deficits Neurotuberculosis, sellar or perisellar tumours, brain
tumours treated with radiotherapy
Previous surgeries: intestinal resection Short bowel syndrome
Medications like glucocorticoid Glucocorticoid induced growth suppression
Feeding history (feeding difficulties, total calorie Feeding difficulties during first year in PWS and poor
and protein intake) nutrition affects growth (weight > height)
Parental height Required to assess genetic potential to grow
Tempo of puberty in parents To look for familial pattern of delayed puberty
Family history To look for a genetic cause
Delayed milestones, mental retardation Genetic syndromes and metabolic disorders
Social environment To look for emotional deprivation
Physical examination
Underweight Malnutrition, malabsorption, hypocortisolism,
metabolic disorders,SGA
Obesity Hypothyroidism, Cushing’s syndrome, IGF-1
deficiency, Pseudohypoparathyroidism
Microcephaly Birth asphyxia, symmetric SGA, syndromes
Macrocephaly Hydrocephalus, achondroplasia, storage disorders
Short trunk or short limbs Skeletal dysplasias
Dysmorphic features Primary growth disorders (syndromes)
Frontal bossing, mid-facial hypoplasia IGF-1 deficiency
Round facies, facial plethora, virillisation Cushing’s syndrome
Pharyngeal examination Look for adenotonsillar hypertrophy
Bradycardia, dry skin, goiter Hypothyroidism
Hypertension Kidney disease, Cushing’s syndrome
Hepatosplenomegaly Hepatic or metabolic disorder
Pubertal stage Early, normal or late puberty
Micropenis Hypogonadism, hypopituitarism
Fundoscopy, visual field defect Central nervous system pathology
Signs of neglect or abuse Emotional deprivation

MANAGEMENT in these disease states are shown in Table 3. Growth hormone is

Identification and appropriate management of the systemic given as daily subcutaneous injections before bedtime. IGF-1
illnesses improves growth in most of the disorders. Chronic treatment is effective in GH insensitivity.
infections like tuberculosis should be treated with appropriate
(anti-tubercular) medications. Haemolytic anaemias like Table 3: Indications and Doses of Growth Hormone Therapy in
thalassaemia should be treated with regular blood transfusions Children
and iron chelating agents. Gluten free diet is the treatment of Indication Dose of
choice for coeliac disease. Nutritional rickets is treated with GH (mg/kg/wk)
supplementation of vitamin D and calcium. Hypophosphataemic Growth hormone deficiency 0.18 to 0.3
rickets is treated with phosphate supplementation and calcitriol Chronic kidney disease 0.35
while vitamin D dependent rickets are managed with normal to Turner syndrome 0.375
high doses of calcitriol. Distal renal tubular acidosis is treated with
SGA children with failure to catch up growth 0.47 to 0.48
Shohl’s solution and potassium supplementation while proximal
Idiopathic short stature 0.48 to 0.37
renal tubular acidosis is treated with sodium bicarbonate and
Prader Willi syndrome 0.24
potassium supplementation. Hypothyroidism should be treated
Noonan syndrome 0.46
with L-thyroxine. Conditions which have received FDA approval
for growth hormone (GH) therapy and the doses of GH advocated SHOX gene haploinsufficiency 0.35 449
 Figure 3: An algorithm depicting approach to a child with short stature.
*Consider psychosocial dwarfism at any step if features of abuse/neglect are identified; **Only if clinical features are suggestive. CBC = Complete blood count; ESR =
Erythrocyte sedimentation rate; FSH = Follicle stimulating hormone; GH = Growth hormone; IgA tTG: IgA antibodies to tissue transglutaminase; IGF = Insulin-like growth
factor; LDDST = Low dose dexamethasone suppression test; IGFBP3 = IGF binding protein-3; MRI = Magnetic resonance imaging; PO4 = Phosphorous; SD = Standard
deviation; SDS = Standard deviation score.

TALL STATURE
Tall stature is defined as a height that is 2 SD above the mean
for age and sex. Excessive growth could also manifest as height
acceleration across two major percentile lines on the growth
chart. It is important to distinguish the pathological causes from
physiological causes of tall stature.Though only few tall children
have a defined pathology, tall stature or height acceleration may
be the initial manifestation of serious underlying diseases, such
as congenital adrenal hyperplasia. Causes of tall stature are listed
in Table 4 and an algorithmic approach to a tall child is depicted
in Figure 5.

Management of Tall Stature

Reassurance of the family and the patient is the key to the
management of normal variant tall stature. Hypogonadism is
treated by replacement with appropriate sex steroids. For
eugonadal, extremely tall children whose parents feel strongly
about treatment, a trial of sex steroid may be considered.
However, it should be restricted to patients with predicted adult
height more than 3 SD above the mean. Since, sex steroids act
Figures 4A to H: Children suffering from one of the common disorders leading by accelerating puberty and epiphyseal fusion, initiation of
to short stature. therapy in prepubertal or early pubertal phase has better results.
A = Cushing’s syndrome; B = Prader Willi syndrome; C = Primary hypothyroidism; Children with excess GH status are managed with one or more
450 D = Nutritional rickets; E = Growth hormone insufficiency; F = Pseudoparathyro-
of the following modalities of treatment viz, excision of pituitary
idism type 1a; G = Turner syndrome; H = Coeliac disease.
adenoma, somatostatin analogues (Octreotide LAR, Lanreotide),
 Disorders of Growth and Development
Figure 5: An algorithm depicting approach to a child with tall stature.
BMI = Body mass index; DHEAS = Dehydroepiandrosterone sulphate; E2 = Oestradiol; FSH = Follicle-stimulating hormone; GH = Growth hormone; GnRH = Gonadotropin-
releasing hormone; hCG = Human chorionic gonadotropin; IGF-1= Insulin-like growth factor-1; LH = Luteinising hormone; MRI = Magnetic resonance imaging; PGGH =
Post-glucose growth hormone; USG = Ultrasonography.
*The clinical criteria for the diagnosis of Marfan syndrome, which requires a combination of findings in different organ systems.

Table 4: Causes of Tall Stature GH receptor antagonist (Pegvisomant) or radiotherapy.

Suppression of adrenal androgens with appropriate
Foetal overgrowth replacement of glucocorticoids (hydrocortisone, prednisolone
Maternal diabetes mellitus or dexamethasone) with or without mineralocorticoids
Cerebral gigantism (Sotos syndrome)
(fludrocortisone) forms the essential treatment of precocious
Weaver syndrome
Beckwith-Wiedemann syndrome
puberty with congenital adrenal hyperplasia. Central precocious
Other IGF-2 excess syndromes puberty is treated with GnRH analogues (Leuprolide acetate).
Post-natal overgrowth leading to childhood tall stature CONCLUSION
Familial (constitutional) tall stature
Cerebral gigantism Disorders of growth, especially short stature are common
Beckwith-Wiedemann syndrome problems in paediatric age group. Thorough clinical assessment
Exogenous obesity using auxological parameters can lead to correct differential
Excess GH secretion (Pituitary gigantism) diagnosis and hence appropriate evaluation and management.
Precocious puberty Prudent use of endocrine tests can clinch diagnosis in most of
Marfan syndrome the patients. Management options largely rest on correct
Klinefelter’s syndrome diagnosis. Monitoring of therapy with appropriate dosage
Weaver syndrome schedule modification and patient education to ensure
Fragile X syndrome
compliance are keys to long-term success.
Homocystinuria
XYY RECOMMENDED READINGS
Hyperthyroidism
1. Dattani M, Hindmarsh P. Growth hormone deficiency in children. In:
Post-natal overgrowth leading to adult tall stature Jameson LJ, De Groot LJ, editors. Adult and Paediatric Endocrinology; 6th
Familial (constitutional) tall stature Ed. Philadelphia, PA: WB Saunders; 2010: pp 517-40.
Androgen/oestrogen deficiency or estrogen resistance in males 2. Oostdijk W, Grote FK, de Muinck Keizer-Schrama SM, Wit JM. Diagnostic
Testicular feminisation approach in children with short stature. Horm Res 2009; 72: 206-17.
Excess GH secretion 3. Rosenfeld RG, Cohen P. Disorders of growth hormone/insulin like growth
Marfan syndrome factor secretion and action. In: Sperling MA, editor. Paediatric Endocrinology;
Klinefelter’s syndrome 3rd Ed. Philadelphia, PA: WB Saunders; 2008: pp 254-334.
4. Rose SR, Vogiatzi MG, Copeland KC. A general paediatric approach to
XYY 451
evaluating a short child. Paediatr Rev 2005; 26: 410-20.
 10.11 Disorders of Gonads

Shashank R Joshi

Gonadal disorders in females are treated by gynaecologists. Post-pubertal loss of testicular function results in slowly evolving
Hence only gonadal disorders which occur in males are subtle clinical symptoms and signs. In ageing men, these
discussed here. symptoms and signs may be difficult to appreciate because they
are often attributed to ‘getting older’. The growth of body hair
PHYSIOLOGY
usually slows, but the voice and the size of the phallus and
Testosterone is the primary male hormone, not only responsible prostate remain unchanged. Temporal hair recession and
for normal development of the male characteristics and balding usually do not occur and would not be expected to
maintenance of bone and muscle, but also due to its positive prompt a patient to seek medical attention. Patients with
effect on mood, energy levels and sexual drive. Testosterone is hypogonadism may have the following findings (Table 2).
mainly produced in the Leydig cells located in the interstitial
spaces of the testes. Normal adult men produce 4 to 10 mg of Table 2: Post-Pubertal Hypogonadism
testosterone per day in a circadian pattern, with maximal plasma
Progressive decrease in muscle mass
levels reached in early morning and minimal levels in the
Loss of libido
evening. Testosterone is the principal androgen of which 95%
Impotence
is made in testes, 5% in adrenals. It is synthesised from
Oligospermia or azoospermia
cholesterol at approximately 6 mg/day and metabolised by liver
Occasionally, menopausal-type hot flushes (with acute onset of
and excreted in urine. Testosterone can be bioconverted into
hypogonadism)
two other steroids at target tissues—dihydrotestosterone and
oestradiol.
Dihydrotestosterone (DHT) binds more readily to androgen The risk of osteoporosis and attendant fractures is increased.
receptors. Conversion takes place in the prostate, seminal Many cases of hypogonadism are disclosed during the course
vesicles and pubic skin. DHT is 10 times more powerful than of infertility evaluations.
testosterone, thus conversion amplifies the action of Evaluation
testosterone. DHT may be responsible for male pattern baldness A comprehensive history should be elicited and a complete
and benign prostatic hypertrophy. physical examination should be performed to help determine
Oestradiol is an oestrogen of which 25% is made by testes and the cause and extent of the hypogonadism.
75% bioconverted in the liver and the brain from testosterone. History
It is responsible for aggressiveness in men.
Any history of loss of libido, sexual dysfunction, or impotence
HYPOGONADISM should be generally noted. A history of use of medications,
Hypogonadism is defined as ‘inadequate gonadal function, as herbal preparations, or home remedies and any history of
manifested by deficiencies in gametogenesis and/or the possible exposure to oestrogens should be elicited.
secretion of gonadal hormones’. A history of anosmia or hyposmia, midline defects, or
General Manifestations cryptorchidism may be suggestive of Kallmann’s syndrome or
Hypogonadism may manifest with testosterone deficiency, other types of hypogonadotrophic hypogonadism. A family
infertility, or both conditions. Symptoms of hypogonadism history may indicate an underlying genetic basis.
depend primarily on the age of the male patient at the time of Primary testicular failure is usually associated with genetic
development of the condition. Hypogonadism is seldom syndromes such as Klinefelter’s syndrome or congenital
recognised before the age of puberty unless it is associated with disorders such as anorchism. Testicular failure may also be
growth retardation or other anatomic or endocrine abnormalities. associated with a history of testicular trauma, certain surgical
When hypogonadism develops before the age of puberty, the procedures in the area, cryptorchidism, mumps orchitis,
manifestations are those of impaired puberty (Table 1). and, occasionally, toxic exposures, radiation treatment or
chemotherapy.
Table 1: Pre-Pubertal Hypogonadism
A post-pubertal onset of hypogonadotrophic hypogonadism,
Small testes, phallus, and prostate scant pubic and axillary hair
generally manifesting as loss of libido, sexual dysfunction, or
Disproportionately long arms and legs (from delayed epiphyseal
impotence, should suggest the likelihood of a pituitary tumour.
closure)
Indications of other endocrine deficiencies such as central
Reduced male musculature
hypothyroidism or secondary adrenal insufficiency, visual field
Gynaecomastia
disturbances, headaches, or seizures may also be associated
Persistently high-pitched voice
findings.
452
 Disorders of Gonads
Physical Examination Testosterone circulates principally in bound form, mainly to sex
The amount and distribution of body hair, including beard hormone-binding globulin (SHBG) and albumin. It tightly binds
growth, axillary hair, and pubic hair, should be noted, as should to SHBG and is not biologically available, whereas the
the presence of a male pattern escutcheon. (The ethnic origin testosterone fraction associated with albumin is weakly bound
of the patient should be considered in this assessment. Some and can dissociate to free, active testosterone. Only about 2%
communities are more hairy than others). of testosterone is in the free form, 30% is bound tightly to SHBG,
and 68% is weakly bound to albumin.
The presence and degree of gynaecomastia should be recorded.
The presence of galactorrhoea would suggest pronounced Although a testosterone determination is the threshold test in
hyperprolactinaemia. the evaluation of suspected male hypogonadism, the total
testosterone concentration may be within the normal range in
The testes should be measured (length and width) by using a men with primary testicular disorders such as Klinefelter’s
Prader orchidometer or callipers. Some testicular disorders may syndrome. Low production of testosterone stimulates
selectively affect production of sperm without influencing production of SHBG from the liver. Male patients with
production of testosterone. These disorders may sometimes hypogonadism often have high SHBG levels because of
be detected by careful physical examination, including enhanced production of oestradiol from increases in
determination of testicular size and consistency. Because intratesticular aromatisation. Therefore, if the clinical findings
approximately 85% of testicular mass consists of germinal tissue, indicate that hypogonadism is present and the total
a reduced germinal cell mass would be associated with a testosterone levels are normal or borderline low, an SHBG or
reduced testicular size and a soft consistency. Testicular growth free testosterone level should be determined. Free testosterone
is a reliable index of pubertal progression in peri-pubertal boys, assays are method-dependent and may be difficult to interpret.
in whom hypogonadism may frequently be difficult to Because albumin binds testosterone weakly, the amount of free
distinguish from delayed puberty (Table 3). testosterone measured will vary with the technique. Equilibrium
Table 3: Approximate Ranges of Testicular Size
dialysis free testosterone measurements are used to determine
the amount of testosterone not bound to SHBG, but are
Age Testicular Testicular Testicular generally not available.
volume (ml) length (cm) width
Conversely, a low testosterone level may also be misleading
Pre-pubertal 3 to 4 <3 <2
under some circumstances. Slightly subnormal levels of total
Peri-pubertal 4 to 15 3 to 4 2 to 3
testosterone may occur in men with low levels of SHBG and
Adult 20 to 30 4.5 to 5.5 2.8 to 3.3
normal circulating levels of free testosterone. A low SHBG level
Testicular consistency should be noted. If the germinal may be associated with hypothyroidism, obesity, or acromegaly.
epithelium was damaged before puberty, the testes are SHBG or free testosterone levels may be helpful for clarifying
generally small and firm. If post-pubertal damage occurred, the the underlying disorder, especially when the clinical findings
testes are usually small and soft. are not suggestive of hypogonadism.

On examination of the scrotum, the presence of any masses or Gonadotropins

varicocoeles should be noted for further evaluation. For If a low testosterone level has been established, further
assessment of any potentially significant varicocoele, the patient laboratory testing is used to determine whether the
should be asked to perform a Valsalva manoeuvre. hypogonadism is related to a primary testicular disorder
In prepuberty, the length of the stretched penis is about 4 to 8 (hypergonadotrophic hypogonadism) or to pituitary disease
cm, and the width is less than 2 cm in a flaccid state. In the adult, (hypogonadotrophic hypogonadism). The primary feature of
the length of the penis ranges from about 10 to 17 cm, and the hypogonadotrophic hypogonadism is the failure of a reciprocal
width in the flaccid state is more than 3 cm. increase in gonadotropins in the setting of a sub-stantially
decreased testosterone level. In patients with signs and
With prepubertal onset of hypogonadism, the stature may symptoms indicative of hypogonadism, determining luteinising
assume eunuchoidal proportions, with a crown-to-pubis hormone (LH) and follicle-stimulating hormone (FSH) levels
divided by a pubis-to-floor ratio of <1 and an arm span more together with the initial testosterone level in a single sample is
than 6 cm greater than the height. usually most efficient.
Laboratory Investigations
FSH and LH may have variable biologic activity, depending on
Testosterone their carbohydrate content. Unlike standard radioimmuno-
Testosterone levels vary from hour to hour; an overall diurnal assays, highly sensitive, two-site radioimmunometric assays for
rhythm is also present, and the highest levels of circulating gonadotropins yield results that generally correlate well with
testosterone occurring in the early morning hours. Therefore, biologic assays. Because the biologic to radioimmunologic ratio
testosterone levels should be determined in the morning, of activity of gonadotropins may vary in aging and various
and patients with subnormal levels should have repeated disease states, the most accurate results will be obtained with
studies, especially those with no definite signs or symptoms these highly sensitive assays. Assays for gonadotropins currently
of hypogonadism. For a reliable testosterone determination, lack the sensitivity to detect values below the normal range.
use of three pooled morning testosterone samples will Additional studies, such as gonadotropin-releasing hormone
minimise errors attributable to the variation in testosterone (GnRH) testing, by an endocrinologist may help in the further
levels. assessment of these patients. 453
 Both FSH and LH are secreted in short pulses. FSH has a longer within 2 hours. Variability between specimens is common; with
half-life than does LH and is more likely to provide adequate low or borderline samples, follow-up consisting of evaluation
results on a single blood sample. In addition, most patients with of three or more samples should be done during a 3-month
progressive hypogonadism will have increased FSH levels well period. A fertile sample is usually associated with a motility of
before LH levels increase. Because LH has a shorter half-life than more than 50% and a count that exceeds 20 million/mL.
does FSH, errors may be introduced in measurements made on In general, semen volume should range from 1.5 to 6 ml.
single samples. Pooled samples for LH done 20 to 30 minutes Morphologic features should be examined for abnormalities.
apart are more accurate than single-sample determinations
A fructose test should be done on a semen sample showing
(albeit less convenient). Persistent borderline values may be
azoospermia. Because fructose is secreted by the seminal
further evaluated with dynamic endocrine testing. These tests
vesicles, absence of fructose may indicate complete obstruction
may include the GnRH stimulation test, the clomiphene
of the ejaculatory ducts or congenital absence of the vas
stimulation test, and the human chorionic gonadotropin (hCG)
deferens and ejaculatory ducts.
stimulation test. These specialised, dynamic studies should be
conducted and interpreted by an endocrinologist and may have Most often, a semen analysis is done in an otherwise
limited clinical value. asymptomatic man during the course of an infertility evaluation.
Of note, in the evaluation of infertility of a couple, a semen
Dynamic Tests
analysis should be done early to determine appropriate further
GnRH stimulation test evaluation and therapeutic options.
In the GnRH stimulation test, intravenous injection of 100 mg Other Studies
of GnRH causes serum LH levels to increase three-fold to six-
Bone densitometry
fold during a period of 30 to 45 minutes and FSH levels to
increase between 20% and 50%. Various degrees of primary Because hypogonadism frequently results in low bone density,
testicular failure cause higher than expected peak values for osteoporosis, and future increased fracture risk, a baseline
LH and FSH. Men with hypothalamic or pituitary disease may bone densitometry study should be performed to assess the
have a reduced or normal response that is often inadequate initial situation and allow future interventions to be based on
for distinguishing between a pituitary and a hypothalamic any deterioration in bone density that may occur overtime.
disorder. If the pituitary gland is primed with repeated doses of Treatment options to maintain bone mass may include
GnRH, the stimulation test may provide a more sensitive and testosterone therapy, calcitonin, or bisphosphonates, in addition
reliable result. to the standard regimen of calcium, exercise, and vitamin D.
From 1 to 2 years after therapy is initiated, a follow-up bone
Clomiphene stimulation test density study should be done to determine whether bone mass
In the clomiphene stimulation test, 100 mg of clomiphene is being appropriately maintained.
citrate is given for 7 days as an evocative test of the hypothalamic-
Pituitary imaging
pituitary axis. Clomiphene acts by interrupting the negative
feedback loop and thereby stimulating release of gonadotropin In cases of acquired hypogonadotrophic hypogonadism (low
from the pituitary. A doubling of LH and a 20% to 50% increase testosterone with low-normal FSH and LH) not clearly
in FSH are normal results indicative of an intact hypothalamic- attributable to a specific cause, pituitary imaging studies with
pituitary response. MRI or computed tomography may be needed to evaluate for
structural lesions in the hypothalamic-pituitary region. MRI
hCG stimulation test generally provides better pituitary images, but bony changes
Various protocols are used for hCG stimulation testing. In in the sella may be better characterised by computed
general for post-pubertal male patients, a single dose of hCG tomography. In general, MRI done with and without a contrast
(5,000 IU intramuscularly) is administered, and pre-therapy and agent is recommended as the initial pituitary imaging study
72-hour post-therapy testosterone measurements are in patients requiring delineation of a pituitary pathologic
done (some protocols use 1,000 to 4,000 IU of hCG or multiday condition.
dosing). Generally, a post-therapy testosterone level of > 100
Genetic studies
ng/dL is considered normal.
Patients with hypergonadotrophic hypogonadism and
Prolactin level impaired pubertal development associated with small, firm
In men with acquired hypogonadotrophic hypogonadism, who testes and often with gynaecomastia are likely to have
usually have a reduced libido and impotence, a prolactin level Klinefelter’s syndrome or a variant. Classically, a buccal smear
should be determined to evaluate for a prolactinoma or other was done to establish the diagnosis by revealing Barr bodies.
cause of hyperprolactinaemia. About 5% of men who complain Currently it is recommended to do genetic karyotype testing
of impotence will have an increased prolactin level. Further to confirm the diagnosis in a patient with these findings at initial
endocrinological evaluation with magnetic resonance imaging assessment. Fluorescent in situ hybridisation (FISH) studies
(MRI) scanning of the pituitary gland is indicated for increase the sensitivity of detecting Klinefelter’s syndrome
unexplained hyperprolactinaemia. associated with mosaicism.
Semen analysis Testicular biopsy and scrotal exploration
A semen analysis is the primary test to assess the fertility Since the advent of sensitive FSH assays, germinal cell function
potential of the male patient. Semen should be collected by is now most often assessed through the FSH assay alone
454 masturbation after 2 to 5 days of abstinence and evaluated rather than testicular biopsy. In general, however, men with
 Disorders of Gonads
azoospermia, normal FSH levels, and normal testicular size
should usually undergo testicular biopsy and scrotal exploration
to determine whether a germinal cell abnormality, an obstruction,
or a congenital abnormality of the vas, is present.
Testicular ultrasonography
Testicular ultrasound examination should be done in patients
with clinical findings suggestive of a scrotal or testicular mass.
Differential Diagnosis
The differential diagnosis of hypogonadism includes a large and
diverse group of disorders affecting the testicles directly or
affecting hypothalamic-pituitary regulation of the testes. The
clinical setting, history, physical examination, and clinical
judgement will, to a large degree, determine which possible
aetiologic factors are present.
The different causes are listed in Table 4.

Table 4: Aetiology of Male Hypogonadism

Gonadal defects
Genetic defect—Klinefelter’s syndrome, myotonic dystrophy,
Prader-Willi syndrome
Polyglandular autoimmune failure syndromes (e.g. Schmidt
syndrome)
Anatomic defects
Toxins—cytotoxic agents, spironolactone, alcohol
Radiation
Orchitis—usually due to mumps
Hypopituitarism
Idiopathic
Tumour
Other causes
Hyperprolactinaemia
Usually due to pituitary adenoma
Idiopathic increased prolactin production
Hormone resistance
Androgen insensitivity
Luteinising hormone insensitivity
Gonadotrophin deficiency
Hypogonadotrophic hypogonadism
Isolated congenital idiopathic GnRH deficiency
GnRH deficiency with anosmia—Kallman syndrome
Acquired GnRH deficiency is very uncommon
Respond to pulsatile GnRH administration
Hypothalamic insufficiency
Figure 1: Tall stature and gynaecomastia in a patient with Klinefelter’s syndrome.
LH or FSH deficiency
Systemic diseases
and increased gonadotropin levels. Although production of
Chronic diseases
Malnutrition/starvation testosterone is low, high levels of SHBG may result in normal-
Massive obesity range testosterone levels in about 40% of patients with
AIDS/HIV Klinefelter’s syndrome. These patients have azoospermia, but
those with mosaicism may have some spermatogenesis and
may produce some pregnancies early in their reproductive lives.
The common syndromes are briefly discussed below. They can
Virilisation may begin with puberty but frequently fails to
be broadly classified into hyper- and hypogonadotrophic.
progress. Gynaecomastia is often present and frequently
Hypergonadotrophic Hypogonadism Situations necessitates surgical therapy. Bone density is significantly low.
Autoimmune disorders are present with increased frequency
Klinefelter’s syndrome
in patients with Klinefelter’s syndrome and may respond
Klinefelter’s syndrome (Figure 1) is caused by extra X favourably to testosterone therapy.
chromosomes present in the male karyotype and occurs in
about 1 in every 400 men. The most common karyotype is 47/ 47/XYY syndrome
XXY; mosaicism is sometimes present (in about 1 in every 400 The 47/XYY karyotype, which occurs in about 0.1% of males, has
men). Men with Klinefelter’s syndrome classically have small, been thought to be associated with aggressive behaviour in some
firm testes (generally <2 ml), gynaecomastia, eunuchoid habitus, men with the disorder. Affected patients may have azoospermia 455
 in association with maturation arrest of the germinal epithelium. descend. Thus, the 1-year incidence is about 0.8 per cent.
Usually, serum FSH levels are increased, but Leydig cell function Because normal testicular descent requires normal pituitary
is normal, as are testosterone and LH levels. function and dihydrotestosterone levels, the incidence of
cryptorchidism is increased in patients with Kallmann’s
Dysgenetic testes
syndrome. Problems associated with the management of
Dysgenetic testes may occur in conjunction with mosaicism; cryptorchidism include distinguishing between crypt-
the patient may have an XO karyotype, a mixed XO/XY orchidism and retractile testes and recommending medical
karyotype, or pure XY with streak gonads. Occurrence of pure treatment with hCG or surgical therapy in an infant. Generally,
gonadal dysgenesis in conjunction with an XY karyotype and the objective is to bring the undescended testicle into the
streak gonads imposes an increased risk of malignant disease, scrotum before 1 to 2 years of age—to decrease the risk of
which necessitates gonadectomy. Such patients generally have gonadal malignant lesions associated with abdominal testes
genital ambiguity. and to improve fertility potential. In pre-pubertal boys, hCG
Androgen receptor defects treatment should generally be used initially for 4 weeks to
determine whether descent occurs before operative
Patients with androgen receptor defects have an XY genotype
intervention is considered. Discussion of these problems is
and variable phenotype, depending on the degree of receptor
beyond the scope of these guidelines; appropriate specialty
defect. Such syndromes include testicular feminisation,
consultation should be obtained.
Reifenstein’s syndrome, and other partial defects, as discussed
in the following paragraphs. Vanishing testes syndrome (congenital anorchism or
pre-pubertal functional castrate)
Testicular feminisation
The initial manifestation of the vanishing testes syndrome is
Patients with testicular feminisation have a female phenotype
sexual immaturity in a male patient. The cause is unclear, but the
but a blind vaginal pouch. Testosterone receptor is non-
syndrome may be due to testicular torsion during foetal life after
functional or absent. Laboratory testing shows normal to high
sufficient testosterone exposure to produce masculinisation of
male range testosterone and increased gonadotropin levels. The
the reproductive tract. Impalpable testes suggest the possibility
testes should be removed after puberty because of an increased
of cryptorchidism. FSH and LH levels are increased, and
risk of a malignant lesion. Administration of testosterone yields
testosterone levels are low. If the LH levels are only minimally
no response.
increased, hCG stimulation testing of the gonad should be done.
Reifenstein’s syndrome With vanishing testes syndrome, no response would be
In Reifenstein’s syndrome, patients have a male phenotype with demonstrated. A response to hCG stimulation would raise the
variable pseudohermaphroditism. A partial androgen receptor possibility of intra-abdominal testes, which would necessitate
defect is present; testosterone and gonadotropin levels are further evaluation because of the possibility of malignant
increased. Abdominal testes should be removed because of the transformation. In this setting, an MRI is recommended to assess
risk of a malignant lesion. If hypospadias is present, surgical the possibility of a retained intra-abdominal dysgenetic gonad
correction of the genitalia may be needed. Any significant because this would be associated with an increased risk of a
gynaecomastia may also need surgical correction. Patients may malignant lesion and would necessitate removal.
respond to high doses of testosterone. Haemochromatosis
Other syndromes Iron overload may lead to primary gonadal failure or sometimes
Some male patients with gynaecomastia or oligospermia may hypothalamic-pituitary dysfunction that results in secondary
have partial androgen insensitivity in association with mild gonadal failure. The diagnosis is made in the setting of
increases in testosterone and gonadotropin levels. associated findings of haemochromatosis in conjunction with
an increased ferritin level and is generally confirmed with a liver
5-alpha reductase deficiency or bone marrow biopsy.
An autosomal recessive condition, 5-alpha reductase deficiency
External Testicular Insults
is associated with an XY genotype. The patients, however, have
genital ambiguity until puberty, when increasingly male Trauma
features develop.The diagnosis is based on clinical manifestations The patient may have a history of direct traumatic injury.
and an increased testosterone/dihydrotestosterone ratio both Testicular torsion sometimes is associated with a ‘bell-clapper’
after puberty and in response to hCG before puberty. Sexual abnormality in which the testes lie horizontally because of
assignment is an issue, and patients may need corrective surgical incomplete closure of the surrounding tissues.
procedures that necessitate speciality consultation.
Mumps orchitis
Myotonic dystrophy In patients with postpubertal mumps, a 25% risk of orchitis
Myotonic dystrophy occurs only in male patients, by exists. More than 50% of those with orchitis will be infertile.
transmission from father to son. Because testicular failure Increased FSH concentrations and oligospermia or azoospermia
usually occurs around age 40 years, patients often have children are present. Mumps orchitis can progress to produce low
at risk for the disease. testosterone and high LH levels in some men.
Cryptorchidism Radiation treatment or chemotherapy
Unilateral or bilateral cryptorchidism can occur. The incidence With irradiation or chemotherapy, testicular exposure can occur
456 of this condition is 3% to 4% at birth, but most testes ultimately from treatment of another disease or inadvertently. A dose-
 Disorders of Gonads
dependent recovery potential and variable Leydig cell Fertile eunuch syndrome
dysfunction have been noted. Pretreatment sperm banking is Hypogonadotrophic hypogonadism in patients who have
possible if future ‘fertility’ is desired and sperm counts are normal. modest FSH secretion and selective LH deficiency is known as
Autoimmune syndromes the fertile eunuch syndrome. Fertility may be present in some
of these patients.
Anti-Leydig cell antibody-associated disorders or conditions
associated with anti-sperm antibodies are autoimmune Pituitary disorders
syndromes related to hypogonadism. These syndromes are Acquired hypogonadotrophic hypogonadism may indicate the
poorly characterised, and further research is needed to presence of pituitary insufficiency or a pituitary tumour. Unless
determine diagnostic criteria and possible treatment options. the reason for the pituitary defect is clear, imaging studies of
Sertoli cell only syndrome the pituitary gland are indicated to determine whether a
pituitary tumour is present. Hypothalamic tumours, metastatic
The absence of germ cells in patients with small testes, high
tumours, granulomas, abscesses, and haemochromatosis may
FSH levels, azoospermia, and normal testosterone levels should
also be discovered.
suggest the presence of Sertoli cell only syndrome. The
diagnosis can be made only by testicular biopsy. The cause is Hyperprolactinaemia is a potential cause of hypogonad-
currently unknown. otrophic hypogonadism and generally, manifests with a low
libido and impotence. A prolactin level should be determined
Hypogonadotrophic Hypogonadism Situations
in men with acquired hypogonadotrophic hypogonadism. High
Kallmann’s syndrome prolactin levels are usually associated with a prolactinoma, but
Classic Kallmann’s syndrome is a congenital disorder inherited certain medications may also cause hyperprolactinaemia.
as an X-linked recessive trait manifesting as prepubertal
Hypogonadotrophic hypogonadism from pituitary disease may
hypogonadism with an incidence of about 1 in 10,000 male
also occur with granulomatous and infiltrative disorders, cranial
births. Low testosterone levels are present because of an
trauma with or without stalk transection, irradiation, and
impaired release of LH and FSH as a result of variable GnRH
hypophysitis.
deficiency. LH and FSH are released in response to priming
followed by stimulation with GnRH. The gene on the X Haemochromatosis
chromosome for classic Kallmann’s syndrome and associated See earlier discussion in hypergonadotrophic hypogonadism
anosmia has been identified and cloned. Autosomal recessive section.
and autosomal dominant variants of hypogonadotrophic
hypogonadism also exist and are referred to as idiopathic Serious illness, acquired immunodeficiency syndrome and
hypogonadotrophic hypogonadism. stress
Transient hypogonadotrophic hypogonadism may occur in
Classically, Kallmann’s syndrome is associated with anosmia as
patients with serious disorders or malnutrition. Acquired
a result of defective development of the olfactory tract in the
immunodeficiency syndrome (AIDS) may be associated with
brain. The GnRH-containing neurones originate in the
low testosterone levels and generally low gonadotropin levels
developing olfactory tract and therefore do not develop
(consistent with hypothalamic-pituitary involvement). In some
properly in this syndrome. This defective development of the
patients with AIDS, gonadotropin levels are increased
olfactory tract can be diagnosed by MRI scanning. In some cases,
(consistent with testicular disease).
other defects such as cerebellar dysfunction, cleft palate, and
congenital deafness are present. Cryptorchidism may occur Ageing, andropause or male menopause
because gonadotropins contribute to normal testicular descent. Considerable controversy exists over the concept of a male
The pre-pubertal testes in patients with Kallmann’s syndrome climacteric. Growing evidence indicates that some aging men
tend to be larger than in patients with Klinefelter’s syndrome have reduced production of testosterone associated with
and are appropriate for age up to puberty, in as much as normal decreased libido, impotence, decreased growth of body hair,
initial amounts of germinal tissue are present. Partial pubertal decreased muscle mass, increased risk of myocardial infarction,
development may be present in patients with partial defects; and decreased bone mass in conjunction with osteoporosis.
thus, Kallmann’s syndrome may be difficult to distinguish from Measurements of free testosterone or SHBG with total
delayed puberty up through the teenage years. Once a patient testosterone are usually needed to demonstrate the
with Kallmann’s syndrome has been identified, other family abnormality. Often the FSH and LH levels are mildly increased;
members at risk (on the basis of mode of inheritance) should an indication that a primary testicular disorder may be present
be assessed, if possible. in conjunction with a secondary abnormality in LH burst
Other related syndromes frequency. Dynamic testing may disclose more subtle
abnormalities of hypothalamic function. Data from long-term
Congenital hypogonadotrophic syndromes are associated with
research studies are desperately needed to clarify the criteria
secondary hypogonadism and other somatic findings. Prader-
for therapy considerations in aging men. Currently, men with
Willi syndrome is characterised by hypogonadism, short stature,
symptomatic hypogonadism and clearly low testosterone levels
mental retardation, hypotonia at birth, and obesity. Laurence-
(free or total, in consideration of SHBG) are potential candidates
Moon-Bardet-Biedl syndrome is an autosomal recessive trait
for therapy, although no specific recommendations can be given.
characterised by mental retardation, retinitis pigmentosa,
polydactyly, and hypogonadism. These syndromes may be due Short-term research studies have demonstrated improved lean
to a hypothalamic deficiency of GnRH. body mass, increased haematopoiesis, decreased low-density 457
 lipoprotein (LDL) levels with a constant LDL to high-density intervals are more convenient but are associated with greater
lipoprotein (HDL) ratio, improved libido, and improved well- fluctuations in testosterone levels. Higher doses of testosterone
being in men with low testosterone levels after treatment with produce longer-term effects at the expense of higher peak
testosterone. Generally, prostate size does not change in levels and wider swings between peak and nadir circulating
comparison with otherwise normal men, but prostate-specific testosterone levels; the result is fluctuating symptoms in many
antigen (PSA) levels have been found to increase in some men. patients. The use of 100 to 200 mg every 2 weeks is a reasonable
compromise. Use of 250 to 300 mg injections every 3 weeks is
Treatment Options
associated with wider fluctuations of testosterone levels. With
The goals of therapy are to restore sexual function, libido, well- use of these longer-interval regimens, many men will have
being, and behaviour; produce and maintain virilisation; pronounced symptoms during the week preceding the next
optimise bone density and prevent osteoporosis; possibly injection. In such instances, a smaller dose at closer intervals
normalise growth hormone levels in elderly men; potentially should be tried. As a guide, testosterone levels should be above
affect the risk of cardiovascular disease; and restore fertility in the lower limit of normal, in the range of 250 to 300 ng/dL, just
cases of hypogonadotrophic hypogonadism. before the next injection.
Testosterone therapy in adult male patients with When full androgen replacement is not required, lower doses
hypogonadism of testosterone are used. One such category includes adult male
Ideally, testosterone therapy should provide physiologic patients with pre-pubertal onset of hypogonadism who are
range of testosterone (between 300 and 1,200 ng/dL) and going through puberty for the first time on therapy and who
physiologic range of dihydrotestosterone and oestradiol levels, often may require psychologic counselling, especially when a
which would allow optimal virilisation and normal sexual spouse is involved as well. In these patients, testosterone
function. Testosterone therapy is used in the male patient with therapy should be begun at 50 to 100 mg every 3 to 4 weeks
hypogonadism who is not interested in fertility or not able to with a gradual increase during subsequent months, as tolerated,
achieve fertility. In late teenage male patients with delayed up to full replacement within 1 year. Men with appreciable
puberty, testicular size should be monitored for evidence of benign prostatic hypertrophy who have hypogonadism and
onset of puberty. In this setting, testosterone therapy should symptoms may be given 50 to 100 mg every 2 weeks as an initial
be withdrawn to determine whether spontaneous puberty will regimen and maintained on this dosage with careful monitoring
occur. of urinary symptoms and prostate examinations; therapy can
The following preparations of testosterone may be used: long- be withdrawn, if necessary.
acting intramuscular preparations, short-acting intramuscular Attaining full virilisation in the patient with hypogonadism
preparations, pellets, scrotal patches or transdermal patches. may take as long as 3 to 4 years. Follow-up intervals should
Orally administered testosterone is quickly metabolised by the be between 4 and 6 months to monitor progress, review
liver and cannot achieve sufficient blood levels overtime to be compliance, and determine whether any complications or
useful. The orally administered alkylated androgen preparations psychologic adjustment problems are present.
currently available are generally not recommended because Transdermal testosterone therapy
of poor androgen effects, adverse lipid changes, and hepatic
side effects, such as haemorrhagic liver cysts, cholestasis, and Transdermal testosterone delivery system—normal skin: A
hepatocellular adenoma. Testosterone undecanoate may be testosterone patch with permeability enhancement allows
a more acceptable oral alternative, but erratic testosterone testosterone delivery through normal skin. Daily evening
levels, frequent dosing, high dihydrotestosterone levels, and application generally results in normal-range testosterone
occasional gastrointestinal side effects may limit the usefulness levels, which mimic the normal diurnal changes in testosterone
of this preparation. Testosterone pellets are sometimes used, in normal men. In contrast to the situation with use of the scrotal
and further study may prove them to be suitable for many men. patch, dihydrotestosterone levels remain within the normal
For patients with hypogonadotrophic hypogonadism wishing range. Oestradiol and bioavailable testosterone levels also
fertility, hCG with or without human menopausal gonadotropin remain within the normal range. Skin irritation may be a
(FSH), or pulsatile GnRH therapy and hCG with or without problem in some patients. Therapy consists of two patches
assisted reproduction are options. applied to normal skin. As with scrotal patches, treatment is
more expensive than injections, but convenience of use,
Parenteral testosterone preparations maintenance of normal diurnal testosterone levels, and
These are the mainstay of therapy for all practical purposes. elimination of office visits for injections may make this form of
Testosterone enanthate and testosterone cypionate are long- treatment useful in many patients.
acting testosterone esters suspended in oil to prolong
Scrotal patch testosterone delivery system: Scrotal testosterone
absorption. Peak levels occur about 72 hours after intramuscular
patches are available in 40 and 60 cm 2 sizes, which deliver,
injection and are followed by a slow decline during the
respectively 4 and 6 mg of testosterone daily. The patch is
subsequent 1 to 2 weeks.
applied to the scrotal skin after preparation of the scrotum with
For complete androgen replacement, the regimen should be dry shaving. The patch is non-adhesive, and a new patch is
between 75 mg, 150 mg and 250 mg of testosterone enanthate applied each morning. The testosterone levels mimic the diurnal
or cyprionate administered intramuscularly every 7 to 10 to 21 rhythm present in normal men. Because genital skin contains
days, which will allow relatively normal levels of testosterone high concentrations of 5-reductase, the dihydrotestosterone
458 throughout the time interval between injections. Longer time levels in treated patients increase initially but may return to
 Disorders of Gonads
normal in some men. The cost of using the scrotal patch is Gonadotrophin therapy for induction of spermatogenesis
greater than for testosterone injections, but the convenience Males with pre-pubertal onset of hypogonadotrophic
of use may make this therapeutic option acceptable for many hypogonadism have not completed pubertal development and
patients. have testes generally smaller than 5 ml. These patients usually
Side effects of testosterone therapy require therapy with both hCG and human menopausal
Periodic follow-up of patients receiving testosterone therapy gonadotropin (or FSH) to induce spermatogenesis. Men with
is recommended. During the first year of therapy, the patient partial gonadotropin deficiency or who have previously (peri-
should have the progress and the side effects monitored at pubertally) been stimulated with hCG may initiate and maintain
3 to 4 month intervals. Examination of the prostate should be production of sperm with hCG alone. Men with post-pubertal
done routinely. PSA levels should be determined annually in acquired hypogonadotrophic hypogonadism and who have
older men receiving testosterone replacement therapy, and the previously had normal production of sperm can also generally
haematocrit should be determined at least yearly. An initial lipid initiate and maintain spermatogenesis with hCG only. Fertility
profile should be recorded, and a follow-up profile should be may be possible at sperm counts much lower than what would
done after 6 to 12 months of therapy. Testosterone, and otherwise be considered fertile. Counts of less than 1 million/
especially dihydrotestosterone, stimulates the growth of the mL may be associated with pregnancies under these
prostate and seminal vesicles. circumstances. It is imperative that the female partner undergo
assessment for optimal fertility before or concurrently with
Gynaecomastia may result from the aromatisation of consideration of therapy in the man.
testosterone to oestradiol and changes in SHBG levels. The use
of aromatase inhibitors, such as testolactone, or surgical therapy GnRH therapy
may be considered for some patients. In patients with hypogonadotrophic hypogonadism, GnRH can
be given in a pulsatile fashion sub-cutaneously through a pump
Supraphysiologic levels of testosterone stimulate the bone
every 2 hours. GnRH therapy is monitored by measuring LH,
marrow production of erythrocytes. The result is an increased
FSH, and testosterone levels every 2 weeks until levels are in
haematocrit with the possibility of hyperviscosity side effects.
the normal range, at which point monitoring can be adjusted
Lipid disturbances in testosterone treated male patients are to every 2 months. GnRH can be used to initiate pubertal
generally not a problem because of the aromatisation of development, maintain virilisation and sexual function, and
testosterone to estradiol. The HDL: total cholesterol ratio initiate and maintain spermatogenesis. In most patients, these
generally remains constant. Anabolic steroids that are not effects may take from 3 to 15 months to achieve sperm
aromatised increase LDL and lower HDL levels and could production. As with gonadotropin therapy, fertility can be
increase cardiovascular risk. achieved with very low sperm counts—often in the range of
Sleep apnoea may also be a problem in some men, and 1 million/mL. GnRH may be more effective than gonadotropin
testosterone therapy should be discontinued until the sleep stimulation in increasing testicular size and initiating
apnoea problem can be adequately addressed. spermatogenesis in many patients with hypogonadotrophic
hypogonadism.
Gonadal Stimulation in Hypogonadotrophic
Hypogonadism Contraindications to Testosterone, GnRH, and
Gonadotrophin Therapy
Because gonadotrophin or GnRH therapy is effective only in
hypogonadotrophic hypogonadism, this diagnosis must be Testosterone replacement, pulsatile GnRH therapy, and
firmly established before consideration of therapy. Although gonadotrophin therapy are contraindicated in men with
these agents may also be used to induce puberty in boys prostate cancer or male breast cancer. Treatment with these
and to treat androgen deficiency in hypogonadotrophic medications can stimulate tumour growth in androgen-
hypogonadism, the major use of these preparations is in dependent neoplasms. Careful examination of the male breast
the initiation and maintenance of spermatogenesis in and prostate is required initially and at follow-up visits. In
hypogonadotrophic men who desire fertility. addition to prostate examination, baseline and follow-up PSA
levels should be determined in older men at increased risk for
Gonadotrophin therapy in androgen deficiency
prostate cancer. Sleep apnoea and hyperviscosity states are
hCG binds to Leydig cell LH receptors and stimulates the relative contra-indications to the use of testosterone therapy.
production of testosterone. Peri-pubertal boys with hypo-
gonadotrophic hypogonadism and delayed puberty can be Other Treatment Considerations
treated with hCG instead of testosterone to induce pubertal Anti-oestrogen therapy in oligospermia
development. The initial regimen of hCG is usually 1,000 to 2,000 Long-term use of low-dose clomiphene citrate at 25 mg daily
IU administered intramuscularly two to three times a week. The or tamoxifen to increase pituitary stimulation of testicular
advantages of hCG over testosterone in this setting include the function has often been attempted in men with oligospermia
stimulation of testicular growth, which may be an important with limited success.
issue for some men. hCG may also yield greater stability of
testosterone levels with fewer fluctuations in hypogonadal Assisted reproductive technology
symptoms. In addition, hCG treatment is necessary for The ability to perform in vitro fertilisation (IVF) with
stimulating enough intratesticular testosterone to allow the intracytoplasmic sperm injection (ICSI) directly into the egg has
initiation of spermatogenesis. Problems with hCG include the revolutionised the approach to male sub-fertility. A single sperm
need for more frequent injections and the greater cost. or immature form retrieved from the testicle is sufficient to 459
 fertilise an egg and give a reasonable chance at pregnancy. menopausal gonadotropin (or FSH) therapy may stimulate
In vitro fertilisation with intracytoplasmic sperm injection may spermatogenesis and result in pregnancies. Surgical therapy
be a viable option in many men with hypogonadism who should especially be considered for significant pituitary tumours
cannot otherwise be induced to produce enough sperm to that are not prolactin-secreting adenomas. Surgical treatment
result in pregnancy as well as in the presence of a female factor may also be an option in prolactin-secreting adenomas, if
that may further make pregnancy by the couple difficult or patients have severe side effects from medications or prefer this
impossible. The procedure is expensive and seldom covered by approach after being appropriately informed of the risks and
health insurance; therefore, this technology will generally not benefits of medical versus surgical management.
replace conventional gonadal stimulation protocols.
Gynaecomastia
Intrauterine insemination (IUI) may also be a low-cost option in
suitable women when the man has mild-to-moderate Many men have psychologic problems resulting from
oligospermia. gynaecomastia. This problem should be taken seriously and
discussed with the patient. Aromatase inhibitors, such as
Pituitary tumours testolactone, tamoxifen or even clomiphene citrate may be
Patients with acquired hypogonadotrophic hypogonadism helpful in some patients. Consultation with a plastic surgeon
require assessment for a pituitary tumour with appropriate may be necessary in appropriate cases.
pituitary imaging studies, such as MRI, and determination of a Psychologic counselling
prolactin level. Depending on the presence or absence of a
Men with hypogonadotrophic disorders frequently have
tumour, other hormonal testing may be indicated, including
associated mood disturbances, including depression,
thyroid and adrenal function tests. Further evaluation and
aggression, poor self-esteem, and learning problems. In such
treatment options would depend on what hormonal deficits
cases, psychologic counselling is often needed to allow proper
are present, the size and site of the tumour, the operability of
identification and treatment of these problems. Counselling
the tumour, and the patient’s preferences in specific
should also include parents, spouse and relatives, if possible.
circumstances. If a prolactinoma is present, therapy would be
directed toward correcting this problem before initiation of
RECOMMENDED READINGS
other therapy. Medical therapy with bromocriptine or pergolide
1. Ishiwaka T, Ooba T, Kondo Y, Yamaguchi K, Fujisawa M. Assessment of
may effectively reduce prolactin levels sufficiently to allow gonadotropin therapy in male hypogonadotrophic hypogonadism. Fertil
gonadal function to resume or allow stimulation with Steril 2007 Feb 1.
gonadotropins. Even when prolactin levels cannot be 2. Simoni M, Nieschlag E. Genetics of hypogonadotrophic hypogonadism.
normalised, hCG therapy alone or in conjunction with human Horm Res 2007; 67 Suppl 1:149-54.

460
Section 11
Dermatology
Section Editor: Vibhu Mendiratta
11.1 Introduction and Principles of Diagnosis in Dermatology 462
Vibhu Mendiratta
11.2 Cutaneous Infections 470
Vineet Kaur, Gurmohan Singh
11.3 Infestations and Insect Bites 475
Devinder Mohan Thappa, Laxmisha Chandrashekar
11.4 Eczemas 480
Ashok Kumar Bajaj
11.5 Drug Reactions 487
M. Ramam
11.6 Abnormal Vascular Responses 491
A.K. Jaiswal, T.S. Nagesh
11.7 Papulosquamous Disorders 494
K. Pavithran
11.8 Autoimmune Bullous Disorders 498
K.K. Raja Babu
11.9 Disorders of Pigmentation 501
Bhushan Kumar
11.10 Disorders of Skin Appendages 507
Raj Kubba, Tanvi Pal
11.11 Cutaneous Responses to Physical Factors 512
S. Criton
11.12 Genodermatoses 515
Vibhu Mendiratta
11.13 Skin in Connective Tissue Diseases 520
Sandipan Dhar
11.14 Skin in Systemic Diseases 526
Uday Khopkar
11.15 Leprosy 534
B.K. Girdhar
11.16 Sexually Transmitted Infections 541
Vinod K. Sharma, Naresh Jain
11.17 Premalignant Conditions and Malignant Tumours of the Skin 546
Arun C. Inamadar, Aparna Palit
11.18 Therapy of Dermatological Diseases 549
M.K. Singhi
 11.1 Introduction and Principles of
Diagnosis in Dermatology
Vibhu Mendiratta

SKIN AS A VITAL ORGAN Epidermis

Skin or the integument is the largest organ of the body and Epidermis is the outermost visible layer. The thickness is variable
constitutes 16% of the body weight. It is composed of skin and (0.05 mm on eyelids and the thickest on the palms and soles
appendages (sweat glands, sebaceous glands, hair and nails). It at 1.5 mm). Epidermis is thrown into folds over dermis in order
is not merely a covering for internal organs but is an active, to increase the area of absorption and for stronger cohesion
functional organ that performs diverse functions, such as, to the dermis. Epidermis is composed of keratinocytes,
protection from noxious environmental factors, as a sensory melanocytes, Langerhans cells. It bears receptors for touch,
organ, participates in immunological defence mechanisms (skin pressure, temperature and free nerve endings. Epidermis is
has antigen presenting cells, and skin associated lymphoid further composed of four sublayers, as described below:
tissue), endocrine functions (synthesis of vitamin D) and
1. Stratum corneum
thermoregulation through sweating. The appendages of skin
(nails, hair, sweat and the sebaceous glands) also perform It is the outer layer which consists of keratinised epithelial cells.
various functions. The cells are flattened and anucleated. Thickness of the layer
varies from 5 to 10 layers. Stratum corneum is regularly shed of
STRUCTURE OF SKIN and it renews itself every 14 to 30 days.
Skin is composed of three distinct zones — the epidermis, 2. Stratum granulosum
dermis and the subcutis (Figure 1). The epidermis is the outer Measures 3 to 5 cell layers of keratinocytes and contains
layer of skin and is composed of keratinised stratified squamous keratohyaline granules. These granules are involved in the
epithelium. The dermis is mesodermally derived and consists process of keratinisation.
of collagenous connective tissue that lies below epidermis and
3. Stratum spinosum
interdigitates with it. The hypodermis contains loose connective
tissue with varying amounts of adipose tissue. It is the thickest layer of epidermis and measures 5 to 8 layers.

Figure 1: Skin structure with three distinct zones—epidermis, dermis and subcutis.
462
 Introduction and Principles of Diagnosis in Dermatology
It is composed of cuboidal cells and appears more flattened Table 1: Different Types of Cutaneous Lesions (Primary/
than the underlying stratum basale. Secondary)
4. Stratum basale Primary lesions Secondary lesions
It is the lower most layer of the epidermis, which is composed Macule Erosion
of a single layer of cells that are columnar in shape, proliferate Patch Crust
actively and lie interspersed with other cells. Stratum basale Papule Ulcer
also has cells with dendritic processes which produce pigment Plaque Scale
(melanin). These are called the melanocytes. They remain Nodule Lichenification
in contact with keratinocytes. Langerhans cells also bear Vesicle Atrophy
dendritic processes and belong to the macrophage-monocyte Bulla Scar
series. They lie in the living layers of the epidermis and Pustule
perform the important task of antigen presentation to the T- Wheal
lymphocytes. Merkel cells are special cells that are found in Burrow
Comedone
the basal layer of epidermis and act as touch receptors.
Telangiectasia
Dermis
Thickness of dermis is variable and measures 0.3 to 3 mm. It 1. Macule: It is a flat, circumscribed area of skin showing an
comprises of elastin, collagen and glycosaminoglycans. It alteration in the skin colour, e.g. melasma, pityriasis and
contains extensive vasculature, neurones, smooth muscle, vitiligo (Figure 2).
fibroblasts, sweat and the pilosebaceous apparatus with their 2. Patch: A larger macule (>1 cm) is referred to as a patch.
ducts. It is the principal mechanical barrier of skin. Its network Patches are seen in leprosy, vitiligo and purpura (Figure 3).
of elastic fibres functions to support the epidermis and binds
the skin to the deeper hypodermis. The dermis contains two
layers, the papillary layer and the reticular layer. The papillary
layer is loosely woven, contains superficial connective
tissue and interdigitates with the epidermal ridges and the
deeper reticular layer. The dermal ridges contain Meissner’s
corpuscles, encapsulated nerve endings, and capillary loops
that provide nutrients to the avascular epidermis. Dermis
provides tensile strength, elasticity, and thickeness to the skin.
Subcutaneous Tissue/Hypodermis
It is the deepest part of skin composed of adipose tissue. The
hypodermis provides insulation, shock absorption, energy
storage, and the ability of skin to slide over joints. It also contains
the major blood vessels of the skin.

PRINCIPLES OF DIAGNOSIS
Skin is the largest organ of the body. It reflects the state of
internal organs. Various lesions based on their morphology are Figure 2: Depigmented macules over tips of fingers in vitiligo.
classified as primary or secondary lesions. A step-wise approach
aids in correct diagnosis and includes the following steps:
History
History of drug intake, atopy, sexual history, recent travel, type
of house, emotional status, illicit drug use and family history
of skin diseases should be sought. Systemic diseases such
as tuberculosis, diabetes, hypertension, hepatitis, blood
transfusion, hospitalisations and major operative procedures
should be recorded. History of local treatment, associated
symptoms like pruritus, pain, stinging, burning, or anaesthesia
should be enquired about.
Examination
Examination is performed in a well lit room. Skin, hair, nails,
and mucous membranes should be examined. The clinician
should recognise the primary lesions of a skin rash, determine
pattern of distribution, and arrangement of eruption.
Identification of primary lesions of a skin rash
Primary lesions arise on the previously normal skin and have
Figure 3: A large purpuric patch over thigh in autosensitisation syndrome.
been classified further into various subtypes (Table 1). 463
 3. Papule: It is a circumscribed, raised elevated lesion which 12. Telangiectasia: Are the superficial, dilated capillaries, appear
measures less than 0.5 cm, e.g. acne papules, lichen planus, as wavy, thin, reddish blue lines (Figure 13). They are seen
molluscum contagiosum (Figure 4). in connective tissue diseases.
4. Plaque: A circumscribed area of skin which shows a
change in the consistency of skin (Figure 5). Plaques are
seen in lichen planus, psoriasis and neurodermatitis.
5. Nodule: An elevated, palpable lesion with greater depth
than its height or width (Figure 6).
6. Vesicle: It is a clear fluid containing lesion measuring
< 0.5 cm. Vesicles are seen in herpes zoster (Figure 7).
7. Bulla: A fluid filled lesion which measures more than 1 cm
(Figure 8). The bullae are seen in pemphigus.
8. Pustule: A tiny lesion containing pus measuring less than
0.5 cm in size (Figure 9).
9. Wheal: Constitutes an erythematous, oedematous, transient,
itchy papule or plaques seen in urticaria (Figure 10).
10. Burrow: It is a linear, thread like lesion in the web spaces
of fingers, flexural folds of wrists, ankles and constitutes
the primary lesion of scabies (Figure 11).
11. Comedone: It is a dark papule filled with keratin debris.
Closed comedone is white in colour (Figure 12).
Comedone is the primary lesion of acne. Figure 6: Nodule over cheek (arrow).

Figure 4: Raised papule of acne over cheek. Figure 7: Vesicles in herpes zoster.

Figure 5: Scaly plaque over the lower back in psoriasis. Figure 8: A large fluid filled bullae in erythema multiforme.
464
 Introduction and Principles of Diagnosis in Dermatology
Figure 12: Comedone. Greyish-black, tiny, dark papules over cheeks in acne.

Figure 9: Multiple pustules over knee and legs in pustular psoriasis.

Figure 13: Telangiectasia. Multiple telangiectasia over nose and cheeks

in systemic sclerosis.

Secondary lesions
Secondary lesions are changes in the primary lesions due to
scratching, infection or treatment.
1. Excoriations: These are linear marks caused by scratching
of skin (Figure 14). Excoriation marks are seen in scabies,
dermatitis herpetiformis.

Figure 10: Wheals. Erythematous, raised, itchy lesions over back in urticaria.

Figure 11: Burrows. Curvilinear, thread like structures over palms(arrows) Figure 14: Excoriations. Linear marks with oozing of blood and crusting due
burrows in scabies. to scratching in prurigo.
465
 2. Erosion: Partial loss of epidermis constitutes an erosion 4. Scales: Shedding of stratum corneum cells forms scales
(Figure 15). Erosions are seen in toxic epidermal necrolysis (Figure 17). Scale may be silvery, dry and abundant as in
(TEN). psoriasis.
3. Ulcers: Loss of epidermis and partial loss of dermis forms 5. Crust: Drying up of the exudates forms crust (Figure 18).
ulcer (Figure 16). Ulcers arise secondary to trauma, burns, A crust may be purulent, honey-coloured as seen in
ischaemia or lack of nerve supply. impetigo contagiosa, chocolate coloured in ecthyma.
6. Lichenification: Skin is thickened, leathery, pigmented with
accentuated skin markings. It occurs in chronic eczema
such as lichen simplex chronicus or neuro-dermatitis
(Figure 19).
7. Atrophy: Decrease in the thickness of skin leads to atrophy.
Epidermal atrophy is seen as smooth, shiny and wrinkled
skin with easily visible dermal blood vessels. Dermal and
subcutaneous tissue atrophy leaves behind a pit on the skin
(Figure 20).
8. Scar: Destruction of skin and the underlying dermis results
in scar which appears as a wrinkled area with loss of normal
skin markings. It can be an atrophic (Figure 21) or hyper-
trophic scar. Atrophic scars are seen in acne, morphoea,
post-burn. Keloid is a scar which is raised beyond the
Figure 15: Erosion. Partial loss of epidermis causing a raw area in pemphigus.
original lines of injury.

Figure 16: Ulcer. Loss of epidermal cover with partial loss of dermis in an ulcer. Figure 18: Crusts. Dried up exudate.

Figure 17: Scales in hand eczema. Figure 19: Lichenification.

466
 Introduction and Principles of Diagnosis in Dermatology
Targetoid: Lesion in concentric circles forming a target board
that mimics the various zones of a target as in erythema
multiforme (Figure 24).
Zosteriform or segmental: Distribution along one side of the body
along a dermatome (area on the skin which is supplied by a
dermal nerve) (Figure 25).

Figure 20: Atrophy in linear morphoea.

Figure 22: Linear lesions (in linear lichen planus on face).

Figure 21: Scar. An atrophic scar over leg.

Distribution of lesions
Lesions can be localised (limited to a discrete area) or
generalised (widespread/affecting many areas). Distribution Figure 23: Annular lesions in borderline leprosy.
can be extensor (as in psoriasis) or flexural (neck, axillae,
sub-mammary folds, groins). Intertrigo and candidal infections
involve the flexural surfaces. Photosensitive disorders
(systemic lupus erythematosus, photo-allergic dermatitis,
polymorphous light eruptions) show photo distribution over
the face, nape and V of the neck, extensor aspect of arms and
dorsum of hands.
Identification of arrangement/configuration of lesions
Arrangement of lesions may vary. It may be linear, grouped,
annular, targetoid, zosteriform, geographic, reticulated, and
serpiginous.
Linear: Lesions arranged along a line as in linear lichen planus,
linear psoriasis (Figure 22).
Grouped/Herpetiform: Lesions are closely clustered together, e.g.
Herpes.
Annular: Arrangement in the form of a ring-plaques in borderline
Figure 24: Targetoid lesions in erythema multiforme.
leprosy (Figure 23). 467
 Geographic: Refers to large, bizarre lesion which have a map -
like irregular outline. Borderline: borderline leprosy, geographic
tongue (Figure 26).
Reticulated: Refers to a net work like distribution—oral lichen
planus, cutis marmorata (Figure 27).
Serpiginous: Running along a zig-zag track like a snake-cutaneous
larva migrans (Figure 28).
Blaschkoid: Along the lines of Blaschko as in epidermal naevi
(Figure 29).

Figure 25: Zosteriform lesions in herpes zoster.

Figure 28: Serpiginous lesions in cutaneous larva migrans.

Figure 26: Geographic tongue showing map-like pattern.

Figure 29: Blaschkoid lesions in hypomelanosis of Ito.

Final Categorisation of Skin Rash

Based on the morphological type of lesions the best way to
categorise rashes would be presented as in Table 2.

Table 2: Morphological Types of Cutaneous Eruptions

Papulosquamous—As seen in psoriasis, pityriasis versicolour,
lichen planus and P. rosea
Vesiculobullous—Herpes zoster, chickenpox, pemphigus
vulgaris, bullous pemphigoid
Maculopapular—Drug rash, measles, rubella, toxic shock syndrome
Urticarial rash—Urticaria, erythema multiforme, vasculitis
Purpuric rash—Thrombocytopenia, drug hypersensitivity, vasculitis
Nodular rash—Syphilis, lepromatous leprosy
Pustular rash—Psoriasis, candidiasis, drug eruptions
Eczematous rash—Atopic dermatitis, seborrhoeic dermatitis,
468 Figure 27: Reticulate lesions in livedo reticularis. contact dermatitis
 Introduction and Principles of Diagnosis in Dermatology
LABORATORY TESTS/LABORATORY TESTS AND PROCEDURES acantholytic cells can be demonstrated in chickenpox and
The various tests are discussed below and summarised in pemphigus group of diseases, respectively.
Table 3. Gram’s Stain
Smear is prepared from the pus filled lesions. It shows
Table 3: Common Investigative Procedures for Skin Diseases
Gram-positive and negative cocci in pyodermas. It also
KOH Fungal infections, candidiasis demonstrates Gram-positive pseudohyphae of Candida.
Gram’s staining Pyodermas, pustular lesions Absence of bacteria in the smear from a pus filled lesion
Tzanck smear Viral diseases, autoimmune bullous diseases indicates sterile pustules as in pustular psoriasis and drug-
Skin biopsy All kinds of rashes induced pustular eruptions.
Slit-smear preparation Leprosy
Skin Biopsy
(Ziehl-Neelsen’s Mycobacteria (Tuberculosis and leprosy)
staining) Histopathological examination of skin is carried-out by
Immunofluorescence Autoimmune bullous disease, connective taking a tiny bit (0.4 to 0.6 mm) of the affected skin. Biopsy is
tissue disease taken with biopsy punche which come in various sizes (0.3 to
0.6 mm). Size of the punch is selected based on the depth
of specimen required. An incisional biopsy is taken after
KOH Examination administering local anaesthesia. It is an outdoor procedure. The
In case of itchy scaly lesions, the most active part of the lesion, specimen is transported in formalin (1%) for sectioning and
(generally the border) is scraped gently with the help of a sterile, staining.
no. 14 blade and the scrapings are transferred onto a clean glass
Immunofluorescence
slide over which a drop of KOH (10%) is placed. Examination
under the light microscope shows fungal hyphae as branching, The technique is used in the diagnosis of autoimmune blistering
septate, refractile filaments. Candida is seen as short, pseudo- diseases and autoimmune connective tissue diseases like
hyphae which may show budding at places. systemic lupus erythematosus.
Slit-Smear Examination
Wood’s Lamp Examination
It is a useful procedure to demonstrate the presence of
Wood’s lamp contains a barium trisilicate filter that filters out
Mycobacterium leprae in the skin. It is prepared from the ear
all light except 311 nm. The lamp is used for examining the
lobes, eyebrows or from skin lesions. The site is cleaned with
hair in suspected cases of tinea capitis as some causative
the help of sterile spirit swab, and kept pinched between the
dermatophytes fluoresce under ultraviolet light. It serves as a
thumb and fingers for half a minute. A small nick (2 to 3 mm) is
useful tool in the diagnosis of fungal infection of scalp. It is also
given with the help of a sterile surgical blade (No. 13-14). The
used for examining the urine and teeth in certain congenital
area is gently scraped from the blunt margins of the blade. A
porphyrias and erythrasma.
smear is prepared on a clean glass slide. It is air dried and heat
Tzanck Smear fixed and then stained with Ziehl-Neelsen stain. It is examined
Fresh blister is de roofed using a sterile blade after cleaning it under the oil emersion lens for mycobacteria.
with spirit swab. Fluid is drained. The base of the blister cavity is RECOMMENDED READINGS
scraped gently and smear is made on a clean glass slide. The
1. Pasricha JS, Gupta R. Illustrated Textbook of Dermatology; 3rd Ed. New Delhi:
smear is air dried and heat fixed and stained with Geimsa stain Jaypee Brothers Medical Publishers; 2006.
(1%). The smear is examined under the oil immersion lens of 2. Sehgal VN. Textbook of Clinical Dermatology; 4th Ed. New Delhi: Jaypee
the light compound microscope. Multinucleate giant cells, Brothers Medical Publishers; 2004.

469
 11.2 Cutaneous Infections

Vineet Kaur, Gurmohan Singh

BACTERIAL INFECTIONS OF SKIN (PYODERMAS) Good hygiene and regular baths in summer are helpful in
The skin of newborn baby is sterile. Virgin skin is immediately prevention. Some cases of streptococcal impetigo may develop
colonised with non-pathogenic bacteria which include glomerulonephritis after 2 to 4 weeks.
staphylococci, micrococci and diphtheroids. Staphylococcus Ecthyma
aureus may also get colonised in neonatal period. Resident flora
It is a deeper variant of impetigo occurring in older children
inhibits colonisation by pathogenic bacteria (bacterial
with poor hygiene, malnutrition and repeated trauma, usually
interference). Hydration of skin promotes bacterial growth and
as a secondary infection. The crusts are thick chocolate coloured,
desiccation limits the number of bacteria.
more adherent with indurated base and surrounding erythema.
Impetigo Contagiosa It occurs mostly on lower extremities.
It is a superficial infection of the skin caused by S. aureus and/or Folliculitis
Streptococcus beta haemolyticus. It is highly contagious in
infants and young children. It is more frequent in hot and humid It is staphylococcal infection of the hair follicle (Figure 2). It may
climates. be superficial or deep depending on the part of the hair follicle
involved. Follicles may be infected after epilation or after oil
Staphylococci produce exotoxins which provoke inflammation massage. Deep folliculitis involves the whole depth of follicle. It
of even intact skin. Streptococci can only infect the inflamed or commonly occurs on beard area (sycosis barbae) or neck
traumatised skin. (sycosis nuchae). Infection occurs through abrasions on shaving.
It starts as vesicles on an erythematous base, containing clear Generally there is no destruction of hair follicles.
fluid which becomes turbid in a day or two. In staphylococcal
impetigo vesicles enlarge and become bullae and rupture
after few days. In streptococcal impetigo, vesicles rupture fast,
forming a honey coloured, loosely adherent crust (Figure 1).
There may be regional lymphadenitis.
Diagnosis is straightforward. In recurrent cases one has to look
for pre-existing skin condition like pediculosis capitis, mosquito
bites or atopic eczema. Culture is seldom done unless it is not
responding to treatment or is recurrent.

Figure 2: Folliculitis.

Furunculosis (Boils)
There is extended involvement of hair follicles including the
perifollicular region in the dermis. It is caused by S. aureus. The
boils are common during adolescence and early adulthood and
are common during rainy season. Generally subjects are
otherwise healthy but have poor hygiene or are carriers of S.
aureus. In older patients factors like diabetes mellitus and intake
of corticosteroids may be responsible for their increased
frequency and greater severity.
Carbuncle
It is a group of boils which show deep infection of contiguous
follicles with S. aureus. Infection spreads from one follicle to the
other through subcutaneous tissue. Common sites are back of
neck, shoulders, hip and thighs. It is usually associated with
diabetes mellitus, exfoliative dermatitis or prolonged steroid
Figure 1: Impetigo contagiosa.
470 therapy.
 Cutaneous Infections
Erysipelas FUNGAL INFECTIONS OF SKIN
It is streptococcal infection of the skin, mainly upper There are two main groups of fungal infections of superficial
subcutaneous tissue and lymphatic vessels. The organism skin: (i) those due to dermatophytes and (ii) those due to yeasts.
enters through a wound, injury or even a subclinically A few fungi invade deeper tissues. These are the deep mycoses.
traumatised skin. Usually, there is a history of antecedent
Dermatophytoses (Tinea/ Ringworm)
streptococcal throat infection. Skin is tense, erythematous,
oedematous and lesions spread peripherally. Margins are These are classified according to sites affected. They are often
sharply defined. Sites of involvement are abdominal wall in self treated or wrongly treated with topical steroids which may
infants and face in children. confuse the picture (tinea incognito).

Cellulitis Tinea Capitis (Scalp Tinea)

It is a deeper variant of erysipelas and may be acute, subacute Usually a disease of pre-adolescents. Fungi may be contracted
or chronic. The borders are less well defined. There may be from family members having tinea anywhere on body, or
associated systemic symptoms of malaise and fever. school-mates with tinea capitis or from infected animals. There
is patchy loss of hair (only broken hair) with variable degrees
Secondary Bacterial Infection of inflammation (to differentiate from alopaecia areata in
Staphylococcus aureus and streptococci can complicate any skin which there is no inflammation and total loss of hair from the
disorder. root). There may be inflammatory tinea with boggy swelling
(kerion) (Figure 3). This is usually acquired from animals and
Management of pyodermas
is often misdiagnosed as pyoderma.
1. Improvement of local hygiene
2. Identification and elimination of immunocompromising
factors, if any suspected
3. Avoidance of insect bites in children
4. Staphylococcal carrier sites (anterior nares) be treated with
twice a day application of fusidic acid or mupirocin
ointment for 3 months
5. Topical antibiotics may be useful in preventing
streptococcal pyoderma when applied three times a day
for minor skin trauma in children. In crusted lesions the
crusts must be removed gently
6. Local application of heat is beneficial in cases of boils.
Topical treatment
Superficial localised skin infections like impetigo and superficial
folliculitis may respond to rigorous topical treatment with
antibiotic creams like fusidic acid or mupirocin. 1% gentian
violet is a cheap but effective option. Bacitracin, polymyxin and
neomycin are available in various preparations, often in
combinations.
Systemic treatment
These are needed for all but the most localised infections.
Streptococci are relatively easily amenable to treatment
with antibiotics. Penicillin group of drugs are effective. Figure 3: Tinea capitis (Kerion).
Staphylococcus has developed resistance to many anti-microbials.
Tinea Corporis
Empirically one can start with tetracyclines (including
doxycycline), or cotrimoxazole. Hospital acquired infections are The lesions are itchy, erythematous and scaly patches with well-
more often resistant and need treatment with cloxacillin, defined borders. The borders are more prominent and often
azithromycin or cephalosporins. Duration of treatment is 5 to 7 have papules and pustules. There may be central clearing so
days for superficial infections and up to 3 weeks for deep that annular or circinate patterns are formed (Figure 4).
infections. Tinea Cruris
It involves groins and buttocks. It is more common in adult
DISORDERS DUE TO OVERGROWTH OF CORYNEBACTERIA
males. Recurrence is usually due to autoinfection from
(DIPHTHEROIDS)
other sites like tinea pedis. Tight clothing and humidity are
These are commensals but persons who sweat more may predisposing factors.
develop malodorous axillae and trichomycosis axillaris (fine
yellowish deposits on axillary hair). In those who have Tinea Pedis and Tinea Manum
prolonged immersion of hands and feet in water develop These are common and often associated with tinea unguium
pitted keratolysis. (Figure 5). There are three distinct forms. 471
 Tinea Barbae
It is invasion of hairs of beard by fungus, resulting in inflammatory
lesion with follicular pustules. Usually due to unhygienic shaving
by road side barbers.
Tinea Faceii
It is infection of face outside the beard area. Face is involved if a
person has tinea of other sites or due to sharing towels with
another family member with tinea.
Treatment
Topical treatment alone is indicated when the disease is of
limited extent and only one site is involved. Clotrimazole,
miconazole, and terbinafine creams applied twice daily for
4 to 6 weeks are effective. On palms and soles where there
are hyperkeratotic lesions, Whitfield’s ointment is more
effective.
Systemic treatments include griseofulvin, triazoles and
Figure 4: Tinea corporis. terbinafine. Griseofulvin is the drug of choice for tinea capitis
in doses of 15 to 20 mg/kg body weight for 8 weeks. Triazoles
1. Tinea interdigitale. There is scaliness or maceration in the include itraconazole and fluconazole. Itraconazole 200 mg to
interdigital space. be given twice per day for 7 days for tinea cruris and corporis
2. Vesicles on sides of feet, extending to rest of soles. and for tinea unguium 400 mg daily for 7 days every month
for 3 months. Fluconazole 150 mg once or twice a week for 4
3. Dry and scaly type, often treated as eczema or psoriasis.
weeks for tinea cruris and corporis and for 6 months for tinea
Presence of typical tinea lesions on the dorsum of the foot
unguium. Terbinafine is given as 250 mg daily for 2 weeks in
and other parts of body may assist in diagnosis. In tinea
tinea cruris, corporis and manum; 3 months for tinea unguium
manum, the scales are powdery and start in creases.
of finger nails and 6 months for toe nails.
Tinea manum is most often unilateral.
YEAST INFECTIONS
Tinea Unguium
Most yeasts are true commensals and only invade skin under
Toe nail infection is common as isolated tinea or associated
certain conditions.
with tinea pedis. Free edge of nail becomes yellowish, crumbly,
then developing subungual hyperkeratosis and separation Pityriasis Versicolour
of nail from its bed (Figure 5). Usually starts with one or two Pityrosporum orbiculare, the causal organism, is a normal
nails, but rarely all are affected. Finger nail involvement is less inhabitant, grows profusely in humid climates and on certain
common and less severe and is always associated with tinea skin types. As the organisms are normal inhabitants, it is not a
manum. contagious disease. It commonly affects upper chest, back and
upper arms. Some patients may have mild itching. Even after
treatment the hypopigmentation may take a long-term to clear.
Recurrences in humid season are common.
Treatment
Topical treatment with selenium sulphide and/or clotrimazole
once weekly for few weeks. Oral fluconazole 400 mg single dose
is an alternative.
Candidiasis
Candida albicans is an opportunistic pathogen, found naturally
in the oral cavity and lower intestinal tract and vagina in half of
the normal population. Predisposing factors for symptomatic
invasion include obesity, high humidity, diabetes, pregnancy,
use of contraceptive pills, topical or systemic steroids or systemic
antibacterials. Its clinical picture varies with the site.
Oral
It is most common in children or the elderly. Persons on oral
antibacterials or immunosuppressants are also more prone.
It presents as thrush, which are white adherent patches that
leave an erythematous or bleeding surface on wiping off.
Figure 5: Tinea unguium.
There may be angular cheilitis.
472
 Cutaneous Infections
Flexures saturated solution of potassium iodide given for long periods
The areas commonly involved are inframammary, axillae, groins of time.
and between fingers. There is glazed erythema and maceration. Fungal mycetomas respond to ketoconazole 200 mg twice a
There may be satellite pustules. Often there is some burning day, or itraconazole 200 mg a day for 6 to 9 months.
sensation.
VIRAL INFECTIONS
Genital
Viral Warts (Verrucae)
White curdy discharge with erythema and pruritis are the features
of candidial vulvovaginitis. This may be associated with inguinal Caused by human papilloma virus (HPV). A few of these have
candidiasis. Conjugal infection in males results in balanitis oncogenic potential. Clinically they present variously
(in circumcised) or balanoposthitis. The glans becomes depending on the site involved.
erythematous and the prepuce is inflamed, indurated and Common Warts
becomes whitish.There is difficulty in retracting the prepuce. On
Rounded or irregularly shaped papules with rough and
forcible retraction fissures may develop on the prepucial orifice.
hyperkeratotic surface, on hands and feet. These may spread
Nail folds by autoinoculation and may be in a linear pattern. In severe
Common in bakers and housewives working with water. Proximal immunosuppression they may be generalised. These are
nail fold and later lateral nail folds get inflamed and swollen. On painful, if present around or under the nail. Lesions on the neck
pressing the nail fold, some cheesy material may be extruded. are often pedunculated (filiform warts).
This is called chronic paronychia. Proteus or Pseudomonas may Plantar Warts
be co-pathogens. Staphylococci or streptococci may secondarily
Warts on the soles are only slightly raised, even when they
infect producing acute paronychia (Figure 6).
assume large size. These may or may not be present on
pressure sites. Corns occur only on pressure points. Both are
painful particularly on walking. Warts if present only on
pressure points can be distinguished from corns by paring,
when oozing capillary loops can be observed in warts.
Plane Warts
These are flat topped, smooth, skin coloured or slightly dark,
usually present on the face in children. Lesions arranged along
scratch lines, if present, help in diagnosis.
Anogenital Warts
These are mostly sexually transmitted. Rarely these may result
from autoinoculation from warts on other parts of the body.
Lesions increase in number and size and coalesce to become
cauliflower like. In women these may also affect the vagina and
cervix. Other sexually transmitted infections (STIs) should be
excluded. In children with anogenital warts, sexual abuse should
Figure 6: Paronychia.
be considered.
Treatment Treatment
Topical gentian violet 1%, clotrimazole and miconazole and oral Topical treatment
fluconazole are effective. Dryness of the affected part needs to Keratolytics: In plane warts, topical tretinoin 0.05% to 0.1%
be maintained. applied at night for few months may be effective. In common
and plantar warts, ‘wart lotions’ or ‘corn lotions’ which contain
DEEP MYCOSES salicylic acid and lactic acid may be used only on the lesions,
There are many deep fungal infections but the most common protecting the surrounding normal skin, preferably after paring
among these is mycetoma. the affected skin. Trichloracetic acid (TCA) may be applied on
the lesions. In anogenital warts, 50% TCA may be applied once
Mycetoma (Madura foot)
or twice a week. On plane warts, this may be applied on the
It is caused by either filamentous bacteria (Actinomyces spp.) or wart with a sharp wooden toothpick.
fungi which are introduced by a penetrating injury. Indurated
nodules develop which enlarge and soften. These are often Cytotoxic agents: Podophyllum 20% is applied on the lesion
neglected and the process extends to deeper tissues and may and washed after 2 to 4 hours and repeated once a week.
even involve bone. The nodules burst on the surface producing Podophyllotoxin is safer to apply.
multiple sinuses discharging pus which is granular. The granules Formaldehyde 5%: Soles or palms can be soaked for 10 to 15
are colonies of infecting organisms. These are diagnostic. minutes per day.
Treatment Destruction: Electrosurgery, cryotherapy or scalpel excision.
Bacterial mycetomas respond to high doses of penicillin, Topical immunotherapy: Sensitisation with DNCB, topical
streptomycin, cotrimoxazole, tetracyclines, dapsone and imiquimod. 473
 Systemic therapy: Immunomodulators like levamisole. acyclovir 200 mg five times a day after food for 5 days may be
Cellular modifying agents like oral retinoids. given. Suppressive therapy is given in cases getting more than
6 recurrences a year. Acyclovir 400 mg twice a day for a year is
Molluscum Contagiosum recommended. Other antivirals for herpes simplex are
It is a common skin infection in school children. It is transmitted valacyclovir and famciclovir.
by direct contact and rarely through swimming pools. In adults
Varicella (Chickenpox)
lesions near genitals are often sexually transmitted. Large
lesions on the face may indicate immunosuppression. It is caused by varicella-zoster virus, which spreads by droplet
infection. Incubation period is around 2 weeks. Constitutional
The lesions are globular whitish or yellow papules which symptoms, which are absent or mild in children, are followed
develop a central depression (umbilication). Cheesy material by appearance of itchy papules which rapidly turn into vesicles.
can be expressed from a well developed lesion.
These become pustular in 3 to 4 days and finally get crusted.
Treatment Lesions appear in crops. The lesions are maximum on the trunk.
Options include topical application of phenol, TCA or 10% KOH The patient is infectious from prodrome to formation of crusts.
with a toothpick, curettage with a hypodermic needle or Treatment
cryotherapy.
This is only symptomatic. Acyclovir is indicated only for severe
Herpes Simplex attacks and for immunocompromised patients.
It is caused by herpes simplex virus, which has 2 strains HSV1 Herpes Zoster
and HSV2. HSV1 causes lesions around the oral orifice but
It is reactivation of V-Z virus lying in a latent phase in the sensory
genital lesions are generally caused by HSV2. The disease is
nerve ganglion. It may, however, transmit the virus to others
acquired by direct contact with an infected person. Once
and result in varicella in non-immune subjects.
infection is acquired it persists in the nerve ganglion all through
life. Recurrence is more common in genital herpes. Initial symptoms are burning sensation and pain, which is
followed by typical herpetic lesions. These are unilateral and
The first infection is often asymptomatic and passes off
distributed dermatomally. The lesions become pustular and
unnoticed in most people. In some children, however, there may
then crusted in 2 to 3 weeks. It may leave depressed scars on
be acute gingivostomatitis characterised by multiple vesicles
healing. If the ophthalmic division of trigeminal nerve is
and ulcers. There is regional lymphadenitis. In genital herpes, a
involved, corneal ulcers may develop. If there are vesicles on
similar picture may be seen. After the primary herpes simplex
side of nose, it indicates the involvement of the above nerve.
infection, the virus becomes latent and may remain so or may
get activated and present as recurrent herpes. The precipitating There may be persistent neuralgic pain after the lesions
factors include stress, fever, common cold, excessive exposure subside. This is usually seen in the elderly (post-herpetic
to sunlight and trauma. neuralgia).

Recurrent herpes I lesions usually occur on the same sites. There Treatment
is tingling or burning followed few hours later by erythema on As secondary bacterial infections are common, topical
which tense grouped vesicles appear. Vesicles dry and crust antibacterials may be used. Treatment is symptomatic, using
or erode. These heal in 7 to 10 days. In genital herpes, lesions analgesics. In older people with higher risk of post-herpetic
are painful. The recurrent, grouped vesicles on erythematous neuralgia and in ophthalmic zoster, oral acyclovir can be given.
base make diagnosis straightforward. Antibody titres do not rise The dose of acyclovir is 4 times that used in herpes simplex, i.e.
with recurrent infections and are of no diagnostic significance. 800 mg 5 times a day. It is useful only if given within first two
days of the attack. If post-herpetic neuralgia develops, this can
Treatment
be managed with long-term use of tricyclic compounds
As it is self-limiting, no treatment is indicated. Topical application (amitryptiline 25 mg BD) or gabapentine 300 mg to 900 mg
of surgical spirit keeps it dry and prevents secondary infection. daily.
Anti-viral drugs like acyclovir reduce viral replication and
shorten attacks. However, these are only effective if started at RECOMMENDED READING
the first sign of recurrence. Acyclovir (5%) needs to be applied 1. Valia RG, Valia AR. IADVL Textbook of Dermatology; 3rd Ed. Mumbai: Bhalani
every 4 to 5 hourly after removing the roof of the vesicles. Oral Publishing House; 2008.

474
 11.3 Infestations and Insect Bites

Devinder Mohan Thappa, Laxmisha Chandrashekar

INTRODUCTION Clinical features

Infestation refers to the state of being invaded or overrun by Often suspicion of scabies is based on nocturnal itching and
parasites. It can also refer to parasites living in or on a host. A family history of scabies. The pathognomonic lesions of scabies
parasite is defined as an organism that depends upon a living are burrows, which appear as fine, tortuous ‘S’ shaped slightly
host for one or more of its essential metabolic requirements. scaly blackish threads a few millimitres long. Sometimes, a
Cutaneous lesions may result from direct damage by or presence papulovesicle is visible near the blind end of the burrow
of the parasite. Scabies, pediculosis and papular urticaria are adjacent to which is the female mite. The burrows and
caused by ectoparasites; patients usually present with itching. associated papules and vesicles are directly related to the
presence of the Sarcoptes whilst the generalised rash is related
SCABIES to the development of sensitisation.
There are two main types—human scabies and animal scabies.
Most worrying to the patient is the papular pruritic eruption,
Human Scabies which is the result of hypersensitivity reaction to the mites
It is a contagious disease caused by the mite Sarcoptes scabiei and mite’s products. Sites of predilection (Figure 2) include
var. hominis contracted through close personal contact or the finger web spaces (Figure 3), borders of hands, sides of
contaminated clothing. Over-crowding and poor hygiene helps fingers, feet particularly the instep, wrists, axillae, areolae,
its spread. umbilicus (Figure 4), lower abdomen, genitals, buttocks
(Figure 5). An imaginary circle intersecting the main sites of
Sarcoptes scabiei var. hominis has an ovoid body, flattened involvement—axillae, elbow flexures, wrists and hands and
dorsoventrally. The adult female measures approximately groins has long been called the ‘circle of Hebra’. This
0.4 mm long by 0.3 mm broad, and the smaller male 0.2 mm predilection may be due to the fact that mites prefer non-hairy
long by 0.15 mm broad. There are 4 pairs of short legs; the anterior skin and areas of low sebum production. The involvement of
2 pairs end in elongated peduncles tipped with small suckers. In genitalia of males (Figure 6) and itching of nipples in females
the female, the rear 2 pairs of legs end in long bristles (setae) are important clues.
(Figure 1). The adult male mite dies after copulation with adult
female mite. After copulation the fertilised female mite excavates In babies, the presentation may be slightly different with vesicles
a burrow in the stratum corneum. Approximately 40 to 50 eggs and vesiculopustular eruption on palms and soles, extensive
are laid by each female during a lifespan of 4 to 6 weeks, during
which time she does not leave the burrow. Six-legged larvae
emerge from the eggs after 3 to 4 days and escape from the
burrow by cutting through its roof. The larvae then dig short
burrows (moulting pockets) in which they transform into nymphs.
After further moults, adult males and females develop. On an
average, an adult has 12 mites and an infant 20 mites.
First episode may take 3 to 4 weeks time to manifest. However,
reinfection provokes immediate symptoms both due to
immediate and delayed type hypersensitivity.

Figure 1: Sarcoptes scabiei var. hominis mite. Figure 2: Characteristic distribution of scabies lesions over the body in adults.
475
 distribution of burrows and crusted nodules including over the
trunk and limbs, and extensive eczematisation is seen. Unlike
in adults, the scalp and face may be involved in infants. In clean
individuals only few scattered papules may be seen and itching
may be mild.

Figure 6: Typical burrows of scabies along with papules over the shaft of the
penis.

Variants of scabies include nodular scabies and crusted scabies.

Bullous pemphigoid like eruption and cutaneous vasculitis are
Figure 3: Finger web spaces involved by papular and excoriated lesions. unusual presentations. Secondary changes may confuse the
clinical picture frequently. Secondary infection manifests as
folliculitis and impetigo and infection with beta haemolytic
streptococci may be responsible for secondary sepsis and post-
streptococcal glomerulonephritis. Eczematous changes are
common and severe.
Diagnosis
Scabies can be easily diagnosed based on history of nocturnal
itching, family history of itching and typical localisation
of lesions. Confirmation of diagnosis if desired may be
accomplished by demonstration of burrows, mites (Figure 1)
and mite’s products like scybala, eggs, etc. from skin scrapings
or epiluminescence microscopy. To identify burrows quickly, a
drop of India ink or gentian violet can be applied to the infested
area, and then removed with alcohol. Thin thread-like burrows
retain the ink.
Anti-scabietic agents used in the treatment include:
Figure 4: Papular eruption of scabies around umbilicus. Topical Agents
 Permethrin 5% cream
 Lindane (gamma benzene hexachloride) 1% lotion or cream
 Benzyl benzoate 10% and 25% lotion or emulsion
 Malathion 0.5% lotion
 Monosulfiram 25% lotion
 Crotamiton 10% cream
 Precipitated sulphur 2% to 10% ointment
 Esdepallethrine 0.63% aerosol
 Ivermectin 0.8% lotion

Oral drugs
In infants and pregnant women, sulphur ointment and
crotamiton is preferred. The 5% permethrin cream may be used
in infants over 2 months of age. In adults and children over
5 years of age, 5% permethrin cream is standard therapy for
scabies. In children less than 5 years of age, the cream must be
Figure 5: Papular and excoriated lesions over the buttocks.
476 applied to the head and neck, as well as the body.
 Infestations and Insect Bites
Single overnight application with permethrin is sufficient. crab louse is the smallest with a short oval body with prominent
However, gamma benzene hexachloride lotion needs to be kept claws resembling sea crabs. Lice feed by piercing the skin with
on the body for 8 to 12 hours. Benzyl benzoate if used, 3 their claws, injecting irritating saliva and sucking blood. The
applications need to be given at 12 hourly interval without female lays approximately 6 eggs or nits each day. The egg
intervening bath. Sulphur ointment though messy is thought hatches in 8 to 10 days and reaches maturity in approximately
to be most effective treatment given once daily for 3 days. 18 days. Nits are glued to the bases of hair shafts (Figure 8). The
Similarly, crotamiton may be used. Additional advantage with incubation period of pediculosis is about 30 days.
crotamiton is its antipruritic effect. Monosulfiram is available as
soap. Now even, gamma benzene hexachloride is marketed as
soap. Ivermectin, an antihelminthic agent can be given in a
single oral dose (200 μg/kg body weight, adult dose is 12 mg).
Side-effects include headache, pruritus, pain in the joints and
muscles, fever, maculopapular rash, and lymphadenopathy. It is
contraindicated in patients with an allergy to ivermectin and
central nervous system disorders. It is increasingly being used
in the treatment of scabies in India.
Symptomatic relief of itching can be achieved with antihistamines.
The older sedative antihistaminics are to be preferred over
newer non-sedative ones. Prior to anti-scabietic treatment,
secondary pyoderma and eczematisation should be treated
appropriately. Treatment of other family members is important.
Clothing and bedding can be laundered and put in sunlight. Figure 7: Pediculus humanus var. capitis (head louse) and Phthirus pubis (pubic
or crab louse).
Nodular Scabies
In some cases, itching nodules persist for several months on
the genitalia. They are found most commonly on the scrotum.
Topical therapy, intra-lesional steroids, tars or excision are
methods of treatment. Histologically, it may suggest lymphoma.
Crusted Scabies (Norwegian or Hyperkeratotic)
It is found in immunocompromised or debilitated patients,
including those with neurologic disorders, Down’s syndrome,
organ transplants, graft-versus-host disease, adult leukaemia,
leprosy, or AIDS. It is characterised by psoriatiform or warty
lesions accompanied by nail hyperkeratosis but no burrows and
minimal itching is present. The average number of mites in
these cases is 2 million; it is highly contagious and may be the
source of epidemics. Ivermectin is the treatment of choice in
addition to keratolytics.
Scabies incognito occurs on inappropriate use of topical steroids
as steroids suppress the inflammation to the mites and reduce
Figure 8: Viable nit (top left) and non-viable nit, empty egg case (bottom right)
itching, so there is less scratching and destruction of burrows. glued to hair.
Animal Scabies
Pediculosis Capitis
Various itch mites affect animals with which man comes in close
contact. These animals are dogs, cats, birds, etc. Itchy papular Lice infestation of the scalp is most common in children
eruption is localised to site of contact of animal with human especially girls with long hairs. Itching and secondary pyoderma
skin. The eruption is self-limiting, with no burrows. Animals in the scalp are presenting manifestations. The diagnosis is
need to be treated with anti-scabietic agents and symptomatic made by seeing the lice in the scalp or more often, nits glued to
treatment is given to the person concerned. the hair shaft (Figure 9) in the retro-auricular and occipital
region of the scalp. Ova close to the scalp are only viable; along
PEDICULOSIS the distal hair shaft are empty egg cases. Peripilar keratin hair
casts are remnants of inner root sheath that encircle the hair
Infestation with lice is called pediculosis. Lice are called
which can be mistaken for nits. While nits are firmly cemented
ectoparasites because they live on the body. Close personal
to the hair, casts move freely along the hair shaft.
contact or contact with objects shared by others helps in the
transmission of lice. They are classified as wingless insects Pediculocidal treatment with 1% permethrin rinse or gamma
because they have three pairs of legs. Three kinds of lice infest benzene hexachloride lotion/shampoo may be instituted.
humans: Pediculus humanus var. corporis (body louse), Pediculus Malathion, crotamiton and lindane have also been found to
humanus var. capitis (head louse) and Phthirus pubis (pubic or be effective. Combing with a metal or plastic comb after
crab louse) (Figure 7). The body louse is the largest and the conditioner (8% formic acid solution) is an adjunctive measure. 477
 In case of secondary infection of the scalp, cotrimoxazole may do frequently seasonal in incidence, and affecting predominantly
the dual function of treating pyoderma and killing all adult lice. children between the ages of 2 and 7 years. Adult cases are
Repeat treatment with pediculocidal agents may be necessary seen but are less common than childhood cases.
after 1 week, as they may not kill nits. Shaving the head will cure
Aetiopathogenesis
head lice but has poor patient compliance. Orally, ivermectin has
also been used. Family members and contacts should be treated. Papular urticaria is an allergic hypersensitivity reaction to
arthropod bites. The role of arthropods in papular urticaria
gradually gained support because of the following
observations:
1. The lesions usually appear in the summer months;
2. The disease is more common in lower socioeconomic
groups; and
3. Papular urticaria is seen with greater frequency among
households with pets.
The most commonly implicated arthropods are the mosquitoes,
bed bugs and the fleas.
Clinical Features
The condition consists of small, 3 mm to 10 mm diameter,
pruritic, urticarial papules, sometimes surmounted by a vesicle,
that are present on exposed areas of the body (Figure 10).
The papules may last from weeks to months and, in some
Figure 9: Nits glued to scalp hair. cases, years. They form in clusters and are characteristically
distributed on the extensor surfaces of the arms and legs.
Pediculosis Corporis (Vagabond’s Disease)
Pediculosis corporis is a disease of the unclean. Body lice live
and lay their nits in the seams of clothing and return to the skin
surface only to feed. It induces pruritus that leads to scratching,
copper coloured macules, wheals, lichenification and secondary
infection. The diagnosis is positively established by finding the
lice or nits in the seams of clothing. Body lice are vectors for
relapsing fever, trench fever and epidemic typhus.
Treatment is directed at clothing and bedding. Simple
laundering and ironing is successful. Permethrin or malathion
spray can be used to disinfect clothing.
Pediculosis Pubis
Phthirus pubis infestation is found in the pubic region, as well
as hairy areas of legs, abdomen, chest, axillae, arms and also
eyelashes (pediculosis palpebrum) and scalp rarely. Itching or
crawling sensation of something are the complaints in the
majority of patients. It is transmitted by close sexual contact,
hence a screening for sexually transmitted diseases should
be done. Diagnosis is made on seeing black speck like
bodies attached to the root of hair at an angle—the crab lice.
Occasionally, in fair skinned individual, one may encounter gray
blue macules (maculae caeruleae) varying in size from 1 to 2 cm
in the groin, inner thighs and sides of trunk. They are probably
caused by altered blood pigments.
Gamma benzene hexachloride lotion or permethrin may be used
topically for pediculosis pubis. For eyelash involvement a thick
layer of petrolatum can be applied twice daily or fluorescein can
be used. Shaving of pubic hairs is another alternative treatment.
Sexual partners should be treated simultaneously.

PAPULAR URTICARIA
Definition
Papular urticaria is a term used to describe a chronic or recurrent
Figure 10: Papular excoriated lesions over the lower limb of a child.
478 eruption of pruritic papules, often grouped in irregular clusters,
 Infestations and Insect Bites
The genital, perianal and axillary regions are not usually Treatment
involved. Excruciating pruritus frequently leads to excoriations, The treatment is based on identification and removal of the
which may become secondarily impetiginised. The lesions cause. Mild topical steroids and oral antihistamines can be used
generally persist for 2 to 10 days and may result in temporary to control pruritus. Oral antibiotics can be used for secondary
hyper-pigmentation once they resolve. infections. Disinfection of all pets along with fumigation of the
home in recommended. Patients should use insect repellent
Differential Diagnosis creams on the skin before venturing outdoors.
Differential diagnosis includes:
RECOMMENDED READINGS
 Scabies,
1. Flinders DC, Schweinitz PD. Pediculosis and scabies. Am Fam Physician 2004;
 Prurigo simplex, 69: 341-8.
 Urticaria, 2. Karthikeyan K. Treatment of scabies: Newer perspectives. Postgrad Med J
2005; 81: 7-11.
 Atopic dermatitis,
3. Nair TVG, Nair BKH, Jayapalan S. Diseases caused by arthropods. In: Valia
 Papular drug reaction, RG, Valia AR, editors. IADVL Textbook of Dermatologyl; 3rd Ed, vol. 1. Mumbai:
Bhalani Publishing House; 2008; pp: 397-431.
 Miliaria rubra and
4. Steen CJ, Carbonaro PA, Schwartz RA. Arthropods in Dermatology. J Am
 Allergic contact dermatitis. Acad Dermatol 2004; 50: 819-42.

479
 11.4 Eczemas

Ashok Kumar Bajaj

INTRODUCTION Exogenous Eczema

Eczema or dermatitis is a group of inflammatory skin diseases When the patient develops eczema as a result of the exposure
provoked by a wide variety of stimuli, i.e. direct injury from toxic of the patient’s skin to environmental noxious agents.
chemicals, mechanical trauma and immunological reactions.
In many cases both external and internal factors contribute to
The word eczema is derived from the Greek word ‘eczein’
the pathogenesis of eczema.
meaning ‘to boil over’ or ‘to effervesce’. The terms, dermatitis
and eczema are often used as synonyms, but the term eczema ATOPIC DERMATITIS (ATOPIC ECZEMA)
is preferably used for exudative dermatitis.
Atopic dermatitis is a common form of endogenous eczema
Depending upon the clinical manifestations, eczema can be and its incidence is increasing in India. The exact aetiology is
subdivided into the following three stages: unknown but genetic and environmental factors are probably
Acute Eczema equally important in the development of atopic dermatitis. A
family history of asthma, hay fever (rhinitis and conjunctivitis),
It represents wet dermatitis characterised by intense pruritus,
atopic dermatitis and even urticaria is common in patients with
erythema, oedema, papules, vesicles, oozing, crusting, and even
this condition. Around half of the children with atopic dermatitis
blister formation.
go onto develop asthma or hay fever or both. These disorders
Subacute Eczema are inherited as autosomal dominants with incomplete
It is characterised by diffuse erythema, oedema and scaling. In penetrance. The environmental factors which act as triggers for
this stage, oedema, vesiculation and oozing components come atopic dermatitis are climatic changes, food items (eggs, dairy
down. The lesion starts scaling. products, nuts, etc.), bacterial infection and dry skin.
Chronic Eczema Clinical Features
It is represented by severe itching, hyperkeratosis and Atopic dermatitis usually develops around the age of 3 months
lichenification (thickening, hyper-pigmentation and accentuated and is labelled as infantile eczema. It classically affects the cheeks,
skin markings). scalp and extensor surfaces of the limbs and trunk (Figure 1).
Just like clinical features, histopathology varies with the stage There is erythema, oedema and papulovesicular oozing lesions
of eczema. In the acute stage, there is spongiosis (intercellular with severe itching. It is the itch which produces the lesions rather
oedema) and intraepidermal spongiotic vesicle formation. than the lesions which cause itching. The affected children may
Features that predominate in the chronic stage are acanthosis sleep poorly and may be hyperactive. After a variable course of
(thickening of stratum malpighii with elongation of rete relapses and remissions the disease subsides in over 80% of the
ridges), hyperkeratosis (thickening of stratum corneum) and children by the age of 18 months. In the rest of them it continues
parakeratosis (nuclei seen in stratum corneum). In the subacute into childhood phase which is characterised by itchy papular
stage, there is combination of these two reaction patterns. lesions in the cubital and popliteal fossae, ankles, wrists, and sides
of the neck. The skin may also become thickened and rough
CLASSIFICATION
Eczematous disorders are classified according to the aetiology
(Table 1) as follows:
Table 1: Classification of Eczema
Endogenous eczema Exogenous eczema
Atopic dermatitis Irritant contact dermatitis
Seborrhoeic dermatitis Allergic contact dermatitis
Nummular eczema Photodermatitis
Pompholyx (Dyshidrotic eczema) Infectious eczematoid dermatitis
Asteatotic eczema
Stasis dermatitis
Juvenile plantar dermatitis
Lichen simplex chronicus

Endogenous Eczema
In this type of eczema, the course of the problem arises mainly
from the patient’s inherent constitutional factors and partly due
Figure 1: Atopic dermatitis (infantile eczema).
480 to the superimposed environmental factors.
 Eczemas
(lichenification). Patients often have fairly dry skin. Multiple (c) Oral antihistamines with sedative effects such as
scratch marks and abrasions are seen in patients with severe diphenhydramine, promethazine hydroxyzine and doxepin
itching. It affects the school and social life of such children. should be preferred to relieve pruritus.
In about two-thirds of the childhood eczema patients, the (d) Oral antibiotics like dicloxacillin, cephalexin and other
disease subsides by the age of puberty, and in the remaining it cephalosporins are useful in improving dermatitis by
continues on to the adult phase. The distribution in the adult controlling colonisation and secondary infection by
phase is similar to childhood phase with morphology of staphylococci.
subacute or chronic eczema. Relapses and remissions depend (e) In severe recalcitrant cases, to improve the quality of life,
upon the activation of various trigger factors like mental and systemic steroids, cyclosporine, azathioprine, mycophenolate
physical stress, climatic changes, secondary infection, etc. mofetil, low-dose methotrexate have been found to be
Common complications include secondary bacterial infection effective. Interferon gamma, narrow band ultraviolet B (UVB)
with staphylococci and viral infections. Most patients of atopic and psoralen and ultraviolet A (PUVA) have also been
eczema are colonised by Staphylococcus aureus all the time advocated in such cases.
with or without apparent evidence of infection and anti- Atopy means a genetically determined state of hypersensitivity
staphylococcal therapy frequently leads to improvement. This to environmental allergens and includes asthma, hay fever and
emphasises the role of bacteria in perpetuation of dermatitis. dermatitis. Early age of onset, severe itching, face and flexural
Common viral infections complicating atopic eczema are involvement, family or personal history of atopy, dry skin and
molluscum contagiosum and herpes simplex which can raised IgE are suggestive of atopic dermatitis.
become widespread. Kaposi‘s varicelliform eruption (eczema
herpeticum) is disseminated herpes simplex infection in an SEBORRHOEIC DERMATITIS
atopic dermatitis patient and it can be life-threatening if it is
Seborrhoeic dermatitis is a common chronic inflammatory
primary infection by the herpes virus.
disorder with a characteristic distribution of lesions in the areas
Management rich in sebaceous glands. The exact cause of the disorder is as
There are hardly any confirmatory laboratory investigations for yet unresolved, but overgrowth of the yeast Malassezia furfur/
the diagnosis of atopic eczema. The classical morphological Pityrosporum ovale has been implicated as a causative factor.
pattern, i.e. dry skin, severe itching, clinical course, history This is further supported by increased incidence of seborrhoeic
of atopy in the family/patient, and raised IgE serum levels dermatitis in acquired immune deficiency syndrome (AIDS)
strongly suggest the diagnosis. The management has to be patients with extensive involvement. Seborrhoeic dermatitis has
individualised depending upon severity, age, complications and a bimodal occurrence and can manifest in early infancy
associated disorders. (infantile seborrhoeic dermatitis); or adult life (adult seborrhoeic
dermatitis), but the two are not related.
General principles
(a) Avoid aggravating external factors like extreme variations Infantile Seborrhoeic Dermatitis
of temperature, contact with woollen and synthetic clothes. It generally appears in the first three months of life. The areas
(b) Skin barrier should be restored by using mild neutral pH affected are the scalp, face, axillae, and napkin areas. The scalp
soaps and liberal use of emollients. shows erythema and sticky scales (cradle cap). The napkin area
(c) Food items like dairy products, nuts, eggs, fish, etc. may be may be sore and weepy but there is no itching unlike atopic
avoided though their role is questionable. eczema. It usually remits in a couple of months. Oil applications,
mild shampooing may suffice in most of the cases, but some may
Pharmacotherapy require application of steroid and antifungal agents topically.
The pharmacotherapy is aimed at controlling the acute attacks
Adult Seborrhoeic Dermatitis
and keeping the disease under control till remission. Various
effective topical and systemic agents are: Occurs commonly in the age group of 20 to 40 years. Pityriasis
capitis (dandruff) is probably the mildest form of the disease. In
(a) Topical corticosteroids of appropriate potency taking into
severe cases there is marked erythema, scales, and even
consideration the age of the patients and extent of
exudation on the scalp. Red, somewhat greasy-looking scales are
involvement. Prolonged use of topical steroids should be
also seen on other areas rich in sebaceous glands like the face,
discouraged to minimise side effects like skin atrophy nasolabial folds, front and back of the upper chest, retroauricular
and side effects due to systemic absorption. Potent areas , eyebrows, and eyelids (blepharitis). Some patients develop
corticosteroids are quite affective but should be used in lesions in the axillae and groins which may be mild or quite
short bursts to overcome acute attacks and then followed- troublesome. Though the severity of the disease may fluctuate,
up by low potency steroids and other agents. the tendency persists throughout life. Dandruff is treated with
(b) Topical immunomodulators like tacrolimus 0.03 to 0.1%, shampoos containing selenium sulphide, zinc, pyrithione, tar,
pimecrolimus are effective alternatives for topical ketoconazole or fluconazole. To treat mild to moderate cases of
corticosteroids especially for the face and flexural skin due seborrhoeic dermatitis, mid-potency topical steroids and topical
to their minimal side effects, except initial burning and antifungal agents are sufficient. More severe cases may require
irritation. Pimecrolimus can be used under the age of oral ketoconazole or fluconazole and systemic steroids. Oral
2 years while tacrolimus should be preferred for older age antibiotics and antihistamines can be prescribed as and when
groups. required. Isotretinoin in smaller doses of 20 mg on alternate days
is also quite effective in treating seborrhoeic dermatitis. 481
 Seborrhoeic dermatitis commonly affects the face, scalp, front bilateral symmetrical lesions, fungal infection of the feet should
and back of chest of adults in the 20 to 40 years age group. be ruled-out by KOH examination and contact sensitivity should
be ruled-out by patch testing. Nickel and chromate as well as
NUMMULAR ECZEMA (DISCOID ECZEMA) neomycin and quinoline contact sensitivity have been
Nummular eczema is a chronic and recurrent endogenous implicated to produce pompholyx lesions. Ingestion of nickel,
eczema of unknown aetiology. Many cases have an atopic chromate and cobalt can elicit lesions even if the patch
background. It manifests as itchy, multiple, sharply demarcated, tests are negative. The acute form is treated with soaks and
coin shaped or oval lesions with papulovesicles (Figure 2) or compresses of potassium permanganate and topical steroids.
papules and scales on an erythematous base. It is more Subacute and chronic stages are treated with topical steroids
commonly seen in the elderly with dry skin and usually affects and dapsone. In severe cases oral steroids and even
the extensor aspects of extremities. The course of the disease methotrexate (15 to 20 mg weekly) may be required. Majority
varies from a few months to a few years with recurrences and of patients who are sensitive to metals improve markedly on
remissions. Treatment consists of avoidance of contact with low nickel diet (avoid canned foods, beans, mushroom, onions,
irritants, mid-potency topical steroids, and resistant cases may corn, spinach, tomatoes, peas, whole grain flour, cocoa,
require systemic steroids,antibiotics and sedating anti-histamines. chocolate, baking powder, etc.).

ASTEATOTIC ECZEMA (WINTER ECZEMA; ECZEMA CRAQUELE)

Asteatotic eczema is an endogenous eczematous disorder
that is caused by excessive dryness and chapping of the skin.
Factors leading to dryness are reduced skin surface lipid, low
humidity and decreased water binding capacity of the stratum
corneum. It is a form of subacute eczema that is low grade with
aggravation in winter season. Clinically, it is characterised by
dry scaling and cracking giving the skin a fissured appearance
(Figure 4). Later, the skin may become red and inflamed. It
commonly affects the lower limbs, trunk, arm, and hands of
elderly males but the face and moist flexural areas are often
spared. Rarely, similar changes may be widespread requiring
exclusion of underlying lymphoid malignancy. Treatment
of asteatotic eczema involves the removal of underlying
aggravating factors and rehydration of the skin surface by
advocating the use of greasy emollients, bath oils and emollient
Figure 2: Nummular eczema. cleansers. Mild or mid-potency topical steroids for a short period
may be required, but oral steroids should be avoided.
POMPHOLYX (DYSHIDROTIC ECZEMA)
Pompholyx is a distinctive, chronic relapsing, vesicular
eczematous dermatitis of unknown aetiology. It affects young
adults and is characterised by sudden crops of highly pruritic,
deep-seated sago-like vesicles on the palms, sides of fingers
and/or soles (Figure 3). The disease may be isolated,
asymmetrical or bilaterally symmetrical. Summer aggravation
is common and lesions frequently get secondarily infected.
Vesicles resolve slowly over 1 to 3 weeks. In patients with

Figure 4: Asteatotic dermatitis.

STASIS DERMATITIS (GRAVITATIONAL ECZEMA/VARICOSE

ECZEMA)
Stasis dermatitis is a chronic relapsing eczema that occurs
secondary to venous incompetence and hypertension. It
commonly affects middle-aged or elderly individuals. It usually
begins as pruritic, dry scaling skin on the medial aspect of the
leg above the ankle that later becomes fissured, erythematous
Figure 3: Pompholyx (dyshidrotic eczema).
482 and hyperpigmented (Figure 5). The skin may become thin
 Eczemas
and atrophic. Fibrosis may lead to tight, bound-down, indurated The treatment consists of use of potent topical steroids alone
skin prone to chronic ulceration. Secondary spread of or in combination with keratolytic agents under occlusion
eczematous eruptions to distant sites is common and may except in cases with genital involvement. Anxiolytics and
indicate allergic contact sensitivity to topical medicaments sedating antihistamines are helpful. PUVA, UVB therapy and
which is not uncommon in varicose eczema. The management sometimes immunosuppressants may help some patients.
requires rest, elevation of the legs, and use of elastic bandages
or stockings. Only mild topical steroids should be used to relieve CONTACT DERMATITIS
irritation and to minimise atrophy. Surgical intervention may Contact eczema develops as a result of contact with injurious
be helpful in some cases. material. These materials may injure by direct toxic action
(irritants) or may induce immunological reaction of delayed
hypersensitivity type (allergens). The first type of reaction is
known as irritant contact dermatitis whereas the latter is termed
as allergic contact dermatitis.
Irritant Contact Dermatitis
This type of dermatitis occurs due to contact with irritants like
detergents, acids, alkaline chemicals, oils, organic solvents,
oxidants, and reducing agents. The intensity of the inflammation
is related to the concentration of irritant and the exposure time.
Mild irritants cause dryness, fissuring and erythema (cumulative
irritant dermatitis; wear and tear dermatitis) and strong irritants
may produce an immediate reaction characterised by burning,
erythema, oedema, blistering, and possibly ulceration of skin
(Figure 6). Housewife‘s eczema, diaper dermatitis and industrial
dermatitis are common examples of cumulative irritant contact
dermatitis. Housewife‘s dermatitis and industrial/occupational
dermatitis commonly affect the hands.
Treatment of acute irritant dermatitis requires washing quickly
with water or a weak neutralising solution or frequent wet
compresses, followed by the application of a bland or
Figure 5: Stasis dermatitis. antibacterial with mid-potency steroid cream. For chronic cases,
removal of all adverse chemical and physical factors and the
JUVENILE PLANTAR DERMATOSIS (DERMATITIS PLANTARIS use of bland barrier creams and mid potency topical steroids
SICCA) are necessary along with protective gloves.
It is a common dermatosis of childhood characterised by shiny,
dry, fissured skin of the soles with loss of the epidermal ridge
pattern. The sites affected are the weight-bearing areas
particularly the forefeet and undersides of the toes. The toe
webs and instep are spared. It is thought to be due to excessive
sweating and blockade of sweat ducts due to occlusive
footwear. Some consider the condition to be a manifestation
of atopy. The condition is usually worse during winter and
sometimes during dry summer season. It usually subsides
during late teens.
The treatment consists of avoiding occlusive footwear, and
preferably to use cotton socks. Emollients are usually effective
but topical steroids of mid potency may be required in patients
with itching and discomfort.

LICHEN SIMPLEX CHRONICUS

Lichen simplex chronicus also known as neurodermatitis, it is a Figure 6: Irritant dermatitis.
localised patch of chronic eczematous inflammation which is
created by habitual scratching in predisposed individuals. Allergic Contact Dermatitis
The initiation and perpetuation of the lesions is due to the It is a type IV delayed type hypersensitivity reaction mediated
development of an ‘itch-scratch’ cycle. It is characterised by a by T-lymphocytes against certain chemicals coming in contact
lichenified plaque and many of these patients have an atopic with the skin. In India, the common sensitisers are metals (nickel,
diathesis. The areas most commonly involved are those that are chromium), plants (parthenium, also known as congress grass),
conveniently reached. These sites are nape of the neck, ankles, antibacterial agents (neomycin, nitrofurazone), rubber
legs, forearms, wrists, and genitalia (scrotum or mons pubis). chemicals (mercaptobenzothiazole, thiuram) and hair dyes/Kali
Emotional factors have an exacerbating effect. Mehndi (paraphenylenediamine), etc. The eczematous rash 483
 often develops at the sites of skin contact with the allergen
but an irritant dermatitis eruption can develop at distant sites.
Moreover, autoinoculation of the antigen can lead to widespread
lesions. Parthenium dermatitis is the most common and severe
type of allergic contact dermatitis seen in India. It is caused by a
weed Parthenium hysterophorus (Figure 7) which grows wild
along roads, railway tracks and in the fields. It commonly manifests
as air-borne contact dermatitis affecting mainly the face including
the eyelids, neck, flexures of the extremities, and sometimes the
whole body surface may be involved (Figure 8). Distribution
of lesions on sun-exposed areas is not uncommon. There is
worsening during summer and rainy season while the lesions
undergo partial or complete remission during winter.

Figure 9: Ear ring dermatitis.

Figure 7: Parthenium hysterophorus.

Figure 10: Footwear dermatitis.

Figure 8: Parthenium dermatitis.

Nickel sensitivity is quite common and manifests as dermatitis

due to ear rings (Figure 9), bangles, necklace, zips, metal buttons,
and safety pins. Occupational nickel sensitivity affects the hands. Figure 11: Topical medicament dermatitis.
Chromium allergy is also quite common and is usually due
to leather footwear, cement and ink. Footwear dermatitis undetected due to its use with topical steroids. Hair dye
(Figure 10) is another common type of allergic contact dermatitis is also not uncommon and it is becoming common
dermatitis in our country due to the hot and humid weather. due to high concentrations of paraphenylenediamine (PPD) in
Rubber and leather are the most common causes. Topical Kali Mehndi (black henna) (Figure 12). Other types of allergic
medicament dermatitis (Figure 11) is commonly due to contact dermatitis peculiar in our country are bindi dermatitis
nitrofurazone and neomycin. Neomycin sensitivity is quite often (Figure 13), black henna dermatitis (Figure 14), and tooth
484 superimposed on varicose and footwear eczema, and remains powder dermatitis (Figure 15).
 Eczemas
Figure 12: Hair dye dermatitis. Figure 15: Tooth powder dermatitis.

The common allergens in India are metals (nickel, chromium),

rubber chemicals (mercaptobenzothiazole), Parthenium
(a weed), medicaments (nitrofurazone, neomycin) and hair dye
(PPD).
Medicament dermatitis is fairly common in patients of stasis
dermatitis, footwear dermatitis and atopic dermatitis.

PHOTODERMATITIS
It is the result of exposure of skin to sunlight following the
topical or systemic administration of certain photosensitising
agents (drugs and chemicals). Photodermatitis could be either
phototoxic or photoallergic and is mainly distributed over the
sites exposed to light. For further details, refer to the chapter
titled ‘photosensitivity dermatoses’.

INFECTIOUS ECZEMATOID DERMATITIS

Figure 13: Bindi dermatitis. Infectious eczematoid dermatitis or infective eczema or
bacterial eczema is caused by an allergic reaction to micro-
organisms or their products. It manifests as advancing
erythema with exudation and predominantly affects
the retroauricular areas, scalp, legs and areas around
the discharging sinuses and wounds. The eczema responds
to treatment with appropriate topical and systemic
antibiotics.

AN APPROACH TO A CASE OF ECZEMA

Diagnosis of eczema is based on the clinical features (especially
morphology and distribution). The predominant features
depend upon the stage: lesions in acute eczema are often
exudative while chronic eczema is associated with severe
pruritus, scaling and lichenification. The next important step
is to differentiate between endogenous and exogenous
eczema.
Figure 14: Black henna dermatitis.
Clinical features suggestive of an endogenous eczema are
bilaterally symmetrical distribution of lesions and well
Diagnosis of allergy is confirmed by patch testing. Management established patterns of lesions, e.g. atopic dermatitis or
includes detection and avoidance of contact sensitisers, use seborrhoeic dermatitis. Clinical features suggestive of an
of barrier creams and topical steroids of appropriate potency. exogenous eczema are asymmetrical distribution, linear or
For severe attacks, systemic steroids, azathioprine, methotrexate rectilinear configuration of lesions, history of contact with
and even cyclosporine can be used. Azathioprine is quite irritant and/or allergens, and improvement on change of
effective in parthenium dermatitis as a steroid-sparing agent. environment.
485
 INVESTIGATIONS GENERAL MEASURES
Although clinical examination is quite sufficient to suggest the Identification of any offending allergen, irritant or triggering
diagnosis of eczema, as a general rule it is advisable to treat factor is very important. Adequate measures to avoid the
acute eczemas without investigations. On the other hand, offenders may help in treating the dermatitis.
chronic and recurrent eczemas should be investigated
Eczemas like atopic dermatitis and asteatotic dermatitis are
thoroughly to find the cause of eczema.
associated with dry skin and hence increased susceptibility to
Patch Testing irritants. Maintaining proper hydration of the skin is important
It is the only scientific method available to confirm the in treating dry eczema.
diagnosis of allergic contact dermatitis but is not useful Topical Treatment
for irritant contact dermatitis as it detects the allergens
Wet compresses with a solution of either potassium
responsible for type IV allergy only. It should be performed
permanganate (0.01%/light pink colour) or aluminium sulphate
after the acute stage subsides. A series of allergens in adequate
(0.65%) followed by application of steroid lotion/cream is
concentration are applied on the back with adhesive tape and
best in the oozing stage of eczema. These compresses help by
left on for 2 days. The readings are taken on day 2 and day
suppressing inflammation, removal of crusts, have antibacterial
4. The offending allergens will produce erythema and
action and cause drying of the lesions.
papulovesicles at the site of application. A good patch test
should indicate contact sensitisation and produce no false In the subacute stage, wet compresses should be discontinued
positive reactions. and only mid-potency topical steroid cream can be prescribed.
Photopatch Testing Chronic eczema requires potent steroid in ointment base for
These tests are performed to find the cause of photo allergic topical application. In lichenified lesions, a topical steroid can
contact dermatitis. It should be performed in photo distributed be combined with keratolytic agents like salicylic acid or urea.
dermatitis. In photopatch testing also, the patches of chemicals For secondary bacterial infection a topical antibiotic can be
are applied as for ordinary patch testing, except that they are combined with a steroid.
applied in duplicate and after 24 hours one set of patches is Systemic Treatment
removed and the underlying skin is irradiated with ultraviolet
A short course of systemic steroids may be needed for extensive
light. After irradiation, the patch sites are covered again and
lesions and when an irritant dermatitis eruption (spread of an acute
evaluated at day 2 and day 4.
inflammatory dermatitis to distant sites is termed irritant dermatitis
Prick Testing eruption or autosensitisation) develops in acute eczema.
These are performed to detect the type I hypersensitivity Systemic antibiotics are required for infected lesions.
reactions. Relevance of positive prick tests in establishing the
cause of the eczema is questionable. Oral antihistamines may be prescribed, as and when required,
but may not be helpful in contact dermatitis. Steroid sparing
Serological Testing agents like methotrexate in small weekly doses, azathioprine,
Estimation of total serum IgE and IgE antibodies specific and even cyclosporine may be required in recalcitrant cases like
to certain antigens are useful diagnostic criteria for atopic atopic dermatitis, parthenium dermatitis, etc.
dermatitis. Radio-allergosorbent test (RAST) is helpful to detect
specific dietary environmental allergens, which could be RECOMMENDED READINGS
aggravating the dermatitis, especially in atopics. 1. Bajaj AK, Sharma R, Dhar S. Dermatology, Leprosy and Sexually Transmitted
Infections; 2nd Ed. New Delhi: Jaypee Brothers Medical Publishers;2010:
Skin Biopsy pp. 43-51.

A skin biopsy is rarely required to diagnose the eczema and 2. Graham-Brown R, Bourke J. Mosby’s Colour Atlas and Text of Dermatology.
2nd Ed. Noida, India: Elsevier Ltd.; 2008: pp182-205.
histopathological findings will depend upon the stage.
3. Habif TP. Clinical Dermatology; 4th Ed. New Delhi: Mosby (Elsevier); 2007:
pp 41-128.
TREATMENT
4. Rycroft RJG, Robertson SJ. Colour Handbook of Dermatology. International
Successful management of dermatitis requires a multipronged Ed. London: Manson Publishers Ltd; 2008: pp14-25.
approach. Apart from the specific therapy, appropriate general 5. Valia RG, Valia AR. IADVL Textbook of Dermatology; 3rd Ed. Mumbai: Bhalani
measures are very helpful in treating the eczemas. Publishing House; 2008: pp 490-527.

486
 11.5 Drug Reactions

M Ramam

INTRODUCTION All eruptions that develop following drug intake are not drug
A fairly large number of drug reactions present with a skin rash. eruptions. The eruption may be related to the underlying
Patients who are taking medicines and develop a skin eruption disease and may have manifested itself later in the course of
pose an important clinical challenge because a decision needs the illness after medication was begun, e.g. viral exanthems or
to be taken whether the drug can be continued safely or should rashes of connective tissue disease. Or, the eruption may be due
be changed. to an unrelated disorder of the skin that developed during
treatment for another illness, e.g. pityriasis rosea developing in
A simple way to avoid this problem would be to stop using those a child on anticonvulsant therapy or scabies in a man receiving
drugs that cause reactions. But if we look at the list of drugs antituberculosis therapy.
causing reactions, we find that these are medications which are
commonly used (Table 1). Unfortunately, there is no way of TYPES OF ACUTE CUTANEOUS DRUG ERUPTIONS
predicting which patient will develop a reaction and which It is commonly stated that drug eruptions are great mimics
patient will not and so there is no good way of preventing drug and that any eruption can be caused by drugs. Fortunately,
reactions. We will continue to be faced with this problem as there is a limited number of ways in which the vast majority
long as we use drugs to treat our patients. of important drug eruptions present and this is helpful in
recognising them. But it is good to remember that eruptions
Table 1: Drug Groups Usually Causing Eruptions
that closely resemble drug eruptions can be caused by other
Nonsteroidal anti-inflammatory drugs agents including viral infections, connective tissue diseases and
Antibiotics other skin diseases, among other causes.
Anti-tuberculosis drugs
Urticaria and Anaphylaxis
Anti-convulsants
This is probably the most common type of drug reaction and
A genetic suspectibility to certain drug eruptions has been presents with itchy wheals. Typically, the wheals are irregular
identified, e.g. HLA B*1502 is associated with carbamazepine and amoeboid in shape. Individual lesions last a few minutes
reactions and in South-Asian populations where this allele is to hours but new wheals often continue to appear leading
frequent, it is recommended that HLA typing be performed some patients to state that the wheals do not subside. If
before prescribing the drug. The presence of certain infections the reaction is severe, wheals may be widespread and
make drug eruptions more likely, e.g. infectious mononucleosis accompanied by hypotension, bronchospasm, abdominal pain
and human immunodeficiency virus infection. However, in and syncope. Non-steroidal anti-inflammatory drugs are a
the vast majority of patients there are no identifiable factors common cause.
that can be used to predict (and prevent) the development of
Exanthematous Eruptions (Figure 1)
drug eruptions. At the level of a community, the strongest
determinant of which drugs cause reactions appears to be the This is also a common type of drug eruption. Exanthematous
prescription practices of its physicians. The most robust method or morbilliform rashes present as symmetrical, generalised, itchy,
of preventing drug reactions is to use drugs only when required. erythematous, small and large inflamed papules with a

Typically, drug reactions do not occur at first exposure to a drug.

Usually, the drug has to be first taken for about a month before
a reaction develops. However, once a reaction has developed,
subsequent exposure to the drug will lead to a reaction within
a few hours after re-exposure. Stopping the drug leads to
improvement of the eruption over the next few days.
Development of a drug eruption after the drug has been
stopped is distinctly unusual and indicates that the diagnosis
may be incorrect.
Drug eruptions can be suspected if a widespread, symmetric,
itchy, rapidly progressive rash develops in a patient taking
medications. In such a situation, it is wise to stop the drugs being
taken and seek an urgent medical/dermatological consultation.
If the rash is accompanied by fever, a feeling of being ill, or
blisters and ulcers in the skin and mouth, a severe drug reaction
Figure 1: Exanthematous (or maculo-papular) drug rash. Symmetrical, extensive,
is likely. Less severe drug eruptions may manifest as localised
itchy erythematous eruption.
areas of redness and inflammation. 487
 tendency to coalesce. In the early stages, it may be difficult to
differentiate the oedematous papules of an exanthem from a
wheal, but persistence of individual lesions for longer than 24
hours excludes urticaria.
Erythroderma
Persistent exanthematous eruptions evolve into erythroderma
or exfoliative dermatitis. Some eruptions begin as erythroderma
from the beginning. There is redness and scaling over most of
the skin surface accompanied by severe itching.
Photosensitive Drug Eruptions (Figure 2)
Some drugs produce an eruption only on areas exposed to
sunlight. The appearance of the rash can range from erythema
to papules and blisters. The distribution of the rash
predominantly on exposed skin with relative or complete
sparing of covered areas is the most important clue to this type
of reaction.

Figure 3: Toxic epidermal necrolysis. Extensive, confluent, superficial brown

necrosis of the skin.
Figure 2: Photosensitive eruption. Erythema and oedema in a butterfly
distribution. The patient was taking doxycycline.

Vesicular/Bullous/Pustular Eruptions
When inflammation is severe, fluid-filled lesions may develop
leading to clear vesicular eruptions. Some eruptions consist
predominantly of pustules (which are typically sterile).
Constitutional symptoms often accompany these eruptions.
Erythema Multiforme/Stevens-Johnson Syndrome/Toxic
Epidermal Necrolysis
This group of disorders is characterised by necrosis of the
skin of varying extent. In erythema multiforme, there are
erythematous papules and small plaques which show central
darkening due to necrosis. Stevens-Johnson syndrome shows
similar skin lesions accompanied by severe mucosal erosions
and fever. Toxic epidermal necrolysis is characterised by dark
Figure 4: Fixed drug eruption. Circumscribed, pigmented, inflamed macule.
brown necrosis of large areas of the skin accompanied by fluid
collection and erosions (Figure 3). The mucosae of the eyes,
mouth and genitals is often affected and bronchial mucosa may The lesions tend to be circular and to be limited in number but
also be involved. These patients are usually very ill. some patients may develop widespread lesions that may be
difficult to differentiate from Stevens-Johnson syndrome or
Fixed Drug Eruption toxic epidermal necrolysis. Lesions subside with a characteristic
In fixed drug eruptions, intake of a drug leads to inflammation brown-black pigmentation that is very persistent. Subsequent
of the skin and or mucosae at exactly the same sites in every exposures to the drug lead to inflammation of all previously
episode (Figure 4). In the acute phase, there is redness affected sites and may be accompanied by the development
488 accompanied by blistering and erosions if the reaction is severe. of new lesions.
 Drug Reactions
SUBACUTE/CHRONIC DRUG ERUPTIONS In severe reactions, systemic corticosteroids are required, and
These eruptions develop over a longer period of time and are usually administered as a short, sharp course that is tapered
can take long to subside, in spite of the causative drug having rapidly over 2 weeks. There is controversy about the use of
been stopped. Such eruptions include lichen planus-like drug systemic corticosteroid therapy in toxic epidermal necrolysis
eruptions, lupus erythematosus-like drug eruptions and but most workers believe that the drugs are effective in the
pemphigus and pemphigoid-like eruptions. The resemblance early, inflammatory stage of the disease. Slower tapering over
of the eruption to the idiopathic disease can be remarkably about 4 weeks is recommended in exanthematous drug
close on clinical, histopathological and immunological criteria. eruptions and even longer therapy is required in drug-induced
The diagnosis is usually made on careful history-taking and erythroderma.
subsidence of the eruption on discontinuing the causative drug Supportive care is paramount in the treatment of severe drug
(though this may be delayed). eruptions as these may lead to reduced intake and painful
micturition because of oral and genital erosions, fluid and
SYSTEMIC MANIFESTATIONS
electrolyte imbalances, renal failure, pneumonitis following
Severe drug eruptions may be accompanied by constitutional bronchial mucosal erosions and transaminitis as a consequence
symptoms, signs, and laboratory abnormalities. Fever, of liver involvement.
pneumonitis, eosinophilia and transaminitis are frequently
noted. Typically, they resolve along with the drug eruption DRUG THERAPY DURING AND FOLLOWING A DRUG
though subsidence may be delayed till after the rash has REACTION
subsided. Which drugs are safe in a patient who has had a drug reaction?
LABORATORY TESTS This question comes up while caring for patients suffering
from a drug reaction (and also after they have recovered from
There are no laboratory tests that reliably help to diagnose an the reaction but require treatment for another illness). The
eruption as a drug rash or to identify the causative drug. simple answer is that all drugs are safe except the causative
Haematological, biochemical, and radiological investigations drug. There is no need to prescribe ‘safe’ drugs that are
provide information on the involvement of other organ systems, reported to cause eruptions less frequently. To spell this out,
such as the liver, lungs and bone marrow. there is no safe antibiotic, anti-convulsant, nonsteroidal anti-
TREATMENT inflammatory drug or anti-tuberculosis drug that can be
uniformly given to a patient who has developed a drug
Once an eruption is confirmed or strongly suspected as being
reaction. The list of drugs that are safe will vary from one
a drug eruption, the first principle of treatment is stopping the
patient to another depending on the drugs taken before the
causative drug. Unfortunately, there are no reliable methods to
onset of the reaction.
identify the causative drug quickly in the setting of an acutely
ill patient with a drug reaction. It is common practice to stop In real life, this situation is complicated by the fact that a large
the most recently introduced drug in the belief that it is the number of drugs may be suspected to be the cause. In such
most likely causative drug, but this may not be correct. Similarly, cases, the group of drugs suspected to be the cause of the
educated guesses about which one of the several drugs caused eruption should be avoided; drugs from chemically dissimilar
the eruption can be mistaken. In view of this, when the reaction groups can be used. Additional challenges include the
is severe, all but absolutely essential drugs should be stopped. multiplicity of brand names under which a particular
Essential drugs should be substituted by chemically unrelated molecule is sold in different markets. This makes it difficult
drugs, if these are available. When the reaction is less severe to identify the drug even when the patient is carrying a
and it would be difficult to stop all drugs, one or a few drugs prescription. Over-the-counter (OTC) dispensing of
that are suspected to be the cause can be stopped and the medications without a prescription or other record by
patient closely monitored. If the rash improves, it is likely that chemists, practitioners of alternative systems of medicines,
the causative drug was correctly identified. However, if the rash and even doctors, is another hurdle in evaluating drug
does not improve, or it worsens, other drugs will also need to eruptions. Hostility to the prescriber of drugs that caused a
be stopped. reaction also makes it difficult to find out the medicines that
were prescribed. A phone call to the prescribing physician is
The second principle of the treatment of drug eruptions is
a simple technique that can provide much useful
suppression of inflammation. If the reaction is mild or
information.
diagnosed early, stopping the drug may be enough to achieve
this goal. In urticarial eruptions characterised by the Techniques to identify the causative drug include intradermal
development of wheals, anti-histamines are specifically and testing, patch tests and in vitro tests using the lymphocyte
highly effective in controlling the eruption. However, other transformation test or the lymphocyte toxicity assay, but there
types of drug eruptions are not mediated by histamine and are problems with the availability, applicability and reliability
antihistamines are not as effective and provide only some of these tests. Challenge or provocation tests consist of the
relief in itching. They should not be considered ‘anti-allergic’ administration of a small dose of the drug under medical
drugs useful in all types of drug reactions. Other measures to supervision in an in-patient setting where reactions can be
relieve symptoms of itching and burning include the use of diagnosed and treated early. The goal of challenge testing may
cold compresses. Anaphylactic reactions require adrenaline be to identify the causative drug, or more conservatively and
injections along with other measures used in the treatment pragmatically, it can be used to generate a list of drugs that
of urticarial eruptions. can be safely taken. The procedures and the precautions 489
 required are similar but the risks are lower with the latter goal. RECOMMENDED READINGS
If a drug is strongly suspected to be the cause of an eruption, 1. Mehta TY, Prajapati LM, Mittal B, Joshi CG, Sheth JJ, Patel DB, et al.
it is not administered. The risk of adverse effects during Association of HLA-B*1502 allele and carbamazepine-induced Stevens-
Johnson syndrome among Indians. Indian J Dermatol Venereol Leprol 2009;
supervised administration is relatively small. When assessing
75: 579-82.
the utility and safety of challenge testing, it should be
2. Pasricha JS, Khaitan BK, Shantharaman R, Mital A, Girdhar M.Toxic epidermal
remembered that adverse effects are likely to be significantly necrolysis. Int J Dermatol 1996; 35: 523-7.
more severe if a patient who does not know the causative drug
3. Pudukadan D, Thappa DM. Adverse cutaneous drug reactions: Clinical
is inadvertently prescribed the drug and takes it in full doses pattern and causative agents in a tertiary care center in South India.
at home. Indian J Dermatol Venereol Leprol 2004; 70: 20-24.
4. Ramam M, Bhat R, Jindal S, Kumar U, Sharma VK, Sagar R, et al. Patient-
In exceptional circumstances, it may be considered imperative
reported multiple drug reactions: clinical profile and results of challenge
to administer a drug that the patient has reacted to. testing. Indian J Dermatol Venereol Leprol 2010; 76: 382-6.
Desensitisation protocols have been described that allow 5. Sharma VK, Sethuraman G, Kumar B. Cutaneous adverse drug reactions:
successful re-administration of the drug but the procedure must Clinical pattern and causative agents – a 6-year series from Chandigarh,
be undertaken with due care and caution. India. J Postgrad Med 2001; 47: 95-9.

490
 11.6 Abnormal Vascular Responses

AK Jaiswal, TS Nagesh

The phenomenon of abnormal cutaneous vascular response transient, well defined, erythematous or pale swellings of the
plays an important role in the aetiopathogenesis of many dermis (Figure 1). The lesion may appear pale centrally during
dermatoses. This chapter aims at providing a brief overview of the initial stage of fluid collection. Very rarely, a vesicle or a bulla
some of the common dermatological conditions with abnormal can develop in an urticarial plaque. Individual wheals rarely
vascular response. persist longer than 12 to 24 hours. No mark is usually left behind
when wheals resolve. The lesions are usually pruritic and
URTICARIA AND ANGIOEDEMA stinging and often preceded by pricking sensation. Urticarial
Definition lesions may be localised or generalised.
Urticaria is a vascular reaction pattern characterised by transient,
erythematous, oedematous papules or plaques (wheals) of
varying sizes and shapes which are usually pruritic. Angioedema
is the same process but involves the deep dermis, subcutaneous
and submucosal tissues.
Epidemiology
Around 20% of the population suffers from this condition once
in their lifetime. Common in young adults (female > male). In
children it is frequently associated with infection. Figure 1: Urticaria showing wheals of varying sizes.

Classification Angioedema is the term used to describe giant wheals or wheals

The simplest classification of urticaria and angioedema is involving mucous membrane surface lasting longer that
according to their aetiology (Table 1). urticaria. Angioedematous swelling may occur over the face
(primarily periorbital area, lips, tongue), an entire extremity or
Table 1: Aetiological Classification of Urticaria and Angioedema within a vital organ system (Figure 2). Urticaria and angioedema
Drugs Aspirin, penicillin, nonsteroidal anti- may coexist in 50% of cases. Systemic symptoms like malaise,
inflammatory drugs (NSAIDs), sulphon- abdominal pain, dizziness, arthralgia, hoarseness, syncope or
amides and others even anaphylaxis may sometimes be associated with urticaria
Ingestants Nuts, eggs, fish, milk, wheat and others and angioedema.
Inhalants Pollens, house dust, animal dander, fungi
Injectants Vaccines, serum, blood
Infections Foci of bacterial, viral, parasitic and fungal
infections
Contactants Cosmetics, animal and plant products
Physical urticarias (15%) Dermographism (4% to 5%)
Heat
Cold
Pressure
Solar
Cholinergic
Aquagenic
Hereditary Angioneurotic oedema
Vibratory angioedema
Other conditions
Systemic Collagen vascular diseases, thyroid
disorders, polycythemia vera, uraemic states
Dermatologic Pemphigoid, dermatitis herpetiformis,
Figure 2: Angioedema of the eyelids.
urticaria pigmentosa
Psychogenic Variants of urticaria with distinctive clinical features:
Clinical Features Dermographism
Urticaria can be acute (<6 weeks) or chronic (>6 weeks) It is characterised by the rapid appearance of linear itchy wheals
depending on the duration of episodes. Clinically urticaria with a surrounding bright red flare at sites of scratching or
manifests as wheals of varying sizes and shapes which are rubbing (Figure 3). The prevalence is 4% to 5%.
491
 Figure 3: Dermographism.

Cholinergic urticaria
One of the most common physical urticaria.Usually induced
by exercise. The lesions are characterised by extremely pruritic,
small 2 to 3 mm scattered wheals surrounded by large
erythematous flare.
Pathophysiology
Histamine and chemokine release from mast cells and
basophils is the basic pathogenetic mechanism in urticaria and
angioedema. These chemical mediators act on the blood vessels
causing vasodilatation (erythema), sensory nerve stimulation Figure 4: Pharmacologic therapy of chronic urticaria and angioedema.
(itch), increased vascular permeability and leakage of fluid into
the skin leading to dermal oedema.
 Meticulous history helps in determining the cause of
The activation of mast cells and basophils may be both
urticaria more than any tests.
immunologic and nonimmunologic. Immunologic activation
 Cyproheptadine 2 to 4 mg tid is the treatment of choice in
involves Type I—Type IV hypersensitivity reactions depending
upon the cause, whereas nonimmunologic activation happens cold urticaria.
due to direct degranulation of mast cells by certain agents  Epinephrine should be used for acute attacks in the
(drugs—morphine, codeine; foods—strawberries and shell fish). presence of angioedema of the respiratory tract.

Diagnosis INTERESTING HISTORICAL HIGHLIGHT

The diagnosis of urticaria and angioedema is essentially based In 1772, Herbeden described urticaria as follows: “the little
on clinical observation and detailed history. If a complete review elevations upon the skin in the ‘nettle’ rash often appear
of systems is normal and physical urticarias are ruled-out, it is involuntarily, especially if the skin be rubbed or scrubbed and
often futile to carry-out extensive laboratory investigations to seldom stay many hours in the same place, and sometimes not
determine the offending agent in chronic urticaria. However, many minutes. There is nobody exempt from ‘them’ and by far
investigations like complete blood count (CBC), stool and urine the greatest number experience no other evil from it besides
examination, thyroid function tests, hepatitis screening, anti- the intolerable anguish arising from the itching….”. This
nuclear antibodies (ANA), total IgE, skin prick test, serological appropriately designed description of urticaria holds good even
ELISA test, autologous serum skin test and ultrasonography may after more than 200 years.
be carried-out if any underlying illness is suspected.
Management ERYTHEMA MULTIFORME
 The goal of managing urticaria is to identify and then Definition
remove the offending agent/cause. Erythema multiforme (EM) is an acute, self-limiting, usually
mild, often recurrent inflammatory syndrome characterised
 Aspirin and other nonsteroidal anti-inflammatory drugs
by symmetrically distributed erythematous papular, urticarial
(NSAIDs) may aggravate urticaria and should be avoided.
and typical iris/target shaped lesions. This classic form of EM
 Soothing lotions (calamine) and cool compresses are given is currently defined as EM minor. The more severe variant with
for relieving pruritus. extensive mucous membrane involvement and constitutional
 A trial of elimination diet or a course of antibiotic, antifungal symptoms is called EM major (Stevens-Johnson Syndrome).
and antihelmintic drugs may be useful in some cases. Epidemiology
 H 1 anti-histaminic drugs (AHD) are the mainstay of EM affects primarily children and young adults (male > female).
treatment. Algorithm for the pharmacologic management Mostly seen in spring and fall.
is shown in Figure 4.
Aetiopathogenesis
Key Points EM appears to be a symptom complex secondary to many
 Urticaria and angioedema are easily identifiable symptoms, triggering agents causing the responsible hypersensitive
not a disease. phenomenon.
492
 Abnormal Vascular Responses
The common causes are: Diagnosis
Infections—Herpes simplex, Mycoplasma, Streptococci, The diagnosis is usually not difficult in the presence of
Drugs—Antibiotics, anti-convulsants. symmetrical distribution of typical target lesions.
Idiopathic (up to 50%)—Probably also due to undetected Treatment
herpes simplex or Mycoplasma infections. As majority of cases of EM resolve spontaneously in 2 to 3 weeks,
Clinical Features treatment is only symptomatic in the form of oral antihistamines
and topical corticosteroids.The underlying precipitant cause,when
The lesions of EM are predominantly erythematous papular,
appreciated, should be treated.A short course of prednisolone (0.5
macular urticarial and classical iris or ‘target’ lesions. The lesions
to 1 mg/kg/d) may be given in patients with extensive skin lesions.
appear suddenly in crops for 2 to 3 weeks and are usually
symmetrical with a predilection for palms, soles and extensor Recurrences can be suppressed with long-term treatment for
surface of limbs. The characteristic iris (target) lesion is urticarial herpes simplex infections (acyclovir 400 mg bid).
with a dusky center that may blister and have successive bright Key Points
red bordering rings (Figure 5). There is little or no mucous
 Herpes simplex infection is the most common cause of
membrane involvement. Vesiculobullous lesions may be seen
recurrent EM.
at times.
 Classical target or iris lesions are characteristic of EM.

VASCULITIS
The term vasculitis is used to describe a group of diseases
characterised by an idiopathic primary inflammation and necrosis
of blood vessels, having many common clinical features. The
primary cutaneous lesion in vasculitis is palpable purpura.
Classification
The vasculitis has extensively been discussed in section
Rheumatology chapter “The Vasculitides”.

RECOMMENDED READINGS
1. Beltrani VS. Urticaria and angioedema. Dermatologic Clinics 1996; 14: 171-94.
2. Cox NH, Jorizzo JL, Bourke JF, Savage COS. Vasculitis, neutrophilic dermatoses
and related disorders. In: Burns T, Breathnech S, Cox N, Griffiths C, editors.
Rook’s Textbook of Dermatology; 8th Ed. Oxford: Wiley-Blackwell; 2010.
3. Halder B, Ghosh S, Halder S. Cutaneous vascular responses. In: Valia RG,
Valia AR, editors. IADVL Textbook of Dermatology; 3rd Ed. Mumbai: Bhalani
Figure 5: Erythema multiforme with typical target lesions.
Publishing House; 2008: pp 681-715.

493
 11.7 Papulosquamous Disorders

K Pavithran

Papulosquamous disorders are a group of unrelated skin Psoriasis: Key Diagnostic Points
diseases that share the morphological feature of scaly papules 1. Erythematous scaly plaques
and plaques. Important conditions in the group are psoriasis,
2. Well-defined border
lichen planus, and pityriasis rosea.
3. Scales dry loose and micaceous
PSORIASIS 4. Koebner phenomenon seen
Psoriasis is one of the common skin diseases characterised by
5. Auspitz sign positive
scaly papules and plaques. Prevalence of psoriasis in different
parts of the world varies from 0.1% to 3%. Onset of psoriasis is 6. Regular, circular pits on nail plates
most common in the second to fourth decades of life though 7. Involvement of distal interphalangeal joints of fingers and
it can appear just after birth or in old age. A high familial toes
occurrence of psoriasis (7% to 36%) suggests that genetic 8. Histopathological: Spongiform pustules of Kogoj
factors play a role in its aetiology. Psoriasis occurs in equal
frequency in males and females. Koebner phenomenon is more common during the acute
or eruptive stage of psoriasis or in patients with florida or
Aetiopathogenesis progressive psoriasis. Psoriasis as a Koebner phenomeon may
Genetic factors develop at sites of mechanical, physical, chemical or allergic
Twin and population genetic studies support the hypothesis trauma.
of multifactorial inheritance which requires both polygenic and Clinical Variants of Psoriasis (Table 1)
environmental factors for its clinical expression.
Guttate psoriasis
The immunologic basis of psoriasis This is usually seen in children, follows streptococcal infection
T-lymphocyte mediated T-helper cell (Th-1) type of immune and tends to resolve spontaneously. Pinhead to pea-sized
response is responsible for psoariasis. Unidentified triggers or erythematous papules erupt abruptly and are distributed
infective agents like bacteria, HIV, drugs, etc. induce antigens bilaterally symmetrically all over the body.
which are presented to T-lymphocytes by Langerhans cells
of skin leading to T-cell activation. Activated T-cells secrete Table 1: Various Clinical Types of Psoriasis
cytokines that promote dermal inflammation and resultant Guttate psoriasis
hyperproliferation of the epidermis. Chronic plaque psoriasis (psoriasis vulgaris)
Triggering factors Exfoliative psoriasis (psoriatic erythroderma)
Psoriasis is a chronic disease marked by periods of remissions Pustular psoriasis
and exacerbations. Remissions may last for a few weeks to many Generalised—Von-Zumbusch type
years. Triggering factors may be local or systemic and include Exanthematic type
trauma (Koebner phenomenon), season (worsens in winter), Annular type
emotional stress, upper respiratory tract infections and drugs Localised pustular psoriasis
like beta-blockers, lithium and chloroquine. Withdrawal of Psoriasis unguis
systemic steroids can lead to precipitation of pustular psoriasis. Mucous membrane lesions in psoriasis
Psoriatic arthritis
Histopathology
Classical type
Characteristic histopathological features of psoriasis are regular Rheumatoid type
elongation of rete-ridges, parakeratosis, hypogranulosis, and Arthritis mutilans
presence of Munro’s microabscesses in the horny layer and Oligoarticular arthritis
spongiform pustules of Kogoj. The psoriatic epidermis shows Psoriatic spondylitis
rapid transition of epidermal cells in as fast as 2 days as Follicular psoriasis
compared to 13 days in normal epidermis. Psoriasis verrucosa
Linear psoriasis
Clinical Features
Psoriasis is characterised by the development of erythematous, Chronic plaque psoriasis
well-defined, dry, scaly papules and plaques of sizes ranging This common type of stable psoriasis manifests as coin-sized
from a pinhead to palm-sized or larger. The scales are abundant, to large palm-sized well defined erythematosquamous
loose, dry and slivery white or micaceous. On skin scraping, plaques-distributed bilaterally on extensors of body (Figure 1).
capillaries at the tips of elongated papillae are torn leading to The extensor surfaces of the body, the elbows and knees
494 multiple bleeding points (Ausptiz sign). lumbosacral area and back are commonly involved.
 Papulosquamous Disorders
Figure 1: Chronic plaque psoriasis, erythematosquamous lesions.

Palmoplantar psoriasis
This common form usually affects only the palms or soles but
may extend to the dorsa of hands and feet or occasionally may
evolve into psoriasis vulgaris.
Flexural psoriasis
Affliction of axillae and groins may simulate dermatophyte
infection or erythrasma. Rapid response to topical steroids is a
rule.
Nail psoriasis
Nails are commonly affected in psoriasis. Pitting, thickening of Figure 2: Psoriatic-erythroderma, involving more than 90% of body surface area.
nail plate, subungual hyperkeratosis, onycholysis and oil spots
are some of the frequent nail findings in psoriasis.
Exfoliative psoriasis (psoriatic erythroderma)
It is a generalised form of the disease and is characterised by
erythema and scaling of more than 90% of the body surface
area (Figure 2).
Pustular psoriasis
When tiny, superficial, sterile pustules top a plaque of psoriasis,
it is called pustular psoriasis. Pustular psoriasis is broadly
classified into a localised form and a generalised form. Localised
form may affect only the palms and soles or may be more
widespread.
Generalised pustular psoriasis is the most severe form of
pustular psoriasis. The skin lesions start abruptly as multiple
erythematous, tender plaques which soon become studded
with pinhead-sized, tiny sterile pustules that appear in waves. Figure 3: Psoriatic arthritis; multiple small skin distal joint uncolourment.
Features of systemic toxicity such as fever, chills, polyarthralgia
and malaise may be associated. Geographic tongue and with psoriasis. Onset of arthritis is concurrent with the skin
hypocalcaemia may be associated. The disease may last for disease in 10% of cases but may precede it. There are 5 clinical
weeks or even months. patterns of psoriatic arthritis: classical psoriatic arthritis affecting
distal interphalangeal joints; rheumatoid type of psoriatic
Psoriasis in HIV-infected persons arthritis; arthritis mutilans; oligoarticular arthritis (commonest
The prevalence of psoriasis seems not to be increased in HIV- type) and psoriatic spondylitis.
infected patients. But psoriatic arthritis, dactylitis and enthesitis
Treatment
are more common in them.
Psoriasis usually has a chronic but unpredictable course with
Psoriatic arthritis periods of remissions and exacerbations. The aim of psoriasis
Psoriatic arthritis (Figure 3) is an inflammatory arthritis therapy is to control the disease, to improve quality of life, rather
associated with psoriasis usually with a negative test for than to cure it. Avoiding alcohol and reducing weight, help in
rheumatoid factor. Arthritis occurs in about 5% to 0% of patients better control of psoriasis (Table 2). 495
 Table 2: Treatment of Psoriasis exacerbate psoriatic lesions. Topical calcipotriol, a vitamin D
derivative is free of serious side-effects but is expensive.
Topical therapy
Emollients Systemic therapy
Topical corticosteroids
The systemic drugs commonly used for the treatment of
Dithranol
psoriasis include oral retinoids, methotrexate and photo-
Tars
Salicylic acid chemotherapy (PUVA) and narrow band UVB phototherapy.
Vitamin D analogues—Tacalcitol, calcipotriol Availability of cyclosporine and biological agents like etanercept
Tazarotene or infliximab has increased options but these drugs are
Tacrolimus and pimecrolimus still prohibitively expensive for most patients. Systemic
Systemic therapy corticosteroids, although dramatic in short-term effectiveness
Oral retinoids are contraindicated in psoriasis as they cause rebound increase
Methotrexate after stoppage.
Cyclosporine
Hydroxyurea Oral retinoids: Acitretin, a second-generation oral retinoid, is
Mycophenolate mofetil useful in severe unstable disease, including pustular and
Razoxane erythrodermic psoriasis. Elevation of transaminases and
Corticosteroids triglycerides need to be watched for during the 3 to 6 months
Biologicals required for complete response. Oral retinoids are absolutely
Alefacept contraindicated in women of childbearing potential.
Etanercept
Infliximab Methotrexate: Methotrexate improves psoriasis by its action on
Efalizumab T-cells. It is indicated in disabling or widespread psoriasis
Other drugs unresponsive to topical therapies, pustular psoriasis and
Gold erythrodermic psoriasis. Methotrexate is also helpful to control
Colchicine
psoriatic arthritis. Contraindications include pregnancy or those
Dapsone
Methimazole who desire to get pregnant, moderate-to-severe hepatic or renal
Tacrolimus compromise, blood dyscrasias, peptic ulcer and chronic
Sulfasalazine alcoholism. Cytopaenia occurs in 10% to 20% of patients
Fumaric acid on long-term methotrexate therapy (> 6 weeks) for psoriasis
Other forms of therapy and manifests as leucopaenia, thrombocytopaenia or
UVB phototherapy pancytopaenia. Hepatotoxicity is a major concern, with a 7%
Photochemotherapy overall risk of severe fibrosis/cirrhosis in psoriatics. It is
Excimer laser
administered as 7.5 to 22.5 mg in 3 equally divided weekly oral
Treating psychological factors
Photodynamic therapy
doses at 12 hourly intervals or a single dose of 10 to 25 mg
Surgical treatment methotrexate every week.
Hyperthermia (Balneotherapy)
UVB phototherapy and PUVA therapy
Sea bathing
Diet control Modern narrow band UVB phototherapy has its emission almost
exclusively in the narrow band between 311 nm and 313 nm.
Topical therapy This minimises the potential for causing skin cancer and avoids
Majority of the cases of psoriasis can be controlled with topical skin effects associated with the use of oral psoralens in PUVA
therapy. Emollients like white soft paraffin and liquid paraffin form therapy. Patients with extensive stable psoriasis are candidates
the mainstay of topical psoriasis therapy but are best suited for for UVB phototherapy.
unstable psoriasis cases who cannot tolerate other topicals.
PUVA therapy consists of administration of 8-MOP, 0.6 mg/kg/
Stable plaque psoriasis responds well to strong topical steroids
body weight, on alternate days followed by exposure to
and keratolytics, like salicylic acid. Efficacy of topical steroids can
ultraviolet rays 2 hours later. Nausea, vomiting, headache,
be improved by occlusion therapy or by intra-lesional injection.
vertigo, erythema, pruritus, blistering and worsening of psoriasis
Use of strong topical steroids like clobetasol, betamethasone,
may occur as side-effects of PUVA therapy. Long-term side-
over large areas of body can lead to systemic absorption with its
effects include cataracts, and in white skinned persons, skin
resultant side-effects. Modern topical steroids like mometasone
cancers.
or fluticasone in ointment form are preferred as they do not cause
much skin atrophy or systemic absorption. LICHEN PLANUS
Non-steroidal topical options for psoriasis include topical tar Lichen planus (LP) is a pruritic disease affecting the skin,
and dithranol. Tazarotene, a topical synthetic retinoid is used mucous membranes and hair follicles. The characteristic
for the treatment of plaque psoriasis. It has a rapid onset of primary lesions are tiny, shiny, violaceous, flat-topped,
action and its beneficial effect is sustained for up to 12 weeks polygonal papules. Surface shows scant adherent scales.
after cessation of therapy. Tazarotene’s potency is comparable Koebner phenomenon may occur. Sites commonly affected
to that of mid-to-high-potency corticosteroids.This drug should are the front of wrists, shins, trunk, medial thighs and glans
not be given to pregnant or lactating women or women not penis. The cutanesous lesions (Figure 4) are intensely pruritic
496 practicing adequate contraception. But they can sometimes and the lesions on legs may become hypertrophic. The oral
 Papulosquamous Disorders
mucosal lesions of LP may be reticular, annular, atrophic, or
erosive. The buccal mucosa is commonly affected though
tongue and gingiva may also be involved (Table 3).

Figure 5: Hypertrophic lichen planus.

and low dose systemic steroids or oral pulse steroids, dapsone,

anti-malarials, oral retinoids, systemic PUVA and mycophenolate
Figure 4: Lichen planus purple, papulosquamous flat topped lesions.
mofetil in generalised lichen planus. Topical tacrolimus is used
to treat cutaneous, oral and genital erosive lichen planus.
Table 3: Lichen Planus: Key Diagnostic Features Appearance of new lesions, increase in size of existing lesions
Intense pruritus and Koebner’s phenomenon indicate the activity of the lesions
Erythematous-to-violaceous colour for early lesion and requires therapy. Long standing lesions run a small risk of
Flat topped polygonal papules developing squamous cell carcinoma.
Intense black pigmentation on healing
Koebner phenomenon present PITYRIASIS ROSEA
Lace-like pattern for oral lesions
Pityriasis rosea (PR) is an exanthem characterised by oval, or
Nail changes occur in 5% to 10% patients and manifest as circinate salmon-coloured macules that are covered with finely
pterygium, longitudinal streaks and atrophy. Clinical variants crinkled epidermis which often desquamates leaving a
of LP include linear, annular, ulcerative, hypertrophic (Figure 5) collarette of scaling. Sometimes the eruption may be papular,
and bullous forms (Table 4). purpuric, urticarial, lichenoid, bullous, or vesicular.The exanthem
is often preceded by a single herald plaque which is much larger
Table 4: Lichen Planus: Clinical Types than the succeeding lesions. The eruption has a characteristic
Annular ‘bathing suit’ distribution (trunk and proximal parts of limbs).
Linear Mild pruritus is often present and the rash persists for 6 to 8
Atrophic weeks and subsides spontaneously. Recurrence may occur in
Hypertrophic 2% of the cases.
Eruptive (Guttate)
Follicular (Lichen planopilaris) The exact aetiology of PR is not known though HHV-6 and -7
Lichen planus pigmentosus have been implicated.
Vesicular/Bullous
Erosive/Ulcerative There is no specific treatment of PR. Antihistamines may relieve
Actinic pruritus. UVA and UVB therapy and oral erythromycin and
Inverse acyclovir also are reported to be beneficial. Topical emollients
often relieve pruritis.
The exact aetiology of LP is not fully understood. Some cases
are associated with HCV infection. LP may co-exist with many RECOMMENDED READINGS
diseases with an immunologic basis for their aetiopathogenesis, 1. Christophers E, Mrowietz U. Psoroasis. In: Freedberg IM, Eisen AZ, Wolff K,
e.g. lupus erythematosus thymoma. The immunologic reaction Aysten KF, Goldsmith LA, Katz SI, (eds); Fitzpatrick’s Dermatology in General
in LP is mediated by T-cells. Medicine; 6th Ed. New York: McGraw-Hill; 2003: pp 407-27.
2. Koo J, Lee E, Lee CS, Lebwohl M. Psoroasos. J Am Acad Dermatol 2004; 50:
The course of the disease is unpredictable. The spontaneous 613-22.
remission is known but the period is variable with different
3. Pavithran K. Disorders of keratinisation. In: Valia RG, Valia AR, (eds); IADVL
types of lichen planus. Treatment include antihistamines, topical Textbook and Atlas of Dermatology; 2nd Ed. Bombay: Bhalani Publishing
steroids, intralesional steroids, topical PUVA in localised cases House; 1999: pp 799-846.

497
 11.8 Autoimmune Bullous Disorders

KK Raja Babu

Autoimmune bullous disorders are a group of immunobullous Pemphigus foliaceous presents as very superficial blisters and
diseases of unknown aetiology where circulating antibodies erosions in a seborrhoeic distribution. Intact blisters are rarely
target specific components in the epidermis and the adhesion found. Nikolsky’s sign is strongly positive. Extensive disease may
complex that links the epidermis and dermis. present as erythroderma. Oral lesions are rarely seen. Fogo
selvagem is a special form of pemphigus foliaceous that is
INTRAEPIDERMAL AUTOIMMUNE BULLOUS DISORDERS endemic to Brazil and other South American countries. The
Pemphigus affected skin has a burnt appearance and patients experience
Pemphigus is the most common and also potentially the most a painful burning sensation in the lesions (fogo selvagem = wild
severe immunobullous disorder involving the skin and mucous fire).
membranes. The disease has a worldwide distribution with an Pemphigus erythematosus presents with erythematous, scaling
incidence of 0.1 to 0.5 per 100,000 population. Circulating plaques over the nose and malar skin, upper part of the back,
IgG autoantibodies targeting antigens in the intercellular chest and intertriginous areas closely mimicking the rash of
attachment plaques (desmosomal complexes) of the epidermal systemic lupus erthyematosus (SLE).
keratinocytes, identified as desmogleins, lead to acantholysis
and cell separation, and intraepidermal blister formation. The Other important variants of pemphigus are drug-induced
reason for this anomalous antibody activity is not known. HLA- pemphigus and paraneoplastic pemphigus. Drugs with highly
linkage analysis suggests that there may be some genetic reactive sulfhydryl groups like penicillamine and captopril can
predisposition. induce pemphigus. Enalapril, penicillin, cephalosporins and
rifampicin are other drugs that are occasionally responsible.
Broadly two types of pemphigus are recognised, each with Both immunological and non-immunological mechanisms
one variant: Pemphigus vulgaris and its variant, pemphigus operate in the occurrence of drug-induced pemphigus.
vegetans; and pemphigus foliaceous and its variant, Most examples of drug-induced pemphigus are of the
pemphigus erythematosus. In P. vulgaris blisters occur in the foliaceous type. Eighty percent of patients show direct
immediate suprabasal layers, and in pemphigus foliaceous immunofluorescence positivity.
they develop subcorneally. Desmoglein1 is the target antigen
in pemphigus foliaceous and desmoglein 3 and less frequently Paraneoplastic pemphigus is characterised by severe, persistent
desmoglein 1 are the target antigens in P. vulgaris. The clinical and painful mucosal erosions and a polymorphic skin eruption
phenotype of pemphigus is defined by the anti-desmoglein that is resistant to treatment. The underlying malignancies are
antibody profile. generally lymphoproliferative and approximately 80% of cases
are linked to non-Hodgkin’s lymphoma, chronic lymphocytic
Pemphigus vulgaris is a very common disease in India and leukaemia and Castleman’s disease.
young adults of both sexes are preferentially affected. In more
than 50% of cases, the disease begins with oral erosions and Light microscopy reveals acantholytic intraepidermal blisters.
90% have oral lesions at some stage of their life. Oral erosions Direct immunofluorescence of the perilesional skin is of singular
are painful and tender and heal very slowly. They frequently value in the diagnosis of pemphigus. A fish net-like intercellular
occur on the buccal and palatine mucosae. Conjunctival, nasal, fluorescence is characteristic. Indirect immunofluorescence
pharyngeal, laryngeal, anal and genital mucous membranes are detects circulating IgG antibodies directed against antigens of
uncommonly affected. Skin lesions are generalised flaccid the desmosomal complex. Recently ELISA tests that can detect
blisters of varying sizes that quickly rupture to leave large IgG autoantibodies to desmoglein 1 and 3 have been developed
denuded raw areas which crust and continue to spread without and these have paved the way for a rapid diagnosis of different
further blistering at the same site. Blisters frequently appear on forms of pemphigus.
a normal looking skin without any background erythema. Scalp, General supportive measures, attention to fluid and electrolyte
face, axillae and groins are the common sites of involvement. balance and control of infection are of paramount importance
Tangential shearing pressure on the unaffected skin may cause in the management of fulminant forms of pemphigus. Systemic
separation of the epidermal layers and denudation of skin. This corticosteroids (prednisolone 1-2 mg per kg body weight per
is called Nikolsky’s sign. Lateral or perpendicular pressure day) along with cytotoxic immunosuppressive agents like
applied on intact blisters may lead to their extension and is cyclophosphamide or azathioprine (1 mg/kg/day) are the
called bulla spreading or Asboe-Hansen’s sign. mainstay drugs in the treatment of pemphigus, especially
Pemphigus vegetans is a much milder disease compared to of the severe forms. Cyclophosphamide pulse therapy
pemphigus vulgaris, and intertriginous involvement is common. or cyclophosphamide+steroid pulse therapy have been found
The disease may begin either as vesicles and blisters or as to be beneficial for severe and recalcitrant examples of
pustules and eventually evolve into hypertrophic, granulomatous pemphigus vulgaris. Topical and intralesional steroids help
498 or vegetative lesions. Oral lesions may occasionally occur. milder forms.
 Autoimmune Bullous Disorders
With appropriate treatment, most cases of pemphigus go into demonstrates a linear pattern of IgG and C3 deposition
extended remissions. Untreated pemphigus vulgaris carries across the basement membrane zone (BMZ). On indirect
significant morbidity and mortality. immunofluorescence, approximately 70% of patients have
circulating anti-BMZ IgG antibodies. DIF of biopsy samples of
SUBEPIDERMAL AUTOIMMUNE BULLOUS DISORDERS perilesional skin that have been incubated in 1 molar saline skin-
Bullous Pemphigoid splitting buffer at 4 °C for 36 to 72 hours results in a split in the
Bullous pemphigoid (BP) (Figures 1 and 2) is an autoimmune, lamina lucida of the BMZ. In BP, the IgG deposits are mostly
subepidermal blistering disorder of the elderly. Men are likely to found on the epidermal (roof ) surface of the blister while in
be affected twice as frequently as women. BP is mediated by IgG epidermolysis bullosa acquisita, the antibodies are detected on
autoantibodies directed against hemidesmosame-associated the dermal side (floor) of the blister.
proteins. Two pathogenetically important BP antigens are
recognised: BP 230 and BP180. Though BP230 is the principal
antigen, serum levels of antibodies to BP 180 correlate well with
disease activity. Association between HLA DQ7 and DRB1 and
susceptibility to BP has been reported. Recent studies reveal that
a small, nonetheless significant, association between BP and
visceral malignancy exists. Drugs sometimes induce pemphigoid-
like eruptions. Examples are frusemide, sulphasalazine,
penicillamine, penicillins, captopril and PUVA therapy. BP has also
been reported to be associated with a variety of disorders like
SLE, multiple sclerosis, diabetes mellitus, rheumatoid arthritis,
psoriasis and lichen planus. Bullous pemphigoid also shares
many immunopa-thological characteristics with pemphigoid
gestationis and cicatricial pemphigoid.

Figure 2: Bullous pemphigoid. Tense blisters and erosions.

Localised disease can be treated with topical or intralesional

steroids. Systemic steroids are indicated for a generalised
disease. Moderate doses (prednisolone 30 to 40 mg per day)
are enough to control the disease unlike in pemphigus vulgaris.
Azathioprine, cyclophosphamide or methotrexate can reduce
steroid dependency. Tetracycline or erythromycin along with
nicotinamide has been found to help some patients of BP in
whom corticosteroid use is contraindicated.
Cicatricial Pemphigoid
Cicatricial pemphigoid (CP) is another subepidermal blistering
disorder and primarily affects the mucous membranes of the
Figure 1: Bullous pemphigoid. Erythematous oedematous plaques, tense mouth, eyes and genitalia. Occasionally oesophagus, pharynx
blisters and erosions. and larynx are involved. Scarring and its attendant sequelae are
frequent. Skin lesions are uncommon and are predominantly
Large, tense blisters arising on an erythematous and oedematous seen on the head and neck. Both scarring and non-scarring
background are typical of BP. The blisters are filled with thick, lesions occur on the skin.
fibrinous fluid and can occasionally be haemorrhagic. The
common sites of involvement are the lower abdomen, inner BP180 is the most frequently recognised autoantigen. Direct
thighs, groins and the flexor aspects of the limbs. Nikolsky’s sign immunofluorescence findings are similar to those seen in BP.
is negative, and so is Asboe-Hansen’s sign. Blisters do not quickly On indirect immunofluorescence, circulating IgG anti-BMZ
rupture. Additionally patients may also have erythematous antibodies in low titres are detectable in 10% to 25% of patients.
macules, papules and urticarial plaques. Occasionally eczematous Localised oropharyngeal lesions are treated with topical or intra-
eruptions occur. All these clinical lesions may sometimes precede lesional steroids. Systemic steroids (0.5 to 1 mg/kg per day of
blisters by weeks or months (Prodromal bullous pemphigoid). prednisolone) are indicated in more severe disease. Dapsone
Mucosal lesions are uncommon. Pruritis is often present but may or azathioprine help resistant cases. Surgical intervention is
range in severity. Ruptured blisters heal rapidly leaving behind required in the presence of scarring and strictures of vital
post-inflammatory pigmentary changes. Scarring does not occur. structures.
Several clinical variants of BP exist. Dermatitis Herpetiformis
Histologically, BP manifests as a subepidermal blister with a Dermatitis herpetiformis (DH) is a rare (at least in India), chronic,
mixture of inflammatory cells. Direct immunofluorescence (DIF) intensely itchy papulovesicular disease associated with gluten- 499
 sensitive enteropathy. The enteropathy is mostly asymptomatic. in LAD is a 97 kDa antigen and this reacts with IgA1 subclass of
Less than 10% of patients with DH have gastrointestinal antibodies.
symptoms suggestive of coeliac disease. Some patients manifest
The onset of CBDC is rather abrupt with large tense bullae filled
diarrhoea, steatorrhoea, abdominal distension and weight loss.
with clear or haemorrhagic fluid on or near genitalia. The
Both the skin lesions and the enteropathy respond to a strict
eruption gradually extends to involve such areas as buttocks,
gluten-free diet, and recur when gluten-containing products
scalp and face, particularly the perioral and periocular areas.
are ingested. Gluten is present in wheat, barley, oats and rye
Clustering of blisters is common. New, small, tense blisters may
but not in rice and corn. The enteropathy is believed to be due
appear around a crusted, healing, erythematous plaque giving
to non-allergic sensitivity to the gliadin fraction of gluten.
a ‘string of jewels’ appearance. Mucosal lesions are sometimes
Circulating IgA2 antibodies directed against gliadin and
found.
connective tissue autoantigens (reticulin and endomysium) are
found in the sera of DH patients. There is a strong association LAD generally has its onset in the fifth decade. There is
between HLA B8, DRw17 and DQw2 and DH. considerable variation in the morphology and distribution of
DH most often is seen in the second and third decades. The lesions. Flexural and truncal involvement with scattered vesicles
disease is slightly more common in males. The skin eruption is and tense blisters, as in BP, is common. Bullae occasionally are
characteristically polymorphic although at any given time, only linear and sausage-shaped. DH-like eruptions may appear in
one type of lesions (papules, vesicles, wheals or bullae) some patients. Oral lesions, though mild, are frequent. There is
predominater. The lesions are typically grouped or herpetiform. increased incidence of lymphoproliferative disorders in patients
Itching is intense and excoriations are common. Lichenification of LAD. Drug-induced LAD has been reported following
may follow chronic scratching. The areas of predilection are the vancomycin, diclofenac and captopril use.
elbows, knees, shoulders, buttocks, sacrum and scalp. Facial Histologically, a subepidermal blister is seen. Direct
involvement is uncommon and mucous membranes are rarely immunofluorescence of uninvolved skin demonstrates linear
affected. Iodides exacerbate the disease. Patients with DH deposition of IgA along the BMZ. Circulating anti-BMZ
manifest a high incidence of autoimmune abnormalities. There antibodies are demonstrable in 30% of adults and 80% of
is an increased risk of developing lymphomas, especially of the children.
gastrointestinal treat.
Dapsone in a dose of 1.5 to 2 mg/kg per day is a very useful
Histologically, neutrophilic microabscesses at dermal papillary drug for both children and adults, and has to be given for a long
tips are typical of DH. Eventually unilocular subepidermal time. Some patients additionally require prednisolone (0.5 to
blisters form. On direct immunofluorescence of the perilesional 1 mg/kg per day) to control their disease. In two-thirds of
skin, granular deposits of IgA are found in the dermal papillae. children, remission occurs by the time they reach their puberty.
No circulating anti-BMZ antibodies are detectable by indirect In others, the disease may persist into adult life. In adults, the
immunofluorescence. disease is chronic but eventually remits.
Gluten-free diet and dapsone therapy are the mainstay Other Subepidermal Autoimmune Bullous Diseases
treatment of DH. In most cases, with an initial dose of 100 mg of
Other important autoimmune bullous disorders are
dapsone per day, burning and itching ceases within 24 hours.
pemphigoid gestationis that occurs in pregnancy and
If there is no response after 2 weeks, the dose should be
puerperium, epidermolysis bullosa aquisita, and bullous
increased by 50 mg every 2 weeks. Doses higher than 300 mg
systemic lupus erythematosus which develops in a setting of SLE.
per day are rarely required. Once the disease is under control, a
maintenance dose of dapsone (as low as 50 mg once a week) is
RECOMMENDED READINGS
all that is needed. Patients who are intolerant of dapsone may
1. Bolognia JL, Lorrizo JL, Tapini RP. Dermatology; Vol.1. Edinburgh: Mosby;
respond to sulfasalazine (500 mg three times a day, increased
2003: pp 415-508.
to 2.0 g per day). Cochicine (0.6 mg three times a day) may
2. Wojnarowska F, Venning VA, Burge SM. Immunobullous diseases. In: Burns
occasionally be helpful. T, Breathnach S, Cox N, Giffiths C, editors. Rook’s Textbook of Dermatology;
Linear IgA Bullous Dermatosis 7th Ed, Oxford: Blackwell Science; 2004: pp 41.
3. Wolff K, Goldsmith LA, Katz SI, Gilchrest B, Paller AS, Leffel DJ. Fitzpatrick’s
Linear IgA bullous dermatosis (LAD) is a rare subepidermal
Dermatology in General Medicine; 7th Ed, New York: McGraw Hill Medical;
blistering disorder characterised by a linear deposition of IgA 2008: pp 447-505.
along the dermoepidermal junction. Chronic bullous disease 4. Yancey KB. Autoimmune and inherited subepidermal blistering diseases:
of childhood (CBDC) although clinically distinctive, is Advances in the Clinic and the Laboratory. In: James WD,editor, Advances in
the childhood variant of LAD. The best characterised antigen dermatology: St. Louis: Mosby; 2000: pp 113-58.

500
 11.9 Disorders of Pigmentation

Bhushan Kumar

Normal human skin colour is produced by skin pigments – red irradiation. Pigmentation, the synthesis and distribution of
(haemoglobin), yellow (carotenoids), brown (melanin). Of melanin in the epidermis, involves several steps. Disruption in
these, melanin which is produced by melanocytes forms the any of these steps results in hypopigmentation. Melanin in the
major component of the skin colour. Normal human skin colour melanocytes is produced in two forms—the brown black,
is primarily related to size and the arrangement of melanosomes eumelanin and the light coloured red, yellow, pheomelanin.
in melanocytes. Tyrosinase, a melanocyte specific copper binding enzyme
catalyses the oxidation of catechols to their corresponding
MELANIN SYNTHESIS quinones. In vivo tyrosinase converts tyrosine through DOPA
Melanocytes originate from neural crest and then migrate to and various precursors to brown or yellow/red melanin.
populate the skin, inner ear, choroid, iris, leptomeninges, mucous
membranes and the hair. The skin melanocytes are located in MELANIN PIGMENTARY DISORDERS
the epidermal basal layer and project their dendrites into Broadly there are three categories of melanin pigmentary
the malpighian layer of the epidermis where a melanocyte disturbances:
secretes melanosomes into a finite number of neighbouring 1. Hypomelanosis or lighter than individual’s skin colour or
keratinocytes (approximately 36); this partnership of a complete loss—leucoderma,
melanocyte and a neighbouring group of keratinocytes is called
2. Brown hypermelanosis (melanoderma), and
an epidermal melanin unit. Melanocytes in the hair follicle
3. Gray, slate or blue hypermelanosis (ceruloderma).
provide the melanin for hair shaft pigmentation.The major
differentiated function of melanocytes is to synthesise melanin All these disorders for the purposes of better understanding
in specialised organelles within the melanocytes, the can be described under the heading as melanotic,
melanosomes, and to transfer melanosomes to neighbouring melanocytotic and non-melanocytotic. Classification of various
keratinocytes to provide protection from ultravoilet (UV) disorders of pigmentation is given in Tables 1 and 2.
Table 1: Hypopigmentation: Clinicopathologic Classification
Aetiologic Melanocytopaenic Melanopaenic Non-melanotic
factors (Melanocytes decreased or absent) (Melanin decreased or absent) (No melanin defect)
Chemical Catechols Arsenicals, Chloroquine, Glucocorticoids, —
Monobenzylether of hydroquinone Hydroxychloroquine, Hydroquinone, Retinoids —
Para-substituted phenols —
Sulphydryls
Endocrine — Addison’s disease, Hypopituitarism, Hypothyroidism —
Genetic Ataxia telangiectasia Albinism Naevus anemicus
Piebaldism Chediak-Higashi syndrome —
Vitiligo Homocystinuria —
Vogt-Koyanagi-Harada syndrome Fanconi’s syndrome —
Waardenburg syndrome Hypomelanosis of Ito, Naevus depigmentosus —
Xeroderma pigmentosum Tuberous sclerosis —
Inflammatory Actinic reticuloid Leprosy, Pityriasis alba, Post-inflammatory Woronoff’s ring
Mycosis fungoides (hypopigmentation
around psoriasis lesions)
Onchocerciasis —
Pityriasis lichenoides chronica (Discoid lupus, Eczema, psoriasis), —
Pinta —
Yaws —
Post-Kala-azar, Sarcoidosis,
Syphilis: (endemic, secondary), Pityriasis versicolour —
Neoplastic Halo naevus Melanoma —
Leucoderma acquisitum centrifugum Halo around primary or metastatic lesions —
Nutritional Vitamin B12 deficiency Chronic protein loss— Kwashiorkor, Malabsorption, —
Nephrosis—Ulcerative colitis —
Physical Burns (Ionising, Thermal, UV) Post-dermabrasion —
Trauma Post-laser —
Miscellaneous Alopaecia areata, Scleroderma Canities, Idiopathic guttate hypomelanosis Anaemia oedema 501
 Table 2: Epidermal Hypermelanoses: Clinicopathologic Classification
Epidermal Melanocytotic Melanotic
factors (Increase in number (Increase in melanin)
of melanocytes)
Heritable or Lentigines, neurodysraphic Cafe-au-lait macule, Neurofibromatosis, Neurocutaneous melanosis
developmental Centrofacial lentiginosis Albright’s syndrome, Bloom’s syndrome, Familial periorbital hyperpigmentation
Peutz-Jegher syndrome Becker’s melanosis, Naevus spilus, Dowling-Degos disease
PUVA therapy Ephelides (freckles) Dyskeratosis congenita
Acropigmentation of Dohi
Reticulate acropigmentation of Kitamura
Metabolic Porphyria cutanea tarda
Haemochromatosis, Gaucher’s disease,
Niemann-Pick disease
Endocrine Melasma, ACTH- and MSH-producing tumours,
Exogenous ACTH therapy,Pregnancy,
Addison’s disease, Oestrogen therapy
Chemicals Arsenicals, Busulfan, Photochemical agents 5-fluorouracil, cyclophosphamide
and drugs (psoralens, tar), Berloque dermatitis nitrogen mustard, topical bleomycin
Nutritional Kwashiorkor, Pellagra, Sprue
Vitamin B12 deficiency
Physical Lentigo, solar, ultraviolet Ultraviolet radiation- (sun tanning),
(radiation tanning) Thermal radiation, Ionising radiations
Trauma (e.g. chronic pruritus)
Inflammation Post-inflammatory melanosis (exanthems, Lichen simplex chronicus, Atopic
and infection drug eruptions) dermatitis, Psoriasis, Lichen planus
Discoid lupus erythematosus
Neoplastic Melanoma, Mastocytosis, Acanthosis nigricans
with or without, adenocarcinoma and lymphoma
Miscellaneous Lentigines, eruptive Systemic scleroderma, Chronic hepatic
lentigo insufficiency Whipple’s syndrome

HYPOMELANOSIS typical vitiligo macule has a chalk or milky white colour, round
Table 1 shows that pigmenatry disturbances may be congenital to oval in shape often with convex margins which are usually
or acquired, localised or generalised and the loss of colour is well defined, varying from few millimetres to many centimetres
either partial (hypomelanosis) or complete (amelanosis). De- in diameter. Trichrome vitiligo refers to the presence of an
pigmentation is applied for the condition when there is complete intermediate colour (uniform tan colour), an interface between
loss of pre-existing normal pigmentation. Localised or the white lesions of vitiligo and the normally pigmented
circumscribed hypomelanosis refers to islands of hypopigmented/ skin. Quadrichrome refers to fourth colour—perifollicular or
depigmented skin amidst clinically normal skin.Hypopigmentation marginal pigmentation seen in some cases of re-pigmenting
here may be amelanotic and progressive (vitiligo, chemical vitiligo. Inflammatory vitiligo has an erythematous raised border
leucoderma), amelanotic congenital and stable (piebaldism, similar to the one sometimes seen in pityriasis versicolour.
Waardenburg syndrome),hypomelanotic and progressive (pityriasis
CLASSIFICATION AND TYPES OF VITILIGO
versicolour, post-inflammatory) or hypomelanotic and stable
(tuberous sclerosis, naevus depigmentosus). Focal, segmental, generalised and universal are the most
common patterns of vitiligo. Vitiligo is also classified as
Certain features in circumscribed hypomelanotic macules
facilitate diagnosis, which include size, shape, hue, arrangement,
etc. Small 1 to 2 mm macules may be seen in vitiligo, chemical
leucoderma, and tuberous sclerosis. Lesions of Pityriasis alba and
post-inflammatory hypopigmentation are larger but have fuzzy,
indistinct margins, unlike the sharp margins in idiopathic
guttate hypomelanosis. Convex borders are usually seen in
vitiligo or chemical leucodema. The lance ovate shaped white
lesions are characteristic of tuberous sclerosis. Macules of vitiligo
and piebaldism are milky or chalk white as compared to the off
white colour of naevus depigmentosus (Figure 1), tuberous
sclerosis or post-inflammatory hypopigmentation. Vitiligo: It is
a common acquired disorder characterised by milky white
macules with the likely incidence between 1% to 2%. All races
are affected. Both sexes are affected equally. Vitiligo occurs more
commonly on the sun exposed areas and in darker skin types.
Figure 1: Naevus depigmentosus.
502 Vitiligo may develop at any age—birth to 81 years of age. A
 Disorders of Pigmentation
segmental, acrofacial, generalised and universal or by pattern occur.Vitiligo may be associated with leukotrichia, prematurely
of involvement as focal, mixed and mucosal. gray hair, halo nevi, and alopaecia areata. Depigmented hair are
often found in isolated vitiligo lesions. Leucotrichia (poliosis)
Focal Vitiligo has been reported in up to 45% of cases of vitiligo. Rarely vitiligo
There is either a single or few macules limited in both size and patients may have pigmentary abnormalities in iris and retina.
number. About 20% of the children have this pattern. Many authors have reported an association of vitiligo and
thyroid function abnormalities. Pernicious anaemia though
Segmental Vitiligo
uncommon occurs with increased frequency in patients with
The lesions are distributed in a dermatomal or quasi- vitiligo. Association with systemic lupus erythematosus,
dermatomal pattern. This is earlier in onset but is considered a diabetes mellitus, Addison’s disease, inflammatory bowel
stable type of vitiligo. disease, rheumatoid arthritis, etc. is well known.
Generalised Vitiligo Aetiology and Pathogenesis
It is the most common type of vitiligo and is characterised by Though vitiligo is mostly a single entity, the aetiology is complex.
few to many to widespread macules. The lesions are often Several hypothesis to explain its aetiopathogenesis have been
symmetrical and involve extensor surfaces, areas over small and propounded which include-genetic, autoimmune, self destruct,
large joints. Periungual involvement may occur alone or with neural and composite hypothesis. Familial cases of vitiligo are
simultaneous involvement of lips, distal penis and nipples. The common, suggesting a genetic basis. However, the transmission is
names lip tip and acrofacial vitiligo are given to this peculiar more complex, most likely polygenic.In the self destruct hypothesis,
distribution of lesions (Figure 2). formation of hydrogen peroxide (H2O2), certain tyrosine analogues
and intermediates in melanin synthesis are thought to cause the
destruction of melanocytes. In the autoimmune hypothesis,
presence of antibodies against the melanocytes, various
melanocyte antigens and transcription factors have been cited as
the evidence. Diagnosis is easy in the presence of progressive chalk
white macules in typical sites.Wood’s lamp examination may help.
Differential Diagnosis
The picture is mostly classical but it should include chemical
leucoderma, leprosy (Figure 3), post-inflammatory hypo-
pigmentation, pityriasis alba, pityriasis versicolour, tuberous

Figure 2: Generalised vitiligo.

Universal Vitiligo
It indicates almost total involvement of the body with few
remaining areas of pigmentation and has been associated with
various endocrinopathy syndromes. Koebner’s phenomenon is
not uncommon and on sites of burns, injury or laceration, the
depigmentation appears in that shape. Mucosal involvement
is not infrequent, genitalia, lips, gingiva are often involved.
Figure 3: BT leprosy.
Involvement of palms and soles though uncommon does 503
 sclerosis (Figure 4), piebaldism, etc. Small lesions of naevus structure of melanocytes. Characteristic ocular changes include
depigmentosus, and idiopathic guttate hypomelanosis have to nystagmus, iris translucency, reduced melanin in the retinal
be considered when the vitiligo lesions are focal. pigment epithelium. It results in a characteristic albino with
white hair, white skin and blue eyes.
Piebaldism
This is an uncommon, autosomal dominant, congenital, stable
leucoderma characterised by chalk or milk-white macules like
that of vitiligo and a typical white forelock.
Chemical Leucoderma
Acquired hypomelanosis is due to repeated exposures to specific
chemical compounds particularly phenols and sulphydryl
compounds. Monobenzylether of hydroquinone (MEBH) was the
first compound identified producing leucoderma in tannery
workers. The lesions of chemical leucoderma resemble lesions of
vitiligo, but usually do not have sharp margins. They appear not
only at the site of contact with the offending compound but also
remotely.The sites affected may be specific or very odd which
come in contact with these chemicals due to footwear, watch
straps, waist bands of undergarments, condoms, purses left in
contact with the breast, bindi and hair dye, etc.
Post-Inflammatory Hypopigmentation
A number of inflammatory dermatoses may be associated with
or resolve to leave hypopigmented lesions corresponding to
areas of involvement and are seen commonly after healing of a
lesion of dermatitits and psoriasis, etc.
Pityriasis Alba
It usually affects young children of both sexes equally. The
macule is pale or light brown with indistinct margins.
Erythema if present fades over weeks to leave behind off-
white or tan-white macule with fine scales. All parts of
the face, forehead, malar prominences, around the mouth
are common sites. Pityriasis alba is probably a non-specific
eczematous dermatosis with post-inflammatory hypomelanosis.
Pityriasis Versicolour (Tinea Versicolour)
It is caused by lipophilic yeast Malassezia furfur.
Typical lesion is a round, scaly, hypomelantoustic macule,
which sometimes may be raised and has erythematous raised
Figure 4: Ash leaf macules of tuberous sclerosis.
margins. Affected sites are the upper back and chest but
Treatment also occur on upper arms, neck and even face. The lesions are
Most patients require reassurance and an understanding more extensive in patients living in tropics. The lesions can
be tan, hyperpigmented and erythematous or a mixture with
of their affliction. Re-pigmentation is the basic aim of the
the hypopigmented lesions. Various topical and systemic
treatment. Currently available options include psoralens, topical
antifungals are effective in treating this condition.
calcineurin inhibitors (tacrolimus, pimecrolimus), topical and
systemic corticosteroids, topical and systemic PUVA, narrow HYPERMELANOSIS
band UVB, immunosuppressives and skin grafting according to
the type of vitiligo. Table 2 shows that hypermelanosis may be melanotic or
melanocytotic in origin which may be congenital or due to
Topical steroids are probably first-line therapy for most patients nutritional, hormonal, chemical factors or due to neoplasia or post-
with limited disease. Topical tacrolimus (0.03% and 0.1%) inflammatory. Epidermal hypermelanosis refers to brownish
ointment has been found to be safe and effective in childhood pigmentation due to increased melanin in the epidermis (Figure 5).
vitiligo. Narrow band UVB is currently considered the treatment Some of the hypermelanoses may be associated with a dermal
of choice for generalised vitiligo. Surgical techniques include component (mixed hypermelanoses) characterised by melanin
skin grafting, cultured/non-cultured melanocyte grafting, in dermal macrophages. Hypermelanosis may be diffuse or
punch grafting, etc. localised (ephelids, café- au-lait spots, Dowling-Dego disease).
Albinism Lentigines
Albinism refers to genetic abnormalities of melanin synthesis These are small (usually less than 0.5 cm in diameter), circumscribed,
504 (in hair, skin and eye) associated with normal number and brown to dark brown to black, variegated to uniformly coloured
 Disorders of Pigmentation
Figure 5: Becker’s naevus.

macules.They may be found as isolated macules or multiple lesions

mostly on sun-exposed areas. Mucosal lesions are localised to lips,
oral mucosa, palate and tongue in Peutz-Jeghers syndrome.
Although most of the hamartomatous polyps are benign, there is
a chance of them turning malignant.
Café-au-lait macules (CALMs)
These are discrete, well-circumscribed, 2 to 20 mm, uniformly
pale brown macules characterised by serrated or irregular
margins, appearing at or soon after birth. CALMs are common Figure 6: Melasma.
cutaneous findings but can be markers for multisystem
disease such as neurofibromatosis.
Melasma
It is an acquired symmetric hypermelanosis, with light brown
to gray brown macules or patches on sun exposed areas of
the skin. The most common sites involved are centrofacial
pattern affecting the cheeks, forehead, upper lip, nose, and
chin (Figure 6). It is much more common in women and is
seen more often in people with dark skin. Important aetiologic
factors are genetic predisposition, UV radiations (sun
exposure), endocrine disorders, nutritional deficiencies, female
sex hormones and certain drugs. The majority of cases appear
related to pregnancy or oral contraceptives. Melasma like
hyperpigmentation has been described in HIV disease. High
expression of α-MSH in the lesional keratinocytes may play
an important role in the melanisation of skin. Increased
number of melanocytes have been reported in the lesions. Use
of sun block and bleaching forms the mainstay of treatment
though majority of the times the treatment is unsuccessful
and the relief is temporary as long as the treatment lasts. The
sun screen must be a broad-spectrum, chemical sunscreen
(both UVA and UVB protecting) or an opaque physical (zinc
oxide, titanium dioxide).Topical hydroquinone (2% to 4%) with
retinoids and or steroids is the usual treatment. Steroids should
be used with care.
Post-inflammatory hyperpigmentation
In many dermatoses, pigmentation follows the healing of the
lesions. Eczemas and various dermatoses can lead to post-
Figure 7: Lichen planus pigmentosus.
inflammatory hyperpigmentation (Figure 7). The pigmentary 505
 macules are discrete, with hazy feathered margin corresponding RECOMMENDED READINGS
to the primary eruption. 1. Gupta S, Kumar B. Epidermal grafting for vitiligo in adolescents. Pediatr
Dermatol 2002; 19: 159-62.
DERMAL HYPERMELANOSIS (CERULODERMA) 2. Kanwar AJ, Dogra S, Parsad D. Topical tacrolimus for treatment of
childhood vitiligo in Asians. Clin Exp Dermatol 2004; 29: 589-92.
This results from the presence of pigment in the dermis.
3. Kanwar AJ, Dogra S, Parsad D, et al. Narrow band UVB for treatment of
Circumscribed dermal melanocytotic melanoses are generally
vitiligo; an emerging effective and well-tolerated therapy. Int J Dermatol
developmental and mostly occur among Asians like Mongolian 2005; 44: 57-60.
spots, naevus of Ota, naevus of Ito, etc. Circumscribed dermal 4. Lapeere H, Naeyaert JM. Hypomelanosis and hypermelanosis.
melanotic hyperpigmentation are—incontinentia pigmenti, Dermatology in General Medicine; In. 7th Ed.: Wolff K, Austen KF, Goldsmith
macular amyloidosis, etc. AF, et al. editors; McGraw-Hill Publishers; 2007: pp 623-40.
5. Rose PT. Pigmentary disorders. Med Clin North Am 2009; 93: 1225-39.
Fixed Drug Eruption
6. Yu SS, Pai S, Neuhaus IM, et al. Diagnosis and treatment of pigmentary
This is a very special type of process where the lesions occur disorders in Asian skin. Facial Plast Surg Clin North Am 2007; 15:
repeatedly on the same spot and the pigment darkens every time. 367-80.

506
 11.10 Disorders of Skin Appendages

Raj Kubba, Tanvi Pal

Hair follicles, sebaceous glands (pilosebaceous units), eccrine ACNE VULGARIS

(sweat) glands and nails are the key appendages of the skin. Acne vulgaris (literally meaning common acne) is a chronic
This section identifies and describes the solitary, most relevant inflammatory disorder of sebaceous follicles, predominantly
disease entity in each of these, namely, miliaria, acne vulgaris, seen in adolescence. It affects 80% of the population in the age
rosacea, and alopaecia areata. group of 11 to 30 years. Acne has a major impact on the quality
of life (QOL).
MILIARIA
Definition Aetiopathogenesis
Miliaria results from blockage of the acrosyringium, the long Acne is hormonal in origin. Acne results from a complex interplay
thin duct that carries sweat from the coiled secretory portion of increased sebum production, ductal hypercornification,
located in the reticular dermis and the subcutaneous fat to the follicular colonisation with Propionibacterium acnes, and
skin surface, with secondary leakage of sweat in the epidermis inflammation. Acne lesions begin with the microcomedo, a
and papillary dermis. microscopic lesion not visible to the naked eye. With time, the
follicle fills with lipids, bacteria and cell fragments. Ultimately, a
Aetiopathogenesis clinically apparent lesion occurs, either a non-inflammatory
Immaturity of the acrosyringium is the most likely reason for lesion (open or closed comedo) or an inflammatory lesion.
miliaria in newborns. Sudden, excessive, unaccustomed Comedogenesis is unique to acne and ductal hypercornification
sweating and febrile illnesses are some of the known is a key step in it. There is hyper proliferation and abnormal
triggers in both children and adults. Miliaria affected skin is cellular differentiation in the follicular infundibulum, resulting
reported to have three fold greater counts of bacteria such as in accumulation of excess and sticky keratinocytes that turn into
Staphylococcus epidermidis and Staphylococcus aureus, plugs (comedones). Propionibacterium acnes, a Gram-positive,
suggesting yet another aetiologic factor. rod-like bacterium, resides in sebaceous follicles and
contributes to comedogenesis and inflammation in acne
Clinical Features
through production of lipases and proteases, through
Depending upon the level of the blockage, three sub-types of elaboration of cytokines (TNF-α, IL-1α, IL-8), and through
miliaria are recognised. The details are given below: activation of toll-like receptor 2 (TLR 2).
Miliaria crystallina Clinical Features
The acrosyringium is blocked superficially—in the stratum Acne is readily recognised by its age of onset, anatomic
corneum—resulting in sheets of uniform, delicate, 1 mm sized, distribution, and folliculocentric morphology. However, it
vesicles with clear serous contents on the scalp, face, neck, and displays considerable range and variation. Typically, it precedes
upper torso. This subtype is seen mostly in newborns. puberty by a year or two, peaks between 14 and 16 years
Miliaria rubra in females, and 17 and 19 years in males. Acne displays
cephalocaudal evolution. The first lesions, usually comedones,
Also known as ‘prickly heat’, this subtype is clinically characterised
develop on the forehead (pre-adolescent acne). At its peak, acne
by uniform, non-follicular, 1 to 3 mm, erythematous papules,
covers the entire face (adolescent acne), and in mature adults
occurring in sheets with a predilection for back, flexures and
(25 years plus) it settles on the jaw area and the adjacent neck
frictional areas. Itching is intense and there is a propensity for
(persistent acne/adult acne). Acne is reportedly more common
secondary bacterial infection as impetigo and ‘boils’.
in males, 55% versus 45% for females, although the latter
Miliaria profunda frequently seek consultation from dermatology clinics. Also, our
When the acrosyringium is blocked at a deeper level the sweat female patients have more severe acne, often with added
leaks into papillary dermis producing 1 to 3 mm, flesh coloured stigmata of cutaneous hyperandrogenism, namely, seborrhoea,
papules that are typically non-itchy. The anatomic distribution hirsutism, and alopaecia.
is similar to Miliaria rubra. Typically, face is the only site of involvement or is distinctly more
Treatment involved. Less commonly, back is more involved (acne corporis)
(Figure 1), and such cases represent greater severity. Acne
Physical readjustment, in the form of confining to a cooler
corporis also involves the chest, shoulders and upper arms, and
environment, avoiding known triggers, frequent cold baths
rarely, buttocks and thighs.
and applying a soothing lotion containing calamine, menthol
or boric acid is all that is required to treat a typical case of Acne is a polymorphic condition showing an array of
Miliaria rubra. Topical antibiotics and topical steroids are comedones, inflammatory lesions and sequelae. Besides open
required for complicated cases. There are no sequelae. comedones (blackheads) (Figure 2), and closed comedones
Recurrences are common. (whiteheads) (Figure 3), there are macro-comedones (larger 507
 Figure 1: Acne vulgaris on back. Erythematous conical papules. Figure 4: Severe acne vulgaris. Several inflammatory nodules, cysts and sinuses.

lesions are painful or tender. Acne may be associated with

itching. Sequelae include post-inflammatory pigmentation and
scars. There are several grading systems. An easy to use acne
grading system is described in Table 1.

Table 1: Grading of Acne

Grade 1: Mild acne Comedones < 30
Predominance of comedones Papules < 10
No scarring
Grade 2: Moderate acne Comedones any number
Predominance of papules Papules > 10
Nodules < 3
Mild scarring ±
Grade 3: Severe acne Comedones any number
Predominance of nodules/cysts Papules any number
Nodules/cysts > 3
Extensive scarring
Figure 2: Acne vulgaris. Numerous blackheads (open comedones) and a few
inflamed nodules. Acne tends to aggravate in hot and humid weather, under
stress, and by injudicious use of oils and oily skin care products.
Premenstrual flares are common and indicate hormonal
imbalance. In time, acne remits, usually before the age of 25
years. Increasingly, it may persist longer, in some instances beyond
the age of 50 years. There are also individuals who develop acne
for the first time after the age of 25 years (adult acne).
Diagnosis
Acne is diagnosed clinically. Laboratory tests are only done to
evaluate for hormonal imbalance and to screen and monitor
for certain treatments. Differential diagnosis includes acneiform
drug eruptions, folliculitis, and rosacea.
Treatment
Acne treatment plans are based on severity, and presence of
associated features such as cutaneous hyperandrogenism.
Combination treatments are preferred. Available modalities and
their respective mode of actions are listed in Tables 2 and 3.
Figure 3: Acne vulgaris. Inflammatory papules and pustules,‘closed comedones’ First line treatments for all forms of acne are topical retinoid
pitted and ice-pick scars.
and benzoyl peroxide. Moderate acne often requires systemic
than 1 mm). A diagnosis of acne in the absence of comedones antibiotics. Severe acne should be treated with oral isotretinoin.
is not tenable. However, 10% of acne patients may not show Acne in the context of cutaneous hyperandrogenism requires
comedones at first clinic visit. Inflammatory lesions include antiandrogens. Topical agents should be applied on the entire
macules, papules, pustules, papulopustules, nodules, pseudo susceptible area, for example, the entire face. Topical retinoids
508 cysts, and sinus tracts (Figure 4). Only larger inflammatory are photoreactive and are best applied at bedtime. Adapalene
 Disorders of Skin Appendages
is the least irritating topical retinoid and also has anti- asymptomatic, monomorphic, papular or pustular eruption on
inflammatory effect. Topical antibiotics should never be used the upper torso in a post-pubertal individual, with or without
as monotherapy for risk of bacterial resistance. Oral isotretinoin previous acne, who has received systemic steroids. It does not
has potential for serious adverse effects and should only be scar and tends to resolve spontaneously or with mild topical
administered under expert supervision. An algorithmic acne medications after the steroids have been withdrawn.
approach to management of acne is described in Figure 5.
ROSACEA
Table 2: Topical Treatment Options in Acne Rosacea is a chronic, waxing and waning, vascular reaction
Predominantly anticomedonal pattern, involving the central area of the face, occurring
Adapalene 0.1% in mature adults. It is characterised by episodic flushing,
Tretinoin 0.25% and 0.05% erythema, telangiectasia, recurrent papules and pustules.
Tazarotene 0.05% and 0.1%
Azelaic acid 10% and 20% Aetiopathogenesis
Predominantly antimicrobial Hypotheses include potential roles for vascular abnormalities,
Benzoyl peroxide 2.5% and 5% environmental factors, and micro-organisms such as Demodex
Clindamycin 1% folliculorum and Helicobacter pylori. Steroid rosacea refers to a
Erythromycin 4%, clarithromycin 2% rosacea-like clinical state, induced by prolonged use of topical
Combinations steroids.
Adapalene/clindamycin
Benzoyl peroxide/erythromycin Clinical Features
Four clinical patterns are recognised: Erythemato-telangiectatic,
Table 3: Systemic Treatment Options in Acne papulopustular, phymatous, and ocular. Rosacea typically
Antibiotics (antimicrobial, anti-inflammatory) involves the central face viz. glabella, nose, cheeks and chin.
Tetracycline 500 mg bid Besides central location, later onset, and flushing, rosacea is
Doxycycline 100 mg od distinguished from acne by the absence of comedones. However,
Minocycline 100 mg od acne and rosacea may co-occur (acne rosacea). Ocular changes
Retinoids (sebosuppressive, anti-comedonal, anti-inflammatory, are irritation, lacrimation, blepharitis, episcleritis, keratitis, corneal
anti-microbial) vascularisation, and iritis. Rhinophyma describes a sequel where
Vitamin A 50,000 units bid
the hypertrophied nose shows craggy, bulbous swelling with
Isotretinoin 0.5 to 1.0 mg/kg
prominent follicular ostia filled with keratinous debris.
Anti-androgens (sebosuppressive, anti-comedonal)
Combination OCP (cyproterone acetate 2 mg + ethinyl Treatment
oestradiol 35 μg)
Metronidazole 0.75% gel and/or oral antibiotics are the first-
Combination OCP (drospirenone 3 mg + ethinyl oestradiol
30 μg) line treatments. Doxycycline 100 mg once daily; minocycline 100
Spironolactone 25 to 50 mg bid mg daily; or clarithromycin 250 mg twice daily or 500 mg once
daily, for 4 to 12 weeks are all effective. However, the condition
tends to relapse.

ALOPAECIA AREATA
Human skin bears approximately 5 million hair follicles of which
around 100,000 hair follicles are located on the scalp. The hair
grow in a cyclical manner and exhibit four phases: Growth
(anagen), regression (catagen), resting (telogen), and shedding
(exogen). Hair disorders may result from defects in hair cycle, or
hair growth (excess—hirsutism; sparse—hypotrichoses), and
from hair follicle destruction by per follicular inflammation
(Lichen planus, Lupus erythematosus).
Definition
Alopaecia areata (AA) is the most notable example of non-
scarring, non-patterned alopaecia, characterised by sudden/rapid
appearance of circumscribed, circular/ oval bald patches in hair
bearing areas especially the scalp (Figure 6).The alopaecia results
Figure 5: Acne treatment algorithm. from arrest of hair follicles in late anagen phase.
BPO= Benzoyl peroxide.
Epidemiology
DRUG-INDUCED ACNE The prevalence in general population is 0.1% to 0.2%; life-time
Acne can be triggered or aggravated by androgens, risk for developing AA is 1.7%, and it comprises 0.7% to 3% of
progestogens, anabolic steroids, topical and oral corticosteroids, all patients seen by dermatologists. A positive family history has
halogens, isoniazid, diphenylhydantoin, phenytoin, thiouracil, been recorded in 10 to 20%. AA can occur at any age but
cyclosporine A, disulfiram, lithium, vitamin B12, and PUVA the highest susceptibility has been observed in the age group
therapy. Steroid acne refers to the sudden onset of an 15 to 29 years. 509
 steroids, intralesional steroids (triamcinolone acetonide 2.5 to
5 mg/ml), and 5% minoxidil lotion. For active/spreading AA
systemic therapy with levamisole (50 to 150 mg on two
consecutive days each week for 3 to 6 months) and/or
prednisolone as oral minipulse (0.5 mg/kg dose on two
consecutive mornings each week) are popular in our country.
Aggressive systemic steroids, as daily dosing for limited periods,
may be justifiable for severe and psychologically disabling
disease. Systemic steroids are therapeutically very effective but
relapses are a rule when they are withdrawn.

NAIL CHANGES
Nails, another skin appendage, are subject to abnormalities both
internally as well as by disorders of the skin. Understanding the
biology and anatomy of the nail allows the treating physician
to ascertain the location of pathology and treat accordingly. The
nail unit comprises of the proximal and lateral nail folds, nail
matrix, nail bed, and hyponychium (Figures 7 and 8). Described

Figure 6: Alopaecia areata. Circumscribed patchy alopaecia with no

inflammation or scarring.

Aetiopathogenesis
AA is postulated to be a T-cell mediated autoimmune disease
directed against hair follicles in late-anagen phase. AA is believed
to be a polygenic condition with environmental and life-
style factors acting as triggers and causing aggravation. AA is
associated with atopy, type 1 diabetes mellitus, autoimmune
thyroid disease, autoimmune polyendocrinopathy syndrome,
vitiligo, pernicious anaemia, inflammatory bowel disease and
Down’s syndrome.
Clinical Features
Alopaecia areata is common in both men and women. A solitary
patch is the initial presentation in 80%, and spontaneous re-
growth in 3 to 6 months is the rule. The natural course is variable
and unpredictable. Recurrences are common and, with each
recurrent episode, the severity tends to increase and probability
of spontaneous re-growth diminish. The presence of
‘exclamation mark hair’ at the margin of the alopaecia is
indicative of activity. Re-growth in AA patches commences from
the centre and progresses centrifugally. AA patches are typically
Figure 7: Diagramatic presentation of nail structure.
skin coloured and asymptomatic.
Based on distribution and severity, several clinical patterns are
recognised, namely, focal, reticular, ophiasis (band-like hair loss
in the occipital and temporal scalp), sisaipho (predilection for
parietal scalp mimicking androgenetic alopaecia), totalis (loss
of all scalp hair), and universalis (loss of all scalp and body hair).
Nail involvement, mostly as pitting, has been noted in 6.8 to
49.4%. AA significantly impacts the quality of life.
Diagnosis and Prognosis
AA is a clinically distinctive disease. The prognosis is variable,
being good in mild disease and initial episodes. However,
recurrent disease, severe disease (particularly ophiasis, totalis
and universalis), early age at onset, nail involvement, and co-
morbidities such as atopy, are adverse prognostic signs.
Treatment
A wide range of therapeutic options are available for
Figure 8: Nail unit in cross-section.
510 management of AA. First choice modalities include topical
 Disorders of Skin Appendages
below are few of the common nail signs affecting the nail plate, Paronychia
nail bed, and nail folds. Paronychia means inflammation of the nail folds. It is categorised
Koilonychia into acute and chronic. Acute form is one of the most common
infections of the hand, with Staphylococcus aureus, Streptococci
It is spooning of the nails, where the lateral edges of the nail
and Pseudomonas being the likely pathogens. Chronic paronychia
plate are elevated above a depressed centre. Endocrinological
is caused by repeated trauma to the nail folds either physical
diseases such as hypothyroidism and iron deficiency anaemia
(excessive manicuring) or chemical (water, contact irritants).
are the main causes way.
Tinea Unguium
Pitting
The infection of the nail unit with dermatophytic fungi is known
Pitting occurs in response to a defect in the nail matrix, mainly
as Tinea unguium. Dermatophytes are keratinolytic fungi and
the proximal matrix. They are shallow depressions in the surface
normally invade keratins of skin, hair and nails, most common
of the nail and can be regular, irregular, large, or small depending
being Trichophyton rubrum and T. mentagrophytes (Figure 10).
on the duration and extent of pathology. Most common causes
Toenails are infected 25 times more than the finger nails.
of pitting are psoriasis, alopaecia areata and eczematous
conditions.
Clubbing
It is a over-curvature of the nail, with or without hypertrophy
of the soft tissues and cyanosis. Clubbing is characterised
by an increase in the angle (> 180°) between the proximal nail
fold and nail plate, and it is mostly seen in cardiovascular,
gastrointestinal and familial disorders.
Beau’s Lines
A growth disruption in the nail matrix results in horizontal
(transverse) depressions in the nail plate (Figure 9). Any
systemic disease or event that is severe enough to cause
disturbance of nail growth can result in Beau’s lines. Figure 10: Distal onychomycosis showing yellow-brown discolouration.

RECOMMENDED READINGS
1. AlKhalifah A, Alsantali A, Wang E, et al. Alopaecia areata update: Part I. Clinical
picture, histopathology, and pathogenesis. J Am Acad Dermatol, 2010; 62:
pp. 177-88.
2. AlKhalifah A, Alsantali A, Wang E, et al. Alopaecia areata update: Part II.
Treatment. J Am Acad Dermatol, 2010; 62: pp. 191-202.
3. Berker DAR, Baran R, Dawber RPR. Disorders of Nails. In: Burns T, Breathnach
S, Cox N, Griffiths C, editors. Rook’s Textbook of Dermatology; 7th Ed. Oxford,
Blackwell Science Publishing; 2004: pp. 62.
4. Coulson IH. Disorders of sweat glands. In: Burns T, Breathnach S, Cox N,
Griffiths C, editors. Rook’s Textbook of Dermatology; 7th Ed. Oxford, Blackwell
Science Publishing; 2004: pp. 45.
5. Kubba R, Bajaj AK, Thappa DM, et al. Acne in India: Guidelines for
Management – IAA consensus document. Indian J Dermatol, Venereol, Leprol
2009; 75 (supp 1): pp. S1-S64.
6. Simpson NB, Cunliffe WJ. Disorders of the Sebaceous Glands. In: Burns T,
Figure 9: Beau’s lines. Transverse depressions in the nail plate. Breathnach S, Cox N, Griffiths C. Rook’s Textbook of Dermatology; 7th Ed.
Oxford: Blackwell Science Publishing; 2004.

511
 11.11 Cutaneous Responses to Physical Factors

S Criton

Sun is the perennial source of energy and it sustains life on Vibration can cause vibratory angioedema and hand-arm
earth. Though it has beneficial effects, at times sunlight vibration syndrome. Vibratory angioedema is a form of physical
can cause harmful effects to man. This may range from trivial angioedema which disappears when the stimulus is withdrawn.
transient pigmentation to lethal cutaneous as well as systemic In ‘hand-arm vibratory syndrome’, initially there is tingling and
malignancies. numbness. As the disease progresses, anaesthesia occurs. This
is followed by blanching. As the disease progresses further, there
Sunlight has many components such as gamma rays, X-rays,
is reduction in touch sensation and difficulty in doing fine work.
ultraviolet rays, infrared light and radio waves. Common harmful
The condition may be improved with use of nefedipine and α-
effects of sunlight are due to ultraviolet rays. The ultraviolet rays
andrenoreceptor antagonist.
have three components such as ultraviolet A (320 nm to 400 nm),
ultraviolet B (290 nm to 320 nm) and ultraviolet C (200 nm to THERMAL INJURIES
290 nm). When light falls on skin some are reflected and some are
absorbed. The penetration into skin is dependent on the wave Thermal injuries include burn, electric injury and lightening
length (the longer wavelengths penetrate more). As the rays injury. The spectrum of burn may be trivial and inconsequential
penetrate, part of it is absorbed by chromophores, part is to very severe leading to death. The type, depth, extent, age of
transmitted and part is reflected back.Once the energy is absorbed, the patient, associated illness, time elapsed between burn and
the chromophores become excited and form photoproducts. treatment and general status of the patient either singly or in
These photoproducts are responsible for the skin changes. combination determine the outcome of burn. While treating
the patient with burn cardiac status, renal status, the infection
CUTANEOUS EFFECTS OF ULTRAVIOLET EXPOSURE and coagulation abnormalities are monitored and corrected
The cutaneous effects of ultraviolet ray, exposure may be divided appropriately. Once the acute phase is over, long-term
into early and late effects. The early effects are inflammation, complications such as scarring and contracture are addressed.
tanning, hyperplasia, immunological changes, vitamin D synthesis Electricity can produce burns. This may be divided into high
and photo onycholysis. The late effects of ultraviolet exposure tension and low tension burns. With high tension injury, there
include pseudoporphyria, photoageing, photocarcinogenesis. will be injuries at the entry site as well as at the exit point. The
Skin Phototypes management of electric burn include general supportive care
Fitzpatrick developed the concept of skin types based on the and specific wound management.
person’s responses to sunlight. Based on this, the skin is typed When lightening strikes, focal entry and exit wounds are lacking
as Type I through VI. Persons with types I and II usually burn in many. In some at the site of entry, there may be superficial
more easily. The types V and VI individuals tan easily and have streaking burns, known as ‘lightening figures’, and at the exit
least propensity to develop skin cancers. Type III individuals have site there may be a charred defect.
moderate susceptibility to sun burn and good tanning ability;
whereas type IV skin has low sun burn susceptibility but very COLD INJURIES
good tanning potential. Cold environment is harmful to human body. Inherently body
MECHANICAL INJURY has developed protective mechanisms from cold injuries. When
body is exposed to cold, a number of responses occur such as
Mechanical injuries are common on human skin due to pressure
cutanenous vasoconstriction, increase in viscosity of blood,
and shearing force. This may occur as a consequence of
change in platelet adhesiveness, diminished conduction
occupation, recreational activity or due to deformities. Constant
velocity in cutaneous nerves and slowing of dissociation of
friction produces callosities, corns and calluses. It can also lead to
oxyhaemoglobin to haemoglobin. These factors will help the
bullae. Corns are circumscribed areas of hard skin in the shape of
body to maintain its core temperature. Prolonged cutaneous
a nodule commonly seen over the dorsal surface of toes. Calluses
vasoconstriction leads to ischaemia and later necrosis. This is
are more diffuse. Pressure ulcer is due to localised area of
prevented by subsequent vasodilatation which is known as
ischaemia and necrosis following prolonged compression of soft
tissues over a bony prominence. Suction can also produce‘suction ‘hunting reaction of Lewis’.
blister’, which is a mechanical injury due to negative pressure. Disease of Cold Injury
‘Computer palms’ and ‘mouse fingers’ are emerging injuries due The type and gravity of cold injuries depend on various factors
to mechanical stress to palms and fingers. Pressure, shear, such as absolute temperature, duration of exposure, individual
moisture and friction are attributed factors causing these susceptibility and altitude at which injury occurs. The factors
injuries. ‘Spectacle frame acanthoma’ is another entity controlling individual susceptibility are physical injury, body
developed following pressure and friction of the spectacle and mass, physical fitness level, fatigue, sickness, trauma, peripheral
512 moisture at the site where spectacle is coming into contract. circulation status as well as clothing and age of the patient.
 Cutaneous Responses to Physical Factors
Habits like alcohol consumption, smoking and use of Acrocyanosis
psychotropic drugs will add onto cold injuries. Acrocynosis is a persistent cyanotic or erythrocyanotic-
Classification of Cold Injury discolouration of skin with mottled pigmentation. It mainly
affects the hands; feet and face are also affected in some.
The cold injuries may be broadly divided into freezing and
nonfreezing injuries. Acrocyanosis may be idiopathic phenomenon or secondary to
some diseases and drugs. The diseases causing acrocyanosis
Frostbite
include autoimmune disorders, neoplastic diseases, eating
Frostbite is a type of cold injury caused by acute freezing of disorders, neurological disorders, psychiatric illnesses and
tissues on exposure to extreme degrees of cold. Frostbite chronic arsenic poisoning.
has four phases such as pre freeze (vasospastic) phase, freeze
thaw phase, stasis phase and ischaemic phase. There is no effective treatment for idiopathic condition. But if it
is secondary to diseases, appropriate treatment may help to
Frostbite usually affects fingers, toes, nose or cheeks. Depending
improve.
on the tissue involved it may be graded into first through fourth
degree. The first degree frost bite presents with blanched Livedo Reticularis
anaesthetic skin. In second degree, there will be oedema Livedo reticularis is a mottled cyanotic discolouration of the skin
and blister formation. In third degree, the bullae become with network pattern, which is accentuated with cold. It may
haemorrhagic, while in fourth degree, there will be necrosis. be physiological, idiopathic or secondary to intravascular
Treatment obstruction or vessel wall diseases.
The principle in the management of frostbite is rapid rewarming Cold Urticaria
and avoidance of further trauma. Rapid rewarming is done by This is characterised by development of wheals on rewarming
immersion in water at 40 to 42° C for 20 minutes. The damaged at the site of localised cooling. It may be acquired cold urticaria
part should be elevated and blisters should be left intact. Liberal or familial cold urticaria. In acquired variety there may be
use of analgesics are recommended for relief of pain. Early wheals with constitutional features on exposure to cold; while
administration of heparin and infusion of low molecular weight familial cold urticaria is an autosomal dominant condition. The
dextran are suggested as effective modalities. Oxpentifylline
diagnosis of cold urticaria may be made with ‘ice cube test’. This
and hyperbaric oxygen therapy are other recommendations.
may be negative in familial cold urticaria.
Trench Foot (Immersion Foot)
Cold panniculitis
Trench foot results by prolonged exposure to low temperature
In children on exposure to cold, there will be erythematous,
without freezing.
tender subcutaneous nodules which persist for 2 to 3 weeks.
Clinical features
Winter Xerosis
It start as numbness and tingling. The skin becomes
erythematous initially but later it becomes pale and mottled. If Patients may present with itching during winter. The itching
the condition persists there may be pain, ulceration and may be generalised; it may be more over legs. Predisposing
sometimes gangrene. factors include atopic dermatitis, ichthyosis, old age, hypo-
thyroidism and excessive washing with soap.
Treatment
Photodermatoses: Abnormal Cutaneous Effects of
Rewarming the area and other supportive measures like rest to
Ultraviolet Radiation Exposure
the part, analgesics, and antibiotic. The part should not be
massaged, rubbed and exposed to extreme heat. Photodermatoses can be divided into four categories such as
(1) acquired idiopathic photodermatosis, e.g. polymorphic light
Pernio (Chilblains) eruption; (2) DNA – repair defective photodermatoses, e.g.
Chilblain is characterised by localised, tender, inflammatory, Xeroderma pigmentosum; (3) photosensitisation by exogenous
erythematous, pruritic lesions which blister or ulcerate. The or endogenous drugs or chemicals, e.g. sulphonylureas,
predisposing factors to chilblains include genetic susceptibility, porphyrias; and (4) photoexacerbated dermatoses, e.g. lupus
inadequate nutrition, focal sepsis, hormonal changes and erythematosus.
systemic diseases such as dysproteinaemia, myelodysplastic
disease and anorexia. Acquired idiopathic photodermatoses include polymorphic
light eruption (PLE), actinic prurigo, hydroavacciniforme, chronic
Clinical features actinic dermatitis and solar urticaria.
The characteristic lesions are blue-red oedematous, sharply
bordered nodules. They are distributed on dorsal aspect of Polymorphic (Polymorphous) Light Eruption (PLE)
fingers and toes, shins, inner aspect of knees and thighs, heels, This is a common form of idiopathic photodermatoses
nose, ears or occasionally on breasts. Some of the lesions may characterised by itching and polymorphous skin lesions such
ulcerate. On warming they become pruritic and later painful. as papules, vesicles, plaques, papulovesicles, and erythema
The lesions may persist for 3 weeks or rarely more. multiforme-like lesions. Though the lesions are polymorphic,
Treatment in a given individual, they are monomorphic. The lesions are
distributed in sun exposed areas of the body.
The various drugs used are calcium channel blockers viz.
nifedipine and diltiazem, vasodilators such as nicotinic acid The treatment includes sun protection, topical steroid and anti-
esters as well as pentoxyfylline. malarials. The disease has a good prognosis. 513
 Actinic Prurigo CLINICAL EVALUATION OF THE PATIENT WITH SUSPECTED
A seasonal dermatitis characterised by itching, nodular and CUTANEOUS PHOTOSENSITIVITY
eczematous lesions over legs. It may begin at any age. The While evaluating the patient with photosensitivity, the following
face and distal limbs are commonly affected. Treatment is points are noted: the age, sex, occupation, recreational activity,
mainly photoprotection. Systemic thalidomide is found to prior history of photosensitivity, family history of photo-
be useful. sensitivity, history of seasonal changes, interval between
Chronic Actinic Dermatitis exposure and onset of symptoms, history of medication for the
disease or any other diseases, application of topical agents, the
This is a syndrome encompassing photosensitive eczema,
pattern of dress and aggravating and/or relieving factors.
photosensitivity dermatitis, actinic reticuloid and persistent
light reaction. The disease is reported world wide and affects The morphology of lesion and site of involvement are important
chiefly the elderly. It presents as papules and plaques on a diagnostic clues.The characteristic lesions are patches or papules.
normal or erythematous skin over sun exposed areas. The Pinhead sized hypopigmented papules may suggest PLE. Blisters
disease may persist for a long time and in some there may be with scarring may be of porphyria. Persistent excoriated papules
transformation to lymphoma. over sun-exposed areas are suggestive of actinic prurigo;
The treatment includes avoidance or reduction of sun exposure eczematous lesions may be due to chronic actinic dermatitis.
and photoprotection. Systemic steroid, cyclosporine and Wheals on exposure to sun may suggest solar urticaria.
azathioprine may be used in the treatment with some benefit. The sites of involvement such as malar area, and tip and bridge
Very resistant cases PUVA (Psoralen and UVA) or NB UVB (Narrow of nose, anterolateral forearm, rim of ears,‘V’ area of chest, sides
Band UVB ) may be useful. of neck and dorsum of hands may suggest photodermatitis
Solar Urticaria (these are common sun-exposed areas). In photodermatitis
some areas are not usually involved such as submental area,
Solar urticaria (SU) is characterised by the appearance of wheals
behind the pinna, sun protected areas, web space of fingers are
on exposure to sunlight. It may be primary or secondary. Solar
some among them. Sparing of these areas in the dermatitis in
urticaria is considered as Type I hypersensitivity reaction; while
secondary solar urticaria is due to drug photosensitivity, question may also help to make a diagnosis of photodermatitis.
cutaneous porphyria or lupus erythematosus. Laboratory investigations may help to establish the underlying
Drug and Chemical Induced Photosensitivity cause of photodermatitis, e.g. estimation of porphyrin,
antinuclear antibodies in lupus erythematosus. Photo testing
This may mimic sunburn. A number of patterns may help to
and photopatch testing are some useful tools in evaluation of
suspect this entity such as pricking and burning sensation,
photodermatitis.
immediate erythema on exposure to sun, oedema and urticaria,
hyperpigmentation, exaggerated sunburn, telangiectasia and RECOMMENDED READINGS
angioma, blisters, increased skin fragility and delayed erythema. 1. Burns , Breathnachs, Cox N, Grittiths C, editors. Rook’s Textbook of
Drugs such as sulphonamides, sulphonylureas, phenothiazines, Dermatology; 8th Ed. Wiley-Blackwell; 2010 .
furocoumarins, fragnances, sun screens, NSAIDs are considered 2. Wolffk, Goldsmith LA, Katz SI, Paller AS, Lettell EJ,editors. Fitzpatrick’s
important in causing drug-induced photosensitivity. Dermatology in General Medicine; 7th Ed. McGraw Hill; 2008

514
 11.12 Genodermatoses

Vibhu Mendiratta

DEFINITION 2 has bilateral acoustic neuromas of the vestibulocochlear

Genodermatoses are a group of diseases which are nerve leading to hearing loss. The diagnostic criteria are
transmitted genetically from parents to children. enlisted in Table 1.
Genodermatoses have well-defined cutaneous features
whose recognition plays a key role in its diagnosis and
management.

AETIOPATHOGENESIS
The disorders arise due to defect or alteration in a single or
multiple genes (polygenic disorders), or these may also arise
due to alterations in chromosomal structure. Factors that may
give rise to genetic defects include mutagens such as radiation,
drugs, cytotoxic agents, chemicals, ultraviolet (UV) light, and
viral infections. Single gene disorders have a clear mode of
transmission which may be autosomal dominant, recessive,
X-linked recessive or dominant. The genetic defect may
affect specific protein which may be keratin, DNA or enzymes
required for various metabolic processes. Some common
genodermatoses, namely neurofibromatosis, tuberous sclerosis,
icthyosis, palmoplantar keratoderma, xeroderma pigmentosum
shall be outlined in detail.

NEUROFIBROMATOSIS (SYN. VON RECKLINGHAUSEN’S Figure 1: Multiple nodules (neurofibromas) on face.

DISEASE)
Epidemiology
It is one of the most commonly encountered genetic disorder
which affects both men and women equally. The prevalence is
estimated to be 1 case per 3,000.
Aetiopathogenesis
An autosomal dominant disorder with a defect on the long arm
of the chromososme 17. Children of one affected parent have a
50% chance of getting the disease. Severity in the affected
individuals is variable, some have all the features, while others
are only mildly affected.
Clinical Features
Neurofibromas are skin coloured, soft, fleshy, nodules
distributed on various areas. Some neurofibromas are
subcutaneous lumps (Figure 1). Neurofibromas increase in
number with age. Plexiform neurofibroma are soft, doughy,
subcutaneous swelling having a bag of worm feeling and run
along nerves. Presence of multiple, brownish macules (Café Figure 2: Multiple café au lait macules and freckling in neurofibromatosis.
au lait macules) and tiny specks of brownish macules in the
axilla (axillary freckling) constitute some diagnostic features Complications
(Figure 2). There are multiple bony abnormalities in the form Pressure effects on nerves, seizures, malignant change in
of scoliosis, spina bifida. Examination of the eyes shows Lisch neurofibroma.
nodules which are brownish iris hamartomas (Figure 3).
Neurofibromatosis (NF-1) has bony abnormalities like scoliosis, Treatment
spina bifida. Phaeochromocytoma, precocious puberty, Single plexiform neurofibromas can be removed with the help
tumours of the central nervous system (CNS), seizures and of laser or excision. Genetic counselling should be held for the
mental retardation may be associated. Neurofibromatosis type patient. 515
 be surgically removed if they enlarge or cause bleeding.
Hypomelanotic macules (‘ash leaf spots’) are white- or light-
coloured patches on skin that may appear anywhere on the body.
These are usually the only visible sign of tuberous sclerosis at
birth. Shagreen patches are areas of thick leathery skin which is
dimpled like an orange peel and is usually found on the lower back
or nape of the neck (Figure 5). Café au lait macules can be seen.

Figure 3: Iris hamartomas on the surface of iris.

Table 1: Diagnostic Criteria for Neurofibromatosis Based on the

Clinical Criteria
1. Two or more neurofibromas on the skin or under the skin or one
plexiform neurofibroma
2. Freckling of the groin or the axilla
3. Café au lait spots. Six or more measuring 5 mm in greatest Figure 4: Multiple, brown small, grouped, fleshy papules around nose
diameter in pre-pubertal individuals and over 15 mm in greatest (angiofibromas) in tuberous sclerosis.
diameter in post-pubertal individuals
4. Skeletal abnormalities, such as sphenoid dysplasia or thinning
of the cortex of the long bones of the body
5. Lisch nodules (iris hamartomas, freckling in the iris)
6. Tumours on the optic nerve also known as an optic glioma
7. A first-degree relative with a diagnosis of neurofibromatosis-1

TUBEROUS SCLEROSIS (SYN. BOURNEVILLES DISEASE)

Definition
Tuberous sclerosis is a genetic disorder with an autosomal
dominant pattern of inheritance, and variable penetrance.
Two-thirds of tuberous sclerosis (TSC) cases result from sporadic
genetic mutations. Hence, there may not always be presence
of an affected member in the family.
Epidemiology
Tuberous sclerosis occurs in all races, genders and ethnic groups.
The prevalence is estimated to be between 10 to 13 cases per Figure 5: Shagreen patch and ash leaf macules on the back in tuberous sclerosis.
100,000.
Approach to the Diagnosis of Tuberous Sclerosis
Clinical Features
The physical manifestations of tuberous sclerosis are due to 1. Taking a personal and family history
formation of hamartomas. Hamartomas are present in the brain 2. Examining the skin under Wood’s lamp
(in the form of cortical tubers). Characteristic cutaneous findings 3. Cranial imaging with non-enhanced CT or preferably MRI
appear as multiple, brown, soft, grouped papules present in the (for cortical tubers and subependymal nodules)
perinasal area and cheeks in a butterfly distribution (Figure 4).
These are called facial angiofibromas (misnamed as adenoma 4. Renal ultrasound (angiomyolipoma or cysts)
sebaceum). Their number increases with age. Subependymal 5. An echocardiogram in infants (rhabdomyoma)
nodules in the brain are diagnostic. Patient often presents with 6. Fundoscopy (retinal nodular hamartomas or achromic
seizures at an early age, developmental delay and behavioural patch).
problems. About 50% of patients with tuberous sclerosis (TSC)
have learning difficulties. Between 60 and 80% of the patients Management
have tumours (angiomyolipomas) in kidneys, lung cysts, and Management is symptomatic. Seizures require anti-epileptic
cardiac rhabdomyomas. Ungual or subungual fibromas, (known drugs. Mental retardation should be managed in the
as Koenen’s tumours) are small fleshy tumours that grow developmental clinics. Facial angiofibromas can be removed
516 around and under the toenails or fingernails and may need to with the help of electrosurgery or lasers.
 Genodermatoses
Prognosis features, such as thickening of skin of palms and soles, nail
The prognosis for individuals with tuberous sclerosis depends changes, eye abnormalities like ectropion, reduced sweating and
on the severity of symptoms. Leading causes of death include redness of skin are some of the other associated features.
renal disease, brain tumour, lung cysts and status epilepticus.

ICTHYOSIS
Definition
The ichthyosiform dermatoses are a diverse group of hereditary
skin disorders characterised by the accumulation of ‘fish-like’
scales resulting from abnormal epidermal cell kinetics. Severity
of individual types ranges from mild to life-threatening icthyosis.
Based on the mode of inheritance icthyosis can be autosomal
dominant which includes: Icthyosis vulgaris, X-linked icthyosis
(seen in boys only) and autosomal recessive icthyosis which
includes the lamellar icthyosis and icthyosiform erythroderma.
Recessive forms of icthyosis tend to be more severe than the
dominant types.
Figure 7: Large, dark scale in lamellar icthyosis.
Epidemiology
Icthyosis vulgaris is the most common type of icthyosis Differential Diagnosis
affecting around 1 in 250 people. Non-bullous icthyosiform Drug induced icthyosis, icthyosis secondary to lymphomas.
erythroderma, bullous icthyosis and lamellar icthyosis are more
severe forms but are uncommon. Diagnosis
Aetiopathogenesis Distribution of scales, colour and severity of scaling offer
important clues to the diagnosis. A family history is very useful.
Icthyosis arise as a result of mutation in the gene regulating In some cases, a skin biopsy is done to help confirm the
the keratin synthesis. diagnosis. In some cases, genetic testing and prenatal testing
Clinical Features may be helpful in making the diagnosis.
All icthyosiform dermatoses present with dry, scaly skin which Treatment
shows fish-like or plate-like scales in variable pattern of Treatment for icthyosis includes application of creams and
distribution. Icthyosis vulgaris begins in the first year of life and emollients in the form of petroleum jelly and vegetable oils for
shows dry, scaly skin over the extensor aspects of the arms and hydrating the skin. Oral retinoids are used for severe icthyosis.
legs.The scales are larger over the lower extremities and presence Exposure to sunlight may improve or worsen the condition.
of mild keratoderma or (thickening of the skin over the palms Systemic complications need symptomatic and supportive
and soles) is noted. The dryness becomes worse during winters treatment.
and improves in summers and humid weather. Some patients
also bear a tendency to develop atopic dermatitis. Prognosis
Autosomal dominant icthyosis improves with age and the
X-linked icthyosis affects boys only. The scales are dirty brown in
severity lessens with time. Weather also affects the severity
colour and affect both the extensor and flexural surfaces of the
and icthyosis improves in summers.
extremities with prominent involvement of the neck and trunk
(Figure 6). Severe icthyosis exhibit widespread scaling, scales are XERODERMA PIGMENTOSUM
more diffuse and distributed over both the extensor and flexures
Definition
of the body. Scales are larger and plate-like (Figure 7). Associated
Xeroderma pigmentosum or XP, is an autosomal recessive
disorder of DNA repair.
Epidemiology
It is a very rare disorder. Affects both men and women. Parents
already with a child with XP have a 1 in 4 chance of having
another child with XP.
Pathogenesis
There is a genetic defect in the repair of DNA damaged by UV
light. The most common defect in XP is an autosomal recessive
genetic defect in which nucleotide excision repair (NER)
enzymes are mutated. Patients with XP are at a higher risk of
developing skin cancers such as the basal cell carcinoma.
Clinical Features
Figure 6: X-linked icthyosis showing dirty dark brown, big fish like scales on Disease presents early in life in the infantile period (around 3 to
extremities.
6 months) with the history that the child cries on exposure to 517
 the light. Skin turns erythematous on exposure to sun and there Epidemiology
may be photophobia. Development of freckles and lentiginosis It occurs in a frequency of 1 in 50,000. Epidermolysis bullosa is
on the exposed area of the body, such as the extensor aspect more common in communities where consanguineous
of arms, face and the neck are early signs. With the passage of marriages are common. It is common in South India.
time actinic keratoses, seborrhoeic keratosis, keratitis, corneal
ulcers and pre-malignant lesion appear on the skin and the Clinical Features
conjunctiva (Figure 8). The skin appears dry and pigmented. Epidermolysis bullosa presents at or soon after birth. Depending
Later by adulthood squamous cell carcinoma, basal cell on the keratin defect and the depth of bulla formation there
carcinoma, and malignant melanoma may form, and constitute can be divided into three types: (i) E. bullosa (simplex), (ii)
the common causes of death. junctional; and (iii) dermal or dystropic variant. Simplex varieties
are more common, milder and show improvement in the
severity of blistering with time. Junctional and the dystrophic
variants are more severe and show mucosal blisters, erosions
and deformities in the form of contractures. The disease is
characterised by the formation of blisters on gentle rubbing or
on minimal skin trauma especially over the trauma prone sites
such as the buttocks, elbows, hand, feet, arms and legs (Figure 9).
The blisters rupture to form erosions and crusted lesions
which may be slow to heal and get infected. Severe variants
with mucosal blistering interfere with feeding. There may be
blisters in the pharynx, larynx, eyes and the genital mucosa.
There may be contractures and mitten like deformities of
hands in the severe variants (Figure 10). Pyloric stenosis and
development of squamous cell carcinoma are some of the other
associated complications.

Diagnosis
Figure 8: Multiple actinic keratoses, lentiginosis and conjunctival erythema in
xeroderma pigmentosum. Diagnosis is made on the basis of presence of early, spontaneous
blistering of skin on trauma prone sites and a positive family
Diagnosis history. Confirmation of the diagnosis is by performing electron
Diagnosis is based on the recognition of symptoms and skin microscopy on skin biopsy obtained from the blister.
signs of photosensitivity, dry, pigmented skin with multiple Treatment
freckles, lentiginosis, pre-malignant and malignant skin lesions.
The disease requires a multi-dimensional, multi-speciality
There may be presence of affected members in the family.
approach. Treatment is symptomatic with care of the eroded
Identification of the severity of the enzyme defect is based upon
skin using potassium permanganate compresses (1:8000)
demonstration of defective excision repair of DNA bases on
exposure to the ultraviolet light.
Management
Patients should be counselled strictly to avoid sun light by
wearing hats, goggles and full sleeved garments. Potent, broad
spectrum sun screens should be advised. Oral retinoids
have been used as chemopreventive agents against the
development of skin cancers. Patients should be examined
regulary in the clinic and any suspicious, noduloulcerative lesion
should be biopsied to exclude the possibility of malignant
transformation.
Prognosis
Prognosis is poor in severe cases. Early preventive measures in
the form of strict avoidance of sun exposure might delay the
development of skin cancers.

EPIDERMOLYSIS BULLOSA
Definition
It is a mechanobullous disorder which is caused by an inherited
defect in the keratin formation and is characterised by the
presence of multiple blisters and erosions over the trauma
Figure 9: Leg contracture and mitten like deformities in epidermolysis bullosa.
prone areas of the body.

518
 Genodermatoses
Figure 10: Erosions on neck, hands in a newborn in epidermolysis bullosa.

dilution and application of topical antibiotics like mupirocin Figure 11: Diffuse thickening of skin over soles with fissures in hereditary
cream to prevent superimposed infections. Prolonged palmoplantar keratoderma.
walking and tight foot wear should be avoided to prevent
blisters over feet in localised cases. Severe blistering involving
the mucosae and skin can be improved by administering
systemic steroids or other immunosuppressive agents, such as
cyclophosphamide or cyclosporine. Reconstructive surgery is
required for deformities.
Prognosis
Epidermolysis bullosa is a lifelong disease which does not have
a cure. Epidermolysis bullosa simplex has the best prognosis
as the disease tends to improve a little with age. Limb
deformities, oesophageal stenosis, malnutrition, squamous cell
carcinoma are some of the complications which develop
sometime during the course of the disease and the latter may
be an important cause of death.
Figure 12: Keratoderma over palms.
PALMOPLANTAR KERATODERMA
Definition Diagnosis
Palmoplantar keratoderma are a group of heterogenous Skin biopsy and presence of familial occurrence of the disease
disorders some of which are inherited defects due to mutations help in differentiating it from other acquired causes such as
in the enzymes involved in the synthesis of keratin. They can psoriasis, hyperkeratotic eczema.
be autosomal dominant or autosomal recessive.
Treatment
Epidemiology Liberal application of emollients are advised along with specific
These are uncommon. agents in the form of high concentrations of salicylic acid
(3% to 12%) depending on the severity of thickening. Oral
Clinical Features
retinoids are also employed for severe cases.
The onset of keratoderma is usually seen in childhood. Skin over
palms and soles becomes hard, thick, dry and hyperkeratotic. RECOMMENDED READINGS
There may be fissures and cuts in the skin (Figures 11 and 12). 1. Harper JI, Trembath RC. Genetics and genodermatoses. Rook’s Textbook of
Sometime, the keratoderma may show involvement of the Dermatology; 7th Ed. Blackwell Science: 2004; pp 12.
dorsum of hand and feet with areas of thickened skin. The 2. John McGrath, Irvine Mclean WH. Genetics in relation to skin. In: Fitzpatrick’s
Dermatology in General Medicine; 7th Ed. New York, Mc Graw Hill Medical;
condition is usually asymptomatic but it may interfere with daily 2008: pp 73-86.
activities. Severe variants show abnormal teeth and thickening 3. Spitz, Joel L. Genodermatoses: A Clinical Guide to Genetic Skin Disorders; 2nd
of nails also. Ed. Lippincott Williams and Wilkins; 2004.

519
 11.13 Skin in Connective Tissue Diseases

Sandipan Dhar

This group of diseases is characterised by inflammation of

connective tissues in various parts of the body. These are also
labelled as ‘Collagen Vascular Diseases’. However, there is little
evidence that collagen is primarily involved in causation of these
diseases. Most of the entities have multisystem involvement and
are characterised by distinct histopathological features and
positivity of a number of immunological tests in the blood,
known as ‘collagen profile’. Various connective tissue diseases
with significant cutaneous involvements are shown in Table 1.

Table 1: Various Types of Connective Tissue Diseases with

Significant Cutaneous Involvement
Lupus erythematosus
Systemic lupus erythematosus
Discoid lupus erythematosus
Subacute lupus erythematosus
Scleroderma Figure 1: Systemic lupus erythematosus scaly patch involving the cheeks and
Progressive systemic sclerosis bridge of the nose.
Morphea or localised scleroderma
Scleredema active SLE. A positive anti-dsDNA is confirmatory of SLE. ‘Lupus
Lichen sclerosus et atrophicus band test’ requires direct immunofluorescence testing of skin
Dermatomyositis biopsy sample from the affected skin, exposed unaffected skin
Mixed connective tissue disease and covered skin.
Treatment
SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
Oral corticosteroids are the mainstay of treatment. The dose of
Lupus erythematosus encompasses a group of disorders steroid is decided according to the severity of the disease, i.e.
characterised by chronic inflammatory vasculopathy involving organ system involvement. The usual starting dose is 30 to 40 mg
the skin and almost all the systems of the body. Skin of prednisolone per day. Steroid dosage is then tapered
involvement is the most common clinical manifestation after slowly over a period of 3 to 6 months as per activity of the
joint inflammation and is found in up to 70% of patients during disease. To prevent osteoporosis, oral vitamin D and calcium
the course of the disease and about 25% patients present with supplementation are given as a routine to all patients. Various
cutaneous lesions for the first time. immunosuppressives used as steroid-sparing agents are
Clinical Features azathioprine, cyclophosphamide, methotrexate, chlorambucil,
etc. Newer agents used for this are mycophenolate mofetil,
The most frequent cutaneous manifestations of SLE are malar
tumour necrosis factor (TNF) inhibitors, etc. Use of a good
rash (58%), photosensitivity (45%), discoid rash (10%), livedo
sunscreen is mandatory throughout the day in all patients with
reticularis (14%), and subacute cutaneous lesions (6%). The
lupus erythematosus.
malar rash presents over the butterfly area of the face as an
erythematous, mildly scaly patch involving the cheeks and bridge Prognosis
of the nose (Figure 1). The lesions are quite photosensitive and The prognosis of SLE has improved drammatically over the past
continued exposure to ultraviolet light leads to increased few decades because of availability of systemic corticosteroids
synthesis of antinuclear antibodies (ANAs) in the circulation. and cytotoxic drugs.
Mucous membrane lesions in the form of gingivitis, mucosal
DISCOID LUPUS ERYTHEMATOSUS (DLE)
ulceration and haemorrhage are also seen in this form of the
disease. Epidemiology
It is thought to be seven-fold commoner than SLE and is
Diagnosis
generally seen between 20 to 40 years of age. Females are more
Serologic tests are quite useful not only in the diagnosis but commonly affected with a female to male ratio of 3:1.
also in evaluation of the disease severity and its systemic
involvement. Various serologic tests carried-out are antinuclear Clinical Features
antibody (ANA), deoxyribonucleic acid, dsDNA, antihistone The discoid lesions of DLE are characterised by well-
520 antibody. ANA titre of more than 1:160 is quite suggestive of circumscribed, erythematosus, indurated plaques with adherent
 Skin in Connective Tissue Diseases
scales, patulous follicular openings and telangiectasia (Figure 2). Diagnosis
The lesions, when heal, produce atrophy, scarring, hyper- Diagnosis of DLE is confirmed by histopathological examination
pigmentation and/or depigmentation. The lesions are most of the skin.
commonly found over the face (Figure 3), head (Figure 4) and
neck. However, the involvement of chest, upper arm, back, buttock, Treatment
thighs, legs are not infrequent. Lips are often affected by DLE and For few isolated lesions of DLE, topical moderately potent to
sometimes lichen planus and lupus erythematosus may coexist potent corticosteroids are used for a period of 3 to 6 weeks. For
over lips, mostly lower lip and known as LE-LP overlap syndrome. disseminated lesions, oral chloroquine or hydroxychloroquine
is given for a period of 3 to 6 months depending upon the
response. Prior eye examination and cardiac check-up including
electrocardiogram (ECG) are to be carried out in each patient.
Other drugs used with variable success are dapsone and
clofazimine. When present over photoexposed areas, regular
use of a sunscreen lotion is a must.
Prognosis
Up to 25% to 40% of DLE patients remit spontaneously; 20%
with generalised DLE and 5% with localised DLE go onto
develop SLE.

SUBACUTE LUPUS ERYTHEMATOSUS

Subacute lupus erythematosus presents as annular/polycyclic
lesions or psoriasiform lesions mostly over the trunk and upper
extremities.
Figure 2: Typical discoid lesion of systemic lupus erythematosus on back of
patient. SCLERODERMA
Scleroderma is a chronic disease of unknown aetiology that
affects the microvasculature and loose connective tissues
and is characterised by fibrosis of the skin and internal organs.
Various diseases of importance under this heading are
progressive systemic sclerosis, localised scleroderma/morphea
and scleroderma.
Progressive Systemic Sclerosis (PSS)
It is a generalised disease of the skin, lungs, heart, gastrointestinal
tract, joints and kidneys. The diagnosis of PSS is made on the
basis of some criteria as shown in Table 2.

Table 2: Diagnostic Criteria for Progressive Systemic Sclerosis

Major Criteria
Sclerodermatous alterations
Raynaud’s phenomenon
Figure 3: Discoid lupus erythematosus lesion on the face.
Minor Criteria
Capillary microscopy changes
Vascular changes
Gastrointestinal involvement
Renal involvement
Cardiac involvement
Muscle involvement
Joint/tendon involvement
Serology

Clinical Features
The skin changes are characterised by diffuse and progressive
induration and hardening of the skin. Often the process
starts over the face and acral areas (acrosclerosis). The face looks
hide-bound and expressionless with pinched nose, pursed
mouth and mat-like telangiectasiae (Figure 5). Often there are
pigmentary changes over the face and neck in the form of
hyperpigmentation and depigmentation (pepper-salt
Figure 4: Discoid lupus erythematosus lesion on the scalp.
pigmentation) (Figure 6). Changes over the fingers show 521
 Figure 5: Typical facies in progressive systemic sclerosis.

Figure 8: Sclerodactyly and telangiectasia.

cause of mortality and more than 50% of the patients with PSS
show restrictive lung changes. A variant of scleroderma is known
as CREST syndrome which is an acronym for calcinosis, Raynaud’s
phenomenon, oesophageal hypomotility, sclerodactyly and
telangiectasia (Figure 8).
Diagnosis
Histopathological examination of the skin and detection of
anti scl-70 (anti DNA topoisomerase) and anti-centromere
antibodies are most important and useful tests.
Treatment
Treatment of PSS entails a host of systemic care. General measures
include avoidance of factors leading to vasospasm (tension,fatigue,
stress,cold weather,smoking) and minimising trauma to the hands.
Figure 6: Pepper-salt pigmentation in progressive systemic sclerosis. For Raynaud’s phenomenon, nifedipine or pentoxphylline is used.
For arthritis, nonsteroidal, anti-inflammatory drugs (NSAIDs)
are used and omeprazole/pantoprazole is used for reflux
oesophagitis. In the early oedematous stage of the disease, oral
corticosteroids are useful. Prednisolone is given in a dose of 30 to
40 mg/day for 2 to 3 weeks followed by definitive therapy of the
disease. D-penicillamine has been found to be useful in some
patients. Methotrexate and cyclosporine have also been used with
variable success for long-term control of the disease.
Prognosis
The prognosis of PSS is variable and depends on the
involvement of organ system(s) and rate of progression of the
disease. The cause of death is usually cardiac or respiratory
failure. It usually follows a relatively benign course and in such
cases anti-centromere antibody is positive.
Pregnancy and Systemic Sclerosis
Systemic sclerosis is considered to be a high risk factor for
Figure 7: Sclerodactyly and pitted scars on fingertips. pregnancy because of higher chances of miscarriage, premature
birth and other complications.
sclerodactyly or sausage shaped fingers with taut skin over
the fingers and thimble pitted scars over fingertips (Figure 7). MORPHOEA (LOCALISED SCLERODERMA)
Raynaud’s phenomenon is almost a constant feature in cases Morphoea is a localised type of scleroderma characterised by
of PSS. On exposure to cold, patients complain of pain, burning, localised induration and hyperpigmentation of skin.
pallor, cyanosis, tingling and hyperhidrosis. It commonly affects
fingers and toes. At the early stage of the disease, patients often Clinical Features
complain of arthralgia and limited joint mobility. Patients often It can be subdivided into five types, e.g. plaque, generalised, linear,
522 complain of weight loss, fatigue, reflux and dyspepsia, muscle guttate and deep, according to clinical presentation and depth
weakness and dyspnoea. Pulmonary involvement is a major of tissue involvement. In case of ‘guttate morphea’, the lesions
 Skin in Connective Tissue Diseases
are 1 to 3 mm sized indurated papules. In‘linear scleroderma’ there
may be involvement of the face and/or forehead manifesting
as Parry-Romberg syndrome and ‘en coup de sabre’. Linear
scleroderma involving frontal and frontoparietal regions of the
scalp is called ‘en coup de sabre’.It presents as a depressed sclerotic
groove over the frontal/frontoparietal region of the scalp, usually
unilateral. The groove may extend downwards to involve cheek,
nose, upper lip, and at times mouth, gum, chin or neck. Rarely, the
localised scleroderma may involve the subcutaneous tissue,
muscle and bone and is known as ‘disabling pansclerotic
morphea’. Sometimes, the morphea lesions may have overlying
lichen sclerosus et atrophicus (LSA) lesions.
Plaque-type morphea presents as one or few hyperpigmented
indurated papules of 0.5 to 15 cm diameter. The areas usually
affected are back, buttock, abdomen, thigh and rarely the face
(Figure 9). The lesions resolve with hyperpigmentation and
sometimes atrophy (Figure 10).
Diagnosis
Skin biopsy helps in diagnosis of morphea and localised
scleroderma of all types. ANA positivity occurs in approximately
25% to 65% of cases with linear scleroderma and generalised
morphea. Rheumatoid factors are positive in 25% to 40% cases
and eosinophilia is seen in a good number of cases. Recently,
anti-topoisomerase II antibodies have been detected in 76% of
patients with localised scleroderma and in 85% of cases of
generalised morphea. These antibodies, in contrast to anti-
topoisomearse I/scl-70 antibodies have been found in 14% of Figure 10: Plague-type hyperpigmented lesions on the back.
the patients with systemic scleroderma.
Treatment Prognosis
Treatment of morphea and linear scleroderma is not very Plaque type of morphoea tends to improve within 3 to 5 years.
rewarding. Topical and intralesional corticosteroids help in However, the residual hyperpigmentation and hypo-
resolution of the lesions. Topical calciprotriol has been shown pigmentation and occasional atrophy may persist for long
to help resolution of the lesions particularly when used under periods of time. Lesions of linear scleroderma also tend to
occlusion and at early stage of the disease. For generalised improve with time. However, the residual atrophy and
morphea and linear scleroderma, oral corticosteroids are given pigmentary changes may remain for indefinite period of time.
initially for 2 to 3 weeks followed by methotrexate for a period
of 3 to 6 months which may help resolution of the lesions. Other SCLEREDEMA
therapeutic options are oral calcitriol, cyclosporine and D- Scleredema is a rare disorder that manifest as large area
penicillamine. These treatment modalities are, however, chosen of induration of skin and subcutaneous tissue that must be
for very selective patients. Physiotherapy and corrective distinguished for more commonly occurring scleroderma. The
surgeries are adjunctive treatment modalities. condition most commonly occurs in adult diabetics (scleredema
adultorum of Buschke). However, children often suffer from
this disorder usually after an episode of streptococcal upper
respiratory tract infection. The skin changes often start over the
neck and spread in a cephalocaudal direction to involve the
upper trunk and occasionally the face and arms. It manifests as
slow and insidious onset of non-pitting oedema and induration.
Usually, the patients are asymptomatic, but in some patients a
prodrome of fever and malaise may precede the skin changes
by 2 to 4 weeks. The condition is by and large benign, but
involvement of skeletal and cardiac muscles have been
reported. The pathogenesis of scleredema is unknown. The
condition usually resolves spontaneously over a variable period
of a few months to 2 years or so.

LICHEN SCLEROSUS ET ATROPHICUS

Lichen sclerosus et atrophicus (LSA) is a disease of unknown
aetiology which is mostly seen in females, although, males are
Figure 9: Plaque-type hyperpigmented lesions on back.
also affected. 523
 Clinical Features
The disease is characterised by sharply defined small pink
to ivory coloured papules which coalesce to form plaques of
variable sizes (Figure 11). As the lesions progress, follicular
plugging and atrophy becomes more prominent (Figure 12).
The lesions are asymptomatic and can develop on any part of
the body. Lesions often tend to develop over the sites of trauma,
irritation and surgical scars (Koebner’s phenomenon).

Figure 11: Lichen sclerosus et atrophicus showing plaques of variable sizes.

Figure 13: LSA showing lesions over the genital and perianal area.

Diagnosis
Skin biopsy and histopathological examination clinches the
diagnosis as the condition has some unique histopathological
features.
Treatment
Topical corticosteroids are the treatment of choice. Moderately
potent to superpotent topical corticosteroids used for a period
of 6 to 8 weeks help to resolve the lesions. Topical tacrolimus
(0.1%) and premecrolimus (1%) have recently been found to
be quite helpful. Surgical options like circumcision, plastic
reconstruction and corrective surgeries may be required along
with medical therapy to improve the quality of life of the patients.
Prognosis
Figure 12: Lichen sclerosus et atrophicus showing follicular plugging and atrophy. Some of the lesions may improve spontaneously, particularly
the lesions over the skin. Lesions over the genitalia, however,
The lesions of LSA may top the lesions of plaque-type of show little tendency to resolve spontaneously. Instead,
morphea. Lesions often develop over the genital areas both ulceration, urethral stricture, anal and vaginal stenosis may
in females and males. In females, the lesions of LSA lead to occur. In females, carcinoma may develop over longstanding
the development of kraurosis vulvae. Here the lesions are vulvar LSA.
distributed over the genital and perianal area in an hourglass
configuration or figure of eight pattern (Figure 13). The lesions DERMATOMYOSITIS
are symptomatic and produce pruritus, burning sensation and It is an idiopathic inflammatory myopathy of striated muscles
bleeding from vulvar and perianal area on urination and along with the characteristic cutaneous findings, hence it has
defaecation. There may be vaginal discharge, purpuric lesions, got both cutaneous and muscular components. Disease has got
blistering and excoriation over labia minora and clitoris. In racial predilection. Females are affected twice as commonly as
males, the lesions are known as ‘balanitis xerotica obliterans’ males. Though it can occur at any age but two peaks are seen,
(BXO). one between 5 to 10 years and another is 50 years of age.
524
 Skin in Connective Tissue Diseases
Aetiopathogenesis
The exact cause of dermatomyositis is unknown, but certain factors
have been implicated like genetic factor linked to human leucocyte
antigen (HLA) DR3, DR5, DR7. Infectious agents like coxsackievirus,
parvovirus, echovirus, HTLV-1, human immunodeficiency virus
(HIV), toxoplasma and borrelia can be a trigger factor. Various
drugs like hydroxyurea, penicillamine, statins, quinidine and
phenylbutazone, etc. can cause dermatomyositis.
Clinical Features
Various types of dermatomyositis are enumerated in Table 3.

Table 3: Various Clinical Types of Dermatomyositis

Dermatomyositis
Polymyositis
Dermatomyositis associated with malignancy
Dermatomyositis associated with connective tissue disorders
Juvenile dermatomyositis Figure 15: Calcinosis cutis showing extruding calcium.

The pathognomonic cutaneous features are heliotrope rash dermatomyositis except in the amyotrophic variety. Most
(periorbital confluent macular mauve or violaceous erythema) sensitive enzyme is CPK (creatine phosphokinase). Apart from
and Gottron’s papules (papules having violaceous hue this, aldolase, AST, LDH, may also be abnormal. Magnetic
overlying the dorsolateral aspect of interphalangeal or meta- resonance imaging (MRI) is a useful tool as it not only shows
corpophalangeal joints). Other cutaneous features are malar the presence of inflammatory myopathy but also helps to
erythema, poikiloderma (variegated telangiectasia along with differentiate it from steroid myopathy. It can also serve as a
atrophy and hyperpigmentation) (Figure 14), periungual and guide in selecting the muscle biopsy site.
cuticular changes (cuticular hypertrophy with haemorrhagic
infarcts) and mechanics hands (fingertip erythema and scaling). Treatment
Calcinosis cutis are also seen, which are firm yellow or flesh It includes general measures, treatment of involved skin,
coloured nodules extruding calcium through the skin though affected muscles, and treatment of complications. General
seen only in 4% of children and adolescents (Figure 15). measures include bed rest for severe muscle inflammation,
programmed physical therapy to avoid contractures and joint
complications. Goal of pharmacotherapy is to reduce morbidity
and to prevent complications. Mainstay of the treatment
are systemic corticosteroids. It has been observed that
most patients develop corticosteroid-induced myopathy.
Therefore, it is prudent to use immunosuppressive agents
like methotrexate, azathioprine and cytotoxic agents
(mycophenolate mofetil) as steroid sparing agents. Apart from
these, intravenous immunoglobulin for at least 6 months has
proved beneficial. Rituximab is another effective option.
Therapy for cutaneous lesions is difficult. Education,
avoidance of sun and broad-spectrum sunscreens are helpful
in photosensitive patients. For the treatment of calcinosis
cutis, calcium channel blockers (diltiazem) shows gradual
resolution.
Prognosis
Figure 14: Dermatomyositis on the face of a child. The disease may spontaneously remit in the juvenile variety of
cases, but relapses can be seen. Prognosis also depends upon
the degree of systemic involvement. In adults, it is mandatory
Muscle findings are proximal muscles weakness like difficulty in
to search for underlying malignancy, successful treatment of
rising from chair or bed, climbing the stairs, combing hair, difficulty which can reduce the mortality to a greater extent. Majority of
in swallowing; but walking may be normal as distal muscles the patients survive but may develop residual weakness and
are unaffected. Systemic features which include joint swelling disability.
associated with pulmonary and gastrointestinal involvement
make the prognosis worse. It should be differentiated from lupus RECOMMENDED READINGS
erythematosus,MCTD, steroid myopathy, cutaneous vasculitis, etc. 1. Bajaj AK, Sharma R, Dhar S. Dermatology, Leprosy and Sexually Transmitted
Infections; 2nd Ed. New Delhi: Jaypee Brothers Medical Publishers; 2010.
Diagnosis
2. Kanwar AJ, De D. Systemic collagen disorders. In: Valia RG, Valia A, editors.
Diagnosis is basically clinical and can be made from the skin IADVL Textbook of Dermatology; 3rd Ed. Mumbai: Bhalani Publishing House;
changes. Muscle enzymes are abnormal during the course of 2008: pp1220-66. 525
 11.14 Skin in Systemic Diseases

Uday Khopkar

Skin is a mirror of health and disease and reflects almost all Papular Lesions
systemic disturbances. The skin is available for examination to Systemic infections like cryptococcosis, miliary tuberculosis,
any physician who cares to pay attention to it. neoplastic conditions like leukaemia and histiocytosis X may
CUTANEOUS SYMPTOMS AND SIGNS OF INTERNAL DISEASES present with papular lesions. Tuberculids like papulonecrotic-
tuberculid and lichen scrofulosorum present as papular rashes
Pruritus due to hypersensitivity to tubercular antigen.
Pruritus (itching) in the absence of skin lesions can be a
symptom of internal disease and may even be a presenting SYSTEMIC DISEASES AND THEIR SKIN MANIFESTATIONS
manifestation of it. Patients with infective hepatitis or evolving For the purpose of this discussion, internal diseases that
renal disease may occasionally present with generalised manifest onto the skin may be grouped into: HIV infections;
pruritus without any skin rash. Generalised dry itchy skin internal malignancies; multisystem diseases; individual
may be a feature of Hodgkin’s lymphoma. Pruritus in a case of organ diseases; specific skin signs of diseases affecting
polycythaemia gets worse after bath. individual organs; and non-specific signs of organ failure
Exanthem and Enanthem (Table 1).
Skin rashes (exanthem) and mucosal rashes (enanthem) are well Human Immunodeficiency Virus (HIV) Infection
recognised since ages as signs of systemic viral and occasionally
With a very high prevalence of HIV infection in India, familiarity
bacterial infections. Chickenpox, smallpox, measles, rubella,
with cutaneous manifestations of HIV infection has become a
hand, foot and mouth disease have characteristic morphology
necessity for all physicians.
and distribution of their rashes. The confluent rash of dengue
fever gives an appearance of ‘islands of normal skin in a sea of Since HIV infection is sexually transmitted in most instances,
red’; is late to appear in the course of disease and may be missed other sexually transmitted infections like herpes simplex,
due to its asymptomatic nature. condyloma-acuminata, syphilis and chancroid tend to
Purpura occur more frequently in the HIV-infected. These infections
are also more severe in terms of extent, morphology,
Thrombocytopaenia and disorders of coagulation result in non-
speed of progression, time to healing and complications.
inflammatory purpura (petechiae, purpura, ecchymosis,
Details of various cutaneous manifestations are covered
haematoma), damage to blood vessels in small vessel vasculitis
in the chapter on ‘Sexually Transmitted Infections and
results in inflammatory purpura (palpable purpura). Palpable
HIV’.
purpura is seen as red oedematous papules, which fail to blanch
on diascopy. Skin in Multisystemic Diseases
Ischaemic Necrosis and Ulcers Several multisystem diseases involve the skin in a variety of
Cutaneous infarcts may occur due to vascular occlusion ways. Frequently many of these manifestations are subtle or
resulting from a variety of internal diseases like diabetes, asymptomatic and are therefore not complained of by
atherosclerosis, Berger’s disease, vasculitis, collagen vascular the patient. Seeking these actively will certainly add an edge to
diseases, disseminated intravascular coagulation, coumarin the clinical acumen of a physician. Lupus erythematosus
necrosis, antiphospholipid antibody syndrome or calciphylaxis. in its localised form (discoid lupus erythematosus, Figure 1)
Cutaneous ulcers may be a manifestation of diverse conditions and systemic form [systemic lupus erythematosus (SLE), Figures
like sickle cell disease or ulcerative colitis, Crohn’s disease or even 2 to 4], systemic sclerosis (Figures 5 and 6), dermatomyositis
septicaemia or fungaemia. While taking care of the immediate (Figures 7 and 8) and sarcoidosis (Figure 9) are some of
consequences of such lesions, it is important to detect and the prominent diseases in this category of multisystem
correct the underlying cause. diseases.
Skin Nodules Cutaneous Markers of Internal Malignancies
Nodules on the skin may occur due to plethora of internal Apart from cutaneous metastases and their side-effects
causes like erythema nodosum, erythema nodosum-leprosum, like lymphoedema, internal malignancy may manifest onto
panniculitis, metastasis of internal malignancy, lymphomas, the skin through the immune suppression (candidiasis) or
sarcoidosis or systemic infections like cryptococcosis, penicilliosis, malnourishment (dry skin) associated with advanced
histoplasmosis, leishmaniasis, bacillary angiomatosis or malignancies. Besides, internal neoplasms in genetic diseases
cysticercosis. may be associated with skin signs.

526
 Skin in Systemic Diseases
It is common for lymphoproliferative diseases like lymphomas
and leukaemias to manifest onto the skin at some stage of the
disease. Moreover, several skin signs presage development of
internal malignancies. Some of these may result from the effects
of hormones secreted by the tumour while still others occur
through hitherto undiscovered mechanisms (paraneoplastic
dermatoses). Some of the skin manifestations of internal
malignancies are tabulated in Table 2.

Table 1: Examples of Skin Manifestations of Systemic Infections

Bacterial infections
Bacterial endocarditis Palmar erythema and nodules
Anthrax Malignant pustule over face
Figure 1: Disseminated discoid lupus erythematosus. Erythematous
Tuberculosis dyspigmented plaques.
Miliary tuberculosis Brown-red papules
Scrofuloderma Nodules and sinuses overlying involved
organs
Tuberculids Demonstrable tuberculous focus, no
acid fast bacili (AFB) in skin lesions,
strong Mantoux test and tuberculoid
granuloma on biopsy
Erythema induratum Tender nodules and ulcers over calves
of young ladies
Papulonecrotic Papulopustular lesions healing with
tuberculid scarring
Lichen scrofulosorum Grouped follicular micropapules
Erythema nodosum Tender, erythematous nodules and
plaques over shins
Septicaemia
Septic vasculitis Palpable purpura, haemorrhagic
vesicles, skin infarcts
Figure 2: Discoid lupus erythematosus. Extensive confluent discoid lesions.
Disseminated Skin infarcts and gangrene of digits
intravascular coagulation
Purpura fulminans Large skin infarcts lead to deep
punched out ulcers
Meningococcaemia Palpable purpura, haemorrhagic
vesicles over limbs
Pseudomonas septicaemia Necrotic ulcers with yellow-green
discharge (ecthyma gangrenosum)
Viral infections
Viraemia due to many Maculopapular or papulovesicular
viruses exanthem and enanthem
Hepatitis B Cutaneous vasculitis
Spirochetal infections
Secondary syphilis Symmetric non-pruritic scaly rash
Leptospirosis Rash over shins
Borreliosis Erythema chronicum migrans expanding
rings over limbs
Fungaemia
Cryptococcosis Papules, nodules and ulcers over face
and limbs
Histoplasmosis Nodules and ulcers over mucosae and
mucocutaneous junctions
Parasitic infestations
Post-kala-azar dermal Generalised symmetric hypopigmented
leishmaniasis macules, nodules and diffuse erythema
of face
Cysticercosis Asymptomatic subcutaneous nodules
Figure 3: Systemic lupus erythematosus. Malar rash with erythema and oedema
over trunk
over lips and upper chest.

527
 Figure 4: Bullous lupus erythematosus. Vesiculobullous lesions on erythematous Figure 7: Dermatomyositis. Diffuse violaceous erythema of face with affection
base. of upper eyelid.

Figure 5: Systemic sclerosis. Re-pigmenting vitiligo like patches over hidebound Figure 8: Gottron’s papules. Erythematous lichenoid papules in dermatomyositis.
skin.

Figure 6: Systemic sclerosis. Acrosclerosis with scarring and resorption of tips Figure 9: Sarcoidosis. Reddish brown shiny plaque.
of digits.

528
 Skin in Systemic Diseases
Table 2: Skin Changes Associated with Internal Malignancies
Direct effects of malignant neoplasms
Carcinomas Cutaneous metastases
Haematological malignancies Specific skin infiltrates
Visceral malignancy Infiltration or ulceration of contiguous skin
Effects of infiltration Sclerosis, lymphoedema, lymphangiectasia
Effects of debility Candidiasis, herpes zoster, dry, lusterless skin and hair, hyperpigmentation, xerosis
Genodermatoses with associated
internal malignancy
Gardner’s syndrome Cutaneous lipoma and osteomas are pointers of colonic polyposis and malignancy
in future
Neurofibromatosis Phaeochromocytoma, gliomas, haematological malignancies
Peutz-Jeghers syndrome Lentigines on lips associated colonic polyps with predisposition for malignancy
Paraneoplastic signs of internal malignancy
Acanthosis nigricans Brown-back velvety plaques over neck and flexures
Acute febrile neutrophilic dermatosis Tender, red plaques over limbs and face in a middle-aged lady
(Sweet’s syndrome)
Acquired ichthyosis Dry fish-like skin most commonly in Hodgkin’s lymphoma
Clubbing Severe grades of clubbing with lung carcinoma
Dermatomyositis Up to 10% cases have associated with internal malignancy
Erythema gyratum repens Concentric rings of erythema and scaling over trunk
Hypertrophic osteoarthropathy Subperiosteal new bone formation
Migratory thrombophlebitis Highly malignant lesion with metastases
Myeloma-associated amyloidosis Skin nodules and purpura
States associated with endocrine neoplasms
Addisonian pigmentation Adrenal corticotropin hormone (ACTH) secreting neoplasms
Hirsutism Coarse hair in females in male distribution
Androgenetic alopaecia in females Virilising tumours
Necrolytic migratory erythema Expanding rings of erythema and vesiculation with glucagonoma
Carcinoid tumours Flushing of face and upper trunk

Skin in Diseases Affecting Individual Systems or Organs Acanthosis nigricans is most commonly seen in obese persons
The skin is involved in this group of diseases in two ways. who may have subclinical insulin resistance. The skin changes
The more common skin manifestations are those that are are reversible on weight reduction. The benign type occurs in
caused due to individual organ failure and are therefore not association with various endocrine disorders or syndromes.
part of a specific aetiopathologic entity. Hence, the dryness They include acromegaly, Cushing’s disease, hypothyroidism,
of skin seen in renal failure is not specific for any of the causes insulin-resistant diabetes mellitus, Addison’s disease, Stein-
of renal failure and is therefore not helpful to reach an Leventhal syndrome, etc. The triad of hyperandrogenism,
aetiopathologic diagnosis. On the other hand, cutaneous insulin-resistance and acanthosis nigricans in women is known
inflammatory lesions in a case of Crohn’s disease are specific as HAIR-AN syndrome. Correction of endocrine abnormalities
for the condition and are helpful to reach the diagnosis. may slowly revers the skin changes.

Endocrine Disorders Cardiocutaneous Diseases

With the probable exception of keratinocytes almost every Although it is not common for heart diseases to be associated
component of the skin is influenced by the endocrine system. with skin lesions several multisystem diseases frequently manifest
Hence, careful examination of the skin is an integral part of the with cardiac and cutaneous findings. These include SLE,
workup in endocrinology. Hyper- or hypofunction of individual rheumatic fever, dermatomyositis, systemic sclerosis, rheumatoid
endocrine gland is accompanied by several skin alterations that arthritis, behçet’s disease, periarteritis nodosa, Reiter’s disease and
provide clues to the diagnosis. Some of these are enumerated sarcoidosis. Bacterial endocarditis may present with splinter
in Table 3. Additionally common autoimmune skin diseases like haemorrhages in the nails or palmar erythema or nodules. In
vitiligo, alopaecia areata or lichen planus may occur together addition, several specific cardiocutaneous associations have been
with autoimmune endocrine disorders. identified. These are listed in Table 4.
Acanthosis nigricans Skin Changes in Gastrointestinal Diseases
This important marker of endocrine disease is characterised by Several gastrointestinal symptoms or syndromes have specific
symmetrical velvety hyperpigmented plaques in neck and dermatologic associations (Table 5, Figure 11). In addition to
flexures (Figure 10). Acanthosis nigricans has been classified these, pancreatic and liver diseases frequently manifest
into the five following types: hereditary, pseudoacanthosis themselves onto the skin. Moreover, some common skin
nigricans, benign, drug-induced and malignant. The last two diseases are associated with asymptomatic but significant
types are rare. The hereditary benign type is dominantly gastrointestinal affection. Prominent amongst them are
transmitted, presents during childhood and is not associated dermatogenic enteropathy, dermatitis herpetiformis and
with any internal malignancy or endocrine disorder. pyoderma gangrenosum. Dermatogenic enteropathy indicates 529
 Table 3: Endocrine Disorders and the Skin Table 4: Cardiocutaneous Diseases
Pancreas Heritable diseases
Diabetes mellitus (Please refer to the chapter on Metabolic Progeria (childhood Atherosclerosis with premature ageing
and Nutritional Disorders of the Skin) and adulthood) of skin
Glucagonoma Necrolytic migratory erythema (expanding Neurofibromatosis Hypertension due to pheochromocytoma
rings of superficial vesicopustules and scaly with coarctation of aorta
papules over face, trunk or flexures) Marfan’s syndrome Striae with valve disease or aneurysm of
aorta
Pancreatitis Cutaneous haemorrhage, enzymatic
Pseudoxanthoma Yellowish papules over neck and flexures
panniculitis
elasticum with hypertension, peripheral vascular
Pancreatic carcinoma Migratory thrombophlebitis disease
Pituitary Infective diseases
Acromegaly Skin is coarse, leathery, oily and dark, Bacterial endocarditis Palmar erythema, septic vasculitis, Osler’s
hypertrichosis, cutis verticis gyrata and nodes, Janeway lesions, subungual
acanthosis nigricans are other features splinter haemorrhages
ACTH secreting Cutaneous features of Cushing’s syndrome Lyme disease Myocarditis and erythema chronicum
tumours and addisonian pigmentation migrans in Borrelia burgdorferi infection
Hypopituitarism Lack of axillary and pubic hair, pallor of skin Syphilis Aortic aneurysms, penile scar, gumma
and nipple Viral and rickettsial Myocarditis and maculopapular or
infections haemorrhagic rash
Thyroid
Myxoedema Skin of the face and acral areas is thick and Connective tissue
boggy (non-pitting oedema) disorders
Systemic lupus “Libman-Sack” endocarditis, pericardial
Hypothyroidism Skin is dry, cool and pale yellow (due to
erythematosus effusion, congenital heart blocks in
carotenaemia), hairs are dull, coarse and
neonatal lupus erythematosus
brittle, loss of lateral third of eyebrows, nails
Scleroderma Conduction blocks, cardiomyopathy
are thin, striated and brittle
Metabolic diseases
Graves’ disease Pretibial myxoedema (waxy papules or Hyperlipidaemias Tuberous and planar xanthomas in
plaques with ‘peau de orange’ look) may coronary artery disease due to hyper-
affect hands and feet, thyroid acropachy cholesterolaemia
(drumstick clubbing) Amyloidosis Cardiomyopathy and skin infiltration and
Hyperthyroidism Skin is flushed, moist and smooth, velvety purpura
to touch, hair are thin and friable and Haemochromatosis Cardiomyopathy with hyperpigmentation
alopaecia is common, nails are soft, friable Fabry’s disease Generalised angiokeratomas with
or show koilonychia or onycholysis, hypertension and ischaemic heart disease
generalised pruritus
Adrenal cortex
malabsorption associated with extensive skin disease like
Cushing’s syndrome Skin is thin, fragile with purpura and striae,
redistribution of body fat leads to truncal
exfoliative dermatitis. The intestinal villi are atrophic and general
obesity, moon facies, buffalo hump and thin indicators of malabsorption are present Gluten-sensitive
limbs. Acne, hirsutism and acanthosis enteropathy occurs in association with dermatitis herpetiformis
nigricans are other features though this is probably uncommon in Indian patients with
Addison’s disease Generalised diffuse brown-black pigmen dermatitis herpetiformis. Skin ulcers in pyoderma gangrenosum
(primary tation of skin and mucosae with accentuation are sometimes associated with inflammatory bowel disease.
hypoadrenalism only) over exposed areas (face, hands, forearms),
Hepatic Diseases and the Skin
flexures (axillae, groins), bony prominences
(knuckles, knees, elbows), normally Chronic liver disease manifests itself on the skin with many
pigmented areas (palmar creases, nipples, signs. Icterus is associated with yellowish discolouration of skin
genitalia, pre-existing melanocytic nevi), and pruritus. Spider angiomas occur over the face, neck and
frictional areas (e.g. beltline), mucosae (blue upper trunk in hepatic failure. The nails become clubbed
black colour esp. over oral mucosa), and white and the palms show erythema and Dupytren’s
pigmented bands on nails contracture. The face turns red initially and later dark and the
Sex hormones excess skin becomes thin with telangiectasia (paper-money skin) and
Defeminising and Hirsutism and male pattern alopaecia,thick,oily, purpura. There is gynaecomastia and loss of axillary and pubic
virilising syndromes hyperhidrotic skin with acne and acanthosis hair. Prominent veins around the umbilicus (caput medusae)
nigricans and over chest are a sign of portal hypertension. Viral hepatitis
Deficiency may act as a trigger for autoimmune phenomena in the skin
Hypogonadism Features hypopituitarism, juvenile scalp hair like leucocytoclastic vasculitis.
pattern in
(pituitary) adult males Cutaneous Manifestations of Renal Diseases
Hypogonadism Absence of sparsity of axillary and pubic Renal failure due to any cause leads to dry, pruritic, scaly skin with
hair in males or female type body hair a tendency to develop purpura or ecchymoses on minor trauma.
distribution in male.
Besides, the skin is pale yellow due to associated anaemia and
530
 Skin in Systemic Diseases
Table 5: Gastrointestinal Diseases and the Skin
Diarrhoea
Gluten-sensitive Dermatitis herpetiformis
enteropathy
Ulcerative colitis Pyoderma gangrenosum, aphthae,
pyoderma vegetans, pyostomatitis,
erythema nodosum
Crohn’s disease Pyoderma gangrenosum, perianal
fistule, mucocutaneous
granulomas, erythema nodosum
Mastocytosis Urticaria pigmentosa
Pellagra Photodermatitis over neck, hands
and forearms, glossitis, erythema of
other mucosae
Gastrointestinal bleeding
Henoch-Schönlein purpura Palpable purpura
Hereditary haemorrhagic Spider-like angiomas of skin and
telangiectasia mucosa
(Osler-Weber-Rendu)
Pseudoxanthoma elasticum Small, soft, yellowish papules over
neck and axillae
Gastrointestinal polyposis
Peutz-Jeghers syndrome Acral and periorificial lentigines
Gardener’s syndrome Lipomas, sebaceous cysts, osteomas
Gastrointestinal neoplasms
Glucagonoma Necrolytic migratory erythema
Pancreatic adenocarcinoma Migratory thrombophlebitis
Carcinoid syndrome Flushing of face, upper torso,
pseudoscleroderma
Metastatic carcinoma Umbilical nodule due to metastasis
of stomach carcinoma
Malabsorption Diffuse hyperpigmentation, dry
scaly skin, lusterless fragile hair, thin Figure 10: Acanthosis nigricans. Velvety hyperpigmented plaque.
brittle nails, pruritus, acquired
ichthyosis
Pancreatitis Enzymatic panniculitis: purpura over
periumbilical region (Cullen’s sign)
or flanks (Grey Turner’s sign).
Hyperlipemic xanthomatosis is
associated with pancreatitis
Skin lesions in liver cell failure Icterus, paper-money skin, spider
angiomas, palmar erythema,
hyperpigmentation, white nails,
gynecomastia, loss of axillary and
pubic hair, caput medusae if poral
hypertension

pitting oedema as well as accumulation of urochrome or carotene

pigments. High blood urea levels may reflect onto the skin by
deposition of urea crystals on the nose and malar area forming
‘uraemic frost’. Other non-specific indicators of renal failure
include acquired perforating dermatoses like perforating
folliculitis or Kyrle’s disease and loss of hair from limbs, all of which
result from persistent rubbing and scratching of the skin.
Secondary hyperparathyroidism due to renal failure is probably
responsible for persistent pruritus in some cases. Calcinosis cutis
and pseudoporphyria cutanea tarda are other non-specific signs
of renal failure. Half and half nails in chronic renal failure show
brown red discolouration of their distal half. Occasionally, skin
and kidneys may be affected by the same pathological process.
Some of these instances are enlisted in Table 6.
Figure 11: Peutz-Jeghers syndrome. Lentigines on lips and face.
Haematological Disorders and the Skin
Many haematologic diseases display skin lesions at some stage of T-cell lymphoma or systemic mastocytosis are of diagnostic
of the disease evolution (Figure 12). Some of them like those importance whereas others like purpura in leukaemia are not 531
 Table 6: Renocutaneous Diseases
Hereditary diseases
Fabry’s disease Angiokeratomas, sphingolipid
deposits in kidneys
Sickle cell disease Leg ulcers and pigmentation
Tuberous sclerosis Shagreen plaque, adenoma
sebaceum, ash-leaf macules
Metabolic disorders
Gout Cutaneous and subcutaneous
yellowish nodules (tophi) that
contain urate crystals
Primary and myeloma Papules, nodules, purpura
associated amyloidosis

specific for the disease (Table 7). Occasionally, skin diseases may
be associated with haematologic disturbances. Amongst these
are anaemia induced by persistent exfoliative dermatitis or,
leucocytosis seen in generalised pustular psoriasis or Sweet’s
syndrome.
Respiratory Diseases and the Skin
Most of the multisystem diseases like SLE or sarcoidosis
or vasculitides display both skin and respiratory system
Figure 12: Digital gangrene in antiphospholipid antibody syndrome.
involvement. Tuberculosis of lungs or other organs may be
occasionally associated with skin lesions (Table 1). The skin those, about 5% psoriatics have arthritis whereas about 5% of
may be directly affected due to tuberculous infection or may patients with arthritis have psoriasis. Type II lepra reaction in
show features of hypersensitivity to circulating tuberculous lepromatous leprosy may occasionally present with arthritis.
antigens. The latter condition is termed as a tuberculid to Erythema nodosum, hepatitis B, secondary syphilis, Lyme
distinguish it from actual tuberculous infection. disease and Sweet’s syndrome are other instances where skin
Skin Lesions in Diseases of Bones and Joints rashes are accompanied by joint pains.
Most of the multisystem diseases including collagen vascular Keen observation of skin lesions frequently provides a decisive
diseases are associated with arthritis or arthralgias. Besides clue to diagnosis of an internal disease. Hence, familiarity with

Table 7: Skin Manifestations of Some Haematologic Disorders

Erythrocyte disorders and
haemoglobinopathies
Iron deficiency anaemia Koilonychia, atrophic glossitis, alopaecia
Pernicious anaemia Addisonian hyperpigmentation, vitiligo, glossitis, cheilitis
Haemolytic anaemia Sickle cell anaemia, thalassaemia—Leg ulcers
Polycythaemia Pruritus or flushing after bathing, erythermalgia, urticaria
Meth/sulph/carboxy haemoglobinaemia Violet or brown discolouration of skin, especially face and hands
Porphyrias Photosensitivity and skin fragility
Leucocyte disorders
Leukaemia Chloromas are greenish blue nodules in acute myeloblastic leukaemia. Leukaemia cutis (papules,
nodules or plaques) are specific lesions. Non-specific lesions include purpura, Sweet’s syndrome,
pyoderma gangrenosum, eczematous eruptions or pruritus. Moreover, opportunistic infections
like candidiasis, herpes zoster, molluscum contagiosum or cryptococcosis occur
Chediak-Higashi syndrome Pigment dilution of skin and hair
Platelet disorders Livedo reticularis, chilblain-like lesions, leg ulcers, gangrene
Consumptive coagulopathy Skin infarcts, gangrene
Lymphocyte diseases
Cutaneous T-cell lymphoma Scaly, poikilodermic patches or plaques and infiltrated erythematous nodules, ulcers or
(Sézary syndrome) erythroderma
B-cell lymphoma Secondary cutaneous infiltrates (nodules or plaques) occur in late stages.
Plasma cell disease
Multiple myeloma Skin nodules.
Myeloma-associated Macroglossia, indurated purpuric, nodules or plaques
systemic amyloidosis
Mast cell disease Mastocytosis sysndrome (diarrhoea, abdominal pain), urticaria pigmentosa (hyperpigmented
itchy plaques with positive Darier’s sign)
Cryoglobulinaemia Cold urticaria, Raynaud’s phenomenon or skin lesions resembling vasculitis
Antiphospholipid syndrome and Raynaud’s phenomenon, livedo reticularis, purpura, skin infarcts, gangrene
532 macro or hyperglobulinaemia
 Skin in Systemic Diseases
skin signs of systemic diseases will work as an asset to the clinical Table 8: Neurocutaneous Disorders
acumen of a physician.
Genetic disorders or
Neurocutaneous Disorders nevoid anomalies
The integumentary system and the nervous system are both Neurofibromatosis Neurofibromas, Café au lait macules,
iris hamartoma, gliomas, vestibular
derived from the ectoderm. Hence, it is not surprising that many
neuromas
nervous system disorders are associated with skin changes. Some
Tuberous sclerosis Adenoma sebaceum, ash-leaf macule,
of these neurocutaneous disorders also involve eyes and are
shagreen patch, mental retardation,
called as phacomatosis that include genodermatoses like epilepsy, cortical tubers
neurofibromatosis, tuberous sclerosis, Sturge-Weber syndrome, Cerebriform congenital Over scalp with leptomeningeal
phacomatosis pigmentovascularis, etc. Skin manifestations are melanocytosis melanocytic naevus
obvious pointers to the correct diagnosis in this group. Other Sturge-Weber syndrome Port wine stain, retinal and intracranial
conditions where skin and nervous system may be affected vascular malformation
simultaneously include autoimmune disorders and infections Infections
(Table 8). Tuberculosis Miliary tuberculosis involving skin and
Nutritional Deficiencies nervous system
Protein energy malnutrition (PEM) Cryptococcosis Cryptococcal meningitis, umbilicated
white papules over skin
Children with PEM show numerous skin changes. Kwashiorkor Cytomegaloviruses (CMV) Encephalitis - with perianal ulcers,
presents with dry, scaly skin (flaky paint dermatosis) that is infections CMV retinitis
oedematous and tends to crack with criss-cross fissures (crazy Toxoplasmosis Encephalitis and retinitis
pavement dermatosis). The face is swollen and pale with dry Syphilis Meningovascular or parenchymal
skin. In marasmus, the skin is dry, thin and wrinkled. There is involvement, tabes dorsalis, cerebral
near-absence of subcutaneous fat with lax skin giving a wizened form – General paralysis of the insane
‘old man’ look to the face. The hair are thinner and lighter in (GPI)
colour, sometimes with variation in colour of hair along their Bacterial infection of the Cavernous sinus thrombosis
length (flag sign). dangerous area of face
Phrynoderma Neurocysticercosis Cutaneous cysts in neck area, seizures
CNS haemorrhage
The skin of the elbows and knees becomes rough (toad skin) Severe thrombocytopaenia Petechiae, subarachnoid or intra-
due to follicular keratoses. The conical keratotic papules with cranial bleeding
central plug are also seen over buttocks, lateral aspects of thighs Autoimmune
and arms. Deficiency of vitamin A and essential fatty acids is Antiphospholipid antibody Non-inflammatory palpable purpura,
causative. Night blindness and conjunctival and corneal xerosis syndrome seizures, abortions, positive anti-
may be associated. phospholipid antibodies
Pellagra Systemic lupus Cognitive dysfunctions, seizures, early
erythematosus stroke, malar rash
Deficiency of niacin leads to pellagra. Most common Periarteritis nodosa Painful subcutaneous nodules along
predisposing factor for pellagra in the Indian setting is alcohol arteries, vasculitic ulcers, peripheral
abuse, expecially in the absence of protein supplementation. neuropathy
However, niacin deficiency may also occur in people on a staple Wegener’s granulomatosis Medium sized vasculitis affecting skin,
diet of maize or jowar. Rarely pellagra like lesions occur due to kidney, upper and lower respiratory
drugs (INH, ethionamide). Photosensitivity leading to brownish tract, peripheral neuropathy
red erythematous patches and sharply circumscribed plaques Behçet’s disease Oro-genital ulcers, arthritis, positive
over sunexposed areas characterise the condition. Forearms and pathergy test, meningoencephalitis,
neck are preferentially affected. Sharply outlined brownish brainstem involvement, cranial
plaques around the neck lead to the typical ‘Casal’s necklace’. nerve palsies, cerebral venous sinus
Less frequently, bony prominences, flexures and frictional areas thrombosis
get affected. The tongue is smooth and red.
Riboflavin deficiency RECOMMENDED READINGS
1. Graham RM, Cox NH. Systemic diseases and the skin. In: Burns T, Breathnach
Riboflavin causes oral, ocular and cutaneous changes. The oral
S, Cox N, Griffiths C. editors. Rook/Wilkinson/Ebling Textbook of
mucosa is red and the tongue magenta red and smooth.The nose, Dermatology. 7th Ed. Oxford: Blackwell Science; 2004; p. 59.1-59.75.
eyebrows and other seborrheic areas of face show yellowish 2. Khopkar U. Illustrated Handbook of Skin and Sexually Transmitted Infections
powdery scales (seborrhoea). Riboflavin deficiency commonly co- with an Update on HIV Infection. 6th Ed. Mumbai: Bhalani Publishing House;
exists with pellagra in the setting of alcohol abuse. 2010.

533
 11.15 Leprosy

BK Girdhar

DEFINITION
Leprosy (Hansen’s disease) is a chronic infectious disease caused
by Mycobacterium leprae. The organism mainly affects the skin
and the peripheral nerves.

EPIDEMIOLOGY
The case load has drastically come down with the worldwide
application of multi-drug therapy. Though new patients
continue to be detected, the recent (2007) prevalence rate
across the globe is very small with all but four countries (Brazil,
Democratic Republic of the Congo, Mozambique and Nepal)
having achieved elimination, i.e. having prevalence less than
one per 10,000 population. Within the India, seven states (Bihar,
Chattisgarh, Jharkhand, Maharashtra, Orissa, Uttar Pradesh and
West Bengal) continue to have higher prevalence of the
disease and contribute two thirds of the patients. Figure 1: Pathogenesis of leprosy.
CMI = Cell-mediated immunity
AETIOLOGY AND BACTERIOLOGY
Leprosy is caused by M. leprae, a Gram-positive bacillus which is
weekly acid-fast and stains bright red with carbol-fuschin.

TRANSMISSION
Man is the only natural host and reservoir of this infection,
though a few animals caught in wild have been found to have
the infection. It is mainly the untreated lepromatous patients
who are infectious and spread the disease in the community.
The route of exit of bacilli from the body is mainly from nose
and mouth. Aerosol and close contact are important source of
transmission. The organisms enter the healthy contacts either
through microscopic breaches in the skin or more likely through
upper respiratory tract, in particular the nasal mucosa.

PATHOGENESIS
The incubation period ranges from six months to more than
20 years (in most instances 2 to 5 years. In a small proportion
of infected individuals (less than 1% to 5%), the disease
develops due to impairment of specific cell-mediated
immunity (CMI). The type of disease that the patient develops
depends upon the degree of impairment of cellular immunity
(Figure 1).

CLINICAL MANIFESTATIONS
Based on the outcome, determined by individual’s specific
cellular immunity, six defined types of leprosy have been
classified.
Figure 2: Indeterminate leprosy: Small vague lesion on the elbow.
Indeterminate Leprosy (IL)
This is the earliest diagnosable manifestation of the disease. The Tuberculoid Leprosy (TL)
lesions are small, asymptomatic, vague macules, 1 to 3 in number This type of disease develops in those who have good CMI
and are hypopigmented, may be with mild redness (Figure 2). (Figure 3). Here the disease remains localised to one anatomical
Some impairment of sensations may be found on careful area with 1 to 3 patches which are usually medium to large in
testing for fine touch (with cotton wool or pointed paper) and size and are well defined. Two types of lesions, one raised and
534 temperature (hot and cold). red plaques and the other well-defined hypo-pigmented flat
 Leprosy
macules are seen which have loss of hair, and impairment of
sensations. Local or regional nerve thickening may be there.
Skin smears are negative but lepromin test is strongly positive
(Table 1).

Figure 3: Conceptual representation of spectrum of leprosy.

CMI = Cell-mediated immunity; TT = Tuberculoid leprosy; BT = Borderline
tuberculoid; BB = Mid borderline; BL = Borderline lepromatous; LL = Lepromatous
leprosy.
(Reproduced with permission from L.K. Bhutani. Colour Atlas of Dermatology)

Lepromatous Leprosy (LL)

Lesions can be macules, plaques, and nodules which appear
in generalised symmetrical fashion affecting the extensors
more than the flexors (Table 1). Early lepromatous disease
Figure 5: Lepromatous leprosy. Leonine facies.
may present only as shine, due to smoothening of creases by
infiltration, over the face and/or back. Papules and nodules appear
on the ear, especially the rim of the external ear (Figure 4),
forehead, cheeks and chin and on the extensors of the body.
Lesions are symmetrically placed, small, ill-defined, smooth shiny
and devoid of any sensory impairment.

Figure 6: Lepromatous leprosy. Infiltration and shiny skin of hands.

In untreated cases, skin smears are positive in all sites, often

with large number of organisms in all microscopic fields. In
contrast to tuberculoid disease, lepromin test is uniformly
negative.
Figure 4: Lepromatous leprosy. Infiltration with nodularity of the ear rim. Borderline Leprosy (BT, BB and BL)
This is a large group with variable and unstable immune system.
The eyebrows may be lost starting from the lateral side. In the Depending upon the closeness to the tuberculoid type, the
absence of treatment, appearance of thicker infiltration in the patients are grouped as borderline tuberculoid (BT), while those
form of nodules on the face may give the face a leonine look with features more akin to the lepromatous form are designated
(Figure 5). Sheets of infiltration may appear on the distal parts as borderline lepromatous (BL). Patients with some mani-
of the extremities (Figure 6). There is peripheral anaesthesia of festations of both the types are called mid borderline (BB).
glove and stocking type (Figure 7). Lesions are relatively more localised, fewer, often larger with 535
 Table 1: Clinical Features of Leprosy
Feature Tuberculoid (TT) Borderline Mid borderline (BB) Borderline Lepromatous (LL)
tuberculoid (BT) lepromatous (BL)
No. of lesions 1 to 3 Few Many Numerous Innumerable
Distribution Localised Localised or distant, Widespread Generalised Generalised
mostly regional asymmetrical symmetrical
Size Usually large Usually large All sizes Mostly small Small with sheets of
with satellites infiltration
Margin/edge Well-defined Partly well-defined Ill-defined, inner edge Vague Vague, infiltration
abrupt in annular lesions
Surface Dry, hair loss + Dry, hair loss + Some dry, some smooth Mostly smooth Smooth, shiny or oily
Sensations Impaired or lost Impaired, intact in Impaired in some, Mostly intact Intact in lesions,
satellite lesions intact in others peripheral anesthesia ±
Nerves thickening Limited local Limited local and/or Many regional or distant Many, often Many, symmetrical
and/or regional regional symmetrical
Firm Abscess ± Firm Firm/normal Normal/soft Soft and smooth
Skin smears Negative Negative May be positive in some Positive, usually Positive, often highly
lesions (+/++) moderately
Lepromin +++ +++ +/– – –

goes towards the BL type (Figure 9). Likewise the number of

affected nerves increases and the nerves become softer with
disease progression (Table 1).

Figure 7: Lepromatous leprosy. Acquired ichthyosis and oedema feet.

Figure 9: Borderline lepromatous leprosy. Bilateral, small, vague erythmatous

macules and plaques over the trunk.

Neuritic Leprosy (NL)

In NL there are no skin manifestations (apart from signs and
symptoms of nerve damage) but only nerve thickening. There
may be only one nerve thickening (mono-neuritis) or multiple
nerves may be clinically involved (mono-neuritis multiplex).

ORGAN INVOLVEMENT
Organ involvement is mainly seen in patients with lepromatous
type of disease.
Of the internal organs, liver and kidneys are commonly affected.
Kidney involvement is common, especially in those who have
had repeated attacks of type 2 erythema nodosum leprosum
(ENL) reactions. Glomerulonephritis, interstitial nephritis, less
Figure 8: Borderline tuberculoid leprosy. Well-defined erythmatous plaque with
central clearing.
commonly pylonephritis and amyloid deposits can occur
resulting in proteinuria, cells and cast in the urine.
definite sensory impairment in patients toward the BT group Testes being the cooler organ are frequently involved in
(Figure 8) and progressively wide spread, more in number, lepromatous patients. The disease may per se produce testicular
536 smaller and vague with partial or no loss of sensations as one atrophy with loss of normal testicular sensations. Oligo/
 Leprosy
Azoospermia and decreased testosterone levels may result in
sterility and loss of libido. Acute painful orchitis may occur in
some patients during reactions.
Lymphnodes may get mildly enlarged in a significant proportion
of lepromatous patients.
Bone and muscle affection is seen in a small proportion of
untreated lepromatous disease of many years. Specific
involvement of the eyes due to bacillary spread with
appearance of lepromas in the iris and cornea, resulting in
insidiously appearing granulomatous uveitis and keratitis
respectively, is not uncommon in patients with advanced
lepromatous disease and can reduce vision partially or
completely. In patients with type 2 (ENL) reaction, eyes may
suddenly become painful and red. In the nose there is ulceration Figure 10: Development of primary disabilities.
of the septal and turbinate mucosae, resulting in blood stained
nasal discharge and crusting. Following repeated or prolonged
ulceration, bone and cartilage may get affected and destroyed
with consequent perforation of septum and collapse of nasal tip.
It is noteworthy that brain, spinal cord, heart, lungs and gastro-
intestinal tract have not been observed to have any significant
affection.

DISABILITY AND DEFORMITY

Disability means the diminished ability of a person to perform
normal movements and do his/her normal work. Deformity is
defined as any deviation of appearance of any part or parts of
the body. Nerve damage is the main cause for the above.
Deformities are called primary, if these are due to direct damage
by the disease process, e.g. muscle paralysis, nasal deformity,
eye damage, etc. (Figures 10 and 11). Secondary deformities
are a consequence of sensory loss and thereby loss of tissue
due to burns, trauma and secondary infection, e.g. post-burn Figure 11: Claw hand with trophic ulcers (post-burn blister, ulcers and scars).
blisters, ulcers, scars, contractures and loss of digits on hands,
trophic ulcers on feet and corneal ulcers due to affection of
trigeminal nerve (Figures 12 and 13). Disabilities occurring
due to damage to various nerves are detailed in Table 2.

Table 2: Clinical Effects of Nerve Damage

Site Nerves Features
Face Trigeminal Loss of sensation over the face corneal
anaesthesia if ophthalmic division affected
Facial Facial palsy. If only zygomatic branch affected
– lag ophthalmos on the affected side
Hand Ulnar Loss of sensations and sweat over the little
and medial half of ring finger. Clawing of little
and ring finger initially and later of long and
index fingers
Median Loss of sensations and sweat over the
thumb, index, long and lateral half of ring
fingers. Loss of abductor and opponence Figure 12: Development of secondary disabilities.
function of thumb and later its clawing
Ulnar and Loss of sensations and sweat over whole
median of palm and medial half of dorsum of hand. DIAGNOSIS OF LEPROSY
Clawing of all fingers The diagnosis of leprosy is based on the following three
Radial Sensory and sweating loss over lateral half cardinal signs: (i) hypopigmented or erythematous patch with
of dorsum of hand. Wrist drop definite impairment of sensations, (ii) involvement of
Foot Common Loss of sensations and sweat over lower peripheral nerve(s), demonstrated by palpable thickening of
peroneal half of leg. If only superficial affected, cutaneous (Figure 14) and/or regional nerve trunks and (iii)
sensory loss over dorsum of foot. Foot drop
finding of acid-fast bacilli (AFB) in the skin smears from lesion.
Posterior Loss of sensation and sweat over the
For the definite diagnosis either the first two or the third alone
tibial sole of foot. Claw toes
need to be present. 537
 Skin Biopsy
Histological examination is often required for confirmation of
doubtful cases and for accurate classification of the disease.
Nerve Biopsy
This is required only in a very few cases, especially in those who
do not have any skin signs.
Lepromin Test (Mitsuda/Dharmendra)
Lepromin test has no diagnostic value, particularly in endemic
areas and where BCG vaccination is practised.Though important
for assessing the degree of specific cellular immunity of the
patients and useful for immunological classification, presently
its role is limited to academics and research only.
Other Laboratory Tests for Diagnosis
Serological tests for leprosy (fluorescent antibody absorption
Figure 13: Trophic ulcers. Deep punched ulcers over the pressure points of fore
test, PGL-1 antibody and monoclonal antibody based tests) are
feet. all positive in high proportion (92% to 100%) of highly bacillated
lepromatous cases.

DIFFERENTIAL DIAGNOSIS
As mentioned, careful sensory testing and nerve examination
in suspected cases confirms or rules out leprosy. However, in
patients with hypopigmented patches/conditions like birth
marks (especially, naevus achromicus), pityriasis alba, pityriasis
versicolour, vitiligo, post-inflammatory hypopigmentation and
lesions of post-kala-azar dermal leishmaniasis (PKDL) need to
be differentiated. Nutritional deficiencies, alcoholism, diabetes
and heavy metal effects should be considered in patients
suspected to have leprosy. Entrapment neuropathies involving
the main trunks of the limbs, including that of lateral cutaneous
nerve of the thigh (resulting in meralgia paresthetica or
Bernhardt’s syndrome), and those of trigeminal and facial nerves
may occasionally cause confusion in diagnosis.

REACTIONS IN LEPROSY
Figure 14: Thickened greater auricular and transverse cervical nerves. Occurrence of acute episodes in leprosy have been called
reactions. Basically there is a rapid change in the host response
For testing pain, tip of fine ball-pen can be used. Thermal with temporary increase in T-cell reactivity. In many patients,
sensation can be tested using test tubes containing hot and this is precipitated by intercurrent problems like stress,
cold water. Peripheral nerve trunks and local cutaneous nerves pregnancy, acute or chronic infections and anti-leprosy
should be palpated for thickening, tenderness and consistency. drugs.
Nerve function assessment includes, testing for sensations in Reactions occurring in borderline patients (called type 1 or
the lesions and area supplied by the nerve and assessment of reversal reactions) are mostly the result of increased cellular
power in the muscles supplied by the nerve(s) (the voluntary hypersensitivity and present as lesions becoming suddenly
muscle testing). swollen, angry red and may even ulcerate (Figure 15). New
Bacteriological Examination (Skin Slit Smears) lesion may suddenly appear. Nerves may become acutely
painful, tender, swollen with increased nerve damage leading
This involve making a nick in the suspected lesion and taking a
to motor deficit. Steroids constitute the main treatment.
small amount of blood free dermal tissue on to a glass slide
and staining the same for AFB using 5% sulphuric acid or 1% In lepromatous and some BL patients, the reactions are on
acid (hydrochloric acid) alcohol. Skin smears as above are taken account of antigen-antibody (immune) complexes—either
from a number of sites including ear lobules and lesions. The formed or deposited locally. This type of reaction is known
stained slides are examined, under oil immersion for number as type 2 or ENL reaction. Patients have febrile episodes
of pink stained bacilli per field, averaging after examination of together with crops of painful red papules or plaques over
almost hundred microscopic fields. An average of at least four the face, trunk and the extensors of the limbs (Figure 16).
sites is the bacteriological index (BI). The BI reflects the quantum These episodes are often associated with acute neuritis,
of bacillary load in the body. The BI, in log scale, is usually 4 to peripheral oedema, lymphadenitis, bone pains, arthritis,
6+ in untreated lepromatous patients, while it may be hard to acute uveitis and/or orchitis. Swollen and necrotic lesions
find the bacilli towards the tuberculoid end. may also occur.
538
 Leprosy
properties has been recorded with this drug. The main
component of MDT is rifampicin.
In addition to the above, several new compounds includes
fluoroquinolones, in particular ofloxacin, sparfloxacin and
moxifloxacin, minocycline.
Multi-Drug Therapy (MDT)
A combination of drugs is routinely advocated to prevent drug
resistance. For the purpose of treatment, based on the quantum
of the infecting organisms within the body of the patients, all
leprosy patients are divided into pauci-bacillary and multi-
bacillary groups. Earlier BI was taken as the guide, presently the
number of skin lesions is the criteria for this classification. For
field treatment, set guidelines have been provided by the World
Health Organization (WHO) and adopted by the Government
of India. The regimens are detailed in Table 3.
All other patients, lepromatous, borderline lepromatous (BL),
mid-borderline (BB), borderline tuberculoid (BT) patients with
more than 5 lesions are considered multi-bacillary. As expected,
almost all of them show AFB positivity in skin smears, though
to a variable extent. The MDT for multi-bacillary patients has
been recommended for presently 12 months but the dwrofrai
can be increased up to 18 months (Table 3).

Table 3: WHO Regimens for Leprosy

Doses (mg)
Group Drugs Adult Children Regimens Duration
6-14 0-5
(years) (years)
PB Rifampicin 600 450 300 Once a 6 monthly
Figure 15: Borderline tuberculoid leprosy in type I reaction: Swollen, month pulses in
erythmatous and oedematous plaque. Dapsone 100 50 25 supervised maximum
of 9 months
MB Rifampicin 600 450 300 Once a 12 monthly
month pulses
Clofazimine 300 150 100 supervised
in a
maximum
Dapsone 100 50 25 Daily self-
of 18
Clofazimine 50 50 AD 50 BW administered months

mg = Milligram; PB = Pauci-bacillary; MB = Multi-bacillary; AD = Alternate days,

BW = Twice a week

As in tuberculosis, it is mandatory that patients should be

kept under surveillance following completion of regimens. This
is not only to diagnose and provide care for reaction and/or
nerve damage, that can occur even after completing the
regimens but also to look for relapses, which are mostly late to
appear. All pauci-bacillary patients, including single lesion cases,
Figure 16: Erythema nodosum leprosum (type II lepra reaction): Erythmatous should be seen at least once a year for 2 years and all multi-
tender plaques. bacillary patients should be followed up yearly for at least 5
years.
MANAGEMENT Management of Lepra Reactions
Simultaneous administration of two or more drugs, called the The type 1 reactions, which are the consequence of changes
multi-drug therapy (MDT) has been the recommended therapy (more often increase) in cellular hypersensitivity, result in
since 1982 (Table 3). Dapsone, a sulphonamide derivative, sudden increase in inflammation in skin and nerves in
continues to be basic drug. Clofazimine is mildly bactericidal. borderline patients. Oral corticosteroids are the mainstay for
Having a different mode of action and anti-inflammatory this type of reactions. An initial daily dose of 30 mg to 40 mg
539
 prednisolone equivalent is sufficient in most cases. After 4 to 8 usually respond to rest, aspirin and/or chloroquine in 5 to
weeks when the condition improves, as evidenced by decrease 10 days. However, those with severe reactions, presenting
in lesional redness and swelling, nerve pain and tenderness or with wide-spread skin lesions with fever, acute nerve problems,
improvement in sensory and motor recovery, the steroids are acute lymphadenitis, arthritis, periostitis, uveitis or orchitis
tapered gradually. need to be given steroids.Unlike type 1 reactions,here the steroids
Type 2 (ENL) reactions are the result of local and systemic are required to be given in short courses and rapidly tapered off.
immune complex deposition or formation and are seen in RECOMMENDED READINGS
lepromatous patients. As stated above, attempt should be made 1. Girdhar BK. Multi-drug therapy in leprosy and its future components. Indian
to identify and manage precipitating cause, if any, like J Lepr 1994; 66: 179-208.
concomitant infections, physical or psychological stress etc. 2. Kar HK, Kumar B. IAL Textbook of Leprosy. New Delhi: Jaypee Brothers
Addressing the precipitating factors often relieves the patient Medical Publishers (P) Ltd; 2010.
of reactions. Patients having mild reactions, i.e. with only 3. World Health Organization. Global leprosy situation. Wkly Epidemiol Record
a countable few skin lesions (with or without mild fever), 2009; 84: 333-40.

540
 11.16 Sexually Transmitted Infections

Vinod K Sharma, Naresh Jain

Sexually transmitted diseases (STDs) represent a major public genitals but can be transmitted by sexual intercourse, e.g.
health problem causing acute illness, chronic disability and hepatitis B, HIV, HTLV-1, etc. STDs most commonly affect
long- term consequences in men, women and children. STDs people aged 15 to 44 years, the most economically productive
have a tremendous impact at individual and community level. group. The emergence of HIV has led to changes in the
STDs are responsible for significant proportion of maternal epidemiological patterns of various sexually transmitted
morbidity, ectopic pregnancy, infant illness and death, bacterial and viral infections. The different aetiological agents
malignancies, infertility and increased transmission of HIV for STDs, diseases caused and complications are listed in Table 1
infection. Sexually transmitted infections (STIs) include all STDs and incubation period of common STDs is summarised in
and other infections that may not cause clinical disease of Table 2.

Table 1: Sexually Transmitted Agents and Diseases

Agents Disease or syndrome Complications
Bacteria
Neisseria gonorrhoeae Urethritis, epididymitis, bartholinitis, cervicitis, Infertility, ectopic pregnancy, chorioamnionitis,
endometritis, salpingitis, proctitis, pharyngitis premature rupture of membranes, premature
delivery, conjunctivitis, PID, disseminated gonococcal
infection (DGI)

Chlamydia trachomatis (D-K) Urethritis, epididymitis, bartholinitis, cervicitis, Same as in N. gonorrhoeae, except DGI, Reiter’s
endometritis, salpingitis, proctitis, pharyngitis syndrome, pneumonia
Esthiomene, ano-recto-genital syndrome, proctocolitis,
Chlamydia trachomatis (L1, L2, L3) Lymphogranuloma venereum skin rashes, pneumonia, hepatitis, meningoencephalitis
Treponema pallidum Syphilis-primary and/or secondary, latent Abortions, dementia, death
neurosyphilis, cardiovascular syphilis
Haemophilus ducreyi chancroid Phimosis, sclerosis, meatal stenosis
Calymmatobacterium granulomatis Donovanosis Phimosis, sclerosis, SCC
Mycoplasma hominis Non-gonococcal urethritis, cervicitis, salpingitis PID, post-partum fever
Ureaplasma urealyticum Non-gonococcal urethritis, cervicitis, salpingitis Chorioamnionitis, low birth weight
Gardnerella vaginalis and others Bacterial vaginosis
Group B β-haemolytic Streptococcus Neonatal sepsis, neonatal meningitis
Viruses
Herpes simplex virus 1, 2 Primary and recurrent genital herpes Aseptic meningitis, neonatal herpes and associated
mortality or neurological sequelae, spontaneous
abortion, premature delivery
Human papilloma virus Condyloma acuminata Laryngeal papilloma in infants, squamous epithelial
neoplasia of cervix, anus, vagina, vulva and penis
Hepatitis B virus Acute, chronic and fulminant hepatitis B Cirrhosis, hepatocellular carcinoma
Cytomegalovirus Infectious mononucleosis Congenital infection, birth defects, infant mortality,
cognitive impairment (mental retardation, sensorineural
deafness), variable manifestations in immunocomp-
romised host

Molluscum contagiosum virus Genital molluscum contagiosum Infection, eczematoid dermatitis, erythema annulare
centrifugum
Human immunodeficiency virus AIDS and related conditions Opportunistic infections, death
Human T-lymphotropic virus T-cell leukaemia, lymphoma, tropical Death
spastic paraparesis
Protozoa
Trichomonas vaginalis Urethritis, balanitis, vaginitis
Fungus
Candida albicans Vulvovaginitis, balanitis, balanoposthitis
Ectoparasites
Phthirus pubis Pubic lice infestation
Sarcoptes scabiei Scabies Norwegian scabies in immunocompromised host 541
 Table 2: Incubation Period of Common STDs of H. ducreyi from the genital ulcer by Gram-stain. Polymerase
chain reaction (PCR) and indirect immunofluorescence using
STDs Incubation Period (mean)
monoclonal antibodies are recent techniques. Histopathological
Primary chancre 9 to 90 days (21 days) examination also helps in the diagnosis.
Chancroid One to several weeks (5 to 8 days)
Donovanosis 9 to 50 days (17 days) Treatment
Lymphogranuloma venereum 5 to 30 days (10 days) Azithromycin 1 g orally in a single dose or ceftriaxone 250 mg
Herpes genitalis (primary) 5 to 7 days (5 days) intramuscularly in a single dose or ciprofloxacin 500 mg orally
Genital warts 1 to 8 months (3 months) twice a day for 3 days or erythromycin base 500 mg orally three
Gonococcal urethritis 1 to 14 days (2 to 5 days)
times a day for 7 days. Ciprofloxacin is contraindicated for
Non-gonococcal urethritis 7 to 21 days (10 days)
pregnant and lactating women. Fluctuant bubo should be
Syphilis, herpes genitalis and anogenital warts are discussed in aspirated using a wide bore needle. In the presence of bubo,
separate chapters. the antimicrobial agents may have to be continued for a longer
period till the bubo heals. Sexual contacts within 10 days before
CHANCROID the onset of patient’s symptoms should be examined and
Aetiology treated, even in the absence of symptoms in view of the known
Chancroid is a sexually transmitted ulcerative disease associated asymptomatic carriage.
with inguinal adenitis (bubo) caused by Haemophilus ducreyi, a Follow-up
Gram-negative, facultative anaerobic bacillus, arranged in
After starting the treatment, patients should be reviewed at day
chains of 2 to 4 giving the typical appearance of a ‘school of fish
3 and day 7.
or rail road track’. H. ducreyi is a fastidious organism and culture
is difficult. DONOVANOSIS
Epidemiology Aetiology
Chancroid is most common in many of the world’s poorest Donovanosis (granuloma inguinale) is indolent, progressive,
regions, such as areas of Africa, Asia, and the Caribbean. The ulcerative and granulomatous skin disease caused by
prevalence of chancroid is higher in lower socioeconomic groups. Calymmatobacterium granulomatis. The organism has an
appearance similar to a safety pin.
Clinical Features
After an incubation period that ranges from 1 to 14 days, a small Epidemiology
inflammatory papule surrounded by erythema develops on Donovanosis is endemic in tropical and subtropical regions. In
genitalia, which rapidly progress to pustules followed by India donovanosis is endemic along the East Coast, i.e. Orissa
ulceration.The ulcers are multiple, painful, sharply circumscribed (7.5%), Andhra Pradesh (1.12%) and Tamil Nadu (4.7%).
with ragged undermined edge (Figure 1). The ulcer base is
Clinical Features
composed of granulation tissue that bleeds on manipulation.
Characteristically, the base of the ulcer is non-indurated. The The incubation period may range from 3 days to 3 months. The
ulcers are located primarily on the prepuce, frenulum or glans primary lesion may be a skin-coloured to erythematous papule,
penis in males and labia, fourchette and cervix in females. which ulcerates to form well-defined granulomatous ulcer
Unilateral painful inguinal adenitis (bubo) in 30% to 60% of (Figure 2). The ulcer is usually painless, beefy-red in colour and
the patients within 1 to 2 weeks of the development of ulcer. bleeds easily on touch. In men, the penis, scrotum and glans
The nodes become enlarged, tender and then matted. are most commonly affected and in females, the labia minora,
mons-veneris and fourchette are most common sites. True
Diagnosis adenopathy is rare. The disease spreads by satellite inoculation
Besides the clinical clues, the main tool for definite diagnosis for and daughter lesions and thereby these spread slowly to the
chancroid is bacterial culture of H. ducreyi and direct examination inguinal region where it can mimic a bubo (pseudobubo).

Figure 1: Chancroid-ulcer with ragged edges. Figure 2: Donovanosis-fleshy ulcer.

542
 Sexually Transmitted Infections
During its progression it leads to the destruction of lymphatics tenesmus. At this stage they have multiple superficial ulcers
resulting in lymphoedema and elephantiasis of the genitalia. with irregular borders. As the disease progresses, crypt
Persistent untreated lesions over years can lead to malignant abscesses and fistulas are formed resulting in rectovaginal
transformation. fistula, fistula in ano, etc. Ultimately they heal with fibrosis
and lymphatic obstruction, resulting in rectal stricture and
Diagnosis
lymphoedema of the genitals (ram-horn penis, saxophone
Besides history and clinical appearance, a touch or crush penis) leading to genital elephantiasis (esthiomene).
preparation stained with Wright’s or Giemsa’s stain from a Carcinoma of the rectum develops in 2% to 5% cases of rectal
punch biopsy specimen which shows deeply staining, bipolar, stricture due to LGV. The ano-rectal syndrome is more common
safety pin rods in the cytoplasm of macrophages (Donovan in women.
bodies). The culture of organism is difficult but PCR can help
in the diagnosis. Diagnosis
LGV can be confirmed by: (i) serological procedures like
Treatment
complement fixation test, counter immunoelectrophoresis,
Doxycycline 100 mg orally twice a day for at least 3 weeks and radio immunoprecipitation test, etc.; (ii) demonstration of
until all lesions have completely healed. Azithromycin 1 g orally chlamydial antigens by immunofluorescence; and (iii) isolation
once per week or ciprofloxacin 750 mg orally twice a day or of Chlamydia by tissue culture.
erythromycin base 500 mg orally four times a day or
trimethoprim-sulfamethoxazole one double-strength (160 mg/ Treatment
800 mg) tablet orally twice a day are alternatives. Therapy should Treatment cures infection and prevents ongoing tissue damage.
be continued for at least 3 weeks and until all lesions have Buboes might require aspiration through intact skin or incision
completely healed. All sex partners (within 60 days of onset of and drainage to prevent the formation of inguinal/femoral
patient’s symptoms) should be examined and offered therapy. ulcerations.
Follow-up Recommended regimen to doxycycline 100 mg orally twice a
Review is preferably monthly for first 3 months. day for 21 days, or alternatively, erythromycin base 500 mg orally
four times a day for 21 days.
LYMPHOGRANULOMA VENEREUM
Sexual contacts within the 60 days before the onset of patient’s
Aetiology symptoms should be examined, tested for urethral or cervical
Lymphogranuloma venereum (LGV) is a sexually transmitted chlamydial infection, and treated with standard Chlamydia
disease affecting primarily the lymphatic system, caused by regimen (azithromycin 1 g orally stat or doxycycline 100 mg
Chlamydia trachomatis serovars L1, L2 and L3. Chlamydia are orally twice a day for 7 days).
Gram-negative, intracellular, obligate parasites, measuring from
Follow-up
0.3 to 1.0 micron in size.
Patients should be followed clinically until signs and symptoms
Epidemiology have resolved. Differential diagnosis of genital ulcer disease is
LGV has a worldwide distribution but is endemic in India and discussed in Table 3.
South-East Asia.
URETHRITIS
Clinical Features
Urethritis, inflammation of the urethra can be classified into two
The incubation period is usually around a week (3 to 12 days). types—gonococcal and non-gonococcal urethritis.The former
The portal of entry and the initial symptoms are determined
is caused by Neisseria gonorrhoeae, a Gram-negative intracellular
by the nature of sexual act. The clinical features can be divided
diplococci and it measure 1 to 2 μ in size. The adjacent surface
into primary stage, secondary (inguinal stage) and a tertiary
of the cocci is flattened and long axis of the bean-shaped
stage (complications).
organisms are parallel. They are cultured on Thayer-Martin
Primary Lesion medium. Non-gonococcal urethritis is caused by variety of
The primary lesion is 5 to 8 mm soft, erythematous, painless organisms, Chlamydia trachomatis being the most common.
erosion that heals spontaneously in a few days. Other organisms that are responsibile for non-gonococcal
urethritis are Ureaplasma urealyticum, Mycoplasma, Trichomonas
Inguinal Syndrome (Bubo) vaginalis, Candida albicans, HSV, etc.
Secondary inguinal lymphadenopathy (bubo) begins 1 to 2
weeks after the primary lesion as discrete, movable, tender Epidemiology
nodes that later coalesce to form a firm, fist-sized, elongated, The disease is spread mainly by sexual activity. The commercial
immovable mass. Nodes are bilateral in one-third of cases. These sex workers are the main source of infection in a developing
may occur above and below Poupart’s ligament, giving rise to country like India. Urethritis constitutes 14% to 20% of patients
the “groove” sign. Rupture of the lymph nodes leads to chronic attending STD clinic in India.
sinus formation. At time of rupture of the bubo, patients might Clinical Features
have constitutional symptoms.
After a period of 2 to 10 days of exposure, the disease manifests
Anogenital Rectal Syndrome as acute burning sensation of urethra with copious purulent
Early manifestation of this disease is mucoid rectal discharge discharge. Approximately 25% of males will develop
following over weeks to months by fever, rectal pain and gonorrhoea after a single exposure. Meatal erythema, dysuria, 543
 Table 3: Clinical Features of Common Genital Ulcer Disease
Characteristics Syphilis Herpes Chancroid LGV Donovanosis
Primary lesions Papule Vesicle Pustule Papule, pustule Papule
or vesicle
Number of Usually one but in Multiple and Usually multiple and Usually one Variable
lesions 1/3 more than 1 may coalesce may coalesce
Diameter 5 to 15 mm 1 to 2 mm Variable 2 to 10 mm Variable
Edges Sharply demarcated Erythematous, Undermined, ragged, Elevated round or Elevated,
elevated, round or oval polycyclic irregular oval irregular
Depth Superficial or deep Superficial Excavated Superficial or deep Elevated
Base Smooth non-purulent Erythematous Purulent, bleeds easily Variable Red and velvety,
covered with serious bleeds readily
exudates
Induration Button-like None Soft Occassionally firm Firm
Pain Uncommon, but tender Frequently tender Usually very tender Variable Uncommon
on firm pressure
Lympha- Firm, non-tender, Firm, tender, Tender, may suppurate, Tender, may suppurate, None, may be
denopathy bilateral, and often bilateral loculated, usually loculated usually pseudobuboes
in 1/3 cases it with initial episode unilateral, occasional unilateral
may be tender cord like lymphangitis
Recurrence No Yes, in 80% No No No
Adapted from: Sharma VK, Kumar U. Sexually Transmitted Diseases; 2nd edition. New Delhi: Viva Books; 2009. Table 45.3; Page 771.

i
abnormal bleeding or increased discharge can be seen in infection 2 to 5 times. Because of large ulcerated area and the
females. In addition to urethritis, 1% of male patients develop presence of inflammatory CD4+ cells, which act as receptors of
other complications like tysonitis, periurethral abscess, Cowperitis, HIV, the genital ulcers (Figure 3) provide an ideal route for
epididymorchitis and prostatitis. Disseminated form is seen in transmission by shedding HIV virus. On the other hand, HIV
immunocompromised patients. Complications like pelvic infection by immunosuppression can lead to large, non-healing
inflammatory disease, bartholinitis, perihepatitis, and urethral genital ulcers or treatment resistant genital ulcers.Clinical features
strictures can develop. and treatment of different STDs with HIV are summarised in
Tables 4 and 5.
Non-Gonococcal Urethritis
Non-gonococcal urethritis (NGU) can occur alone or more often Table 4: Variations in Syphilis Presentation in Individuals with
(45%) in association with gonococcal urethritis. They present HIV Infection
after a long incubation period of 3 weeks. The symptoms are Clinical finding
mild and they have scanty mucopurulent/mucoid discharge. In Primary syphilis Painless ulcer becomes painful due to
females, untreated NGU can lead to pelvic inflammatory disease superinfection, giant chancre, multiple
with its consequences. ulcers (in up to 25%)
Diagnosis Secondary syphilis Lues maligna — secondary syphilis with
vasculitis manifested by fever, malaise,
Gram stained preparation helps in the diagnosis and in headache, nodules, indurated plaques with
distinguishing between gonococcal and non-gonococcal ulceration is more frequent
urethritis. A diagnosis of urethritis is made if there were more Latent and tertiary Shorter latent period with rapid progression
than 5 pus cells present per high power field (1 x 1000). In case syphilis to tertiary disease within the first year of
of gonococcal urethritis, there are sheets of pus cells with Gram- infection
negative intracellular dipococci. In case of non-gonococcal Serological response VDRL and treponemal antibody test in blood
urethritis, there are only scanty pus cells with no intracellular to syphilis and CSF may be false negative due to
Gram-negative diplococci. prozone phenomenon. Failure to drop VDRL
titers by one year despite adequate
Treatment treatment (serofast phenomenon)
Uncomplicated gonococcal infections of the cervix, urethra, and Diagnosis If VDRL is negative, dark field microscopy,
rectum – ceftriaxone 125 mg IM in a single dose or cefixime 400 mg biopsy of the lesion and direct fluorescent
orally in a single dose or ciprofloxacin 500 mg orally in a single antibody staining of material from the lesion
dose or ofloxacin 400 mg orally in a single dose or levofloxacin of polymerase chain reaction may be helpful
250 mg orally in a single dose plus treatment for Chlamydia, if Treatment Syphilis treatment is relatively unchanged in
chlamydial infection is not ruled out (Cap. Doxycycline 100 mg HIV co-infected patients, but regular follow-
bid for 7 days or tab. erythromycin 500 mg qid for 7 days). up is required because of increased rates of
treatment failure
HIV and STDs
Adapted from: Kar HK. Sexually Transmitted Diseases; 2nd Edition. New Delhi:
Sexually transmitted diseases and HIV infection have a symbiotic Viva Books; 2009. Table 11.2; Page 224.
544 relationship. Genital ulcer increases the acquisition of HIV
 Sexually Transmitted Infections
Table 5: Variations in Other STDs Presentation in Individuals
with HIV Infection
Chancroid
Clinical findings Genital ulcers tend to be larger and persist
longer. Multiple inguinal buboes. Frequent
occurrence of giant and phagedenic ulcer
Treatment Treatment failure can occur with single-
dose therapy with azithromycin and
ceftriaxone, so erythromycin, 500 mg 6
hourly for 7 days is preferred
Herpes genitalis
Clinical findings As immunosuppression progresses,lesion
may persist or progress to chronic enlarged
painful non-healing ulcers with raised
margin, ulcer may bleed
Treatment Treatment might be extended if healing is Figure 3: Non-healing ulcer of genital herpes in a HIV-positive patient.
incomplete after 7 to 10 days of therapy. For
severe HSV disease, initiating therapy with
acyclovir 5 to 10 mg/kg body weight IV (syndrome) rather than for a specific STD. A genital ulcer, which
every 8 hours might be necessary. is a symptom of both chancroid and syphilis, is treated for both
Suppressive therapy includes acyclovir 400
chancroid and syphilis in an area where both are prevalent.
to 800 mg bid or tid
The urethritis is treated by covering for both gonococcal and
Granuloma inguinale
chlamydial infection. The ‘4C’s of syndromic approach are
Clinical findings Lesion may be larger, extensive, pseudobubo
counselling, condom usage, compliance and contact tracing.
ave- formation which may burst producing
The main drawback of syndromic approach is wastage of
usly ulceration; slow response to the treatment
Treatment Doxycycline 100 mg orally bid or erythromycin resources, use of multiple drugs and development of drug
500 mg orally qid for 2 to 3 weeks. If no resistance. As laboratory tests are expensive, time consuming
improvement, add gentamicin 1 mg/kg and not available at the primary level, the syndromic approach
intravenously is validated. It also helps in prompt treatment of STD at primary
LGV health centre and reduce transmission of STDs including HIV
Clinical findings Acute inflammation with bilateral inguinal infection.
bubo which may burst into ulceration
Treatment Same regimen (doxycycline, 100 mg orally RECOMMENDED READINGS
bid or erythromycin, 500 mg orally qid for 21
1. Centres for Disease Control and Prevention, Atlanta. Recommendations
days, but prolonged therapy may be required for treatment of sexually transmitted diseases 2006. (www.cdc.gov)
Adapted from: Kar HK. Sexually Transmitted Diseases; 2nd edition. New Delhi: 2. Sexually transmitted diseases. In: Park K editors. Preventive and
Viva Books; 2009. Table 11.3; Page 229. Social Medicine; 18th Ed. Jabalpur: Banarasidas Bhanot; 2005: pp 265-9.
3. Sharma VK, Khandpur S. Changing patterns of sexually transmitted diseases
SYNDROMIC APPROACH TO STD MANAGEMENT in India. Natl Med J India 2004; 17: 310-19.
The main motive under this approach is to diagnose and 4. Sharma VK. Sexually Transmitted Disease and AIDS; 2nd Ed. New Delhi: Viva
treat patients on the basis of groups of symptoms or signs Publishers; 2009.

545
 11.17 Premalignant Conditions and
Malignant Tumours of the Skin
Arun C Inamadar, Aparna Palit

INTRODUCTION Table 1: Causes of Leucoplakia

Premalignant and malignant skin lesions are commoner among Aetiology Types Risk of malignancy
white races. Malignancies like primary cutaneous melanoma are
Infective Chronic Candidal Increased risk but
extremely rare among Indians.
origin leucoplakia malignancy
Exposure to solar and artificial ultraviolet rays (UVRs) and uncommon
contact with carcinogenic chemicals are few of the predisposing Syphilitic leucoplakia Rare condition,
(tertiary stage) high malignant
factors for development of cutaneous malignancies.
potential
Genetic susceptibility to the development of skin malignancies is Oral hairy leucoplakia Malignancy not
well known. High-frequency, low-penetrant genes are responsible (Epstein Barr virus) recorded
Leucoplakia associated Slow progression to
for sporadic occurrence of skin cancers whereas rare, low-
with chronic renal failure SCC over decades
frequency,high-penetrant genes are associated with familial cancer (Epstein-Barr virus)
predisposition syndromes. Immunosuppressed state [organ- Proliferative verrucous
transplant recipients and human immunodeficiency virus (HIV) leucoplakia
infection] confers a susceptibility to non-melanoma skin cancers. (Human Papilloma virus)
Common premalignant skin lesions are actinic keratosis and Chronic Smoking Higher risk, but rare
irritation Tobacco chewing
leucoplakia. Chewing of Betel leaves
and areca nut
ACTINIC KERATOSIS Snuff-dipping
These are hyperkeratotic lesions with malignant potential Idiopathic — —
occurring on photodamaged skin of elderly individuals. Paraneoplastic May occur in association —
(in association with visceral malignancies,
Fair-skinned outdoor workers are common sufferers and with internal specially those of upper
occurrence is directly related to the degree of UVR exposure. malignancy) aerodigestive tract.
The common sites are scalp, face and dorsa of hands. The In association Dyskeratosis congenita
lesions are multiple, asymptomatic, brownish macules or with genetic Olmsted syndrome
papules (1 mm to >2 cm) with rough, scaly surface. There may disorders
be pain and traumatic bleeding.
Histopathologically there are features of dysplasia. Many lesions MALIGNANT EPIDERMAL TUMOURS
may undergo spontaneous resolution or may progress (< 0.1%) Common malignancies of epidermal origin are SCC, basal cell
to invasive squamous cell carcinoma (SCC). Management carcinoma (BCC) and primary cutaneous melanoma. These
includes restricting outdoor activities, use of sunscreen and skin tumours constitute part of some of the genodermatoses
destruction of existing lesions with 5-fluorouracil (5-FU) cream, like Bloom’s syndrome, xeroderma pigmentosum (XP), Gorlin’s
cryotherapy or photodynamic therapy. syndrome, Muir-Torre syndrome, Bazex’s syndrome, etc.

LEUCOPLAKIA Squamous Cell Carcinoma

Leucoplakia is a white patch or plaque on the mucous Cutaneous SCC is the malignant proliferation of the epidermal
membrane which is not removable by rubbing, cannot be keratinocytes.
attributed to any specific underlying cause by its morphology Aetiopathogenesis
and requires a diagnosis by exclusion (WHO). Some leucoplakias
have premalignant potential and may slowly progress to Exogenous risk factors for SCC include chronic exposure to UVR,
malignancy (2 to 5%) over several years. carcinogenic chemicals like tar, arsenic and physical agents
like ionising and thermal radiation. Latent infection with human
Various causes of leucoplakia have been presented in Table 1.
papilloma virus is a factor precipitating SCC.
It is common in elderly with an incidence rate of about 1%. Oral
mucosa is the most common site, involving palate, tongue or Clinical features
floor of the mouth. Clinically the lesions are asymptomatic The sites of predilection are photodamaged areas of face and
diffuse, speckled or striated, fixed white plaques with or without
neck, burn scar, keloid, non-healing ulcer, existing pre-malignant
reddish reticulation on the surface (erythroplakia).
lesions or any site with long-term infection (lupus vulgaris)
All lesions should be biopsied to rule-out dysplasia. Moderate or inflammation. It starts as indurated areas or irregular,
to severe dysplasia indicate higher risk for malignancy. Such raised, painless nodules on such lesions. It enlarges rapidly with
lesions should be managed by topical bleomycin (0.5%), surgical variegated/ulcerated surface, bleeding easily. In late stage, the
546 excision or laser ablation. Risk factors must be avoided. lesion becomes cauliflower-like (Figure 1) and malodorous.
 Premalignant Conditions and Malignant Tumours of the Skin
raised, translucent, pearly papule with or without pigmentation
and prominent blood vessels. These are slow growing with a
rolled-out border, gradually destroying the underlying tissue
(Figure 2). Neglected, advanced lesions may invade eye,
underlying lacrimal duct and sinuses, facial and skull bones and
even meninges, known as ‘ulcus terebrans’ (penetrating ulcer).

Figure 1: Cauliflower like fungating lesion of squamous cell carcinoma.

There are regional and distant lymphadenopathies. Visceral

metastasis occurs through lymphatics.
Figure 2: Large lesion of basal cell carcinoma with rolled-out border and
Clinical variants distortion of inner canthus of eye.
Intraepidermal, in situ SCC with a small potential for invasiveness
are Bowen’s disease and erythroplasia of Queyrat on genitalia. Clinical variants
In India (Kashmir), prolonged contact with Khangri (pot with
coal fire) in winter season is one of the precipitating factors Various morphological patterns of BCC include:
causing SCC on abdominal wall (Khangri cancer). SCC that arises  Noduloulcerative (most common)
from chronically scarred skin is known as Marjolin ulcer.  Cystic
 Morphoeic (cicatricial)
Key diagnostic points
 Superficial spreading (multicentric)
Histopathologically, the lesions may be well-differentiated
 Pigmented.
(individual cell keratinisation and horny pearls), or poorly
differentiated (anaplastic keratinocytes invading the dermis; Key diagnostic point
“windblown” appearance). Histopathological picture includes islands of dark blue basal
Differential diagnosis cells with peripheral palisading, invading the dermis. Mitotic
Early lesions of SCC may be mistaken with actinic keratosis or BCC. figures and apoptotic bodies are seen in plenty.

Treatment Differential diagnosis

Treatment include topical 5-FU, photodynamic therapy, Mohs The lesions have to be distinguished from keratoacanthoma,
micrographic surgery, surgical excision with wide margin early SCC, seborrhoeic keratosis and melanoma.
(high-risk lesions <1 cm and any lesion >2 cm), radiotherapy, Treatment
chemotherapy or combination of these.
Different treatment modalities for BCC are topical imiquimod
Basal Cell Carcinoma (5%) cream, 5-FU, interferon-α, surgical excision, Mohs micro-
BCC is the most common cutaneous malignancy worldwide, graphic surgery, radiotheraphy, cryotherapy, curettage, cautery
accounting for about 90% of malignant tumours. Commonly and photodynamic therapy. There are chances of recurrence or
known as rodent ulcer, it arises from basal cells of the epidermis. appearance of new lesions.
It is locally invasive and metastasises very rarely. Cutaneous Malignant Melanoma
Aetiopathogenesis This is a malignant tumour of epidermal melanocytes resulting
Predisposing factors include exposure to UVR [mostly from UVR exposure in genetically susceptible individuals. This
ultraviolet B or medium wave (UVB)], occupational contact malignancy occurs exclusively among white races. There is a
with tar, pitch and ingestion of arsenic. UV-induced mutations gradual increase in melanoma in Australia, New Zealand and
in the TP53 tumour-suppressor gene (chromosome 17p), have different parts of United States. Primary cutaneous melanoma
been implicated in some cases of BCC. Multiple, early onset is extremely rare in Indian skin.
BCC may be seen in familial cancer syndromes. Aetiopathogenesis
Clinical features Intermittent, unaccustomed or recreational solar exposures are
It occurs in the elderly, fair-skinned individuals, predominantly the risk factors for cutaneous melanoma rather than chronic
in the periorbital region (lower eyelid 70%, followed by inner exposure. Other risk factors include positive family history (2%),
canthus, upper eyelid and outer canthus).The initial lesion is a small, presence of multiple benign melanocytic naevi and past history 547
 of melanoma. Mutation of the tumour suppressor gene CDKN2A  Clark’s levels (five levels, starting from in situ to invasion
(chromosome 9p21) is found in 10 to 30% patients, particularly into fat, indicating extent of penetration of primary
in familial cases. Mutation of CDK4, melanocortin 1 receptor lesion).
(MC1R) gene (chromosome 17) polymorphism and presence of
Several prognostic factors in cutaneous melanoma have been
oncogene BRAF are other susceptibility factors.
presented in Table 2.
Clinical variants
Table 2: Prognostic Factors in Primary Cutaneous Melanoma
 Superficial spreading melanoma (most common),
 Nodular melanoma (rapid growth, poor prognosis) Factors Prognosis
 Lentigo maligna melanoma (Hutchinson’s lentigo) Clinical
 Acral lentiginous melanoma (Darker races) Age Increasing age, worse prognosis
 Subungual melanoma Gender Female, better prognosis
Location of tumour Proximal extremity lesions have better
 Mucosal melanoma
prognosis than trunk lesions.Those on
 Secondary melanoma without detectable primary site. head, neck and acral location have
Clinical features worst prognosis
Histopathological
Common body sites involved are the trunk in men and lower
Cell type Presence of amelanotic cells, signet
legs in women. This malignancy affects younger people than ring cells, naevoid cells and small cells
other cutaneous carcinomas. Head and neck melanoma may indicate worse prognosis Spindle cells
result from cumulative solar exposure in older people. have better prognosis
Cellular atypia Marked cellular atypia worsens
In nodular melanoma, melanin pigment may be sparse. Lentigo
prognosis
maligna melanoma is very slow-growing, occurring on the
Angiotropism, vascular Presence of any of these factors
face of elderly patients as brownish-black, irregular, flat lesions. invasion and neurotropism worsens prognosis
Acral lentiginous melanoma occurs on palms and soles as a Ulceration Worsens prognosis
central raised area surrounded by a pigmented macule. Mitotic figures Increased mitotic figures, worse
Subungual melanoma is commonly misdiagnosed as other prognosis
benign conditions and definitive diagnosis is usually late. Tumour vascularity Increased vascularity, worsens
Key diagnostic points prognosis
Breslow’s tumour thickness Increasing thickness, worse prognosis
A naevus with erratic behaviour (increased size, change in
Clark’s level Increasing level, worse prognosis
shape/colour) is suspicious.The ‘ugly duckling’ sign, as proposed
Radial and vertical growth Vertical growth is worse than radial
by some French authors is that ‘a naevus different from its phase growth
‘brother’ naevi can be a melanoma’. Suspected lesions should Tumour volume Higher tumour volume, worse prognosis
be biopsied with 1 to 2 mm of surrounding clinically normal
skin. Histopathologically, invasion of the dermis by malignant Differential diagnosis
melanocytes is the diagnostic feature.
Benign melanocytic naevi in young adults and seborrhoeic and
There are systems to aid clinical diagnosis of melanoma; the actinic keratosis in older age group are to be differentiated from
American ABCDE (A = asymmetry, B = irregular border, C = melanoma.
irregular colour, D = diameter >1 cm, E = evolution) and Glasgow
Treatment
seven-point check-list are commonly used. The latter includes
3 major and 4 minor features as follows: Tumour node metastasis (TNM) staging system is followed to
make decisions on treatment.
Major features:
 Change in size Management includes surgical excision, sentinel lymph
node biopsy in case of thicker primary lesion and adjuvant
 Change in shape
chemotherapy/radiotherapy in the advanced stage of disease.
 Change in colour.
Primary preventive measures include awareness campaigns
Minor features: regarding sun protection and identification of early lesions.
 Diameter more than 5 mm
Several vaccines for melanoma are in the process of
 Inflammation development. These are used in affected melanoma patients
 Oozing/bleeding instead of prophylactic use. Interferon α 2b and anti-CTLA-4
 Mild itching/altered sensation. antibody (iplimumab, ticlimumab) are under trial for the
treatment of melanoma.
In adult patients, presence of one major feature is an indication
of removal of the lesion, and additional minor features are RECOMMENDED READINGS
additive to the clinical suspicion.
1. Newton Bishop JA. Lentigos, melanocytic naevi and melanoma. In: Burns
Pathological prognostic guides include depth of invasion of T, Breathnach S, Cox N, Griffiths C, editors. Rook’s Textbook of Dermatology,
Vol-3; 8th Ed. Oxford: Wiley-Blackwell; 2010: p-54.
tumour cells as expressed by the:
2. Quinn AG, Perkins W. Non-melanoma skin cancer and other epidermal skin
 Breslow’s tumour thickness (distance between granular tumours. In: Burns T, Breathnach S, Cox N, Griffiths C, editors; Rook’s Textbook
548 layer and the deepest invasive area of primary lesion in mm). of Dermatology, Vol-3; 8th Ed. Oxford: Wiley-Blackwell; 2010: p-52.
 11.18 Therapy of Dermatological Diseases

MK Singhi

Dermatology, as with all fields of medicine, is continuously purposes, viz. aluminium acetate lotion, Burow’s solution, Eusol,
evolving. Introduction of newer drugs, surgical procedures and and potassium permagnate solution.
lasers have revolutionised the treatment of various skin diseases.
Dermatological therapies can be divided in three parts: TOPICAL STEROIDS
1. Topical therapy Topical steroids are the most widely used therapeutic agents
for the treatment of inflammatory skin disease (Table 2).
2. Systemic therapy
3. Surgery Mechanism of Action
Topical corticosteroids (TCS) are known to act in four ways:
TOPICAL THERAPY
Anti-inflammatory and immunosuppressive effects
Topical therapy remains the mainstay for the treatment of most
of skin diseases. Treatment by topical methods lead to intimate TCS reduce the recruitment of neutrophils and monocytes in the
contact between the drug and skin and the risk of systemic affected area and inhibit phagocytosis. They also inhibit capillary
side-effects is minimised. In topical therapy the drug is first proliferation, fibroblast proliferation, collagen deposition. They
incorporated into a vehicle before application. A clinician must also cause inhibition of phospholipase A2 and thereby decreasing
know the appropriate vehicle that should be used for a particular the formation of prostaglandins and leukotrienes and hence
dermatosis. Table 1 gives the vehicles used in dermatology. decreasing the inflammatory process.
Wet Therapy Antimitotic effects
Wet dressings and baths are used to clean the wounds and for TCS affect cell differentiation and have been found to be
dressing purposes. A wide variety of solutions are used for these antimitotic to several tissues.

Table 1: The Various Vehicles and their Use

Ointments Creams Gels Lotions
Composition Water in oil emulsion Oil in water Semisolid emulsion Powder in water
emulsion in alcohol base (sometimes oil)
Potency Strong Moderate Strong Low
Hydration property Hydrating Some hydration Drying Drying
Sensitisation risk Very low High High High
Irritation risk Low Low High Moderate
Used on body sites Non-intertriginous All sites Hairy areas Intertriginous, scalp
Stage of dermatitis treated Chronic Acute to subacute Acute to subacute Acute

Table 2: Potency of Topical Corticosteroids (TCS) and Considerations for their Use
Potency Type of Amount of TCS and Location of Usage in State of
dermatoses duration of usage dermatoses children epidermis
Superpotent Dermatosis Use TCS for short Do not use on Avoid use Best for thick,
Clobetasol resistant to high duration and avoid atrophogenic area such in children lichenified or
Halobetasol potency TCS extensive application as face, axillae, groins <12 years hypertrophic skin,
( >50 gm/week) and submammary area of age avoid with thin skin
High potency Severe Use TCS for short Do not use on atrophogenic Avoid use Best for thick,
Halcinonide duration and avoid area such as face, axillae, in children lichenified or
Betamethasone extensive application groins and submammary <12 years hypertrophic skin,
Mometasone ( >50 gm/week) area of age avoid with thin skin
Methylprednisolone
Medium potency Moderate Used for extensive Best on trunk and Do not use Use for short duration
Hydrocortisone butyrate use in adults extremities for extended on thin skin, less
Triamcinolone acetonide periods (1 to 2 effective on thick skin
Fluocinolone weeks only)
Low potency Steroid Used for treatment Best choice for Best for Best for thin skin,
Desonide sensitive of large areas and atrophogenic area infants and not effective
Hydrocortisone for long-term use children on thick skin
549
 Vasoconstrictor effect nadifloxacin. They are used for wound care, skin infections such
TCS inhibit histamine, bradykinin and prostaglandins and as impetigo, folliculitis, burns, leg ulcers, bruises and lacerations.
potentiate norepinephrine leading to vasoconstriction. This Topical drugs used for acne and rosacea include benzoyl
vasoconstriction potentiates anti-inflammatory effect. peroxide, clindamycin, erythromycin, clarithromycin,
Effects on mast cells and immediate reactivity metronidazole, azelaic acid. Benzoyl peroxide (BP) is non-specific
oxidising agent, is bactericidal for Propionibacterium acnes and
TCS on prolonged use decrease the histamine content of the
decreases inflammation of acne lesions. Combination therapy
mast cells. Histamine levels did not decline until after 3 weeks
of BP with topical antibiotic is more effective and decreases
of treatment.
antibiotic resistance. BP may cause erythema, burning, peeling
Indications of Topical Corticosteroids and dryness and may cause bleaching of hair and clothes.
 Dermatitis and papulosquamous disorders such as Metronidazole is indicated in the treatment of rosacea.
atopic dermatitis, lichen planus, lichen simplex chronicus,
ANTIFUNGALS
psoriasis.
Various antifungals used in dermatology, their mechanism of
 Bullous dermatoses such as bullous pemphigoid, pemphigus
action and spectrum are listed in Table 3.
foliaceous.
 Behcet’s syndrome, vitiligo, sarcoidosis, alopaecia areata. TOPICAL AND INTRALESIONAL ANTIVIRALS
Adverse Effects of Topical Corticosteroids Antiviral drugs used in dermatology are divided into three main
categories-viricidal drugs, immunoenhancing drugs and
Systemic
cytodestructive drugs. The major drugs in these categories are
 Suppression of hypothalamic-pituitary-adrenal axis listed in Table 4.
 Cushing syndrome
TOPICAL RETINOIDS
 Growth retardation in children
Retinoids are a group of compounds that have biological
Local activity as that of vitamin A. Topical retinoids currently used in
Epidermal atrophy- shiny, wrinkled skin with hypopigmentation, india are tabulated in Table 5.
telangiectasia, striae, purpura.
SYSTEMIC CORTICOSTEROIDS
Hypertrichosis, contact dermatitis, folliculitis, increased
Systemic corticosteroids are synthetic derivatives of the natural
susceptibility to infections, perioral dermatitis, rosacea, acne,
steroid, cortisol, which is produced by the adrenal glands.
delayed wound healing, glaucoma, cataracts.
They are called ‘systemic’ steroids if taken by mouth or given by
TOPICAL ANTIBACTERIALS IN DERMATOLOGY injection as opposed to topical corticosteroids, which are
applied directly to the skin (Table 6).
Topical antibiotics are divided into two categories – drugs used
for wound care and drugs used for acne and rosacea. Topical Mechanism of Action
use helps to achieve high local drug concentration with minimal
Corticosteroids bind to the receptor on the cell membrane,
systemic absorption, thereby reducing adverse effects.
translocate to the nucleus and act as agonist or antagonist to
Drugs used for wound care include bacitracin, neomycin, multiple genes. They inhibit NFKB and AP-1 genes leading to
gentamicin, silver sulphadiazine, mupirocin, fusidic acid and decreased production of multiple cytokines such as IL-1, TNF,

Table 3: Antifungals and their Route of Administration

Drugs Mechanism of action Spectrum
Polyenes Binds to cell membrane sterols and causes Yeasts (Candida)
Nystatin (topical) change in cell permeability and cell leakage
Azoles Inhibits lanosterol demethylase leading to Dermatophytes,
Topical: miconazole, clotrimazole, inhibition of ergosterol synthesis Candida, M. furfur
oxiconazole, sertaconazole
Topical and oral: ketoconazole,
flucanazole, itraconazole
Allylamines Inhibit squalene epoxidase leading to Dermatophytes,
Terbinafine (oral and topical), inhibition of ergosterol synthesis Candida (only Terbinafine)
Naftifine (topical)
Benzylamines Inhibit squalene epoxidase leading to inhibition Dermatophytes,
Butenafine (topical) of sterol synthesis Candida (weak activity)
Griseofulvin (oral) Dermatophytes, mainly
Ciclopirox olamine (topical) Interferes with membrane transport of essential molecular tinea capitis Dermatophytes,
precursors, cell membrane integrity and cell respiratory process Candida, M. furfur
Selenium sulphide (topical) Cytostatic effect on epidermal cells leading to shedding of fungi Used for treatment of tinea versi-
colour and seborrhoeic capitis
550
 Therapy of Dermatological Diseases
Table 4: Antiviral Drugs
Group Drugs Mechanism of action Spectrum Clinical uses Adverse effects
Viricidal Acyclovir Inhibits viral DNA HSV-1, HSV-2, Herpes genitalis and Mild pain, burning,
polymerase VZV Herpes labialis stinging

Cidofovir (under Inhibits viral DNA HSV, MCV, Herpes genitalis and Headache, nausea, rash,
research for synthesis HPV Herpes labialis, pain, ulceration,
topical use) codyloma acuminate, paraesthesia
verruca vulgaris,
Molluscum contagiosum

Immunoenhancing Imiquimod Immunomodulator, HPV, HSV, External genital and Erythema, erosions,
inducer of IL, TNF, IFN MCV perianal warts oedema, burning,
stinging, rash, flu like
symptoms
Cytodestructive Podophyllin Antimitotic, arrests cells Condyloma acuminate Erythema, erosions,
in metaphase burning, contraindicated
in pregnancy
Trichloroacetic Causes hydrolysis of cellular Genital warts, molluscum Local pain, ulceration
acid proteins leading to cell death contagiosum

Salicylic acid Keratolytic Warts located Nausea, vomiting,

on hands and feet tinnitus, delirium

Table 5: Retinoids
Retinoid Mechanism of action Therapeutic effects Clinical uses Adverse effects
Tretinoin Affects cellular differentiation and Comedolysis, epidermal Acne vulgaris, fine Irritation, erythema,
Isotretinoin proliferation, normalises follicular thickening, dermal regeneration, wrinkle, mottled desquamation, pruritis,
epithelial differentiation pigment lightening hyperpigmentation burning, worsening of
Adapelene normalises follicular epithelial Comedolysis Acne vulgaris psoriasis (tazoretene)
differentiation
Tazarotene Modulates the expression of genes Normalises proliferation Psoriasis (< 20% of
that regulate cell differentiation, and differentiation of cells in body surface),
proliferation and inflammation psoriasis, comedolysis Acne vulgaris

Table 6: Classification of Systemic Corticosteroids contact dermatitis, papulosquamous disease such as lichen
planus and neutrophilic dermatoses.
Drug Equivalent Glucocorticoid Minera-
dose (mg) potency locorticoid Contraindications
potency Absolute contraindications are systemic fungal infection, herpes
Short acting simplex keratitis. Relative contraindications are hypertension,
Cortisone 25 0.8 2+ CHF, depression, previous pyschosis, active TB, diabetes,
Hydrocortisone 20 1 2+ osteoporosis, pregnancy, cataract, glaucoma and gastric ulcer
Intermediate acting disease.
Prednisone 5 4 1+
Prednisolone 5 4 1+ Side Effects
Methylprednisolone 4 5 0 Hypothalamic-pituitary adrenal (HPA) axis suppression,
Triamcinolone 4 5 0 addisonian crisis, Cushing’s syndrome, hyperglycaemia,
Long acting increased appetite, hypertension, CHF, hypokalaemia,
Dexamethasone 0.75 20 to 30 0 hypertriglyceridaemia, hypocalcaemia, osteoporosis, avascular
Betamethasone 0.75 20 to 30 0 nacrosis of head of femur, peptic ulcer disease, cataract,
glaucoma, infections, pyschosis, depression, myopathy,
cause lymphocyte and eosinophil apoptosis, alter signal
pseudotumour cerebri and peripheral neuropathy.
transduction by inhibiting phospholipase A 2 leading to
decreased production of various prostaglandins, leucotrienes
ANTIHISTAMINICS IN DERMATOLOGY
and other inflammatory mediators. They also have inhibitory
effect on various white blood cells subsets leading to decreased Antihistaminics represent the standard approach for the
cellular and humoural immunity. Corticosteroids also cause management of various allergic disorders. They block the
vasoconstriction, decreased angiogenesis and decreased effects of the histamine by blocking the H1 receptors. Major
vascular permeability. group of antihistaminics are listed below in Table 7.

Indications Mechanism of Action

Systemic corticosteroids are indicated in various bullous These drugs competitively block the action of histamine at
dermatoses, autoimmune connective tissue disease, vasculitis, the level of H 1 receptors. They block histamine induced
551
 Table 7: Group of Antihistaminics nausea, vomiting, diarrhoea, irritability, mood swing, headache,
vertigo, tinnitus, pyschosis, bleaching of hair, bluish grey
First generation antihistaminics
pigmentation of skin, exacerbation of psoriasis, morbilliform
Highly sedative—Diphenhydramine, Promethazine, Hydroxyzine
rash.
Moderately sedative—Pheniramine, Cyproheptadine, Meclizine,
Buclizine Contraindications
Mild sedative—Chlorpheniramine, Dimethindene, Mebhydrolin, Relative contraindications are pregnancy and lactation, hepatic
Cyclizine, Clematine
dysfunction, neurological defects, psoriasis, visual field defects,
Second generation antihistaminics psychosis, blood disorder, myasthenia gravis, intermittent
Terfenadine, Fexofenadine, Astemizole, Loratidine, Cetirizine, porphyria or variegate porphyria, Glucose-6-phosphate
Mizolastine, Ebastine dehydrogenase deficiency.
Tricyclic antihistaminics
Doxepin SYSTEMIC RETINOIDS
The retinoids are a class of chemical compounds that are related
bronchoconstriction, smooth muscle contraction and triple chemically to vitamin A. Systemic retinoids are divided into
response-wheal, flare and itch. Type I hypersensitivity reactions three groups: First generation (isotretinoin, tretinoin), second
are suppressed. Urticaria, itching and angioedema are controlled. generation (etretinate, acitretin) and third generation
Many H1 blockers antagonise muscarinic effects of acetylcholine. (bexarotene). Isotretinoin and acitretin are available in India.

Side Effects Mechanism of Action

First generation H1 antihistaminics cross the blood-brain barrier Retinoids exert their effect by activating nuclear receptors and
(BBB) and cause sedation, impaired cognitive function, regulating gene transcription. Isotretinoin causes inhibition of
drowsiness. Anticholinergic activity leads to dryness of mouth, sebaceous gland differentiation, proliferation, reduce the size
urinary hesitancy, blurring of vision, constipation. Tachycardias of sebaceous gland and suppression of sebum production. It
and dysrhythmias may occur. Second generation anti- also causes normalisation of follicular epithelial desquamation.
histaminics have significantly less CNS depressant property and Etretinate and acitretin exert antipsoriatic effects by inducing
no cholinergic side effects. cellular differentiation, antiproliferation, antikeratinisation and
anti-inflammation. Bexarotene regulates cellular differentiation
Drug Interaction and proliferation.
Erythromycin, clarithromycin, ketoconazole, itraconazole,
Indications
HIV-1 protease inhibitors, selective serotonin reuptake
inhibitors (SSRI) inhibitors increase the risk of torsades de Psoriasis (acitretin): Erythrodermic psoriasis, pustular psoriasis,
pointes when used along with terfenadine or astemizole. severe plaque psoriasis and recalcitrant psoriasis, acne vulgaris
(isotretinoin), Mycosis fungoides (bexarotene), other indications
Uses are Gram-negative folliculitis, rosacea, hidradenitis suppurativa,
Treatment of allergic disorders such as itching, urticaria, hay Darier’s disease, pityriasis rubra pilaris and lichen planus.
fever, dermographism, pruritides. Dose
ANTI-MALARIALS IN DERMATOLOGY Dose of isotretinoin is 0.5 to 2 mg per kg per day and that of
Hydroxychloroquine and chloroquine are anti-malarial acitretin is 25 to 50 mg per day.
medications used in the treatment of dermatological disorders. Adverse Effects
The exact mechanism by which chloroquine acts is not known Systemic retinoids have potentially serious side-effects. They are
they are believed to act by their effects on light filtration, highly teratogenic and may cause retinoic acid embryopathy and
immunosuppressive actions, anti-inflammatory actions and spontaneous abortions. Women of childbearing age should
DNA binding. practice complete contraception during and one month after
Dose therapy with isotretinoin and acitretin. Systemic retinoids also
Hydroxychloroquine: 200 to 400 mg per day, maximum 6.5 g cause xerosis, palmoplantar desquamation, telogen effluvium,
per day paronychia, dry eyes, cheilitis, epistaxis, headache. They also cause
hypercholesterolaemia, premature epiphyseal closure, myopathy
Chloroquine: 250 to 500 mg per day, maximum 4.0 g per day. and pseudotumour cerebri and depression. Bexarotene may in
Indications addition cause leucopaenia, hypothyroidism and agranulocytosis.
DLE, SLE, photosensitivity disorders pleomorhic light eruptions CYTOTOXIC DRUGS
(PLE) and Porphyria cuternea tarda (PCT), lepra reaction type II.
The common cytotoxic drugs used in dermatology are listed in
Hydroxychloroquine is used much more frequently than
Table 8.
chloroquine, as chloroquine is more likely to cause irreversible
retinal damage. SURGICAL PROCEDURES IN DERMATOLOGY
Adverse Effects Cryotherapy
Visual disturbances include halos, blurred vision, photophobia, Cryotherapy is a commonly used in-office procedure for the
corneal deposits, retinopathy, agranulocytosis, pancytopaenia, treatment of a variety of benign and malignant lesions. The
552
 Therapy of Dermatological Diseases
Table 8: Cytotoxic Drugs
Drug Mechanism of action Indication Side-effects Contraindication Dose Note
Methotrexate Inhibits dihydrofolate Psoriasis (pustular, Hepatotoxicity, Absolute: Pregnancy 0.3 mg/ Folic acid 5 mg
reductase,causes erythrodermic, pancytopaenia, and lactation. kg/week daily reduces
inhibition of extensive plaque malignancy Relative: alcoholism in divided of incidence
cell division in S psoriasis, psoriatic (lymphoma), acute patient, hepatic doses pancytopaenia
phase of cell cycle arthritis), Sezary pneumonitis, disease. and GI side
syndrome nausea, anorexia, effects
alopaecia, fatigue
Azathioprine Active metabolite is Photodermatosis, Malignancy Pregnancy Up to Use cautiously
6-thioguanine which pemphigus and bullous (lymphoma), 2 to 2.5 mg/with
inhibits DNA and pemphigoid, contact pancytopaenia, kg/day concomitant
RNA synthesis leading dermatitis, atopic infections, allopurinol
to decreased T- and dermatitis, SLE, hypersensitivity use
B-cell function connective syndrome, nausea,
tissue disease vomiting
Cyclopho- Active metabolite is Mycosis fungoides, Haemorrhagic cystitis, Absolute: pregnancy 1 to 3 mg/ Take plenty of
sphamide aldophosphamide and pemphigus, dysuria, urgency, and lactation, bone kg/day fluids. Mesna
phosphamide mustard. pemphigoid, pancytopaenia, marrow depression decreases
Cell cycle nonspecific. histiocytosis, increased risk of Relative: impaired the risk of
Inhibits B- and T-cell vasculitis lymphoma and hepatic or renal haemorrhagic
function bladder carcinoma, function cystitis
hair fall, nausea,
hepatotoxicity
Cyclosporine Inhibits calcineurin Psoriasis, lichen Renal dysfunction, Uncontrolled 2.5 to 5 mg/
leading to decreased planus, bullous hypertension, tremors, hypertension, kg/day
production of IL-2 dermatosis, headache, hyper- decreased
which causes decreased trichosis, connective gingivial hyperplasia, renal function
T-cell proliferation. tissue disease, myalgia, hyperkalaemia,
Also causes decreased atopic dermatitis hyperuricaemia,
production of pro- hyperlipidaemia
inflammatory cytokines

mechanism of destruction in cryotherapy is necrosis, which Absolute contraindications include the use of cryotherapy near
results from the freezing and thawing of cells. Treated areas re- the eye margins.
epithelialise. Liquid nitrogen is preferred to other common
refrigerants because of its lower boiling point, ease of use and ELECTROCAUTERY
relative safety. Electrocauterisation is the process of destroying tissue using heat
conduction from a metal probe heated by electric current. Since
Indications the heat does not penetrate deeper then papillary dermis,
Benign lesions such as acne, acne Keloidalis, cherry angiomas, electrocautery is best used for very superficial lesions such as
keloids, lentigenes, molluscum contagiosum, seborrhoeic flat seborrhoeic keratosis or acrochordons.
keratosis, skin tags, warts and xanthomas.
DERMABRASION
Premalignant and malignant lesions such as actinic cheilitis,
Dermabrasion involves resurfacing the skin, from the epidermis,
Bowen’s disease, leucoplakia, basal and squamous cell carcinoma,
through the papillary dermis, maximum up to the junction of
and Kaposi’s sarcoma.
upper and mid reticular dermis either manually, with electrical
Complications abraders or CO2 laser. The wound is allowed to heal by secondary
1. Acute complications include headache, pain, oedema and intention, so as to achieve levelling effect, making the scar less
blister formation. conspicuous. The common indications for dermabrasion are
acne scars and other facial scars, stable vitiligo, hypertrophic
2. Delayed complications include haemorrhage, infection and lichen planus, lichen simplex chronicus hypertropicus, actinic
excessive granulation tissue formation. keratosis, fine wrinkles, tattoo removal and various tumours.
3. Prolonged-temporary complications include milia, Adverse effects
hyperpigmentation and altered sensory nerve function.
Pain, oedema, crusting, hyperpigmentation/hypopigmentation,
4. Permanent complications include alopaecia, atrophy,
keloids, scarring, hypopigmentation and ectropion keloids and hypertrophic scars.
formation. LASERS IN DERMATOLOGY
Relative contraindications to cryotherapy include cold LASER stands for light amplification by the stimulated emission
intolerance, cold urticaria, cryoglobulinaemia, history of radiation. The various types of skin disorders treated by lasers
of pyoderma gangrenosum and Raynaud’s disease. along with type of laser are indicated below:
553
 1. Vascular lesions—vascular malformations, telangiectasias, HAIR TRANSPLANTATION
haemangiomas (Pulsed dye laser). Hair transplantation is a surgical technique that involves moving
2. Pigmented lesions—birth marks, Freckles (PDL, Q switched skin containing hair follicles from one part of the body (the
ND-YAG, Q switched Ruby). donor site) to bald or balding parts (the recipient site). It is
3. Hair removal (800 diode, 1,064 long pulsed ND-YAG, IPL). primarily used to treat male pattern baldness. It is also used to
restore eyelashes, eyebrows, and beard hair, and to fill in scars
4. Keloids, hypertrophic scars, warts, seborrhoeic keratosis
caused by accidents and surgery. The various methods of hair
(CO2 laser).
transplantation consist of punch grafts, mini-and micrografts,
DERMAL FILLERS single hair grafts and follicular unit grafts. Punch grafting causes
fibrosis and paddy field appearance and is generally not preferred
Although soft-tissue augmentation is not a new cosmetic
now a days. Follicular unit grafts give natural and fuller look and
procedure, the discovery of new materials, suitable for injection
is considered to be the best method of hair transplantation.
into subcutaneous tissue and more refined techniques has
enabled many defects to be corrected very well. The materials RECOMMENDED READINGS
commonly used for augmentation are silicone, bovine collagen, 1. Katsambas AD, Lotti TM, eds. European Handbook of Dermatological
autologous fat, hyaluronic acid, fibrel, new fill, etc. Treatment; 2nd Ed. Springer; 2005: pp. 599-802.
2. Savant SS ed. Textbook of Dermatosurgery and Cosmetology; 2nd edition.
Indications
Mumbai: ASCAD; 2008: pp 81-610.
Furrows, wrinkles, depressed scars, lip augmentation and 3. Wolverton SE, Ed. Comprehensive Dermatologic Drug Therapy; 1st edition.
shaping, profile defects of the face. Philadelphia: W.B. Saunders; 2001: pp 12-631.

554
Section 12
Cardiology
Section Editor: Gurpreet Singh Wander
12.1 Basic Considerations in Cardiology 557
Upendra Kaul, Aijaz H. Mansoor
12.2 Cardiovascular Diseases—A Clinical Approach 561
G.S. Sainani
12.3 Electrocardiology 570
M.J. Gandhi
12.4 Exercise Testing 580
Yash Pal Munjal
12.5 Echocardiography 585
Satish Kumar Parashar
12.6 Cardiac Imaging 595
Priya Jagia, Sanjiv Sharma
12.7 Nuclear Cardiology 605
Vikram R. Lele, Parag Aland
12.8 Cardiac Catheterisation and Angiocardiography 610
Lekha Adik Pathak, N.O. Bansal
12.9 Pharmacotherapy of Cardiovascular Disorders 615
J.C. Mohan, Vipul Mohan
12.10 Heart Failure 621
Donald Kikta, Veronica Franco
12.11 Heart Failure Management 624
Veronica Franco, Ragavendra Baliga
12.12 Acute Rheumatic Fever 629
R. Krishna Kumar
12.13 Valvular Heart Disease (I) 637
C.N. Manjunath
12.14 Valvular Heart Disease (II) 643
V.K. Bahl, Ishwar Chandra Malav
12.15 Infective Endocarditis 652
Shyam S. Kothari
12.16 Atherosclerosis 661
K.K. Sethi, S. Lahiri
12.17 Ischaemic Heart Disease 666
Inder S. Anand, Shibba Takkar Chhabra
12.18 Acute Coronary Syndrome 673
Gurpreet Singh Wander, Naveen Kumar Gupta
12.19 Acute Myocardial Infarction 677
Gurpreet Singh Wander, Naved Aslam
12.20 Hypertension 685
M. Paul Anand
 12.21 Management of Hypertension 691
Sandhya Kamath
12.22 Secondary Hypertension 698
B.B. Thakur, Arohi Kumar
12.23 Bradyarrythmias 702
Yash Y. Lokhandwala, Gopi Krishna Panicker
12.24 Tachyarrhythmias 707
Amit Vora
12.25 Sudden Cardiac Death 713
Ashish K. Thakur
12.26 Congenital Heart Disease 716
Sunita Maheshwari
12.27 Heart in Systemic Disease 724
Aspi R. Billimoria
12.28 Disorders of Myocardium 728
K.K. Talwar, Pawan Poddar
12.29 Diseases of the Pericardium 737
Sanjay Tyagi, Amit Mittal
12.30 Surgical Management of Heart Disease 746
Muhammad Abid Geelani, Nikhil Prakash Patil
12.31 Diseases of the Aorta 750
Manotosh Panja
12.32 Vascular Disorders of the Extremities 757
Gurpreet Singh Wander, Bishav Mohan
12.33 Pregnancy and Heart Disease 764
Amal Kumar Banerjee

556
 12.1 Basic Considerations in Cardiology

Upendra Kaul, Aijaz H Mansoor

CARDIAC ANATOMY The RV is the most anterior heart chamber. Its free wall is about
Location one-third the thickness of the LV. The RV consists of an inlet
portion, a trabeculated apical portion and a smooth outflow
Heart is an irregularly conical hollow muscular organ, lying
tract (infundibulum or conus portion). The RV walls show a
obliquely in the middle mediastinum. Right atrium (RA) forms
lattice-work of muscle fibres (trabeculae carneae). The RV
the right heart border, left ventricle (LV) mainly forms the left
contains three papillary muscles, from which extend chordae
border and the inferior border is formed mainly by the right
tendineae, attaching to the leaflet edges. The moderator band
ventricle (RV). Anterior surface is mostly formed by the RV, while
is an intracavitary muscle bridge connecting the RV free wall
the inferior surface consists of the right and left ventricles. The
and the distal interventricular septum. It conveys the right
posterior surface is quadrilateral, formed mainly by the left
bundle branch to the ventricular muscle.
atrium (LA).The base is oriented superiorly while the apex points
leftward, anteriorly, and slightly inferiorly (levocardia). The heart The LA forms the left upper and posterior chamber of the heart.
is retrosternal, two-thirds to the left of the centreline. It is a cuboidal structure and receives four pulmonary veins. It is
The left heart border is formed from above downward by a smaller than RA, has thicker walls (3 mm) and higher pressure.
part of descending thoracic aorta (aortic knuckle on chest Internally it is smooth-walled and does not contain pectinate
radiograph), the pulmonary artery, the left atrial appendage and muscles except in the left atrial appendage. The LA appendage
the LV. The right heart border, mostly retrosternal, is formed overlies the left circumflex artery and is smaller, longer, windsock
by RA with contribution from the venae cavae. The LV apex shaped structure.
generally forms the true apex of the heart. The LV is a high pressure chamber, thicker than the RV (2 to 3
Measurements times). Structurally, it contains the inflow tract, the apical zone
and the left ventricular outflow tract (LVOT).The ventricular heart
The adult heart weighs approximately 325 ± 75 g in men and
muscle is tri-layered (epicardium, myocardium and endocardium).
275 ± 75 g in women. It measures about 5 inches from base to
The outer two-thirds of the myocardium has compact muscle
apex and is 3 inches in width.
layers that twist and spiral from apex to base during contraction.
The Pericardium The LV contains two papillary muscles (anterolateral and
The heart and the origins of the great arteries are enclosed in posteromedial) from which chordae tendineae arise and attach
the conical fibrous pericardium. Within this inelastic fibrous layer to mitral valve leaflet edges. The chordae check leaflet excursion
lies the serous pericardium. The visceral layer closely adheres and prevent valve prolapse. False chordae do not attach to the
to the heart, the parietal layer lines the fibrous pericardium. mitral valve but attach to septum or free wall.
Between the two layers is a potential space (pericardial space) Cardiac Valves
that contains 10 to 25 cc of fluid. The pericardium maintains
Tricuspid valve is the largest, having three leaflets (anterior,
the position of the heart within the mediastinum, lubricates the
posterior and septal). The mitral valve is funnel shaped (Figure 1),
cardiac surfaces and forms a barrier against infection.
The Cardiac Chambers
The RA is a capacitance chamber that receives blood superiorly
from the superior vena cava (SVC) and inferiorly from the inferior
vena cava (IVC), and its Eustachian valve directs blood flow
towards the fossa ovalis. The coronary sinus returns blood from
the heart itself and its orifice is partially guarded by the
Thebesian valve. Chiari net describes large and fenestrated
Thebesian and Eustachian valves. The Thebesian veins directly
drain cardiac blood into the heart via multiple orifices. Running
almost vertically between the venae cavae is a ‘C’-shaped
muscular ridge (Crista terminalis) that separates the smooth-
walled posterior RA (derived from sinus venosus) from the
rough-walled anterior portion, which is prolonged into the
triangular auricular appendage. Tendon of Todaro is a fibrous
band located between the valves of the IVC and coronary sinus.
Between the tendon of Todaro and the tricuspid annulus, is the
triangle of Koch; the apex of this triangle overlies the AV node
Figure 1: Schematic section through the mitral valve.
and bundle of His. 557
 with two leaflets forming the apex and protruding into the LV.
The posterior leaflet is crescent shaped, longer, narrower and
attaches to over two-thirds of the annulus. It has three scallops.
The anterior mitral valve is semicircular or oval shaped. The
mitral chordae do not have insertions into the septum.
The aortic valve, the thicker and stronger of the semilunar valves
(Figures 2A and B), consists of annulus, three cusps and a
commissure. Approximately 2% of aortic valves are bicuspid.The
nodules of Arantius are small fibrous mounds at the centre of
the free edge of each cusp. Aortic valve has no tensor apparatus.
Behind each cusp the wall bulges outward to form sinus of
Valsalva. The aortic cusps are named as right, left and non-
coronary (posterior); the right and left sinuses give rise to the
corresponding right and left coronary arteries. Pulmonary
valve is a mirror image of the aortic valve with similar but thinner
cusps.

Figure 3: Coronary arteries and their branches.

1 = Left coronary artery; 2 = Superior vena cava; 3 = Sino-atrial node; 4 = Right coronary
artery ; 5 = Circumflex artery; 6 = Posterior descending artery; 7 = Inferior vena cava;
8 = Obtuse marginal; 9 = Diagonal branches; 10 = Septal perforator; 11 = Left
anterior descending artery; 12 = Pulmonary artery and valve; 13 = Left main
coronary artery; 14 = Aorta.

circumflex artery supplies the PLBs. A non-dominant RCA is

small and does not reach the crux. The RCA dominates in three
fourths of cases.
The left main trunk is 1 to 4 cm in length and bifurcates into the
left anterior descending artery (LAD) and the left circumflex
artery (LCX). In 30% cases, a third branch arises between the
two (ramus intermedius). The LAD supplies blood to the
Figure 2A: Tensor apparatus of semilunar valve. ventricular septum (through four to seven septal perforators)
and the anterolateral wall (through one to three diagonal
branches). The LCX supplies the lateral wall of LV and LA.
The venous system of the heart consists of coronary sinus,
cardiac veins and the Thebesian veins. The bulk of the venous
drainage of the heart is carried out by veins accompanying
coronary arteries and which drain into the RA via coronary sinus.
The rest of the blood drains via venae cordae minimae directly
into the cardiac cavity.
The electrocardiogram (ECG) can fairly well localise areas of
ischaemia or infarction supplied by individual coronary
arteries. The coronary blood flow is maintained remarkably
constant over a wide range of blood pressures. Any increase in
Figure 2B: Aorta cut open to reveal the aortic valve. myocardial oxygen demand must be met by increased coronary
blood flow.
At the base of the heart, the fibrous cardiac skeleton encircles
the four cardiac valves (annuli, fibrous trigones, intervalvular THE CONDUCTION SYSTEM
fibrosa and conus ligament). The fibrous scaffold is firmly It consists of the sino-atrial node (SA node), the atrio-ventricular
anchored to the ventricle. It electrically insulates atria from the (AV) node, the bundle of His, the right and left bundle branches
ventricles, supports the cardiac valves and provides a firm and the Purkinje fibres (Figure 4). The heart beat is initiated in
foundation against which the ventricles may contract. the SA node (the heart pacemaker), situated in the upper part
of the crista terminalis (just to the right of the SVC-RA junction).
CORONARY CIRCULATION It spreads down via the AV node into the ventricles. The RCA
The coronaries are the first branches arising from the aorta supplies the SA node (65% cases) and the AV node (80% cases).
(Figure 3). The right coronary artery (RCA) is located in the right The nerve supply of the heart is derived from the vagus (cardio-
atrioventricular groove and bifurcates at the crux into the inhibitory) and the cervical and upper thoracic sympathetic
posterior descending artery (PDA) and posterior left ventricle ganglia (cardio-accelerator). The transplanted heart is
branches (PLBs). A dominant RCA provides the PDA and the completely denervated and responds only to circulating
558 PLBs; A co-dominant RCA provides the PDA, but the left substances and not to impulses of the autonomic system.
 Basic Considerations in Cardiology
Figure 4: Conduction system of the heart.

CARDIOVASCULAR PHYSIOLOGY Figure 6: The cardiac cycle.

EP = Ejection period; DFP = Diastolic filling period; IC = Isovolumic contraction;
The Circulation MEP = Maximum ejection phase; mep = Minimum ejection phase; PD = Protodiastole;
The RA receives deoxygenated blood from the SVC and IVC, and IVR = Isovolumic relaxation phase; RF = Rapid filling; SF = Slow filling; AS = Atrial
discharges blood to the RV, which in turn pumps it into the systole.
pulmonary artery. Blood passes through the pulmonary arterial
and alveolar capillary bed where it is oxygenated, then drains The Determinants of Cardiac Output
via four pulmonary veins into the LA.This in turn fills the LV, which
Ejection fraction is the percentage of ventricular volume ejected
delivers blood into the aorta (Figure 5). During ventricular
by the ventricle per beat whereas cardiac output is the volume
contraction (systole), the tricuspid valve in the right heart and
of blood pumped by ventricle per minute. Cardiac output is
the mitral valve in the left heart close and the pulmonary and
a paramount physiological variable that is adjusted as per
aortic valves open. In diastole, the pulmonary and aortic valves
body requirements. It is a product of stroke volume and heart
close and the two AV valves open. Collectively, these atrial and
rate. Influences on stroke volume will impact cardiac output,
ventricular events constitute the cardiac cycle of filling and
and stroke volume can be altered by changes in preload,
ejection of blood from one heart beat to the next (Figure 6).
contractility, and afterload. Preload is the haemodynamic
load (stretch) on the myocardial wall fibres at end-diastole.
Clinically, the end-diastolic volume (EDV) is the best measure
of LV preload. Changes in ventricular preload operate via Frank-
Starling law of the heart. This law states that, ‘with all factors
equal, stroke volume increase as cardiac filling increases’. Several
factors determine preload including intra-thoracic pressure,
venous return, body position, skeletal muscle pump function,
total blood volume, intra-pericardial pressures and atrial
contractility. Contractility is the intrinsic ability and degree of
contraction of the cardiac muscle. Ejection fraction is an
approximate guide to the degree of contractility. Important
factors determining cardiac contractility include sympathetic
activity, circulating/exogenous inotropes, cardio-depressant
drugs, hypoxia, acidosis, and ischaemia. Sympathetic stimulation
Figure 5: Direction of blood flow through the heart. The blue arrows show increases muscle shortening, and therefore, increases stroke
deoxygenated blood moving through the right heart to the lungs. The red volume by decreasing end-systolic volume (ESV). Myocardial
arrows show oxygenated blood moving from the lungs to the systemic contractility is understood well by the LV pressure-volume curve
circulation. The normal pressures are shown for each chamber in mm Hg.
(Figure 7). The curve shifts upwards when cardiac contractility
559
 and thorax affect changes in compliance. Elastance is the linear
relationship between the change in pressure for a given change
in volume at end-systole. Stroke work is represented by the
area of the pressure-volume loop and represents the work of
the heart during each heart beat. Contractility is an intrinsic
attribute independent of loading conditions.
Cardiac Energetics
The myocardial adenosine triphosphate (ATP) pool turns over
every 10 seconds. In adults, 60% to 90% of ATP is derived from
fatty acids, whereas in foetus and neonates, glucose and lactate
are the main ATP sources. In advanced heart failure, the cardiac
energetics shift back to the faetal form. Cardiac energy
requirement is derived primarily from aerobic metabolic
pathways such that cardiac work is tightly related to myocardial
oxygen consumption. A simple index of the energy demands
of the heart is obtained by the product of peak systolic arterial
pressure and heart rate. Determinants of myocardial oxygen
consumption include myocardial muscle mass, wall stress,
Figure 7: Pressure-volume curve of the normal and failing heart. contractility and heart rate.
Normal LV diastolic function implies LV filling to a normal EDV,
is enhanced. In heart failure, the curve is plateau. Afterload is on exercise, as well as rest, without elevating mean LA pressure
the resistance against which the ventricle is contracting. It is above 13 mm Hg. Diastolic dysfunction may be seen in several
also defined as the wall tension generated during cardiac conditions, including systemic hypertension, LV hypertrophy,
contraction. The common measures of afterload are: aortic restrictive cardiomyopathies and pericardial diseases (e.g.
pressure, systemic arterial resistance, arterial impedance, constrictive pericarditis). Diastolic dysfunction eventually leads
myocardial peak wall stress and LV pressure. An abnormally high to heart failure with preserved ejection fraction.
afterload decreases stroke volume by decreasing ESV.
The vascular endothelium has been called the cardiovascular
Pressure-Volume Loops endocrine organ. It produces various compounds (e.g.
These can be constructed in the catheterisation laboratory nitrous oxide, endothelin, prostacyclin, endothelial-derived
using high fidelity catheters. When the ventricular volumes hyperpolarising factor, vascular endothelial growth factor
during one cardiac cycle are plotted against simultaneous and adhesion molecules). A number of enzymes are
pressures within the ventricle, a pressure-volume loop is located on the surface that control the levels of circulating
generated. End-diastolic pressure-volume relationships compounds such as angiotensin, bradykinin and serotonin. It
(EDPVR) and end-systolic pressure-volume relationship also plays regulatory roles (control of vasomotion, thrombotic
(ESPVR) are the key components of a pressure-volume loop. status, immune response modulation and vascular cell
The cardiac muscle length tension behaviour is the underlying growth).
basis for ventricular function. The physiologic measurements
obtainable from pressure-volume loop are: volumes (EDV and RECOMMENDED READINGS
ESV ), pressures (end-systolic and end-diastolic pressures), 1. Agur AMR, Dalley AF. Grant’s Atlas of Anatomy, 12th Ed. Lippincott: Williams
compliance, elastance, stroke work and contractility. and Wilkins; 2009: pp 47-67.
2. Mohrman DE, Heller LJ. Cardiovascular Physiology, 6th Ed. McGraw-Hill
Compliance is the change in volumes for a given change in Medical; 2006.
pressure (Reciprocal of EDPVR). Compliance is greater at lower 3. Nachman RL, Rafii S. Platelets, petechiae, and preservation of the vascular
volumes. Structural and pressure changes in heart, pericardium wall. N Engl J Med 2008; 359: 1261-70.

560
 12.2 Cardiovascular Diseases—
A Clinical Approach
GS Sainani

To evaluate a patient with cardiovascular disorder, one has Table 1: Important Causes of Oedema Feet
to elicit a proper history, carry out clinical examination, and
routine investigations such as roentgenogram of the chest, Congestive cardiac failure
electrocardiogram, pertinent biochemical and haematological Nephrotic syndrome
tests. However, a definitive diagnosis is not made on the basis Liver cirrhosis
of these; further investigations like echocardiography (M-mode, Hypoalbuminaemia (nutritional, protein-losing enteropathy)
2-dimensional, colour Doppler), treadmill exercise test, Holter Venous insufficiency (obesity, old age)
ambulatory ECG monitoring, radionuclide tests (multigated Chronic lymphatic obstruction
blood pool studies, thallium exercise test), digital subtraction Drug induced (steroids, NSAIDs, nifedipine)
angiography, cardiac catheterisation and coronary angiography Idiopathic
may also be needed.
Pain in Right Upper Abdomen
HISTORY This is due to congestive hepatomegaly. Due to systemic venous
A patient may be asymptomatic and unaware of his underlying congestion, the liver becomes enlarged and tender. The patient
cardiac disease. The common symptoms are: may present with pain in the upper abdomen.
Dyspnoea Oliguria and Nocturia
This is a subjective feeling of difficulty in breathing and is due Due to oedema, the patient complains of oliguria particularly
to passive congestion in pulmonary veins and pulmonary during the day. At night, due to redistribution of fluid, the
capillaries secondary to left-sided cardiac failure. patient’s renal perfusion improves and he gets nocturia, with
the result that oedema becomes less in the morning.
Dyspnoea has been graded by the New York Heart Association
(NYHA) into 4 grades in the presence of cardiac disease. Palpitation
Grade I : No dyspnoea on any work Palpitation is consciousness of heart beating. This may be due
to an enlarged, hyperdynamic left ventricle as seen in mitral
Grade II : Dyspnoea on ordinary work
and aortic incompetence, or may occur due to arrhythmias like
Grade III : Dyspnoea while doing less than accustomed work extrasystole, sinus tachycardia and paroxysmal tachycardias.
Grade IV : Dyspnoea at rest
Chest Pain
Dyspnoea may manifest as exertional dyspnoea, paroxysmal
Angina pectoris is chest pain due to impaired coronary flow.
nocturnal dyspnoea, orthopnoea or acute pulmonary oedema.
The classical features are shown in Figure 1.
Orthopnoea is the stage when a patient feels breathless while
he lies flat and is relieved by sitting up. In paroxysmal nocturnal
dyspnoea, the patient gets sudden attacks of dyspnoea
during sleep; these wake him up and force him to sit upright.
The attack may pass off in a few minutes. In acute pulmonary
oedema, which occurs as a result of acute left ventricular
failure, the patient gets a sudden attack of dyspnoea and cough
with white or pink frothy sputum, sweating, tachycardia and
cyanosis.
Cough
Cough of pulmonary venous hypertension is irritating, non-
productive and worse at night. In some cases, such dry cough
occurring during exertion may first raise the suspicion of
underlying cardiac disease.
In severe pulmonary venous hypertension and pulmonary
infarction, blood-tinged sputum is seen while in pulmonary
oedema, the sputum is pink and frothy.
Oedema
Oedema occurs over the dependent parts (feet in an
ambulatory person). In advanced cases, there is generalised
Figure 1: Location of pain in angina pectoris.
oedema with ascites. Table 1 gives other causes of oedema. 561
 1. Site of pain: Retrosternal. Squatting
2. Character: Constricting/crushing. The squatting position is assumed by cyanotic children,
particularly those with tetralogy of Fallot. By squatting, arterial
3. Radiation: Across the chest, both arms and shoulders (more
resistance is increased, thus diverting greater volume of blood
commonly left-sided), interscapular region, neck, jaw,
to the pulmonary circulation for better oxygenation. This
fingers and epigastric region.
relieves the anoxic spells.
4. Duration: Exertional angina lasts 1 to 5 minutes, emotion-
induced angina, 5 to 15 minutes; any pain which lasts for a GENERAL EXAMINATION
few seconds is not ischaemic in origin. The child may be underdeveloped and short statured due
5. Precipitating factors: Exertion, climbing stairs or uphill, anger, to long-standing valvular heart disease or congenital heart
excitement, sudden exposure to cold. (particularly cyanotic) disease. In adults, chronic congestive
heart failure may lead to cachexia. Some congenital heart
6. Relief: Rest, sublingual nitroglycerine or isosorbide dinitrate
diseases are associated with systemic disorders related to the
relieves the pain. This is a stable angina.
musculoskeletal system (Table 2), endocrine system (Table 3),
Unstable angina occurs at any time, even at rest, without obvious metabolic and chromosomal disorders (Table 4), and
precipitating factors. The pain lasts for several minutes. connective tissue disorders (Table 5). One should therefore
look for non-cardiac features.
In acute myocardial infarction, the characteristics of the
pain are the same but it lasts longer, is more severe and is
Table 2: Syndromes Associated with Cardiac and
accompanied by sweating, breathlessness and even circulatory
Musculoskeletal Manifestations
collapse. In pericarditis, pain is constant, not related to exertion,
pricking in character and localised to the mid praecordium. Syndrome Cardiac Abnormality Non-cardiac Findings
Holt-Oram Atrial septal defect Hypoplastic thumb
Syncope
and radius
Syncope is a transient loss of consciousness due to impairment Ellis-van Creveld Atrial septal defect Dwarfism, polydactyly
of cerebral perfusion. In heart disease, due to low output, there Noonan’s Pulmonary valve Webbed neck, pectus
is cerebral underperfusion. dysplasia excavatum
Fatigue Kartagener’s Dextrocardia Sinusitis, bronchiectasis
Laurence-Moon- Variable defects Polydactyly, obesity
This is caused by low cardiac output leading to poor blood
Biedl-Bardet
supply to the muscles. Low cardiac output is due to defective
pumping action of the heart which is secondary to myocardial
muscle disease, valvular heart disease, coronary artery disease Table 3: Endocrine Disorders with Cardiac Manifestations
or even pericardial disease (constrictive pericarditis and Disorder Cardiac Findings Non-cardiac Findings
pericarditis with effusion).
Hypo- Pericardial effusion, Dry thick skin, dry hair,
Cyanosis thyroidism congestive heart loss of lateral eyebrows,
Though patients may complain of cyanosis, usually this is failure slow relaxation phase
of tendon jerk
observed by the physician. Cyanosis may be peripheral or central.
Hyper- Sinus tachycardia, Asthenic build, tremors,
Peripheral cyanosis is restricted to the distal parts of the extremities, thyroidism atrial fibrillation exophthalmos, etc.
i.e. fingers, toes, nails and tip of the nose and ears. It occurs in low Cushing’s Hypertension Moon face, obesity,striae,etc.
cardiac output states with peripheral vasoconstriction. Addison’s Hypotension Pigmentation of skin and oral
Central cyanosis occurs in the mucous membranes (tongue, mucosa, generalised wasting
lips) and nails where it is usually associated with clubbing. The Phaeochromo- Labile hyper- Neurofibromata
cytoma tension
hands are warm in contrast with peripheral cyanosis in which
the hands are cold. Acromegaly Hypertension, Tall stature, prognathism,
cardiomyopathy visceromegaly
It is due to shunting of blood from the venous to the arterial
side at the ventricular, atrial or aortopulmonary level. Another Pulse
cause of central cyanosis is inadequate ventilation and impaired
Brachial arterial pulse is better felt, but conventionally the
oxygenation as seen in interstitial pulmonary fibrosis and gross
radial artery is examined. To assess the volume of the pulse, the
obesity (Pickwickian syndrome). It must be remembered that
palpating finger should compress the artery with pressure just
in patients with severe anaemia, with haemoglobin of 5 g/dL
sufficient to obliterate it during diastole. Thus, the artery can
or less, cyanosis will not be perceptible because for central
re-expand against the palpating finger during systole. Other
cyanosis to appear, capillary content of reduced haemoglobin
arteries, e.g. the opposite radial, femorals, dorsalis pedis,
should be more than 5 g%.
posterior tibials, carotids, subclavians and temporals should be
Differential cyanosis is a rare situation in which cyanosis is palpated and compared for any delay or difference in volume.
restricted to the lower extremities. This is seen in patients with In coarctation of the aorta, the volume of the femoral pulse is
patent ductus arteriosus and pulmonary hypertension with a not only lower than the radial but the femoral pulse is also
right-to-left shunt. delayed.
562
 Cardiovascular Diseases—A Clinical Approach
Table 4: Metabolic and Chromosomal Disorders with Cardiac It is caused by low stroke volume; all stenotic lesions (mitral,
Manifestations aortic, tricuspid, pulmonary), cardiogenic shock,tachycardias,
dilated cardiomyopathy and heart failure have low stroke
Disorder Cardiac Findings Non-Cardiac Findings
volume. The pulse in mitral stenosis is low volume but ill
Mucopolysaccharidosis, Multivalvular Growth and mental sustained (pulsus parvus), whereas in aortic stenosis it is
e.g. Hurler’s and disease retardation, etc. low volume, well sustained and late peaking (pulsus parvus
Hunter’s syndromes
et tardus).
Chromosomal disorders
Down’s syndrome Endocardial Mongoloid facies, C. Varying volume pulse:
cushion defects mental retardation, etc.
(a) Pulsus alternans is regular pulse (sinus rhythm) but
Turner’s syndrome Coarctation Short female, broad
of aorta chest, webbed neck,
alternating beats are strong and weak. It is difficult to
etc. appreciate pulsus alternans by palpating fingers. It is
diagnosed while measuring blood pressure. When the
Table 5: Connective Tissue Disorders with Cardiac Manifestations
mercury is being lowered, the stronger beats are heard
first, and on further lowering, the weaker beats also
Disorder Cardiac Findings Non-Cardiac Findings become audible, thus suddenly doubling the number
Marfan’s Aortic dilatation, Tall thin built, of audible beats. Pulsus alternans is seen in left
aortic and mitral arachnodactyly, etc. ventricular failure.
regurgitation
(b) Pulsus paradoxus is an exaggeration of the normal
Ehlers-Danlos Mitral regurgitation Hyperelastic skin and joints
phenomenon of low-amplitude pulse during inspiration
Pseudoxanthoma Arterial disease Angioid streaks,
and better amplitude during expiration (normal fall by
elasticum and degeneration of skin
elastic fibres <10 mm Hg on inspiration). Thus, the name ‘paradoxus’
Osteogenesis Aortic Fragile bones, is a misnomer.
imperfecta regurgitation blue sclera Pulsus paradoxus is caused by:
(i) Restriction in diastolic filling of ventricles
The pulse is described under the following headings: rate, (constrictive pericarditis, massive pericardial
rhythm, volume, character, condition of arterial wall. effusion). Limitation in the diastolic filling of the
right atrium and right ventricle during inspiration
1. Rate
results in lowering of left ventricular stroke volume.
The normal rate in an adult varies from 60 to 90 per minute.
A rate below 60 per minute is called bradycardia and above (ii) Advanced right ventricular failure. Increase in lung
90 per minute is tachycardia. volume during inspiration accommodates the
reduced right ventricular stroke volume, which in
2. Rhythm turn results in low left ventricular stroke volume.
Normally the pulse is regular except for a slight increase in (iii) Increased respiratory effort (severe asthma). During
rate on inspiration and slowing on expiration (sinus inspiration, owing to enhanced intrathoracic
arrhythmia). An irregular pulse may be regularly irregular negative pressure, there is pooling of blood in
(as in ectopic beats which are unifocal and come at fixed pulmonary veins resulting in lowered left ventricular
intervals) or irregularly irregular (e.g. multiple, multifocal stroke volume. Various types of pulses are shown
ectopics or atrial fibrillation with varying ventricular in Figures 2A to J.
response).
4. Character
3. Volume
Some classical characteristics of pulse can provide clues to
It is the amplitude of pulse wave as judged by the palpating
certain cardiac conditions:
finger. It depends on pulse pressure and is graded as high,
normal, small and poor. A. Water hammer or collapsing pulse: The water-hammer
character is due to a steep rising, forceful, high-amplitude
A. High-volume pulse (water hammer, collapsing or Corrigan’s
percussion wave which gives a sharp tap to the palpating
pulse) is caused by: (a) leakage of blood from the aorta
hand similar to the feeling of a water hammer (a hermetically
(aortic regurgitation, patent ductus arteriosus) or from the
sealed toy glass tube half-filled with water). The collapsing
left ventricle (mitral incompetence, ventricular septal defect);
character is attributed to a sudden disappearance of the
(b) high output states (anaemia, hyperthyroidism, beriberi,
pulse wave from the palpating hand and is due to the
Paget’s disease, arteriovenous fistula); and (c) increased
descending limb of the pulse wave. This is classically seen
stroke volume (complete heart block). Large volume causes
in aortic incompetence.
high systolic pressure and escape of blood during diastole
causes low diastolic pressure, resulting in large pulse B. Anacrotic pulse is a slow rising, small-volume, well sustained
pressure. pulse, seen classically in aortic stenosis. There is a distinct
B. Low-volume pulse: Here the amplitude of pulse wave is anacrotic notch between the slowly rising percussion and
small; this is due to low systolic pressure or raised diastolic tidal waves.
pressure (secondary to peripheral vasoconstriction) or C. Pulsus bisferiens is a double-peak pulse during systole.
both. It is seen in combined aortic stenosis and aortic regurgitation. 563
 The first peak is due to a quick rising percussion wave and
the second peak is due to a delayed tidal wave, with a notch
in between. Thus, it is a double-peak pulse of the same
amplitude during systole.
D. Dicrotic pulse is due to accentuation of the normal dicrotic
wave, giving the feeling of two impulses with each beat.
One impulse comes during systole and is due to the
percussion wave, while a second, lower amplitude impulse
comes during diastole and is due to accentuated dicrotic
wave. It is seen in high-grade fever.
E. Pulsus bigemini or trigemini or quadrigemini: Here the pulse
is regularly irregular and is due to fixed unifocal extrasystoles
coming after every normal beat or after every two or
three normal beats, with the usual pause after the
extrasystole.
5. Condition of arterial wall
This is appreciated by rolling the radial artery with fingers
against the underlying bone. In young persons, it feels soft
and elastic; in the elderly, it may be hard and tortuous.
6. Comparison of other arterial pulses
Delayed and lower amplitude femoral artery pulse
compared to the radials could be due to coarctation of
aorta (post-subclavian), aorto-arteritis, or saddle embolus.
Unequal radial pulses (right having better volume than left)
are due to aortic coarctation (pre-subclavian). Unequal
carotid pulses could be due to atheromatous plaque in one
of the arteries.
Blood Pressure
This is the pressure at which blood is flowing in the arteries. It is
due to pressure exerted by the intravascular blood column
laterally on the vascular wall. Systolic blood pressure depends
mainly on the cardiac output and diastolic blood pressure
depends on peripheral resistance.
Clinically, blood pressure is measured by a mercury
sphygmomanometer. The standard cuff (14 cm width) is for the
average sized upper arm. For children a small sized (10 cm width)
cuff, and for obese persons a large sized (16 cm width) cuff
should be used to avoid wrong readings. In a patient with
hypertension, blood pressure should ideally be taken in the
supine, sitting and standing positions.
Jugular Venous Pressure (JVP)
Examination of jugular veins is of paramount importance to
study right heart events. Since there are no valves between the
right atrium and internal jugular veins, right atrial pressure is
reflected in these veins. Carotid artery pulsations can sometimes
be mistaken for the jugular venous pulsation (Table 6). The
vertical distance from the top of the venous column to the
sternal angle is a measure of the venous pressure. For
measurement, 3 rulers are used; two are held horizontally, one
at the upper level of the blood column in the right internal
jugular vein and the other at the angle of Louis. The third ruler
Figures 2A to J: Type of pulses: (A) normal pulse wave; (B) collapsing (water is used to measure the vertical distance between the first two,
hammer) pulse; (C) pulsus parvus (D) anacrotic pulse; (E) pulsus bisferiens; (F) corresponding to the JVP (Figure 3). The normal mean pressure
dicrotic pulse; (G) pulsus alternans; (H) pulsus bigeminus; (I) pulsus paradoxus; (J) when the patient is supported on a backrest or pillow at 45° to
sinus arrhythmia. the horizontal is 0 to 4 cm. In CCF, JVP is raised with pulsatile
P = Percussion wave;T = Tidal wave; D = Dicrotic wave; N = Dicrotic notch;VS = Ventricular veins, whereas, in superior vena cava obstruction JVP is raised
systole; AN = Anacrotic notch); EB = Extra beat; N = Normal beat.
564 but non-pulsatile.
 Cardiovascular Diseases—A Clinical Approach
Table 6: Differences between Jugular Venous and Carotid systole coincide. The x trough is due to atrial relaxation. The x
Arterial Pulsations descent is absent in atrial fibrillation and tricuspid insufficiency.
Venous Arterial
The v wave that follows the x descent is the wave of venous
filling of the right atrium during ventricular systole. It is
Visible but not palpable Visible and palpable exaggerated in tricuspid incompetence, heart failure and
Obliterated by pressure at root of neck Not obliterated constrictive pericarditis. The trough that follows is the y descent
Two peaks in each cycle Single which is due to emptying of the right atrium. The y descent is
Varies with breathing and position No change accentuated in heart failure, constrictive pericarditis and
of patient tricuspid insufficiency.
Abdominal pressure causes rise in No effect
hepato-jugular reflux Oedema
It may be localised or generalised. Localised oedema is
due to lymphatic or venous obstruction. The causes of
generalised pitting oedema include cardiac, hepatic and renal
disorders, beriberi, and severe anaemia with hypoproteinaemia.
Myxoedema causes generalised non-pitting oedema, while
filariasis causes localised non-pitting oedema.
Cardiac oedema is seen mostly on dependent parts, i.e. over
the legs in ambulatory patients and the sacral area and posterior
aspects of the thighs in recumbent patients; the oedema in
kidney disorders occurs first over the eyelids and is more when
the patient wakes up. In cirrhosis of the liver, ascites is the first
presentation of fluid collection.
Figure 3: Measurement of jugular venous pressure. Patient’s chest, neck and Clubbing
head are at an inclination of 45° to the horizontal.The patient lies with a backrest
so that the neck muscles are relaxed. This is usually classified into 4 grades:
1. Mild (early): Obliteration of the normal angle between the
Jugular veins usually depict 3 positive waves (a, c, v) (Figure 4). nail and the dorsum of the finger.
The a wave is due to atrial systole. The c wave is due to 2. Moderate: In addition to obliteration of the angle, longitudinal
ballooning of the tricuspid valve into the right atrium during curving of the nails.
systole. It is also due to transmitted carotid pulse. At the bedside,
3. Severe: Drumstick appearance of the terminal phalanges
it is very difficult to identify the a and c waves separately.
due to swelling of soft tissues (Figure 5).
The a and c waves are usually fused as an ac complex. The a
wave disappears in atrial fibrillation; it is prominent (giant) in 4. Gross: In addition to severe clubbing of the finger and toe
pulmonary stenosis or hypertension, tricuspid stenosis, tricuspid nails, there is thickening and enlargement around the wrists
atresia, and Ebstein’s anomaly. Cannon waves which are giant and ankles due to thickening of the distal ends of bones.
‘a’ waves occur when atrial contraction occurs against a closed Icterus
tricuspid valve. These are seen intermittently in complete heart
This is seen in patients with chronic hepatic congestion, as in
block and ventricular tachycardia when atrial and ventricular
chronic heart failure and constrictive pericarditis. In pulmonary
infarction, icterus may occur due to lysis of RBCs with release of
bilirubin.
Rheumatic Nodules
A patient with active rheumatic carditis may have subcutaneous,
painless, mobile rheumatic nodules on the dorsal aspect of
fingers, wrists and elbows.
Osler’s Nodes
These are small, red, painful cutaneous nodules usually seen
over the pulp of fingers in cases with infective endocarditis.

EXAMINATION OF PRAECORDIUM
The term praecordium refers to the aspect of the chest which
overlies the heart. The angle of Louis corresponds to the second
costochondral junction. Traditionally, praecordial examination
is carried out under the following heads:
Inspection
1. Look for praecordial bulging which is seen in long-standing
Figure 4: Venous pulse wave.
cases of cardiomegaly or pericardial effusion. 565
 forceful or hyperkinetic apex beat is indicative of a diastolic-
overload type of left ventricular hypertrophy as seen in
aortic incompetence, mitral incompetence, ventricular
septal defect and patent ductus arteriosus. A sustained
heaving apex is suggestive of a systolic-overload type of
left ventricular hypertrophy as seen in aortic stenosis,
hypertension and coarctation of aorta. The apex may not
be palpable if it is lying under a rib and in emphysema or
obese persons.
2. Feel for mid praecordial right ventricular pulsations or heave
in the left 4th space in the parasternal plane. A sustained
powerful heave indicates systolic-overload type of right
ventricular hypertrophy as in pulmonary stenosis and
pulmonary hypertension. An abrupt, forceful and
hyperkinetic pulsation indicates diastolic-overload type of
right ventricular hypertrophy, e.g. tricuspid incompetence.
3. Feel for pulsations in the left second space; these are
indicative of enlarged pulmonary artery. Aortic pulsations
due to aneurysmal dilatation or unfolding of the aorta are
appreciated in the suprasternal notch and right second
space. In pulmonary hypertension, a loud pulmonary
second sound is palpable as a diastolic shock in the
pulmonary area.
Percussion
First percuss the left border of the heart, starting from the left
anterior axillary line and proceeding medially with the
pleximeter finger kept parallel to the left border. Defining the
right border formed by the right atrium is difficult unless there
is gross enlargement of this atrium. One should first find out
the upper border of liver dullness and start percussion one
Figure 5: Various grades of clubbing. space above it from the right mid clavicular plane towards the
right sternal plane. Percuss over the left second space and right
second space parasternally for dull note in case of pulmonary
2. The apex beat is the lowermost and outermost point of artery and aortic dilatation.
cardiac impulse and is formed normally by the left ventricle.
Auscultation
3. Look for right ventricular pulsations in the left 3rd and
4th intercostal spaces in the parasternal area and in the This is done over the mitral, tricuspid, pulmonary and aortic
epigastric region. areas. The mitral area overlies the apex beat; the tricuspid area
is over the 5th intercostal space just left of the sternum. The
4. Pulsations of a prominent pulmonary artery are visible in
pulmonary area is over the left 2nd space along the lateral
the left second space parasternally and those of the aorta
sternal border; the aortic I area is over the right second space
in the suprasternal notch or sometimes in the right second
along the lateral sternal border and the aortic II area (Erb’s area)
space parasternally.
is over the left 3rd space parasternally (Figure 6).
Palpation
Heart Sounds
1. First palpate and define the apex beat. This is best done by
the flat of the palm and accurately localised with the tip of The first and second heart sounds should be identified, and their
the middle finger. This outermost and lowermost point of intensity and splitting determined. The first heart sound is mainly
cardiac impulse gives maximum uplift to a palpating finger due to closure of the mitral and tricuspid valves. This sound
kept perpendicular to the chest wall. The apex beat is coincides with the R wave on the ECG and the beginning of left
normally localised in the left 5th intercostal space 1 cm ventricular pressure rise.
inside the left midclavicular line. Ascertain the character The second heart sound is produced by closure of the aortic and
of the apex beat and feel for a thrill. Thrills are palpable pulmonary valves. The aortic closure sound (A2) corresponds
vibrations (purring sensation) corresponding to loud to the incisura of the aortic pressure pulse, and the pulmonary
murmurs. One may occasionally feel a loud opening snap closure sound (P2) corresponds to the incisura of the pulmonary
or third heart sound. pressure pulse. Both A2 and P2 occur at the end of the T wave
on ECG.
A tapping or slapping apex beat which is characteristic of
mitral stenosis is an ill-sustained, low-amplitude apex beat. The third heart sound is due to stretching of the papillary muscle
566 It represents a palpable loud first heart sound. An abrupt, and chordae tendineae during the maximum filling phase of
 Cardiovascular Diseases—A Clinical Approach
and is classically seen in organic mitral or tricuspid
regurgitation and ventricular septal defect. Long systolic
murmur starts with the first heart sound but falls short of

Figure 6: Position of cardiac valves and chambers.

1 = Superior vena cava; 2 = Aortic valve; 3 = Base of the heart; 4 = Tricuspid valve;
5 = Mitral valve; 6 = Left atrial appendage; 7 = Pulmonary valve; 8 = Pulmonary artery,
Auscultatory areas; M = Mitral area; T = Tricuspid area; A = Aortic area; A2 = Erb’s
area; P = Pulmonary area.

diastole. It may be heard normally as a soft sound in children

0.16 s after the aortic component of the second sound. The
fourth heart sound is produced during atrial systole by tensing
of the mitral or tricuspid cusps; it is not heard normally.
The opening snap of the mitral valve is a sharp snappy sound
due to abrupt opening of this valve under pressure in mitral
stenosis. It occurs 0.06 to 0.12 s after the aortic component of
the second sound. Ejection click is a sharp sound due to a sudden
opening of the semilunar valves under pressure, as in aortic or
pulmonary stenosis. It is heard 0.06 s after the first heart sound.
In mitral valve prolapse, a mid-systolic click is heard; this is due
to tense bulging of floppy mitral cusps into the left atrium.
Murmurs
Murmurs are produced by turbulence of blood flow. It depends
on the anatomical abnormality, the pressure gradient along the
passage, the volume of blood flow and the viscosity of blood.
The anatomical abnormality can be obstruction to forward flow
of blood, as in stenosed valves; regurgitation of blood through
incompetent valves; and abnormal passage of blood, as in
shunts.
The following points should be ascertained about murmurs:
1. Timing in the cardiac cycle
2. Location
3. Conduction
4. Intensity and any special character
5. Influence of posture and breathing
1. Timing
Murmurs may be systolic, diastolic, to-and-fro or continuous
(Figure 7).
A. Systolic murmurs may be pansystolic, long systolic, mid-
systolic or late systolic.
Pansystolic murmur starts with the first sound and merges
Figure 7: Heart sounds and common murmurs.
with the second sound. Usually, it is of uniform intensity 567
 the second sound and is usually heard in functional mild aortic I area, and that of aortic incompetence is best located
mitral or tricuspid regurgitation. Mid-systolic (ejection) at aortic II area.
murmur starts after the ejection click and ends before
3. Conduction
the second heart sound. It is crescendo-decrescendo in
character with maximum intensity during mid-systole. While a murmur of mitral stenosis is localised over the apex,
It is heard in aortic and pulmonary stenosis, systemic the murmur of mitral incompetence is conducted towards
hypertension, atherosclerotic aortic disease and in atrial the posterior axillary or scapular line because the direction
septal defect due to increased flow across the pulmonary of blood flow is from left ventricle to left atrium.The murmur
valve. Late systolic murmur begins in mid-systole, usually of aortic stenosis is conducted to the neck vessels, and the
preceded by a mid-systolic sound. It is usually heard murmur of aortic incompetence is conducted along the left
in floppy mitral valve syndrome and papillary muscle sternal border towards the apex.
dysfunction. 4. Intensity and pitch
B. Diastolic murmurs may be early diastolic, mid diastolic or Levine graded the intensity of murmurs from grades 1-6.
pre-systolic. Early diastolic murmur starts immediately after Grade 1: very faint, just heard in quiet surroundings; 2: easily
the second sound, is decrescendo in character, and is audible; 3: moderately loud but without thrill; 4: loud, with
best heard at the base of the heart. It is classically seen in thrill, audible with full chest piece of the stethoscope; 5: very
aortic and pulmonary regurgitation. In aortic regurgitation, loud, with thrill, heard even with the edge of the chest piece;
it is best heard over aortic II (Erb’s) area with the patient 6: loudest possible, with thrill, audible even with the chest
sitting and leaning forward in expiratory apnoea; it is piece just above the chest wall. This grading is for systolic
associated with peripheral signs of large-volume pulse. In murmurs. Diastolic murmurs are usually classified into 4
pulmonary regurgitation, the murmur is best heard over grades (from 2-5).
the pulmonary area during inspiration and the pulse is of The pitch of a murmur reflects the pressure at which
small volume. turbulence occurs. If turbulence occurs at high pressure the
Mid diastolic murmur, seen typically in mitral and tricuspid murmur is called high pitched, and if turbulence occurs at
stenosis, is a rumbling harsh murmur usually preceded by low pressure it is called low pitched. Small leaks produce
an opening snap. Mitral stenosis murmur is localised over high pitched murmurs and larger leaks produce low
the apex. pitched murmurs.

Carey-Coomb murmur is a short mid diastolic murmur 5. Influence of breathing and posture
heard in acute rheumatic fever, due to acute mitral valvulitis. Mitral murmurs are best heard with the patient in the left
The pre-systolic murmur is a crescendo murmur which ends lateral position, and aortic murmurs, with the patient sitting
in a loud, sharp first sound; it is caused by powerful atrial and leaning forward. Murmurs from the right side of the heart
contraction forcing blood through a stenosed mitral or (pulmonary and tricuspid valve lesions) are accentuated
tricuspid valve. This murmur disappears in atrial fibrillation. during inspiration whereas murmurs from the left-side (aortic
and mitral valve lesions) are better appreciated during
C. To-and-fro (biphasic) murmurs are encountered when there
expiration. With standing, most murmurs diminish except
is a combined stenosis and regurgitation of a valve (e.g.
murmurs of hypertrophic obstructive cardiomyopathy
aortic stenosis with regurgitation). To-and-fro murmurs do
(HOCM) and mitral valve prolapse (MVP) which gets louder.
not cover the second heart sound.
With squatting, most murmurs become louder but those of
D. Continuous murmurs are audible uninterrupted HOCM and MVP usually diminish.
throughout the cardiac cycle. In continuous murmur, the
6. Influence of exercise
blood flow is in the same direction all throughout,
whereas in to-and-fro murmurs the direction reverses in Stenotic murmurs of mitral stenosis (MS), aortic stenosis (AS)
diastole. Continuous murmurs are caused by flow of and pulmonary stenosis (PS) become louder with both isotonic
blood from high to low pressure areas, e.g. in patent and submaximal isometric (handgrip) exercise. Murmurs of
ductus arteriosus, aortopulmonary window, rupture mitral regurgitation (MR), aortic regurgitation (AR) and
of aneurysm of sinus of Valsalva into the right ventricle ventricular septal defect (VSD) also increase with handgrip,
or right atrium, ar teriovenous shunts, and aorto- but murmur of HOCM often decrease with hand grip.
pulmonary collaterals (bronchial collaterals) as seen in 7. Influence of drugs
severe tetralogy of Fallot or pulmonary atresia.
Amyl nitrite inhalation decreases murmurs of MR, AR
Venous hum is a soft, continuous humming sound and VSD and increases murmur of AS. During the later
mimicking a continuous murmur; it is caused by blood tachycardia phase, murmurs of MS and right-sided lesions
flowing through large veins. increase. Vasoconstriction by phenylephrine tends to
produce opposite effects.
2. Location
The location where the murmur is heard with maximum Functional murmurs
intensity is described. For example, murmurs of mitral Organic murmurs are produced due to pathologic changes in
stenosis and mitral incompetence are best heard over the the heart; murmurs which have no underlying anatomical
mitral area, murmur of aortic stenosis is best heard over abnormality are called functional or haemic murmurs.
568
 Cardiovascular Diseases—A Clinical Approach
These are mostly systolic murmurs, invariably without thrill, Veins
mainly audible at the base of the heart and are mostly found in A continuous humming murmur is heard over the jugular
young persons. veins in hyperdynamic circulation, e.g. anaemia, hyper-
Prosthetic Valves Sounds thyroidism. In liver cirrhosis with portal hypertension, a
The sounds produced by prosthetic valves vary. Mechanical venous hum (Cruveilhier-Baumgarten murmur) may be heard
valves produce opening and closing clicks. Absence or over dilated veins connecting the caval and portal venous
diminution of click sounds raises the suspicion of malfunction systems.
of the prosthetic valve. The sounds produced by tissue Friction Sounds
prosthetic valves are more like normal heart sounds and there Friction sounds (rub) synchronous with the heart beat are
are no clicks. diagnostic of fibrinous pericarditis. Pericardial rub is unaffected
Auscultation of Blood Vessels by respiration whereas pleural or pleuro-pericardial friction rubs
A rough continuous murmur with systolic accentuation is heard alter with breathing.
over an arterio-venous fistula. In aortic insufficiency, a loud first
RECOMMENDED READINGS
sound or pistol-shot sound is heard over the femoral arteries.
Duroziez’ murmur is both systolic and diastolic and is brought 1. Barrett MJ, Lacey CS, Sekara AE, et al. Mastering cardiac murmurs: The power
of repetition. Chest 2004;126: 470.
about by appropriate pressure of the chest piece over the
femoral artery. 2. March SK, Bedynek JL, Chizner MA. Teaching cardiac auscultation:
effectiveness of a patient-centered teaching conference on improving
Continuous arterial murmurs can be heard over the skull or cardiac auscultatory skills. Mayo Clin Proc 2005; 80:1443-8.
eyeball in arterio-venous fistula and vascular brain tumours, over 3. Pickering TG, Hall JE, Appel LJ, et al. Recommendations for Blood Pressure
bones in Paget’s disease, over the thyroid in hyperthyroidism, Measurement in Humans and Experimental Animals Part 1: Blood Pressure
and over a pregnant uterus (uterine souffle). Bruits over blood Measurement in Humans: A Statement for Professionals from the Sub-
committee of Professional and Public Education of the American Heart
vessels are due to atheromatous plaques and one should
Association Council on High Blood Pressure Research. Hypertension 2005;
auscultate over the anterior triangle of the neck for the carotid 45:142-61.
artery, posterior triangle for the vertebral artery, infraclavicular 4. The Criteria Committee of the New York Heart Association. Nomenclature
area for the subclavian artery, and flanks or abdomen for renal and Criteria for Diagnosis of Diseases of the Heart and Great Vessels; 9th
artery occlusions. Ed. Boston, Mass: Little, Brown and Co.; 1994: pp. 253-6.

569
 12.3 Electrocardiology

MJ Gandhi

INTRODUCTION Lead Systems

Before the heart contracts, an electric impulse originating in The following leads are taken in a conventional 12-lead ECG-
sinus node activates the heart. Electrocardiogram (ECG) is a (Figure 1, Table 1).
graph obtained when the electrical potentials of an electrical
field originating in the heart are recorded at the body surface.
It has many limitations: it records only projections of voltage
on a particular lead; it is very approximate; lead positions are
not true representations of axis; it has many technical errors.
Despite limitations, it has tremendous clinical utility. ECG
provides information that is essential for diagnosis and therapy
of many cardiac conditions. It reflects anatomic, haemodynamic,
molecular, ionic and drug-induced abnormalities of the heart.
It may serve as an independent marker of myocardial disease.

ACTIVATION OF HEART
The electrical impulse originates in the sinus node and activates
the atria longitudinally and by contiguity. The impulse then
reaches the atrioventricular (AV) node, His bundle, left and
right bundle and activates the ventricles transversely from
endocardial to epicardial surface. Earliest activation is septal
depolarisation from left to right. This gives rise to septal Q in I,
aVL, V5 and V6. This is followed by apical depolarisation of both
RV and LV. This causes R in I, II, III. Then occurs depolarisation of Figure 1: Leads in 12-lead ECG.
entire RV and lateral wall of LV. Finally, the base of LV is activated.
In entire depolarisation of ventricles LV potentials predominate Table 1: ECG Leads
over RV. The activation process will change with bundle branch Lead +ve input –ve input
blocks, and ventricular hypertrophies, presence of accessory
pathway and in ventricular premature beats. Bipolar limb lead
I LA RA
TECHNICAL ASPECTS II LL RA
III LL LA
Electrocardiogram Paper Augmented unipolar limb leads
The ECG paper is a strip of graph paper which has vertical and aVR RA LA + LL
horizontal lines 1 mm apart.The horizontal axis represents time, aVL LA RA + LL
while the vertical axis denotes amplitude. There is a heavy line aVF LL LA + RA
every 5 mm in both the planes. Thus, there are small squares, Praecordial leads
1 mm × 1 mm and big squares, 5 mm × 5 mm. V1 Right sternal margin 4th space Wilson central
terminal
Paper Speed (LA + RA + LL)
Conventional ECG is taken at a paper speed of 25 mm per V2 Left sternal margin 4th space Do
V3 Midway between V2 and V4 Do
second. One small square (1 mm) corresponds to 0.04 s,
V4 Left midclavicular line 4th space Do
while a big square (5 mm) is equivalent to 0.20 s. When the ECG V5 Left ant. axillary line in same plane as V4 Do
paper runs through 5 big squares, 1 sec recording has been V6 Left mid axillary line in same plane as V4 Do
taken. LA = Left arm; RA = Right arm; LL = Left leg.
Sensitivity
Technically Good Electrocardiogram
Voltage is measured along the vertical axis. Usually a 10 mm
deflection is equivalent to 1 millivolt (mV). There is a provision Correct interpretation of ECG requires attention to several
to change the sensitivity in special circumstances, e.g. when ECG technical points:
complexes are too small, the sensitivity can be doubled so that With good standardisation, the corners of the signal form a right
a 1 mV deflection is equivalent to 20 mm. When ECG complexes angle. When the pressure of the stylus over the ECG paper is
are too large, sensitivity may be halved so that 1 mV is equivalent excessive, there is over-damping which results in rounding-off
570 to 5 mm. of these corners. In under-damping, the calibration signal
 Electrocardiology
overshoots the horizontal line. ECG complexes may become measured from the beginning of the P wave to the beginning
spuriously small in an over-damped tracing and small complexes of the QRS complex. It represents the (AV) conduction time. QRS
like q and s waves may disappear altogether and ST depression interval is the total duration of the QRS complex and is measured
may appear. In under-damping the complexes may become from the onset of Q or R wave to the J point of the complex. QT
larger and small complexes like q may look significant because interval is measured from the beginning of the QRS complex
of artefactual increase in amplitude. to the end of the T wave. QT interval corresponds to the duration
ECG should have a stable baseline. It should contain at least 3 of electrical systole. PR segment lies between the end of the P
ECG complexes in each lead. A long strip of II and V1 should be wave and the beginning of the QRS complex. ST segment lies
taken if arrhythmia is suspected or present. There should be between the end of the QRS complex and the beginning of the
absence of alternating current interference and muscle T wave. The point where the QRS complex ends and ST segment
potentials. ECG complexes should be at the centre of the ECG begins is called the J point.
paper, not overshooting the margins.
NORMAL ECG
DEFINITIONS Rhythm
Waves (Figure 2) Normally, heart beats are regular; thus the PP and RR intervals
The P wave is the deflection produced by atrial depolarisation. are constant. There may be a minor variation of these intervals
QRS complex is the deflection produced by ventricular in normal subjects; a variation of up to 10% in adjacent cycle
depolarisation. Q wave is the initial negative deflection in a QRS lengths is considered to be normal.
complex. When small, it is designated ‘q’ but when large or Rate
pathological, it is depicted as ‘Q’. R wave is the first positive
Comment should be made on both the atrial and ventricular
deflection in the QRS complex. It is also depicted as r or R
rates. The atrial rate is derived from the PP interval, while the
depending on its size. It may or may not be preceded by a Q
ventricular rate is derived from the RR interval. At a paper speed
wave. S wave is the first negative deflection after a positive (R)
of 25 mm/sec the formulae are:
deflection. R’ wave is the second positive deflection after an S
wave. S’ wave is the second negative deflection after an R’ wave. 1500
QS complex is the term used when the entire QRS complex is Atrial rate/min =
PP interval in mm
negative, without any positive deflection either preceding or
following it. ST and T waves are produced by ventricular 1500
repolarisation. Atrial repolarisation is represented by a wave Ventricular rate/min =
RR interval in mm
which is not visible in the ECG as it is buried within the QRS
complex. U wave is the deflection between the T wave and the Normal atrial and ventricular rates range from 60 to 100/min.
ensuing P wave. Its origin is uncertain.
For calculation of the ventricular rate when the RR interval is
Intervals and Segments (Figure 2) irregular, as in atrial fibrillation, the number of QRS complexes are
The RR interval is measured between two successive R waves. counted over 5 s in the rhythm strip and this number is multiplied
Either the peak of the R wave or the beginning of the QRS by 12 to provide the number of QRS complexes in 60 s (1 min).This
complex can be taken for the measurement of this interval. method enables measurement of the average ventricular rate.
Ventricular rate can be calculated from the RR interval. The PP Mean QRS Axis in Frontal Plane
interval is the interval measured between either the peak or
the beginning of two successive P waves. The PP interval is The mean QRS vector is the approximation of all main QRS
measured for calculation of the atrial rate. PR interval is vectors due to activation of the heart in the frontal plane. It can
be measured from all frontal plane leads viz. I, II, III, aVR, aVL, aVF.
Attempts are also made to measure the axis in horizontal plane
from praecordial leads. However, as these are unipolar leads they
do not truly represent horizontal plane (HP) and hence axis in
HP, thus measured, is not very reliable.
Methods
Perpendicular method
The mean QRS axis is perpendicular to lead with equiphasic or
small QRS complex. For example, if the QRS is equiphasic in lead
II, the QRS axis must be perpendicular to the axis of lead II.

Leads with Equiphasic QRS QRS Axis in Frontal Plane

I (0°) +90° or –90°
II (+60°) –30° or +150°
III (+120°) +30° or –150°
aVR (–150°) +120°or –60°
aVL (–30°) +60° or –120°
Figure 2: Waves and intervals. aVF (+90°) 0° or +180°
571
 Quadrant method waves may be present in II, III, aVF and V3, V4 also. A QS complex
QRS complexes are viewed in I and aVF. When the QRS is commonly found in aVR. There may be deep Q waves in III
complexes are predominantly upright (i.e. there is a dominant alone in normal individuals; this may become less prominent
R in both leads), the axis is normal. If the QRS complex in I is on deep inspiration. Occasionally, a deep Q or QS complex is
predominantly negative (i.e. dominant S in I) while it is found in V1 and even V2. Barring III, aVR, aVL and V1, V2 the depth
predominantly positive in aVF (i.e. dominant R in aVF), there is of a normal q wave is less than 25% of the height of the ensuing
right axis deviation. If the QRS complex is predominantly R wave. In aVL, the depth of a normal q wave may be up to 50%
positive in I but negative in aVF, left axis deviation is present. of the height of the ensuing R wave. Any Q wave with amplitude
When the QRS complexes in both I and aVF are predominantly more than this is considered to be pathological. Normal q waves
negative, the axis is indeterminate. Normal mean QRS axis in generally do not exceed 0.04 s (i.e. 1 mm) in duration.
the frontal plane varies from –30° to +110°. When the axis is ST Segment
more than +110°, there is right axis deviation, while an axis of The normal ST segment is isoelectric but ST depression < 0.5
less than –30° represents left axis deviation. mm in any lead is not considered to be abnormal. ST segment
Visual method (Table 2) elevation up to 1 mm in limb leads and V5, V6 and 2 mm in V1 to
V4 may be normal. The reference line for ST segment elevation
The same principles can apply to P, T and even ST segment. It
is the TP segment while that for depression is the PR segment.
makes it easy to predict ECG from QRS axis. In fact, Grant
popularised ECG diagnosis by such vectorial analysis. In T Wave
vectorcardiography one can measure each 0.01 s vector as there Normal T waves are upright in I, II, V4 to V6, inverted in aVR and
is lot of information hidden in each such vector. upright, inverted or biphasic in III, aVL, aVF and V1 to V3.
Table 2: QRS in Frontal Plane (Visual Method) Predominant QRS QT Interval
Defection (R or S) The upper limit of normal QT interval is 0.42 s in males and 0.43 s
I II III AXIS aVL aVR aVF AXIS in females. QT interval should be measured in the lead where
the end of the T wave is best discernible. QT interval varies with
R R R + 30° to +90° R +30° to +60°
heart rate and, therefore, a correction for heart rate is done by
S +60° to 90°
Bazett’s formula:
S R R +90° to +150° S +90° to +120°
R +120° to +150° QT (s)
S S R +150° to –150° R +150° to ±180° QTC =
S ±180° to –150° √RR (s)
R R S +30° to –30° R +30° to 0°
ABNORMAL ECG
S 0° to –30°
R S S –30° to –90° R –30° to –60° Abnormal Axis Deviation
S –60° to –90° Right axis deviation may be due to right ventricular hypertrophy,
S S S –90° to –150° S –150° to –120° left posterior hemiblock, Wolff-Parkinson-White (WPW )
R –90° to –120° syndrome, technical dextrocardia and mirror image
dextrocardia. Left axis deviation is commonly due to left anterior
P Wave
hemiblock, WPW syndrome, inferior myocardial infarction,
Normal P wave duration does not exceed 0.10 s. Normal P chronic obstructive airway disease and left ventricular
waves are not more than 2.5 mm tall. P waves are normally hypertrophy.
upright in I, II, aVF and V3 to V6, inverted in aVR and upright,
inverted or biphasic in III, aVL and V1, V2. P wave morphology is P Wave Abnormalities (Table 3, Figure 3)
best studied in II and V1. These may be due to atrial enlargement and intra-atrial
conduction abnormality. Common causes of left atrial
PR Interval
enlargement are mitral and aortic valve disease, coronary artery
Normal PR interval varies from 0.12 s to 0.20 s, i.e. 3 to 5 small disease and cardiomyopathies. Common causes of right atrial
squares. Normally, the PR interval should be constant though enlargement include mitral valve disease with pulmonary
minor variations may be present. hypertension, cor pulmonale and acute pulmonary embolism.
QRS Complex
Table 3: Diagnostic Criteria for LA and RA Abnormalities
Amplitude of QRS in each limb lead (i.e. I, II, III, aVR, aVL and aVF),
should be 5 mm or more. In each praecordial lead (i.e. V1 to V6), LA Abnormalities RA Abnormalities
the QRS amplitude should be 10 mm or more. ECG is termed P mitrale P pulmonale
low voltage below these values. Normal QRS complex duration P Duration >120 ms in II P amplitude >0.25 mV in II
does not exceed 0.11 s (i.e. 2.75 mm) in adults. R wave is P notching in II PR segment P axis >175
dominant in I, II, V4 to V6, S wave is dominant in aVR and V1, V2. >1.6 mm in II
P terminal force in V1 Area in positive part of P in
Either R or S wave may be dominant in III, aVL, aVF and V3
> –0.04 mm-s V1 >0.06 mm-s
depending on QRS axis.
qR in V1 V2 without infarction
Q Wave Low QRS in V1 with three-fold
or more increase in V2
Small q waves are normally present in I, aVL, V5, V6. When the
572 mean QRS axis in the frontal plane approaches +90°, small q Biatrial enlargement is suggested by combined criteria.
 Electrocardiology
Figure 3: P wave in atrial hypertrophy.

Abnormal PR Interval
Short PR interval is found in WPW syndrome, Lown-Ganong-
Levine syndrome, nodal rhythm and atrial premature beats.
Long PR interval (first degree AV block) is commonly observed
in rheumatic carditis, digitalis effect and coronary artery disease. Figure 4: QRS in ventricular hypertrophy.

Abnormalities of QRS Complex

Low voltage ECG, i.e. QRS amplitude of less than 5 mm in all
limb leads and less than 10 mm in all chest leads, may be due to
marked emphysema, myxoedema, pericardial effusion and
cardiomyopathy. High amplitude is most commonly due to
ventricular hypertrophy. Electrocardiographic criteria of RVH are
(Figures 4 and 5) qR or qRS pattern in V1, and tall R wave in V1
R/S ratio >1, (R/S >1 is also found in true posterior myocardial
infarction, WPW syndrome type A and right bundle branch
block), deep S waves in V5, V6, rS pattern in all praecordial leads.
QRS width is within normal limits. ST segment may be depressed
and T wave inverted in V1, V2 (right ventricular strain). Right axis
deviation may be present. P pulmonale is an indirect ECG sign
of RVH. RVH is commonly due to mitral valve disease with
pulmonary hypertension, cor pulmonale, pulmonary stenosis,
tetralogy of Fallot and tricuspid regurgitation.
Left Ventricular Hypertrophy (LVH)
There are several scoring systems which have been suggested
for diagnosing LVH, of which the Romhilt-Estes points scoring
system is most useful (Table 4, Figure 4). ECG criteria for systolic
(pressure) or diastolic (volume) overload are different (Table 5).
Common causes of LVH are mitral regurgitation, aortic valve
disease, systemic hypertension, coarctation of aorta and
Figure 5: Right ventricular hypertrophy.
tricuspid atresia. 573
 Table 4: Criteria for Left Ventricular Hypertrophy
Sokolow-Lyon Index
SV1 + (RV5 or RV6) >35 mm
RaVL >11 mm
Romhilt-Estes point score system (≥ ≥5 points) Points
(i) Any limb lead R or S ≥20 mm 3
SV1 + SV2 ≥30 mm
or RV5 + RV6 ≥30 mm 3
(ii) ST-T changes 3
with digitalis 1
without digitalis 3
(iii) LA + 3
(iv) Left axis (≤30) 2
(v) QRS ≥90 ms 1
(vi) Intrinsicoid deflection in V5/V6 ≥50 ms 1
Cornell voltage criteria
SV3 + SaVL ≥28 mm (men)
≥20 mm (women)

Table 5: ECG Criteria in LVH

Figure 6: Lead V1 and V6 in Bundle Branch Blocks.
Systolic Diastolic
Overload Overload
Examples Aortic stenosis, Aortic incom-
Table 7: Criteria for Left Bundle Branch Block (LBBB)
hypertension petence, VSD, PDA
Septal q in V5 to V6 Attenuated Prominent QRS ≥ 120 ms
Intrinsicoid deflection in V5 to V6 ↑ Normal Broad notched R in V5 V6 and usually in I, aVL
ST changes in V5, V6, I, aVL ↓ Normal or ↑ Small or absent initial r in V1 V2 with deep S
Absent septal q in left-sided leads
T inversion in V5,V6, I, aVL ↓ Upright
Intrinsicoid deflection >60 ms in V5 V6
QRS voltage ↑ ↑

Biventricular Hypertrophy in II, III, and aVF in inferior wall myocardial infarction (Table 8).
ECG criteria of biventricular hypertrophy are definite features Depth more than 25% of the height of the ensuing R wave in
of LVH with right axis deviation or deep S waves in V5, V6 and aVL, Q wave is considered to be abnormal if its amplitude is
definite features of RVH plus tall R waves in V5, V6 or deep Q more than or equal to 50% of the height of the R wave. Deep Q
waves in I, aVL, V5, V6 or large equiphasic QRS complexes in V3, V4 waves in III may be entirely normal. In abnormal Q, the duration
(Katz-Wachtel phenomenon). is more than 0.04 s. Pathological Q waves are mostly due to acute
Abnormal QRS Configuration or old myocardial infarction. Rarely, pathological Q waves may
be due to other causes, they are then known as ‘pseudo-
During sinus rhythm, the causes of abnormal QRS configuration
infarction’ patterns. Deep Q waves may also be found in severe
include bundle branch block, hemiblocks, non-specific
intraventricular conduction defects and pre-excitation. left ventricular hypertrophy but such Q waves are narrow and
are not considered to be abnormal.
Right Bundle Branch Block (Figure 6)
Causes of right bundle branch block (RBBB) include acute Table 8: Q in Myocardial Infarction
myocardial infarction, acute pulmonary embolism, chronic cor Infarction Site Leads Differential Diagnosis
pulmonale and atrial septal defect. RBBB is sometimes found in
Inferior (diaphragmatic) II, III, aVF WPW (PSAP), HCM
healthy persons. The ECG criteria are shown in Table 6.
Inferolateral II, III, aVF, V4 to V6 —
Table 6: Criteria for Right Bundle Branch Block (RBBB) Inferoposterior II, III, aVF, V1 (Tall R) WPW (LT. PSAP), HCM
True posterior V1 (Tall R) RVH, Atypical IRBBB, Left AP
QRS > 120 ms Inferior with RV II, III, aVF + V4R to ASMI
Broad notched R (rsr’, rSR’ or rSR’) in V1, V2 V6R or V1 to V3
Wide, deep S in V5, V6, and I Anteroseptal V1 V2 V3 LVH, COPD, LBBB.
Chest electrode
Left Bundle Branch Block (Table 7, Figure 6) misplacement
The common causes of left bundle branch block (LBBB) are Anterolateral I, II, aVL, V4-6 HCM, VSD
hypertensive heart disease, dilated cardiomyopathy and acute Extensive anterior I, aVL, V1 to V6 —
myocardial infarction. It is most often associated with organic High lateral I, aVL —
Anterior (apical) V3 to V4 —
disease.
Posterolateral V4-6. V1 (Tall R) WPW (left AP)
Pathological Q Waves Right ventricle V4R to V6R or V1 to V3 ASMI
The criteria for pathological Q waves; usually present in a set of PSAP = Posteroseptal accessory pathway; AP = Accessory pathway; HCM = Hypertrophic
574 several leads, e.g. in V1 to V4 in anteroseptal myocardial infarction; cardiomyopathy; VSD = Ventricular septal defect; ASMI = Anteroseptal myocardial infarction.
 Electrocardiology
Abnormalities of ST Segment Table 10: Ischaemic versus Non-Ischaemic T Waves
ST segment elevation
Ischaemic T Waves Non-ischaemic T Waves
It is seen in acute myocardial infarction. ST segment is convex
Deep Shallow
upwards. It is present over the site of infarction. It can also occur
Symmetrical Asymmetrical
when there is transmural ischaemia, e.g. in coronary artery
Relatively sharp and Rounded and vague
spasm (Prinzmetal angina) or occasionally during stress test.
well-defined (arrow head)
Occasionally, it may persist in post-myocardial infarction phase
(ventricular aneurysm pattern). In acute pericarditis ST elevation Myocardial Infarction (Figure 7)
is seen in all leads except aVR. ST segment is concave upwards.
Electrocardiographic hallmarks of acute myocardial infarction
The above two are the commonest. But, there are other causes,
are shown in Figure 7. The electrocardiogram also provides
viz. early repolarisation, in V1-V2 or V3 in LVH/LBBB, or type IC
information about the site of infarction, its extent and stage
anti-arrhythmic drugs, hyperkalaemia, hypercalcaemia, after DC-
and complications like arrhythmias and pericarditis. Depending
cardioversion, intracranial haemorrhage, myocarditis, trauma,
on the location of the infarct, ECG changes of acute myocardial
tumour in LV or Brugada syndrome (RBBB with ST elevation in
infarction occur in different sets of leads (Table 8). Persistent
right praecordial leads).
ST segment depression with T wave inversion signifies
ST segment depression subendocardial or nontransmural infarction while the infarction
is called transmural when new pathological Q waves appear. In
It is an electrocardiographic sign of myocardial ischaemia when
resolving (recent) myocardial infarction the ST segment begins
the entire ST segment is depressed rather than the J point (QRS-
to settle down progressively till it is isoelectric. Persistent raised
ST segment junction) alone. The depression is horizontal or
ST segment after 6 weeks may represent ventricular aneurysm.
down-sloping. The depression exceeds 0.5 mm at a point 80
T wave inversion persists for a longer time but ultimately
ms (2 mm) from the J point. Greater the degree of ST segment
becomes upright except uncommonly when it may persist
depression, more are the chances of this representing
indefinitely. Reciprocal changes disappear concomitantly
myocardial ischaemia. ST depression is however seen in many
with ST-T changes or even earlier. Old myocardial infarction
abnormalities, viz. hypertrophies, bundle branch blocks,
is characterised by persistent Q waves. In most instances
myocarditis, cardiomyopathies, drugs, etc. They are non-specific
pathological Q waves constitute the only electrocardiographic
if such changes can be mimicked by hyperventilation or
evidence of old myocardial infarction. Though pathological Q
standing and are also called labile ST changes.
waves persist indefinitely in most cases, the size may reduce in
Abnormalities of T Wave about 20% of patients. Very rarely, Q waves may disappear
T waves are termed tall when their height exceeds 1 mV (10 altogether, especially following inferior infarction.
mm). Causes of tall T waves include hyperacute myocardial
infarction (tall and wide T) and hyperkalaemia (tall but narrow-
tented T waves).
T wave inversion is most often non-specific and transient.
Causes of T wave inversion are given in Table 9. The most
important issue in the differential diagnosis of inverted T waves
is whether T wave inversion is due to myocardial ischaemia or
not. The differences which may serve to separate ischaemic from
non-ischaemic T waves are given in Table 10.

Table 9: Causes of T Wave Inversion

Physiological Pathological
Young children (V1 to V4) Ventricular hypertrophy (strain)
Young females (V1 to V4) Pre-excitation syndrome
Change of posture Bundle branch block Figure 7: ECG changes in myocardial infarction.
Deep respiration Digitalis effect
Abnormalities of Heart Rate
After heavy meals Myocardial ischaemia
Bradycardia (Figure 8)
Abnormal QT Interval Bradycardia is a heart rate below 60/min. This may be due to
Prolonged QTc may be due to hereditary causes with or sinus bradycardia, junctional rhythm and atrio-ventricular
without deafness as a part of specific syndromes, anti- blocks. Sinus bradycardia is recognised when a P wave precedes
arrhythmic drugs, e.g. quinidine, procainamide, disopyramide each QRS complex with a fixed PR interval. The ventricular rate
and amiodarone, electrolyte disturbances like hypokalaemia, in sinus bradycardia usually does not fall below 45/min. Causes
hypocalcaemia, liquid protein diet; during acute myocardial of sinus bradycardia include athletic training, sick sinus
infarction and idiopathic. QTc prolongation may be associated syndrome, drugs (e.g. beta-blockers), myxoedema, uraemia,
with a form of polymorphous ventricular tachycardia known obstructive jaundice and raised intracranial pressure. In nodal
as ‘torsades de pointes’. QTc shortening may signify hyper- rhythm, no P waves precede the QRS complexes, and the
calcaemia. ventricular rate is generally from 45/min to 60/min (Figure 8). 575
 Figure 9: Ectopic beats.
Figure 8: Abnormalities of heart rate.

Sinus tachycardia complexes. The ventricular rate varies from 170 to 250/min. The
Tachycardia is heart rate above 100/min. It is recognised by a rhythm is absolutely regular, i.e. the RR interval is constant. QRS
normal P wave preceding each QRS complex. Heart rate usually morphology is usually normal. The ST segment may be
does not exceed 150/min, but occasionally may be higher depressed, and T wave may be inverted. PSVT most commonly
especially in children. Causes of sinus tachycardia include occurs in individuals with structurally normal hearts. It is
anxiety, fever, hypoxaemia, drugs, e.g. vasodilators and atropine, precipitated by an atrial premature beat. Occasionally PSVT
thyrotoxicosis, cardiac failure and acute carditis. occurs in association with Wolff-Parkinson-White or Lown-
Ganong-Levine syndrome.
Ectopic beats, ectopic or re-entrant tachycardias
Atrial premature beats (Figure 9) Atrial fibrillation (Figure 10)
Atrial ectopic beats occur due to premature discharge from an In atrial fibrillation, the electrical activation and recovery of the
ectopic atrial focus. The P wave of an atrial ectopic beat occurs atria are chaotic. Waves of depolarisation bombard the AV node
before the next sinus P wave is anticipated. The configuration at frequent (350 to 500/min) and irregular intervals with only
of the ectopic P wave is abnormal because it arises from a focus some of them being able to pass through to the ventricles. The
different from the sinus node. The premature, abnormal P wave baseline is irregular and wavy (fibrillatory waves usually best
of the atrial ectopic is designated P’. The compensatory pause seen in V1). In rheumatic heart disease, the amplitude of the
is incomplete, i.e. the PP interval between the sinus beats which fibrillatory waves exceeds 0.1 mV (coarse fibrillation), while in
precede and follow the atrial ectopic beat is less than twice the coronary artery disease, fibrillatory waves are smaller (fine
PP interval between the two consecutive sinus beats. Atrial fibrillation). Occasionally the deflections are so fine that the
ectopic beats may or may not be associated with heart disease; baseline appears smooth in which case the irregular QRS
more often they are not. Sometimes, these precede development complexes help to diagnose atrial fibrillation. Ventricular rate is
of atrial tachycardia or atrial fibrillation. Causes of atrial ectopics usually 120 to 180/min in atrial fibrillation of recent onset unless
are physiological like anxiety, excess tea, coffee or cola drinks the patient is already digitalised or is receiving beta-blockers
and pathological as in viral infections, rheumatic heart disease, or drugs like verapamil or amiodarone. The RR interval is
coronary artery disease, digitalis toxicity and cardiomyopathies. irregularly irregular. The causes of atrial fibrillation include
rheumatic heart disease, especially mitral stenosis, coronary
Paroxysmal supraventricular tachycardia (Figure 10) artery disease, cardiomyopathies, thyrotoxicosis, and
The most common form of paroxysmal supraventricular rarely constrictive pericarditis. Sometimes atrial fibrillation
tachycardia (PSVT) is due to AV nodal re-entry with dual AV is idiopathic (lone atrial fibrillation) or occurs in chronic
nodal pathways. Identification of P waves is difficult or obstructive airway disease especially during acute respiratory
impossible because atrial and ventricular depolarisations occur infection. Transient or paroxysmal atrial fibrillation may occur
simultaneously. Occasionally, abnormal P waves may follow QRS following any surgery. Other causes of paroxysmal atrial
576
 Electrocardiology
Figure 10: Atrial and ventricular tachyarrhythmias.

fibrillation include WPW syndrome, thyrotoxicosis and elderly between two sinus beats immediately preceding and following
age group. the VPB is twice the RR interval between two consecutive sinus
beats. The coupling interval, i.e. the interval between the VPB
Atrial flutter (Figure 10)
and the preceding sinus beat is constant in unifocal VPBs. The
Atrial flutter (AF) is due to intra-atrial re-entry. Electrocardio- coupling interval remains constant when the VPBs are multiform
graphically, it is characterised by a regular, undulating baseline but is variable when these are multifocal.This is because multiform
(flutter or F waves) resulting in a saw-tooth or corrugated
appearance. There is no isoelectric line in between two P waves
unlike in ectopic atrial tachycardia. Flutter waves are usually best
seen in II, III, aVF and V1. Flutter waves appear at a regular rate of
250 to 350/min. When flutter waves show some irregularity, the
rhythm is designated ‘flutter-fibrillation’. QRS complexes are
normal and the RR interval is regular. Usually two flutter waves
follow one QRS complex (2:1 AV block); however, 1:1 AV
conduction may also occur. Other patterns of AV conduction
like 4:1 may also occur but odd conduction ratios (e.g. 3:1) are
rare. Occasionally, the AV conduction pattern is variable, giving
rise to an irregular RR interval. Causes of atrial flutter are the
same as for atrial fibrillation, i.e. chronic mitral valve disease,
coronary artery disease and thyrotoxicosis.
Ventricular premature beats (VPBs) (Figure 9)
Ventricular premature beats (VPBs) occur due to premature
discharge of a ventricular ectopic focus. There is usually no P
wave preceding the QRS complex, unless the VPB is relatively
late (late diastolic ventricular ectopic).The QRS complex appears
earlier than anticipated, i.e. the RR interval shortens abruptly.
The QRS complex is wide, bizarre and slurred or notched. When
there are frequent VPBs, all may be similar in morphology
(unifocal VPB) or they may show varying morphology
(multifocal or multiform VPB). The ST segment is depressed
and T wave inverted when the R wave is dominant in the QRS
complex of the VPB. A dominant S wave is associated with the
opposite pattern. A retrograde P wave may follow the QRS
complex due to retrograde activation of atria across the AV node.
Figure 11: Atrioventricular block.
The compensatory pause is complete, i.e. the RR interval
577
 VPBs arise from the same focus though their morphology is structural heart disease when it is labelled as idiopathic
variable while multifocal VPBs arise from different foci. The ventricular tachycardia.
term ‘ventricular bigeminy’ is used when every alternate
beat is a ventricular ectopic beat. It often occurs as a part of Ventricular fibrillation
digitalis toxicity and in acute myocardial infarction. Isolated Ventricular fibrillation (VF) is characterised by completely
VPBs may be present in healthy individuals, especially in the chaotic and irregular deflections of various height and
elderly. Other common causes are digitalis toxicity, acute width without any recognisable wave pattern. VF is the most
myocardial infarction, cardiomyopathies and electrolyte common terminal event before death. Other terminal
imbalance. events are complete asystole, agonal rhythm (irregular
ventricular complexes without any meaningful rhythm) and
Ventricular tachycardia (Figure 10) electromechanical dissociation (lack of mechanical contraction
The diagnostic criterion of ventricular tachycardia (VT) is the of myocardium despite organised electrical activity).
occurrence of three or more successive ventricular premature
contractions at a rate exceeding 100/min. Ventricular Atrioventricular block (Figure 11)
tachycardia may be non-sustained or sustained. Non-sustained First degree atrioventricular block (AV block, heart block) when
tachycardia terminates spontaneously within 30 seconds PR interval is >0.2 seconds. Second degree AV block is present
while sustained ventricular tachycardia lasts for >30 seconds. when a QRS complex is missing following a P wave after a fixed
Unless treated, ventricular tachycardia may degenerate into or variable number of cardiac cycles. Second degree AV block
ventricular fibrillation and death. Causes of ventricular is of two types—Mobitz type I block or Wenckebach type is
tachycardia are the same as those of VPBs. Coronary artery characterised by a progressive prolongation of PR interval,
disease, especially acute myocardial infarction and the post- shortening of RR intervals and dropping of a QRS complex
infarction period, account for a large number of cases of following a number of conducted sinus beats. Mobitz type II
ventricular tachycardia. It may also occur in absence of block is characterised by a fixed PR interval without serial

Figure 12: Effects of electrolytes on electrocardiogram.

578
 Electrocardiology
prolongation, and intermittent, abrupt dropping of a QRS escape mechanism may result in death. Common causes of
complex following a number of conducted sinus beats. The QRS complete AV block include acute myocardial infarction (inferior
complex is often wide and may exhibit either RBBB or LBBB and anterior), sclero-degenerative disease of the conduction
pattern. system, and digitalis intoxication. Uncommonly, CHB is congenital
in origin.
Mobitz type I (Wenckebach) block is generally due to failure of
AV conduction at the level of the AV node. Prognostically, it is Electrolyte Disturbances (Figure 12)
not so serious as it is unlikely to be progressive. Complete heart Hypokalaemia is characterised by a prominent U wave which is
block either does not occur or occurs transiently following type generally the earliest change. Other electrocardiographic
I block. Type II block is most often due to failure of conduction features are flattening and inversion of the T wave, ST segment
below the AV nodal level, in the bundle of His or below it. It depression, prolongation of PR interval and predisposition to
is more serious since it may progress on to an irreversible ventricular arrhythmias. In hyperkalaemia the earliest change
complete heart block. Common causes of second degree AV associated is occurrence of tall, peaked and narrow T waves.
block are:- type I-acute inferior myocardial infarction, digitalis Progressive hyperkalaemia leads to a prolonged PR interval,
intoxication and acute carditis; type II-acute anterior myocardial atrial asystole, QRS widening, merging of QRS with T wave
infarction and degenerative disease of the conduction system. leading to sine wave configuration, and ultimately ventricular
Complete heart (atrioventricular) block (CHB) is characterised fibrillation followed by ventricular asystole.
by regular appearance of P waves which do not bear any
relationship to the QRS complexes, i.e. the QRS complexes are Hypocalcaemia causes prolonged QT interval. Hypercalcaemia
dissociated from P waves. The former appear regularly at a rate causes shortening of QT interval, with decreased T wave
of 20 to 40/min and represent discharge from the escape focus. amplitude, sometimes with notching or inversion of the T wave.
The QRS may be normal or wide depending on the site of origin
RECOMMENDED READINGS
of the ventricular impulse. Failure of the escape ventricular focus
to develop immediately or to remain stable after the onset of 1. Castellanos A, Interian A Jr, Myerburg RJ. The resting electrocardiogram.
In: Valentin Fuster, R Wayne Alexander, O’Rourke RA, et al. editors:
CHB, or a very slow rate, results in syncopal (Stokes–Adams) Hurst’s The Heart International Edition. New York: McGraw-Hill; 2001: pp 281-
attacks due to interruption of blood supply to the brain. 314.
Recovery of the escape focus leads to consciousness within a 2. Chug SN. Textbook of Clinical Electrocardiography; 1st Ed. Delhi: Jaypee
few seconds in most cases. However, failure of recovery of the Brothers Medical Publishers (P) Ltd; 2003.

579
 12.4 Exercise Testing

Yash Pal Munjal

INTRODUCTION increase considerably. These two parameters are distinct and

their pathophysiology is at variance with one another.
Exercise testing is a non-invasive test used to evaluate the
cardiovascular system’s response to graded exercise under The Total Body Oxygen Consumption
controlled conditions. Over the past eight decades it has This is the total amount of oxygen extracted from the inspired
provided useful diagnostic and prognostic information in air by the body to perform increased load of work. The CO and
patients of cardiopulmonary disease. With the advent of peripheral arteriovenous oxygen difference are the major
computer technology and digital imaging the various tests to determinants of VO2 Max. Since the body mechanisms restrict
assess the cardiovascular system have shown a remarkable the maximal arteriovenous oxygen (AVO) difference to a
progress and increase in their accuracy. Exercise testing has also maximum of 15 mL/dL to 17 mL/dL. Thus the CO indirectly is a
improved in its technology, interpretation and accuracy of measure of maximal oxygen uptake (MVO2 Max). During
results. This has established ‘the exercise test’ as an important treadmill exercise the VO2 Max may also be presented as the
and useful test. This test in combination with other imaging units of work load achieved. This is expressed as metabolic
modalities like echocardiography or radionucleotide imaging equivalent (MET), and it represents the oxygen consumption
provides much more sensitivity and specificity to this test in litres/min. One MET is equated with the resting metabolic
resulting in better diagnosis, better prognostication, assessment rate (approximately 3.5 mL of O2/kg/min).The MET value achieved
of cardiac perfusion and localisation of lesion. On the flip side during an exercise test is presented as a multiple of the resting
the addition of these modalities significantly adds to the cost. metabolic rate which can be measured directly by the oxygen
This test has also been used to assess the athletic performance uptake or estimated from the maximal workload achieved using
and for cardiovascular research. In association with pulmonary equations. Table 1 shows the level of work load achieved with
gas exchange measurements during exercise it provides unique various levels of exercise and its clinical significance.
and clinically relevant information about the cardiopulmonary
health. Table 1: Clinically Significant Metabolic Equivalents for
Maximum Exercise
EXERCISE PHYSIOLOGY
1 MET Resting
The body adapts itself to the increasing intensity of exercise by 2 METs Level walking at 3.2 kmph
increasing the metabolic rate. The body can increase the 4 METs Level walking at 6.4 kmph
metabolic rate by up to 20 times the basal metabolic rate. During <5 METs Poor prognosis, peak cost of basic activities of daily living
this adaptation the cardiac output (CO) also increases from 5 10 METs Prognosis with medical therapy as good as coronary
litres per minute to 25 litres to 30 litres per minute. The various artery bypass surgery
adaptations mentioned above are achieved by the following 13 METs Excellent prognosis regardless of other exercise
haemodynamic changes: responses
1. Increase in heart rate 18 METs Athletes with high level of endurance
2. Increase in CO (achieved by increase in stroke volume and 20 METs Athletes at world class athletic performance
heart rate) MET = Metabolic equivalent or a unit of sitting, resting oxygen uptake;
3. Increase in systolic blood pressure while the diastolic blood 1 MET = 3.5 mL/kg/min oxygen uptake; kmph = kilometres per hour.
pressure is maintained at basal level or may show a
downward trend
The Myocardial Oxygen Consumption
4. There is a fall in the total peripheral vascular resistance
The myocardial oxygen consumption is the amount of oxygen
To achieve the increase in the metabolic rate there is a utilised by the heart muscle during exercise. This is determined
progressive increase in the consumption of oxygen (mL/min) by various factors like left ventricular pressure and end-diastolic
by various tissues. This is achieved by extracting more oxygen volume, contractile force of the heart and the heart rate.
from the increased volume of circulating blood. Despite exercise Myocardial oxygen uptake is estimated as the product of heart
the arteriovenous oxygen-difference is maintained within the rate and systolic blood pressure (double product). It provides
narrow range of 15 mL/dL to 17 mL/dL. These changes in various clinically useful information as angina on effort often occurs at
parameters are dependent on age, gender, body mass index, the same myocardial oxygen demand (double product). The
type of exercise, body fitness, training and finally presence or greater is the double product the better is the myocardial
absence of cardiovascular disease. It is evident from the above perfusion and prognosis. The double product may be low due
description that to meet the requirement of increased work load to other limiting factors like a heavy meal, abnormal ambient
during exercise the total body oxygen consumption (VO2 Max) temperature, organic coronary occlusion or coronary artery
and the oxygen consumption by the myocardium (MVO2 ) spasm.
580
 Exercise Testing
The clinical and electrocardiographic (ECG) manifestations of Table 2: Indications for Stress Testing
exercise test are due to abnormalities in myocardial perfusion
and function. The ECG response and angina are closely related Evaluation of the status of coronary artery disease in patients of
angina pectoris
to the increasing level of myocardial ischaemia. The other
Diagnosis of coronary artery diseases in patients with atypical chest
manifestations are limitation of the exercise capability, sudden
pain or variant angina
spurt in systolic blood pressure or a fall in the systolic blood
Screening of high risk individuals, patients of diabetes or patients
pressure and aberrant heart rate response to exercise. The with two or more other coronary risk factors
ischaemia can also trigger cardiac rhythm disturbances and Assessment of prognosis, functional capacity and evaluation of
serious forms of cardiac arrhythmias may occur during exercise. therapy
These provide useful parameters to assess the myocardial Assessment of functional capacity in patients of congestive heart
ischaemia and long-term prognosis. failure, congenital or valvular heart disease
To evaluate patients with exercise related arrhythmias
METHODOLOGY OF EXERCISE TESTING
To test the endurance capacity of athletes and those individuals
There are three types of exercise modalities: (i) isotonic exercise who are in high risk vocations like pilots, drivers, etc.
or dynamic exercise, (ii) isometric or static exercise, and (iii)
combination of the two forms of exercise.
Table 3: Contraindications to Exercise Testing
Commonly, it is the isotonic or dynamic exercise which is used
for conducting the exercise test. This can be performed on a Absolute Contraindications
treadmill or a bicycle ergometer. Treadmill test involves greater Unstable angina/acute myocardial infarction
muscle mass and hence achieves a higher level of oxygen Symptomatic cardiac arrhythmias with haemodynamic instability
uptake. Based on this various dynamic protocols for conducting Severe aortic disease like aortic valve stenosis and aortic dissection
stress test have been enunciated. Some of them are Bruce, Severe congestive heart failure
Naughton and Ellstead which are commonly used and, out of Recent pulmonary embolism
these, Bruce protocol is the one which is put to the maximum Test can be done with caution
use. The protocol chosen for a particular patient should be such Use of drugs, e.g. digitalis, β-blockers, etc.
that it lasts for about 8 minutes to 12 minutes for continuous Electrolyte imbalance
progressive exercise so that relevant information can be Arterial hypertension
elucidated. Non-critical cardiac arrhythmias
The test involves testing the heart under the stress of exercise Obstructive hypertrophic cardiomyopathy
and therefore the following prerequisites are essential: Physical disability or unsound mind.

1. The equipment must be properly calibrated and

standardised.
Table 4: Termination of Exercise Testing
2. A detailed history, physical examination and a pretest
electrocardiogram must be done to evaluate the condition Moderate to severe angina
of the cardiovascular system of the patient. Ataxia, dizziness
Fall in systolic blood pressure
3. Emergency resuscitative measures should be available at
Development of cardiac arrhythmias especially ventricular
hand.
tachycardia
4. All due precautions must be taken before the test is Significant ST segment depression (>2 mm of horizontal or down-
performed, during the test (i.e. during the period of exercise) sloping ST segment
and after the termination of exercise. Development of left bundle branch block or high degree of AV block
5. All through the test the following parameters must be Increase in blood pressure more than 200 mm Hg
monitored at all times. These are electrocardiogram, blood Refusal of the patient to continue exercise
pressure and clinical features like chest pain, dizziness,
syncopal feeling or development of a third heart sound
Safety of Exercise Test
gallop or basal crepitations.
Exercise test is relatively a safe procedure with a high yield of
6. After the exercise has been terminated it is important to
diagnosis and prognosis in patients of cardiovascular disease.
put the patient back in supine position and the monitoring
From a large number of series and experience of over 20 years
should continue till all the parameters of electrocardiogram,
it is estimated that there is one event per 10,000 patients.
blood pressure and heart rate have settled. But in normal
Despite the safety record of the test, it is essential to reiterate
individuals it must be done for at least 5 minutes post
that the test must be done in the presence of a trained
exercise.
professional and with all resuscitative measures at hand.
Indications and Contraindications of Exercise Test
INTERPRETATION OF EXERCISE TEST
The indications and contraindications for stress testing are
It is important to interpret the exercise test in a comprehensive
enunciated in Tables 2 and 3 respectively.
manner. This means that non-ECG and ECG parameters have to
In exercise testing, it is important to know when to stop the be taken together for interpretation. Various equations and
exercise so that no harm occurs (Table 4). scores have been devised based on these parameters. It is
581
 estimated that the accuracy of stress test per se can go up to ST segment depression indicates global ischaemia. The ST
80% with the use of these scores. segment depression in inferior leads (II, III, aVF) does not predict
ischaemia correctly. The ST segment depression cannot localise
ELECTROCARDIOGRAPHIC CHANGES the site of ischaemia and the coronary artery involved. The
Normal Electrocardiographic Changes During Exercise horizontal or down-sloping ST segment depression of equal
to or more than 1 mm is definite indicator of ischaemia. ST
The following changes in the electrocardiogram are observed
segment depression in anterior pericardium leads, i.e. V4, V5 and
while exercise in a normal adult:
V6, is quite important. Of all these leads, the changes in lead 5 as
(i) Increase in P wave amplitude a single lead has maximum validity. An upsloping ST segment
(ii) Shortening of PR, QRS and QT intervals with increasing depression has doubtful accuracy in diagnosing ischaemia. ST
heart rate segment depression 0.80 second beyond the J point of more
than 1.5 mm is suggestive of ischaemia. ST segment depression
(iii) PR segment progressively becomes down-sloping in leads
seen in leads with Q wave does not carry the same importance.
II, III, aVF and associated with this is the J point depression
ST segment depression seen during the recovery phase may
Abnormal Response also indicate coronary artery diseases. ST segment elevations
It is predominantly the ST segment changes which are used to seen in leads without Q wave is highly suggestive of coronary
interpret the exercise test. The changes in ST segment can be: artery disease and if it is associated with ST segment depression
in the reciprocal leads, it indicates critical coronary lesion or a
(i) No change in the ST segment severe spasm of the coronary arteries.
(ii) Upsloping depression of ST segment
ST segment depression in patients with left bundle branch
(iii) Horizontal ST segment depression block, Wolff–Parkinson–White syndrome, intraventricular
(iv) Down-sloping ST segment depression with T inversion conduction defects, implanted with pace makers or on drugs
does not have the usual diagnostic power of ST segment
(v) ST segment elevation
depression. Some of the representative exercise tests are shown
These changes are diagrammatically presented in Figure 1. in Figures 2 to 4.

Figure 1: Electrocardiograph nomenclature.

Figure 2: Exercise test showing significant horizontal ST depression. Figure 3: Exercise test showing upsloping ST depression.
582
 Exercise Testing
Figure 4: Exercise test showing ST-T changes and persisting in recovery. Figure 5: Exercise-induced LBBB.

Disturbances in Cardiac Rhythm 200 mm Hg systolic is an indication to stop exercise. There may
Ventricular arrhythmias in patients with known coronary artery be exertional hypotension (i.e. fall in blood pressure of >10 mm
disease or asymptomatic coronary artery disease have an Hg) or the failure of the systolic blood pressure to increase
increased risk of death and disability. In patients with congestive beyond 120 mm Hg indicates triple vessel disease. The
heart failure, presence of murmurs in the heart and existing ECG possibility in such patients of cardiomyopathy, hypovolaemia
abnormalities at baseline, the exercise induced ventricular and left ventricular outflow obstruction has to be kept in mind
arrhythmias carry a grave prognosis. A sustained ventricular and excluded.
tachycardia with a normal baseline electrocardiogram also is Other Parameters
associated with poor outcomes. Supraventricular tachycardias
The myocardial oxygen consumption and the perfusion of the
are an uncommon occurrence and do not seem important
heart are measured by the double product (i.e. heart rate x blood
as ventricular arrhythmias. Similarly, bradyarrhythmias like
pressure). This is also a useful predictor and a double product
development of high degree AV block are suggestive of poor
of more than 25,000 is desirable. It has been seen that the onset
myocardial function and critical coronary artery disease.
of angina most of the time takes place at the same level of
Bundle Branch Block double product and therefore can help in planning of exercise
The development of right or left bundle branch block (LBBB) in for patients of coronary artery disease.
isolation during the exercise does not indicate a bad prognosis The following factors, viz. duration of exercise, maximum heart
(Figure 5). In case there is associated angina pectoris with rate achieved, associated ST segment changes can provide
development of bundle branch block then it is of grave useful information about the diagnosis and prognosis.
importance.
Other Physical Parameters
NON-ECG PARAMETERS The cardiac examination also has to be carried out before and
Heart Rate during the exercise test. The development of cardiac murmurs,
3rd heart sound or evidence of left ventricular failure
The heart rate increases with exercise, and inappropriate
(development of basal crepitations) point strongly to the triple
increase in the heart rate at the beginning of exercise can occur
vessel disease and poor outcomes.
in patients predisposed to atrial fibrillation, poor effort tolerance,
hypovolaemia, anaemia and in patients of left ventricular BENEFITS OF EXERCISE TESTING
systolic dysfunction. The increase in the heart rate in response Diagnostic Utility
to the exercise may be blunted in patients where the
sympathetic tone does not increase with the level of exercise An isolated stress test has a sensitivity and specificity of 68% to
or in sinus node dysfunction, myocardial ischaemia and patients 77%. This is significantly lower in patients of single vessel
on beta-blockers. The delay in heart rate recovery is indicative coronary artery disease but in patients of triple vessel disease
of abnormalities of vagal tone and is associated with high or left main disease, it may reach 80%. Use of various scores,
mortality. especially like Duke Treadmill, increases the sensitivity to over
80%. The test may be false positive in women, patients on
Blood Pressure digitalis therapy, valvular heart disease, hypokalaemia
As described earlier, the increasing work load of treadmill is and anaemia. The diagnostic utility of stress test has been
associated with progressive increase in the systolic blood established in patients with non-specific chest pain or
pressure while no significant change takes place in diastolic screening of high risk cardiovascular patients. It may be used
blood pressure or there may be slight fall. In patients with as a research tool to evaluate the effects of various forms of
increased sympathetic tone, there may a sudden increase in therapy and similarly to test patients in risky vocations like
blood pressure and an increase in blood pressure to more than pilots, drivers, etc. The utility of stress test in assessment of 583
 the functional status in patients of coronary artery disease, to medical history and physical examination. The evidence has
congestive heart failure, valvular heart disease is now well clearly shown that interpretation of stress test using various
established and an objective assessment of improvement can treadmill scores (e.g. Duke Treadmill score) improves the
be done pre- and post-therapy. diagnostic and prognostic capability of the test without
escalating the cost. A well-calibrated instrument and the
Prognosis
performance of the test in an accurate manner is critical for
Stress test has been found to be quite useful to provide obtaining good results.The test should only be done with clearly
information on prognosis in the following clinical situations: defined indications, and it should be avoided strictly in presence
(i) Patients with coronary artery disease who have suffered a of contraindications. In this particular test, it is of vital
cardiac event or have undergone a cardiac intervention importance that the operator should be well versed when to
(ii) Patients with valvular heart disease terminate the exercise test. The knowledge and the limitations
in interpreting the test have to be understood and the result
(iii) Patients with congestive heart failure
should be interpreted in a comprehensive manner using both
The prognosis cannot be given in isolation but is based on the the ECG and non-ECG criteria. The knowledge of the limitations
evaluation of ECG changes, changes in the heart rate, blood in case of abnormal electrocardiogram at the beginning of the
pressure and work load achieved. Patients who achieve a work test has to be properly understood and rightly excluded. The
load of less than 5 MET are associated with poor prognosis. use of diagnostic and prognostic scores, such as Duke Treadmill
Table 1 gives the work load achieved, its clinical implications score, has increased the value of stress test very significantly.
and prognosis. ST segment depression which is either down-
sloping or horizontal and seen in more than 5 leads or ST RECOMMENDED READINGS
segment depression at the beginning of exercise with a heart 1. Fletcher GR, Balady GJ, Amsterdam EA, et al. Exercise standards for testing
rate of less than 100 all carry a sinister prognosis. and training: a statement for healthcare professionals from the American
Heart Association. Circulation 2001;104:1694-740.
CONCLUSION 2. Gibbons RJ, Balady GJ, Bricker JT, et al. ACC/AHA 2002 guideline update for
exercise testing: summary article: a report of the ACC/AHA Task Force on
Exercise stress test is the second most commonly performed Practice Guidelines (Committee to Update the 1997 Exercise Testing
test after electrocardiogram. It is a useful complimentary test Guidelines). Circulation 2002;106:1883-92.

584
 12.5 Echocardiography

Satish Kumar Parashar

INTRODUCTION passage of electrical current and generate ultrasound waves

Echocardiography is the heart of clinical cardiology. In which are transmitted in the body. Part of the ultrasound waves
today’s rapidly evolving fields of interventional cardiology, are reflected back and are electronically processed in the
cardiac surgery, electrophysiology and clinical cardiology, equipment producing characteristic images. Different types of
echocardiography plays a major role like never before. Echo- electronic transducers are available which are used for different
Doppler imaging is a key component in not only establishing imaging A high frequency transducer (4 to 7.5 mHz) is used
diagnosis, but also critical to medical and therapeutic decision- for infants because they have less penetration and better
making and monitoring response to therapy. In a statement resolution, because in infants and small children, the cardiac
by American College of Cardiology ‘Echo has been a fastest structures are closer to the chest wall. In contrast, a low
growing technique, the wealth of information which provides frequency transducer is used in adults, because they need a
is unmatched, and is likely to be the stethoscope of the deeper penetration but with lesser resolution. The current
future’. This is because, not only it provides full anatomical and digital machines have increasingly fast processors allowing the
functional information, but also complete haemodynamic handling of immense quantity of data.
information. Because of its portability and providing immediate M-Mode Echocardiography
diagnosis, its role has extended to critical care areas, cardiac
This was the earliest form of echocardiographic examination. It
catheterisation and electrophysiology laboratories, operating
provides limited information because it is virtually a single point
rooms, etc. The strength of information it provides has mitigated
study and does not provide information in the lateral dimension.
the need of invasive studies in large number of cardiac disorders,
There has been a controversy whether this modality needs to
especially valvular and congenital lesions. One of the many
be abolished. However, it will continue to stay because in a large
dramatic advances in the instrumentation is the miniaturisation
number of centres, it is still being used for various chamber
of the equipment, and now palm-sized equipment is available
dimensions and thickness. As will be discussed later, it still gives
which can be carried in the pocket during clinical rounds
useful information.
(Figure 1). Some of the other technological advancements
have been transoesophageal echocardiography (TEE), 3D 2D Echocardiography
echocardiography, myocardial contrast echocardiography (MCE),
This is the starting point in any echo examination and gives
quantitative tissue Doppler imaging (TDI), etc.
a wider view of the heart. As such multiple structures can be
As echocardiography and Doppler is a very vast subject with seen in one imaging plane. Its main applicability is that it
its application in practically every cardiac disorder, hence due provides complete anatomical and functional information,
to constraint of space, some basic aspects will be discussed. including ejection fraction. However, it does not provide any
haemodynamic information.
Standard Imaging Planes
There are a large number of imaging planes, the description
of which is beyond the scope of this paper. Every plane depicts
different structures and myocardial segments in a different
format. However four scan planes must be used in every
patient. These are: (a) Parasternal long axis view commonly
referred as PLAX view (Figure 2); (b) Short axis view – SAX view,
which is at various levels like aortic valve and great vessels
mitral valve, papillary muscle, apex; (c) Various apical views like
four chamber view (Figure 3), three chamber or long axis view,
two chamber view; and (d) Subcostal view which is the best
Figure 1: A small-sized hand held ultrasonic device weighing only 390 grams view for initiating a paediatric examination. Suprasternal,
(Reproduced with permission from the Editor, Indian Heart Journal).
right parasternal and right supraclavicular views are taken in
special situations. In any particular patient attempt should be
BASIC MODALITIES OF ECHOCARDIOGRAPHY made to obtain all views as twhese are complementary to each
The basic imaging techniques, for the beginners, include other. Every transducer has an index mark which is utilised for
conventional 2D and M-mode imaging, Doppler modalities imaging the structures in a particular format, e.g. in apical four
including colour flow imaging. All these modalities rely on the chamber view, if the index mark is pointing towards the right
presence of a special type of crystals, called piezoelectric shoulder then the LV will be on the left-side of the screen and
elements, located in the transducer which is a very essential if it is at about 3o’ clock position then it will be on right-side of
component of the equipment. These crystals vibrate by the the screen. 585
 is more diagnostic of severity of a lesion rather than peak
gradient which is dependent on the blood flow across a structure.
It is obtained by tracing the Doppler envelope (Figure 4). The
two main Doppler modalities are: (a) pulsed Doppler which
calculates low velocity flow at specific points along the jet of
blood flow; and (b) continuous wave Doppler which records
high velocity flows, hence is used for all diseased states like
valvular lesions, shunt flows, estimation of pulmonary artery
pressure, etc. One of the most important requirements of
Doppler study is that best quantitative results are obtained by
putting Doppler beam as parallel to the flow as possible. All
quantitative parameters are under-evaluated if one is off angle
to the flow. This is unlike 2D examination where best imaging is
obtained if the ultrasound wave is perpendicular to the
structures. This is why PLAX and SAX views are best imaged.
The Doppler velocities are depicted in the vertical axis while
Figure 2: Systolic frame of parasternal long axis view showing opened aortic timing is along the horizontal axis.
valve (AV) within the aortic root, left atrium (LA), right and left ventricles (RV,
LV), closed mitral valve is between LA and LV. Interventricular septum is between
RV and LV.

Figure 4: Doppler spectrum of mitral valve showing a positive shift above the
baseline. By tracing the Doppler envelope (second from right), peak and mean
Figure 3: Apical four chamber view showing both ventricles (LV and RV) and gradients are obtained.
both atria, LA (left atrium), RA (right atrium). The interatrial and interventricular
septum are well seen.The mitral and tricuspid valves are between their respective Colour Flow Mapping (CFM)
atrio-ventricular chambers. The index mark is towards the right shoulder.
CFM is effectively an automated 2D version of Pulsed Doppler
technology, in which one can visualise the actual colour coded
Doppler Echocardiography blood flow. By convention, flow towards transducer is depicted
Currently it is an integral part of any echocardiographic as a red colour and flow away in blue. Normally the flow colours
examination as it provides a comprehensive haemodynamic are smooth while in diseased flow states additional colours are
information. This is the main technique to provide accurate added to the conventional colours known as turbulent ‘mosaic
assessment of severity of any cardiac lesion. In Doppler, the pattern’. In day-to-day practice, the two main advantages of CFM
moving red blood cells are the target from where ultrasound are: (a) by seeing the direction of the Doppler beam can be
waves are reflected. The Doppler principle and computerised placed parallel to the blood flow to get best quantitative results;
analysis of returning Doppler signals allow velocity and and (b) by seeing a turbulent flow, it is immediately evident that
direction of flow to be determined. The blood flowing towards a diseased area is being studied.
the transducer is depicted as a positive wave above the baseline Requisites for a good echocardiographic examination:
and vice versa (Figure 4). Irrespective of any 2D imaging view,
the transducer is always pointing downwards from the top 1. A good clinical evaluation is mandatory to form a clinical
(apex). This helps in determining whether the Doppler spectrum impression.
will be above or below the baseline. Doppler records velocity 2. ECG tracing must be available to know the timing sequence.
of blood flow at a particular area. This allows determination of 3. Patient should be as comfortable as possible.
gradients (difference of pressure between two chambers) by
4. The sequence of study should be 2D, CFM followed by
the well validated modified Bernoulli equation, i.e. 4 × (velocity)2.
Doppler.
If the peak velocity across any valve is 4 m/s, then the peak
gradient is 4 × 42 = 64 mm Hg. The mean gradient, which is an 5. All scan planes should be thoroughly studied.
586 average of multiple instantaneous gradients over a cardiac cycle, 6. All haemodynamic information should be obtained.
 Echocardiography
7. Multiple lesions can be present, so never be satisfied with velocity by not studying all scan planes and Doppler not being
detection of one lesion. parallel to the TR jet.
8. Determine aetiology of a particular abnormal finding, e.g.
COMMON CLINICAL INDICATIONS
if LVH is present, explain whether it is due to aortic valve
disease/cardiomyopathy/hypertension/any other lesion. Though the list is very exhaustive, but few clinical scenarios will
be discussed as seen in day-to-day practice.
HAEMODYNAMIC INFORMATION OBTAINED FROM
Evaluation of Cardiac Functions
ECHOCARDIOGRAPHY
Currently, the cardiac functions are classified into systolic and
One of the major advantages of echocardiography is providing
diastolic.
a haemodynamic information non-invasively. As mentioned
earlier, 2D echocardiography provides a structural and functional Systolic
information while Doppler gives a haemodynamic information, Evaluation of systolic LV function is the most frequently asked
i.e. velocities, gradients, etc. As haemodynamics is an extensive investigation and is a very important component of cardiology
subject hence evaluation of only right atrial (RA), and right practice. It forms the basis of diagnosis, prognosis and treatment
ventricular/pulmonary artery (RV/PA) pressure will be briefly of practically every cardiac disorder.Though there are a number of
discussed. techniques to assess LV function like ventriculography, nuclear
The importance of determining RA pressure (RAP) is mainly two- cardiology, cardiac MRI, cardiac CT, but echocardiography is the
fold: (a) it gives an idea of intravascular volume status and helps most practical in day-to-day practice and has a wonderful track
in management strategy; and (b) RAP is added to various right record in assessment. The most common denominator of LV
heart haemodynamic values to get a correct number. The RA function continues to be the ejection fraction (EF) which is the
pressure is mainly evaluated by inferior vena cava (IVC) diameter stroke volume divided by end diastolic volume.The most common
and its collapsibility during spontaneous respiration. In a normal method for determining EF is Modified Simpsons method. It may
individual the IVC diameter is 1.7 to 2.0 cm and there is a normal be mentioned here that M-mode echocardiography has no role in
inspiratory collapse of >50%. This indicates a mean RA pressure assessing LV volumes and function. Certain factors affect the precise
of about 10 mm Hg. The IVC is scanned from subcostal view validity of EF like preload, afterload, contractility, heart rate,
and measurements are made about 1 to 2 cm from IVC-RA arrhythmias, poor endocardial delineation, grossly distorted left
junction with patient in supine position. The IVC collapsibility ventricle (LV), abnormal septal motion and is very operator-
index is calculated as: IVC maximum diameter –IVC minimum dependent. However, it continues to be the ‘magic word’ for
diameter/IVC max × 100. A greater than 50% collapsibility clinicians. Though the value above 50% is considered normal
indicates RAP of greater than 10 mm Hg (Figure 5). A dilated but according to recommendations of American Society of
IVC with less than 50% collapse indicates an RAP of 15 mm Hg, Echocardiography (ASE), a value above 55% is normal, 45% to 54%
while a dilated IVC and hepatic vein with no significant collapse is mildly abnormal, 30% to 44% moderately abnormal and below
of IVC indicates an RAP of about 20 mmHg necessitating fluid 30% severely abnormal.
restriction and need for diuretics. On the other hand, a small To reduce the intra and inter-observer variability, other
IVC (<1.2 cm) with spontaneous collapse may indicate techniques are available like MCE, live 3D echocardiography,
hypovolaemia requiring fluid replacement. myocardial performance index, strain imaging, etc.
Diastolic dysfunction
Advanced diastolic dysfunction can lead to isolated diastolic
heart failure, now referred to as heart failure with normal
ejection fraction (HFNEF). In Western population it is seen in
about 40% to 50% of cases. Conditions predisposing to HFNEF
are hypertension with or without diabetes mellitus, coronary
artery disease, cardiomyopathy, obesity, sleep apnoea syndrome,
etc. Diagnosis of HFNEF is based on following criteria:
1. Presence of clinical syndrome of heart failure,
2. Presence of normal ejection fraction (>50%),
3. Presence of diastolic dysfunction,
4. E/E’(ratio of mitral Doppler E wave velocity to tissue Doppler
Figure 5: Decreased inspiratory collapse of inferior vena cava (IVC). early diastolic velocity, i.e. E’ greater than 15:1 indicative of
increased LV filling pressure, and
The RV and PA systolic pressures are identical in absence of
any RV outflow obstruction. The quantitation is done by 5. Usually non-dilated heart.
interrogating the jet of tricuspid regurgitation (TR). The TR Echocardiography can confidently assess diastolic functions by
occurs as a result of tricuspid annular dilatation, due to evaluating mitral inflow Doppler, tissue Doppler, pulmonary
persistently increased pressure, and its peak velocity reflects vein, LA volume index, etc.
pressure gradient between RV and RA. So RV/PA pressure is
4 × V2 + RAP. Echocardiography underestimates PA pressure by VALVULAR HEART DISEASE (VHD)
± 10 mm Hg because of two operator related factors: (a) In view of a high incidence of rheumatic heart disease in our
underestimation of RAP; and (b) underestimation of TR jet country, echocardiography has made a tremendous impact 587
 in VHD. This is because of its high diagnostic capability and upon the stage of disease; (b) doming of the cusps, when the
excellent correlation with cardiac catheterisation. As such valve is fully open, is a characteristic sign. Doming is in the
haemodynamic studies are not required unless coronary direction of blood flow, i.e. convexity towards the distal chamber
arteries need to be evaluated. Moreover, echocardiography is (Figures 7 and 8); (c) reduced valve mobility due to thickening
very cost effective. The role of echocardiography in VHD is as or fibrosis of the cusps; (d) decreased valve orifice area; and
follows: (e) increased transvalvular gradients across the stenotic valve,
1. Diagnosis depending on the degree of stenosis, as determined by Doppler.
2. Assessment of severity
3. Presence of other valvular lesions, if any
4. Assessment of left ventricular functions
5. Assessment of indirect haemodynamic effects like PAH
6. Diagnosis of complications like vegetations, LA or
appendage thrombus, etc.
7. Stress echocardiography in subset of patients
8. Guide to timing and type of intervention
9. Serial follow-up
To slightly elaborate few points mentioned above, echocardio-
graphy is ideal for the correct diagnosis of valvular lesions and
the precise severity is assessed by Doppler, though indirect
evidence is obtained by 2D echocardiography. The LV function
(ejection fraction) is one of the important parameter in deciding
intervention in VHD. An EF which could be normal for a normal
person may be considered less for a patient with mitral Figure 7: PLAX view in diastole showing doming of anterior mitral leaflet (arrow)
regurgitation (MR), aortic stenosis (AS) or regurgitation (AR). A with convexity towards left ventricle.
stress echocardiography is performed in a subset of patients,
especially mitral stenosis (MS), when there is discordance
between clinical symptoms and echocardiography findings, i.e.
patient is dyspnoeic on mild exertion but echocardiography
does not show a severe lesion. One is not clear whether
dyspnoea is due to MS or other conditions like COPD, obesity,
poor exercise conditioning, etc. A pre- and post-exercise study
showing effect on gradients and rise of PA pressure gives a clue
to diagnosis. The type of intervention depends upon various
factors like the degree of calcification, status of subvalvular
apparatus, leaflet mobility, thickening, degree of valvular
regurgitation, etc. As such in MS, severe subvalvular thickening,
calcification, large left atrial/appendage clot (Figure 6) or
moderate mitral regurgitation favour surgical intervention.
Stenotic Lesions
All stenotic lesions, irrespective of the valve involved, are
characterised by: (a) thickening/fibrosis/calcification depending
Figure 8: PLAX view in systole showing doming of aortic cusps (arrow) with
convexity towards aorta.

The severity of the stenotic lesion is mainly determined by valve

area and the pressure gradients, especially mean gradient across
it. In MS a valve area of less than 1.0 cm2 is indicative of severe
stenosis, an area between 1.1 cm2 and 1.5 cm2 indicates moderate
stenosis and 1.6 to 2.5 cm2 suggests mild stenosis. The area is
determined from SAX view. In case of aortic stenosis, an orifice
area of less than 1.0 cm2, in presence of normal cardiac functions,
indicates severe stenosis. A mean aortic gradient of greater than
40 mm Hg, as per ASE or greater than 50 mm Hg as per European
Society criteria, indicates severe stenosis.
It is imperative to scan all the valves meticulously.
Concomitant tricuspid stenosis (TS) with MS is being often
missed. The main cause of TS is rheumatic heart disease, but
Figure 6: PLAX view showing a large thrombus (arrow) in left atrium (LA).
588 other aetiologies like tumour, vegetation, valvular damage
 Echocardiography
from catheters or pacemaker leads, etc. should not be Prosthetic Valves
overlooked. The normal TV velocity is 0.5 to 1.0 metres/ Echocardiography with Doppler is currently the modality of
second, and mean gradient is usually less than 2 mm Hg. TS choice for evaluation of prosthetic valve function.The prosthetic
is considered severe if mean gradient is more than 7 mm Hg, valves are basically tissue (biological) or mechanical valves. The
and valve area less than 1.1 cm 2. initial evaluation starts with clinical data followed by 2D echo
Regurgitant Lesions for evaluation of size of cardiac chambers, LV thickness and
systolic and diastolic functions.The opening and closing motion
Echocardiography plays a key role in evaluation of valvular
of moving parts of prostheses are visualised. The presence of
regurgitation.
abnormal echocardiography density attached to various
The diagnosis is mainly aided by CFM which can directly components are seen, if present. It is advisable that magnified
visualise the jet in the receiving chamber. As regurgitant lesions live images are obtained for better visualisation of leaflets and
produce volume overloading of the relevant chamber (LA, LV occluder mechanism. Doppler is vital for assessing valve
in MR and LV in AR), hence a semiquantitative idea of severity is function. It should be kept in mind that all prosthetic valves are
assessed by degree of enlargement and thickening of chambers inherent stenotic and have trivial or mild transprosthetic
which are compensatory mechanisms. A reasonable idea of regurgitation.The gradients and effective orifice area across the
severity is assessed by Doppler and CFM. In MR an idea of valve are obtained. The normal and abnormal gradients depend
severity is based on the traced area of jet, e.g. mild, moderate upon the type and size of the valve.
and severe MR are characterised by jet areas of 4.0 cm2, up to 8
A significantly increased gradients in a symptomatic patient
cm2 and >8.0 cm2 (Figure 9). However, there are various caveats
points to a thrombus or pannus formation. TEE is an ideal
and limitations in assessment. Vena contracta, the narrowest
method to look for certain complications like endocarditis,
portion of the jet just beyond the regurgitant orifice, is a good
thrombosis or pannus formation. Differentiation between
method for assessment of severity of MR. A value more than 7
thrombus and pannus is important as thrombolytic therapy may
mm indicates severe MR. Similarly, in severe AR, the LV diastolic
be life saving in thrombus formation. Compared to pannus
dimension is usually more than 7.5 cm, the area of LVOT
formation, obstruction due to thrombus is associated with a
occupied by AR jet is >60%, there is holodiastolic flow reversal
short duration of symptoms and a history of inadequate
from descending aorta as seen by pulsed Doppler and vena
anticoagulation (INR <2.0). Thrombi are larger and have a soft
contracta diameter is >6.0 mm.
ultrasound density, while pannus is a small dense mass more
common in aortic position.

CONGENITAL HEART DISEASE

Over the past few decades echocardiography has become the
most important technique for the diagnosis of both acyanotic
and cyanotic congenital heart disease (CHD). In most of the cases
a systemic and meticulously performed echocardiography gives
a complete diagnosis to plan the appropriate management.
Some important points in imaging an infant or neonate are as
follows:
Sedation
The child should be quiet during the study. Many a times
neonates and infants can be quietened by giving feed, using
Figure 9: Apical four chamber view showing severe MR with an area of 20.9 cm2. pacifier or keeping warm. If various methods fail, it is
imperative to sedate the child as an echocardiography cannot
LV = Left ventricle; LA = Left atrium.
be done in a struggling child. Sedation can be performed by
oral chloral hydrate in dose of 50 to 100 mg/kg body weight
Key Practical Points in Evaluation of VHD with a maximum dose not exceeding 1.5 g. Alternatively,
1. A full clinical evaluation is mandatory trichloryl in same dose or intranasal midazolam 0.2 to 0.5
2. Always record heart rate, BP and cardiac rhythm as they mg/kg can be given usually up to the age of three years. It
have a bearing on severity should be ensured that infant’s upper clothing is removed
3. Proceed step wise from 2D echocardiography – colour flow before giving sedation.
– Doppler Imaging
4. Evaluate all scan planes to assess full anatomy and function The aim is to image all the structures of the heart and blood
5. Scan all valves vessels in a sequential and systemic, fashion by utilising
6. Note any intercurrent illness which will affect the evaluation all scan planes. The 2D study is followed by CFM and
of severity by altering peak velocity carefully interrogated Doppler of all valves and various other
structures.
7. Match echocardiography findings with clinical findings and
symptoms Transducer
8. Provide full anatomical and quantitative information As mentioned earlier, a high frequency transducer is preferred
including limitations of study, if any. for infants and neonates. Sometimes, a high frequency 589
 transducer and tachycardia gives a false impression of turbulent
flow on CFM giving an appearance of ‘obstruction’. Such flows
should be interrogated by CW Doppler to confirm or rule out
obstruction.
Cyanotic Lesions
In cyanotic lesions a right to left or bidirectional flow must
be demonstrated by CFM or peripheral venous contrast
echocardiography.
Peripheral Venous Contrast Echocardiography
This is a very simple but quite informative technique which
can help in demonstrating a right to left intracardiac shunt
in case of a cyanotic infant if CFM is inconclusive due to any
technical problem. In this technique a small amount of
agitated saline (3 to 5 ml of saline + about 0.5 mL of air are Figure 10: Normal contrast echocardiography showing opacification of only
rapidly agitated with two syringes connected with a 3-way right atrium (RA) and right ventricle (RV) while LV (left ventricle) and LA (left
atrium) are contrast free.
stop cock) is injected rapidly intravenously. As this agitated
saline traverses RA and RV, these chambers get opacified.
Once these microbubbles of air and saline reach the
pulmonary circulation, they are destroyed as they are of a
larger size than the red blood cells. Hence, in a normal
situation, only right-sided chambers are opacified as these
microbubbles are not able to reach the left-sided chambers
(Figure 10).
As such an opacification of left-sided chambers implies that the
contrast agent has bypassed the pulmonary circulation and
opacified the left-sided chambers at any level of right to left
intracardiac shunt (Figure 11).
As mentioned earlier, a meticulous examination obviates
the need for invasive haemodynamic studies. However, it
is important for the operator to have a good knowledge
of basic anatomy and haemodynamics of various congenital
lesions. Besides providing diagnosis, echocardiography plays
a significant role in various catheter intervention procedures. Figure 11: Contrast echocardiography in a case of secundum atrial septal defect
(ASD) with saline contrast opacifying the left atrium (LA) indicating a right to
Table 1 summarises the role of echocardiography in some
left shunt at atrial level.
commonly encountered congenital cardiac defects (Figures
RA = right atrium; LV = left ventricle.
11 to 17).

Table 1: Brief Role of Echocardiography in Some Common Congenital Cardiac Lesions

Lesion Important Echocardiographic Features
Atrial septal defect Type, number and size of defects, degree of RV, RA enlargement, evaluation of PA pressure, adequacy of tissue rims
(ASD) around the defect, in cases of secundum ASD, for percutaneous device closure. Associated anomalies like cleft mitral
valve in ostium primum defect. Sinus venosus defects can be diagnosed by transthoracic echocardiogram (TTE), though
TEE is confirmatory
Ventricular septal Type, number and approximate sizing of defects, associated lesions like pulmonary stenosis, coarctation, etc. PA pressure,
defect (VSD) is it an isolated lesion or part of a complex lesion, complications like aortic regurgitation or vegetations, serial follow-up of
small VSD’s to see for spontaneous closure, assessment for suitability of percutaneous device closure, shunt direction of flow
Patent ductus Size of the defect, direction of shunt, extent of LA and LV volume overload, pulmonary hypertension if any, suitability
arteriosus (PDA) for percutaneous device closure, associated defects
Coarctation of aorta Presence and site of coarctation, diameter and length of coarctation segment, gradient across the coarctation, LV
functions, is there arch hypoplasia, associated anomalies like bicuspid aortic valve, left-sided obstructive lesions
Pulmonary stenosis Site of stenosis, e.g. infundibular, valvular or supravalvular gradients across the site of stenosis, RV dysfunction if any,
associated anomalies like VSD
Tetralogy of Fallot VSD, biventricular origin of aorta (aortic override), site and severity of RVOT obstruction which defines clinical picture
(TOF) and degree of cyanosis, RV hypertrophy, associated anomalies like right-sided aortic arch, concomitant ASD (pentalogy
of Fallot), measurement of pulmonary annulus, pulmonary trunk
Transposition of Demonstrates atrio-ventricular concordance and ventriculo-arterial discordance. Origin of PA from LV and aorta from
great arteries (TGA) RV can be demonstrated. Associated VSD, ASD or PFO, LVOT obstruction and coronary abnormalities can be identified.
Guiding catheter placement and movements during balloon atrial septostomy.
590
 Echocardiography
Figure 12: CFM in a case of secundum atrial septal defect with left to right shunt. Figure 15: PLAX view in a case of teralogy of Fallot showing aortic override
PV = Pulmonary vein; LA = Left atrium; RA = Right atrium. (AO), a large ventricular septal defect (VSD).
RV = Right ventricle; LV = Left ventricle.

Figure 13: Apical four chamber view showing ostium primum ASD (arrow).

Figure16: A case of tricuspid atresia. There is atresia of tricuspid valve with a very
hypoplastic right ventricle (RV), the main chamber is LV and a large ASD is present.

thereby delaying diagnosis and aggressive management. In acute

myocardial infarction (AMI) echocardiography provides a correct
diagnosis in about 95% of cases and hence is a life saving modality.
This is because in the ischaemic cascade, in which the earliest
abnormality is a perfusion defect followed by diastolic and systolic
contraction abnormalities, which is then followed by chest pain,
ECG changes and subsequently rise in cardiac enzymes.The earliest
change of perfusion defects is diagnosed by myocardial contrast
echocardiography, a technology which is still limited to few centres
in India. However, the diastolic and systolic abnormalities are
readily picked-up by conventional echocardiography thereby
giving an immediate diagnosis. However, few practical points
need to be kept in mind. What echocardiography picks-up in
IHD is an ischaemia or injury at the time of study. As such
Figure 14: Short axis view showing patent ductus arteriosus (arrow) with flow
echocardiography can be normal in cases of stable angina,
from aorta (AO) to pulmonary artery (PA).
despite having significant coronary artery disease. However, if
the same patient develops spontaneous or induced angina
ISCHAEMIC HEART DISEASE (IHD) during the study, then echocardiography will reveal regional
In the current era of intense pharmacotherapy, thrombolytics and contraction abnormalities of LV. Hence a practical dictum is that
percutaneous coronary interventions an early diagnosis of IHD a normal echocardiography during chest pain virtually excludes
is mandatory to get maximum benefit of various interventions. IHD. Secondly, the clinician should not have a false perception
Traditionally,the diagnosis of IHD is based on clinical presentation, that a normal resting echocardiography excludes coronary artery
ECG and cardiac enzymes. However, all the three have limitations disease especially in both stable and unstable angina.The two most 591
 Figure 17: The patient in Figure 16 showing a large ASD, almost a common atrium, as seen on contrast echocardiography.
RA = Right atrium; LA = Left atrium.

specific diagnostic findings in AMI are: decreased systolic Stress Echocardiography

thickening of affected myocardial segment (a normal myocardium This modality is being increasingly utilised in diagnosis and
thickens by almost 50% during systole,while an ischaemic segment prognosis of IHD. This is based on the principle that in a resting
shows decreased or absent systolic thickening); and secondly, state, despite significant coronary artery disease (CAD), there
varying degrees of regional wall motion abnormalities (RWMA). is no imbalance between oxygen supply and demand of the
The area affected is localised to the portion of myocardium myocardium. However, if the same individual undergoes
perfused by the involved coronary artery. The extent of RWMA any form of exercise, the oxygen demand of myocardium is
affects LV dysfunction and is one of the factors determining enhanced due to increased heart rate, contractility and rise in
prognosis. The RWMA is always assessed by scanning various blood pressure. However, in the presence of CAD, this increased
imaging planes. On the basis of this the myocardium is conceptually demand of oxygen cannot be met and it leads to systolic
divided in 17 segments, the 17th segment being the apical cap. contraction abnormalities and LV dysfunction which are
The role of echocardiography in IHD is summarised in Table 2. rapidly picked-up by echocardiography. In brief, a resting
echocardiography is first performed, then the patient exercises
Table 2: Role of Echocardiography in Ischaemic Heart Disease
on a treadmill till a standard end-point is reached and again an
Diagnosis immediate post-exercise echocardiography is repeated. Instead
Diagnosis of associated cardiac defects, if any of dynamic exercise, a pharmacological stress echocardiography
Triage in chest pain units with dobutamine can be performed. A normal response to
Assessment of complications such as LV thrombus, acute MR, VSD, exercise is hyperkinetic contractility with increasing LV ejection
LV aneurysm, myocardial rupture, RV infarction which has a bearing fraction. An abnormal response is indicated by decreased systolic
on therapy thickening of affected segment, varying degrees of RWMA,
Assessment of coronary territory involved paradoxical increase in LV chamber size, a decrease in ejection
Post-MI risk stratification/prognosis fraction. The accuracy for detection of CAD varies from 80% to
Assessment of myocardial viability 94% depending on the number of vessels involved.
Assessment of therapy effectiveness/change of therapy
Contribution of new technologies like MCE, tissue Doppler imaging, PERICARDIAL DISORDERS
strain imaging, etc. Echocardiography is one of the best non-invasive technique to
diagnose pericardial disorders. Some of the indications of
There are few situations where early echocardiography can be echocardiography are:
very informative as shown in Table 3.
1. Diagnosis and semi-quantitation of pericardial effusion
Table 3: Early Echocardiography in Whom? 2. Diagnosis of pericardial tamponade
Doubt in diagnosis/early detection 3. Diagnosis of post-intervention or post-surgical effusion
Hypotension 4. Constrictive pericarditis
Heart failure 5. Echocardiography guided pericardiocentesis
Unexplained dyspnoea
Chest pain with left bundle branch block Normally, the two layers of pericardium contain about 5 to
Suspect other complications 10 mL of fluid which acts as a buffering medium between the
two layers. As the fluid accumulates, echo-wise it is seen as an
The role of echocardiography in IHD is so important that it is echo free space between the pericardial layers (Figure 18).
recommended that every emergency room/critical care unit The semi-quantitation depends on the degree of echo free
592 resident should be trained to at least recognise a RWMA. pericardial space and the distribution of pericardial fluid.
 Echocardiography
It is a common cause of sudden death in young athletes.
Echocardiographically, it is characterised by asymmetrical septal
hypertrophy with septal and posterior wall thickness ratio of
more than 1.5:1. The septal thickness is more than 15 mm.
However, the distribution and severity of hypertrophy can be
variable. The LV cavity is small with normal functions. Systolic
anterior motion (SAM) of anterior mitral leaflet (AML) is one of
the important features of HOCM and leads to varying degree
of left ventricular outflow tract (LVOT) obstruction with a
gradient more than 30 mm Hg. This is because LVOT is formed
by AML and interventricular septum. The degree of LVOT
obstruction depends upon the duration for which IVS abuts
against the septum. In the echocardiography lab, SAM and LVOT
obstruction can be provoked by nitrates (Figure 19).

Figure 18: PLAX view showing a large posterior pericardial effusion (PE) as an
echocardiogram free space between pericardial layers.
LV = Left ventricle.

An echo free space of >2.0 cm with a diffuse effusion all around

the heart indicates a large effusion. The diagnosis of pericardial
tamponade and constrictive pericarditis is based on 2D
echocardiography features and Doppler findings, e.g. in
tamponade there is pericardial effusion, diastolic RV collapse,
exaggerated right atrial collapse during atrial systole due to
elevated intrapericardial pressure. IVC is enlarged and shows
less than 50% inspiratory collapse though it is more sensitive
and less specific finding. There are several Doppler findings, Figure 19: M-mode echocardiogram showing systolic anterior motion (arrow)
but one important finding is more than 25% respiratory of mitral valve (MV) following nitrate provocation. The whole LVOT is obliterated
variation of atrioventricular valve velocities, the normal by the SAM abutting the interventricular septum.
variation being less than 15%. The mitral velocity decreases
during inspiration and increases following first expiratory INFECTIVE ENDOCARDITIS
beat.
Infective endocarditis (IE) is an infection of endocardium and
CARDIOMYOPATHIES intracardiac devices by infective organisms, seen macro-
scopically as vegetations. Early diagnosis is vital as, despite
The diagnosis of various forms of cardiomyopathies is based
refinements in medical and surgical therapeutic approaches,
on high index of suspicion, clinical features, ECG and X-ray chest,
the mortality is still between 25% and 30%. No single finding
but echocardiography plays a central role in diagnosis. Basically,
is diagnostic. As such a combination of high index of suspicion,
the different forms of cardiomyopathy are dilated, hypertrophic
clinical scenario and echocardiography are diagnostic. The role
(both obstructive and non-obstructive) and restrictive. However,
of echocardiography in IE is:
RV cardiomyopathy, stress induced cardiomyopathy and LV
non-compaction cardiomyopathy are being periodically 1. Identifying the underlying heart disease including intra-
encountered. cardiac devices,
2. Diagnosis of vegetations, if present,
Dilated Cardiomyopathy (DCM )
3. Size, mobility and location,
This is basically characterised by cardiomegaly with global
LV hypokinesia. There is impaired systolic and diastolic 4. Detecting complications of vegetations,
cardiac functions. Mitral regurgitation is usually present. 5. Serial evaluation to assess efficacy of therapy or aetiology
Echocardiography also plays a role in assessing the prognosis. of worsening,
Some of the determining prognostic factors are: (a) degree 6. Prognostic stratification. Some adverse prognostic features
of cardiomegaly; (b) degree of LV dysfunction; (c) extent of are large (>10 mm) vegetations, hypermobile vegetations,
wall thickness of ventricles; (d) pulmonary hypertension; (e) presence of complications like abscess, leaflet rupture,
restrictive filling pattern as assessed by mitral inflow Doppler; extension to other areas, systemic embolism, heart failure, etc.
and (f) some tissue Doppler imaging parameters.
The echocardiography criteria of vegetations are an irregular,
Hypertrophic Obstructive Cardiomyopathy mobile mass attached to a free edge of leaflet or a wall. It is
Hypertrophic obstructive cardiomyopathy (HOCM) now attached to the upstream side of the valve, e.g. ventricular side
referred as hypertrophic cardiomyopathy (HCM) with LVOT of aortic valve leaflet, atrial side of mitral and tricuspid leaflets
obstruction is a complex, genetic cardiac disorder with and RV side of VSD.The motion of the vegetation is more chaotic
significant heterogeneity in clinical presentation and course. and independent of valve motion. It is seen in multiple scan 593
 planes (Figure 20). Valvular regurgitation is usually present. Critical Care Units
As vegetations once develop usually persist, unless they This is the area where echocardiography is extensively employed
embolise and disappear, hence sometimes there is a difficulty as a bedside study. The role of echocardiography is critical in
in distinguishing between an active or healed vegetation. Firstly, diagnosis and guiding therapy. In some areas it gives vital
there should be a clinical correlation as active vegetation will information whether the clinical manifestation is of cardiac or
be associated with fever, toxaemia and other manifestations of non-cardiac aetiology. Some of the common situations where
sepsis, while old, healed vegetation may be routinely detected echocardiography is utilised are: (a) evaluation of chest pain
in virtually an asymptomatic patient. Secondly, a healing whether it is ischaemic or non-ischaemic; (b) unexplained
vegetations decrease in size and mobility and are more hypotension/shock. Echocardiography evaluates whether it is
echogenic. Thirdly, a past history of IE may be available. cardiac related like acute coronary syndrome, acute valvular
insufficiency, severe pulmonary hypertension, pulmonary
embolism, etc. Echocardiography can also infer if it is non-cardiac
like hypovolaemia, acute sepsis syndrome; (c) evaluation of
dyspnoea and heart failure where echocardiography can
differentiate between systolic or diastolic failure, pulmonary
embolism or a pulmonary aetiology by exclusion; and (d)
aetiology of worsening of clinical status in any patient which was
showing improvement.
Operating Room
As a routine in large number of cardiac centres intra-operative
TEE is routinely utilised especially in monitoring of valvular,
congenital or other complex cardiovascular surgical procedures.
Besides monitoring cardiac functions, it helps in determining
the completeness and success of surgery to avoid any possible
redo surgery.
Figure 20: Vegetation seen on the atrial side of the mitral valve (arrow).
Cardiac Catheterisation Laboratory
HEART FAILURE (HF) There are several non-surgical cardiovascular procedures
Echocardiography is well suited to meet the growing need performed in cardiac catheterisation laboratory or intensive
for non-invasive imaging of heart failure. The role of echo- care unit for which online echocardiography monitoring is
cardiography in heart failure is: (a) diagnosis; (b) prognosis; (c) advantageous. Some of these situations are pericardiocentesis,
guiding therapy; and (d) monitoring follow-up. percutaneous valvuloplasties, closure of ASD, PDA, some VSD’s,
creation of an atrial septostomy in some complex cyanotic CHD.
Because HF patients often have more than one structural and/ Occasionally, an emergency echocardiography may be required
or functional abnormality contributing to their disease state, in catheterisation laboratory to assist in evaluating a patient
echocardiography’s versatility in detecting multiple structural who has acutely deteriorated during a procedure, to exclude any
lesions including myocardial disorders yield obvious benefits. iatrogenic cardiac tamponade or to reassess intravenous function.
Assessment of LV ejection fraction is one of the primary
measures. A normal EF virtually excludes an advanced CONCLUSION
myocardial disorder, i.e. systolic HF and then one looks for HFNEF. The progress in understanding and improvements in equipment
Doppler measurements provide important haemodynamic has catapulted echocardiogram as a very important tool in
information. Some of the adverse prognostic factors in HF diagnosis and functional assessment. The newer innovations
can be degree of LV dysfunction, LV end systolic volume of of virtual 3D imaging, contrast echocardiography, and tissue
>45 ml/m2, right ventricular functions, restrictive ventricular perfusion are going to further lend greater importance to
filling, myocardial viability, etc. Echocardiography provides echocardiogram.
important data for therapeutic decision-making like volume
The echocardiogram helps in, valvular heart disease, congenital
status of the patient by IVC parameters as described earlier,
heart disease, diseases of myocardium and ischaemic heart
need for drugs for LV dysfunction and define candidates for
disease. In valvular heart disease and congenital heart disease
implantable cardiac devices like cardiac resynchronisation
it has obviated the need for invasive testing to a large extent.
therapy or implantable cardioverter defibrillator. One of the
major strengths of echocardiography is repeated follow-up, The addition of miniature echocardiography may obviate the
especially in situations of new symptoms, clinical deterioration use of stethoscope in clinical cardiac assessment.
where it can provide the aetiology.
RECOMMENDED READINGS
ROLE OF ECHOCARDIOGRAPHY BEYOND 1. William F Armstrong, Thomas Rayan, Harvey Feigenbaum, Feigenbaums
ECHOCARDIOGRAPHY LABORATORY Echocardiography, 7th Ed. Lippincott Willimas & Wilkins; 2010.
Since last many years the role of echocardiography has been 2. Focus Issue on Echocardiography. Indian Heart Journal (In Press).
extended much beyond the echocardiography laboratory. In 3. Jour Ind Acad Echocardiogr 2010; 21: 5-42.
many situations it has proved to be a life saving technology. 4. Jour Ind Acad Echocardiogr 2010; 22: 4-59.

594 Some of the areas are mentioned below: 5. Jae K Oh, Seward JB, Jamil Tajik A, The Echo Manual, 3rd Ed. 2006.
 12.6 Cardiac Imaging

Priya Jagia, Sanjiv Sharma

INTRODUCTION  Position of the patient, fundus of the stomach, domes of the

Optimal interpretation of cardiac imaging studies entails a diaphragm, bony abnormalities and the tracheal shadow
judicious synthesis of imaging evaluation with its significance  Cardiac size, contour, borders, chambers and great vessels
within the context of clinical decision making. A basic  Pulmonary vasculature
understanding of cardiovascular haemodynamics and
electrophysiology is essential for optimal interpretation of The proper centring should be assessed looking at distance
imaging information. of medial end of clavicles from midline. The stomach shadow
should be seen normally to the left and the right dome is higher
Plain chest X-ray is the most routinely used cost effective cardiac than the left. The trachea shadow can be seen dividing at the
imaging modality. It has an advantage that it can be repeated carina which is at the level of T4 vertebra.
for serial changes and has been standardised since it is the
oldest and simplest available cardiac imaging modality. Cardiac Size, Contours, Borders, Chambers and Great Vessels

Non-invasive imaging of cardiac structures is technically Cardiac size

challenging due to a variety of reasons. Motion artefacts The plain film radiographs are still a valuable tool for identifying
constitute a major limitation as these degrade the image quality. an enlarged heart that is abnormal. The heart size is assessed
During cardiac imaging, motion artefacts are produced by by cardiothoracic (CT) ratio which is expressed as the ratio
cardiac pulsations, counter-clockwise cardiac rotation during between the maximum transverse diameter of the heart divided
different phases of cardiac cycle, diaphragmatic movement and by the maximum transverse diameter of the thorax (Figure 1).
respiratory motion. Optimal profiling of cardiac structures is also The maximum transverse diameter of the heart is obtained
compounded by the skewed anatomy of the heart since it is by adding the widest distance of the right heart border from
tilted in all three axes and hence routine body axis views are the midline and left heart border to the midline. The midline is
not useful for optimal imaging in disease states. Further, there drawn through mid point of the spine from the sternum to the
is a wide variation in the densities of surrounding tissues and diaphragm. The maximum transverse diameter of the thorax is
these adversely influence the image quality.The haemodynamics
within the heart change very rapidly during various phases of
the cardiac and respiratory cycles. As a result, the window of
opportunity to capture the optimal phase of physiological and
biochemical events is very short and difficult to capture for
desired anatomic and functional imaging. It is thus obvious that
the demands on an optimal technique for cardiac imaging are
tremendous. Each modality is discussed.

CHEST X-RAY IN CARDIOVASCULAR DISEASE

For accurate interpretation of chest X-rays, it is imperative to have
a systematic and standardised approach, based on an assessment
first of anatomy and then of physiology. Any approach must, of
course, be based on an understanding of what is normal.
In the standard PA chest study, the overall heart diameter is
normally less than 50% of the transverse diameter of the
thorax. The heart overlies the thoracic spine, roughly three-
fourths to the left of the spine and one-fourth to the right. The
mediastinum is narrow superiorly and, normally, the descending
aorta can be defined from the arch to the dome of the diaphragm,
on the left. Below the aortic arch, the pulmonary hila are seen,
slightly higher on the left than the right. On both frontal and
lateral views, the ascending aorta (aortic root) is normally
obscured by the main pulmonary artery and both atria.
The plain X-ray chest is usually evaluated in frontal projection
(PA view) and the distance between the X-ray film and radiation Figure 1: Cardiothoracic Ratio = r+l / td (where r +l = transverse diameter of the
source is 72 inches. It should be systematically evaluated as heart and td is transverse diameter of thorax. r and l are measured as the
maximum distance from midline of right and left heart borders respectively).
follows for:
595
 measured as distance between inner borders of thorax obtained Table 1: Abnormal Cardiac Contour
above the costophrenic angles. The normal average CT ratio is:
Features of Cardiac Contour Causes
 ≤0.50 in adults
 >0.50 in children Mitralisation of left heart border Mitral stenosis with
pulmonary hypertension
 ≤0.60 in neonates
Boot-shaped heart Tetralogy of Fallot
A normal heart may appear large because of small AP diameter Flask like or money-bag Pericardial effusion
due to pectus excavatum and straight back syndrome. appearance with a smooth
featureless cardiac border
The heart may appear small even though it is enlarged as in
Triangular or a large rounded Ebstein’s anomaly
downward displacement of cardiac apex in AR, because of large
heart with a narrow pedicle
AP diameter in COPD (Figure 2), due to severe dorsal kyphosis
Snow man or cottage loaf Total anomalous
in elderly patients or, in Addison disease and anorexia nervosa
appearance pulmonary venous
due to the absence of brown fat. connection
Egg on side appearance Transposition of great
(mild cardiomegaly with arteries
narrow pedicle)
Retrosternal double density Left ventricular
with a bulge along the cardiac aneurysm
border
Convex double density in the Enlarged left atrium
right portion of the cardiac
silhouette

Table 2: Cardiac Borders in Chest X-ray Frontal Projection

Right Heart Border Left Heart Border

Superior vena cava (SVC) Aortic knuckle
Right atrium Main pulmonary artery
Left atrial appendage
(when enlarged)
Left ventricle

valve disease and Ebstein’s anomaly. Radiographically, RAE is

considered:
 When it bulges >5.5 cm to the right of the midline or
 When RA border occupies ≥3 intercostal spaces
Figure 2: Chest X-ray PA view of patient with emphysema. Note the tubular The classic signs of right ventricular enlargement are a boot-
appearance of heart with hyperinflated lung fields and low lying diaphragm.
shaped heart and filling in of the retrosternal airspace. The
former is caused by transverse displacement of the apex of the
In present day scenario, with use of portable X-rays AP view is right ventricle as it dilates and leads to an acute cardiophrenic
done due to which CT-ratio can become abnormal. Moreover, angle. In adults, it is unusual for the right ventricle to dilate
with use of smaller films in digital X-rays the usual measurement without left ventricular dilation, so this boot-shape is not often
parameters used to define cardiac chamber enlargements may obvious. It is most commonly seen as an isolated finding
not stand true. in congenital heart disease, classically in tetralogy of Fallot
Cardiac Contour (Figure 4). Right ventricular enlargement is often seen in mitral
valve disease, secondary to pulmonary hypertension.
Any significant deviation from the normal cardiovascular
contour may serve as a clue to the cardiovascular diseases LA Enlargement in mitral stenosis may lead to straightening
(Table 1). of left heart border. The straightened left heart border occurs
due to dilated main pulmonary artery and bulging of the LA
Cardiac Borders, Chambers and Great Vessels appendage (Figure 5). The enlarged LA may lead to elevation
The cardiac borders consist of right and left heart borders of left main bronchus, resulting in increase of carinal angle. It
(Figures 3A and B and Table 2). may cause a convex shadow of double density in the right portion
of cardiac silhouette and may lead to posterior displacement of
In frontal projection, RA forms a gentle convexity with the
barium filled oesophagus in lateral and RAO views
adjacent right middle lobe. The superior border blends
above with SVC and inferior border blends below with IVC, Left ventricular enlargement (e.g. in cardiomyopathies, valvular
meeting the diaphragm at a slightly acute angle. Right atrial heart diseases, LV aneurysms, etc.) is characterised by a prominent,
enlargement (RAE) commonly occurs in organic tricuspid downwardly directed contour of the apex, as distinguished
596
 Cardiac Imaging
Figures 3A and B: Frontal projection of the heart and great vessels. (A) Left and right heart borders in the frontal projection. (B) Line drawing in the frontal
projection demonstrates the relationship of the cardiac valves, rings, and sulci to the mediastinal borders.
A = Ascending aorta; AA = Aortic arch; Az = Azygous vein; LA = Left atrial appendage; LB = Left lower border of pulmonary artery; LV = Left ventricle; PA = Main pulmonary
artery; RA = Right atrium; S = Superior vena cava; SC = Subclavian artery.

Figure 4: Chest X-ray in a patient of tetralogy of Fallot revealing boot-shaped

heart, enlarged right ventricle (1) and oligaemic lung fields.

from the transverse displacement seen with right ventricular

enlargement. Maximal left ventricular enlargement in adults
occurs commonly with aortic insufficiency, often with
associated aortic root dilation, whereas mitral regurgitation
also manifests left atrial dilation. In contrast, aortic stenosis is
characterised by left ventricular hypertrophy rather than
dilation, and the left ventricle dilates only when aortic stenosis Figure 5: Chest radiograph of severe mitral stenosis. Posteroanterior view shows
is accompanied by heart failure. enlargement of the left atrium [double density shadow (1)], straightening of
left heart border (2) (mitralisation) and pulmonary venous redistribution.
Pulmonary Vascularity
The main pulmonary artery bifurcates into left pulmonary artery borders are just visible above the middle of the left hilum. The
(LPA) and right pulmonary artery (RPA) within the mediastinum. RPA, which has a horizontal course within the mediastinum,
The LPA then courses to the left and posteriorly and hence its divides into lobar branches proximal to the right hilum. The 597
 transverse diameter of right descending PA (RDPA) is 10 to compared to lower lobe veins called as ‘cephalisation of
15 mm ± 1 mm in males and 9 to 14 mm ± 1 mm in females. pulmonary veins’. At pressures of 12 to 18 mm Hg, Kerley B lines
appear, which are horizontal, pleuroparenchymal, peripheral
When pulmonary arterial flow is increased, as in patients with a
linear densities. As PCWP increases acutely above 18 to 20 mm Hg
high-output state (e.g. pregnancy, severe anaemia, hyper-
pulmonary oedema occurs, with interstitial fluid present in
thyroidism) or left-to-right shunt, the pulmonary vessels are
seen more prominently than usual in the periphery of the lung. sufficient amounts to cause a perihilar bat wing appearance.
They are uniformly enlarged and can be traced almost to the Aorta
pleura, but their margins remain clear. This is typically referred In PA view, the aortic arch is seen as a projection beyond the
as ‘pulmonary plethora’ due to increased pulmonary vascularity. left margin of the mediastinal shadow, which is known as
It can be seen in acyanotic congenital heart diseases with large aortic knuckle or knob. Aortic prominence may be seen on right
left to right shunts like ASD (Figure 6), VSD, PDA and in cyanotic heart border in patients with AR with dilated aortic root or in
patients with admixture lesions like TAPVC, truncus arteriosus, those with aortic stenosis with post-stenotic dilatation. In elderly
TGA with VSD, etc.
patients with calcified aortic valve, calcification may be visualised
on aortic knuckle.
Pericardium
The pericardium is rarely distinctly definable on plain films of
the chest, but there are two situations in which it can be seen:
effusion and constriction. Classically, the cardiac silhouette
has a ‘money-bag shape’ in the presence of a pericardial
effusion, but such a shape is not in itself diagnostic. Pericardial
calcification is most often seen in constrictive pericarditis
especially of tubercular aetiology. Such calcification is usually
thin and linear and follows the contour of the pericardium.
Moreover, the mechanical prosthetic valves (aortic as well as
mitral) (Figure 7) and devices can be visualised in chest X-ray
in post procedural patients.
Recent advances in both computed tomography (CT) and
magnetic resonance imaging (MRI) have improved our ability
to better image the cardiac anatomy and to some extent define
the haemodynamic events within the heart. Comprehensive

Figure 6: Chest radiograph of patient with atrial septal defect and significant
left to right shunt. Marked plethora with dilated right descending (1) and main
pulmonary arteries (2) with cardiomegaly (3) can be seen.

When pulmonary arterial hypertension (PAH) develops as in

primary pulmonary hypertension or in Eisenmenger’s syndrome,
it leads to ‘pulmonary oligaemia’ with prominence of central
pulmonary arteries like enlarged main pulmonary artery and
its proximal branches. Vascular markings of outer one-third of
both lung fields are not present. Pulmonary oligaemia may be
seen in conditions with decreased pulmonary flow like TOF,
pulmonary atresia, tricuspid atresia, TGA with PS, etc.
In patients with valvular pulmonary stenosis post-stenotic main
pulmonary artery dilatation is seen with normal peripheral
pulmonary vasculature.
In patients with pulmonary venous hypertension, there is a
reasonably good correlation between the pulmonary vascular
pattern and pulmonary capillary wedge pressure (PCWP). At a
PCWP less than 8 mm Hg, the venous pattern is normal. As the
PCWP increases to 10 to 12 mm Hg, there occurs redistribution Figure 7: Chest X-ray PA view post-mechanical prosthetic mitral valve (1)
replacement.
598 of pulmonary blood flow with prominent upper lobe veins as
 Cardiac Imaging
cardiac imaging includes morphological changes in structure spatial resolution, long acquisition times, inability to change
of the heart, identification of the underlying pathoanatomy, orthogonal planes during post-processing and patient-specific
functional and haemodynamic consequences of the insult issues such as claustrophobia, pacemaker implantation and pre-
and resultant biochemical changes. The modalities available existing arrhythmias among others. Recent advances in MRI
for cardiac imaging include conventional radiology echocardio- allow faster acquisition using newer sequences and have helped
graphy, catheter angiography, radioisotope studies, CT and to obtain comprehensive morphological and functional
MRI. An ideal cardiac imaging modality should have very information of the heart. Its inherent soft tissue contrast obviates
short acquisition time (to minimise motion artefact and freeze the need for contrast injection for simple morphological
capture a biochemical event) and capability for ECG-gated assessment. All of the above can be obtained on an out-patient
orthogonal imaging to relate the morphological abnormality to basis. Also, MRI is especially useful in post-operative settings.
a given haemodynamic and biochemical event. For optimal As a result, cardiac MRI (CMR) is fast emerging as a ‘one-stop
imaging, a large field-of-view to capture all desired structures shop’ for cardiac evaluation by providing virtually all the
in an image frame while retaining a high signal-to-noise ratio information needed for complete assessment of heart disease.
in the resultant image is desirable. However, at most times, these
Imaging Sequences
requirements are mutually contradictory. In view of the large
volumes of information required, a fast processing and large The newer faster sequences allow acquisition of data during
storage capacity are essential requirements of an ideal imaging breath hold, thus minimising the respiratory artifacts. The
technique for the heart. Table 3 below lists the diagnostic sequences are ECG-gated and images are acquired mostly in
modalities excluding X-ray chest, and echocardiography useful end-diastole when the heart is most quiescent.
in various disorders. The commonly used sequences include:
Table 3: An Overview of Suitable Techniques for Various Disease
1. Dark blood sequences: The flowing blood appears dark in
States these sequences. These include conventional spin echo,
turbo or fast spin echo (TSE, FSE), HASTE, double inversion
Congenital heart disease For morphology – either CT or MRI. If recovery FSE (Double IR-FSE). These sequences allow
small pulmonary arteries, CT scores
morphological assessment of heart and vessels without
over MRI because of high spatial
interference from bright signal from blood. These are useful
resolution.
for cardiac masses, myocardial and pericardial evaluation.
For functional assessment, including
shunt quantification in ASD, VSD, PDA 2. Bright blood sequences: Steady state gradient echo images
and quantification of flow across shunt/ show blood as bright. The sequences are balanced steady
graft/baffle/stenosis, MRI is advisable. state procession sequences and have different trade names
Ischaemic heart disease For coronary artery assessment – CT for different companies - True FISP, FIESTA, balanced FFE.
angiography. Ventricular analysis and These sequences are useful for cine imaging whereby images
Wall motion abnormality are seen well are acquired throughout the cardiac cycle.These cine images
on both CT and MRI. Perfusion studies are used for functional analysis and to see any turbulent
and viability are best seen on cardiac signal produced due to stenotic or regurgitant pathology.
MRI.
3. Phase contrast imaging sequences: These are used for
Cardiomyopathies MRI with contrast enhancement for quantification of stenotic and regurgitant valvular disease,
(Non-ischaemic) anatomic and functional assessment.
to find out Qp:Qs across a shunt and to do flow analysis
Cardiac masses MRI with contrast enhancement for across a vessel.
anatomic and functional assessment.
CT is helpful in detecting calcification 4. Contrast-enhanced MR sequences: These are especially
in mass. Rest all other features are useful for perfusion imaging and viability assessment. They
better seen on MRI. are also indicated in evaluation of cardiac masses,
Pericardial diseases MRI is more useful in depicting cardiomyopathies and for great vessel visualisation.
pericardial thickness, effusion and Imaging Planes for the Heart
constriction. It helps differentiate
constrictive pericarditis from restrictive Due to skewed anatomy of the heart which is rotated along all
cardiomyopathy. three axes and this rotation varies from patient to patient based
Cardiac CT shows calcification in on the body build and girth, it is important to acquire images
pericardium. Pericardial thickness and along the axes of ‘heart’ rather than along the various ‘body’
constriction is also well detected on axes. Hence, an acquisition technique for images begins with
gated cardiac CT. acquiring body axis views-coronal, sagittal and axial, from which
ASD = Atrial septal; CT = Computed tomography; MRI = Magnetic two-chamber, four-chamber, short axis, LVOT (Left ventricular
resonance imaging; PDA = Patent ductus arteriosus; VSD = Ventricular outflow tract) and RVOT (Right ventricular outflow tract) views
septal defects. are reconstructed.
Congenital Heart Disease
CARDIAC MRI MRI is useful for morphological assessment in patients with
MRI offers many advantages in imaging of the heart. These congenital heart disease (CHD). The situs, atrioventricular and
include the lack of ionising radiation, orthogonal imaging ventriculoarterial communications, great vessels especially
capacity and superior temporal and contrast resolution as pulmonary artery size, pulmonary venous drainage, septal
compared to CT. The relative disadvantages include lower defects, etc. are well identified (Figure 8). 599
 Figure 8: Four chamber T1W spin echo MR image showing perimembraneous
VSD (arrow).

Functional information regarding ventricular function, Qp:Qs and

quantification of regurgitant and stenotic valves can be obtained.
In post-operative cases, the flow across the shunts and baffles
can be quantified and gradients across narrowing determined.
For example, in a case of tetralogy of Fallot, CMR can show
anatomy of pulmonary arteries, the ventricular septal defect
(VSD) with degree of aortic override, pulmonary venous drainage,
large aortopulmonary collaterals and ventricular morphology. Figure 9: Four chamber bright blood TRUFISP cine MR image showing jet due
Functionally, Qp:Qs across the shunt can be determined. RV to mitral regurgitation in dilated LA.
functional analysis can be done. Post-operatively, flow across LA = Left atrium; LV = Left ventricle; RV = Right ventricle.
shunts or pulmonary regurgitation after total correction can be
quantified. Residual VSDs can be picked up easily.
Planimetry for valvular area can be done to measure the stenotic
Valvular Heart Disease valve area.
Cine MRI in four chamber and long axis view helps pick up
CARDIOMYOPATHIES
turbulent jets produced by the stenotic or regurgitation valvular
lesions (Figure 9). These can then be quantified using phase Arrhythmogenic Right Ventricular Dysplasia
contrast sequences, which help classify the severity of valvular There is fatty or fibrous infiltration of myocardium with or
lesion according to the flow and gradient across the valve. without thinning of myocardium (Figures 10A and B).There are

Figures 10A and B: MRI in arrhythmogenic right ventricular dysplasia. (A) Short axis T1W image showing bright fat infiltration (arrow) in RV side of interventricular
septum; (B) Corresponding fat saturated T1W image shows bright signal of fat nulled.
600
 Cardiac Imaging
associated wall motion abnormalities of RV, RV outflow tract or End-diastolic wall thickness is measured besides quantification
LV. MRI, with its inherent soft tissue contrast, is the modality of of cardiac function and flow dynamics of the ventricular outflow.
choice for diagnosing arrhythmogenic right ventricular dysplasia Systolic anterior motion of mitral valve is well seen on cine
(ARVD). Fat is seen as bright signal on T1 and T2 weighted MRI and the mitral regurgitation can be quantified. The total
images and this signal disappears on fat saturation sequence. myocardial mass can be calculated and used for follow-up
Cine images show decreased global function, regional wall studies. Delayed contrast enhancement is, sometimes, seen
motion abnormalities or aneurysms. Delayed enhancement because of fibrosis in the region of hypertrophy and such
images obtained 10 minutes after gadolinium contrast injection patients have higher risk of sudden cardiac death. CMR is useful
shows hyper-enhancement in regions of fibro-fatty replacement. for monitoring functional and anatomical outcome of surgical
This is very useful in guiding the endomyocardial biopsy. and pharmacological septal ablation.
Dilated Cardiomyopathy Restrictive Cardiomyopathy (RCM)
MRI shows biatrial enlargement and increased size of the left There is restrictive filling and reduced diastolic volume of either
and right ventricles (Figure 11). Mitral and tricuspid regurgitation, or both ventricles with near normal systolic function and wall
if present, can be well demonstrated.The pattern of enhancement thickness.
in myocardium helps differentiate LV dysfunction due to dilated
On MRI, there is abnormal diastolic ventricular function and
cardiomyopathy (DCM) or ischaemic heart disease (IHD).
biatrial enlargement with normal systolic ventricular function,
Majority of DCM patients do not have any late contrast
initially. CMR can characterise tissue, quantify myocardial mass,
enhancement. However, when present, it is in mid myocardium
ventricular volumes and ejection fraction.
in non-coronary pattern which means that it does not correspond
to any coronary artery territory. Common causes of restrictive cardiomyopathies include
sarcoidosis, amyloidosis, haemochromatosis, storage disorders
Hypertrophic Cardiomyopathy
and idiopathic causes.
MRI is especially useful in detecting apical hypertrophy that is
not well seen on echocardiography. Cine images demonstrate Amyloidosis
degree and extent of hypertrophy (Figures 12A and B). MRI shows thickening of left and right ventricular walls.
Increased interatrial septal thickness or of posterior atrial wall
greater than 6 mm is quite characteristic for amyloid infiltration.
Associated pericardial and pleural effusions help differentiate
amyloidosis from myocardial hypertrophy. On delayed
enhancement, global subendocardial enhancement, not
matching any specific coronary territory, is seen.
Sarcoidosis
CMR can help detect these cases early which is important to
initiate early corticosteroid therapy that helps prevent
malignant arrhythmias. Focal bright areas with low signal on
T2W images suggest sarcoid granuloma. On delayed contrast
images, mid wall patchy or focal enhancement is seen.

ISCHAEMIC HEART DISEASE

1. Ventricular function: Cardiac MRI is superior to echocardio-
graphy for assessment of ventricular function. Dynamic cine
MRI images are used for volumetric analysis of ventricles
and to see regional wall motion abnormalities.
Figure 11: Four chamber bright blood MR image showing dilated left ventricle
(LV) with thinned out myocardium in a patient with dilated cardiomyopathy. 2. Myocardial perfusion (Rest and Stress): Gadolinium
contrast is injected intravenously and images are acquired
during rest and after achieving pharmacological stress
using intravenous adenosine in the dose of 140 µg/kg body
weight for 4 to 6 minutes.
Hibernating myocardium shows perfusion defect on
stress that may not be present at rest (Figures 13A and B).
The regional wall motion abnormality seen at rest
improves after stress and there is no delayed contrast
enhancement.
3. Myocardial viability: On delayed contrast MRI, infarcted
or dead myocardium appears bright (Figure 14). Potential
improvement after revascularisation depends on extent of
Figures 12A and B: Case of hypertrophic cardiomyopathy. (A) short axis cine infarcted wall thickness. Part of myocardium with more than
MR image in end-diastole showing thickened LV myocardium and (B) almost 75% thickness infarcted, has poorest chances of recovery
complete obliteration of LV cavity in systolic image. 601
after revascularisation.
 Figures 13A and B: Myocardial perfusion imaging. Short axis view showing (A) perfusion defect in inferior wall (RCA territory) on stress MR image which was not
seen in (B) rest images suggesting inducible ischaemia on stress.

morphological assessment, tissue characterisation, mobility

of mass with cardiac cycle is well seen on MRI. Thrombus is
most commonly confused as cardiac mass and it is easy to
differentiate on cardiac MRI. The most common benign cardiac
tumour is myxoma (Figure 15).

CARDIAC COMPUTED TOMOGRAPHY

With the advent of advanced multi-slice CT scanners, it has
become possible to image heart with more accuracy in much
shorter time. Short acquisition time (4-5 seconds vis-à-vis 45
minutes in MRI) and higher spatial resolution makes CT an
investigation of choice for assessment of children with
congenital heart disease.
ECG gating is done to acquire motion free images of cardiac
chambers and coronary arteries. With latest multi-slice (256 and
320 slice scanners) and dual-source CT scanners available in
clinical practice, it is possible to have spatial resolution less than
Figure 14: Delayed enhanced MRI in short axis view shows transmural infarct
in the lateral wall (left circumflex artery territory).

Thus, cardiac MRI helps detect ‘hibernating myocardium’ and

also helps in prognostication of recovery after revascularisation.
However, coronary arteries are better evaluated on CT
angiography since it has a much better spatial resolution.
Pericardial Diseases
MRI is useful to differentiate constrictive pericarditis from
restrictive cardiomyopathy, which is a usual diagnostic
dilemma. In constrictive pericarditis, cardiac MRI shows
pericardial thickness more than 4 mm.There may be associated
SVC, IVC dilatation and RA enlargement. On cine MR images,
abnormal diastolic septal motion (‘septal bounce’) is seen
suggesting constrictive changes. Calcification is seen as a signal
void.
Cardiac and Pericardiac Masses
Cardiac MRI is preferred for evaluation of cardiac masses Figure 15: Bright blood MRI image in four chamber view in a case of left atrial
602 myxoma attached to interatrial septum.
since it has better soft tissue characterisation. Accurate
 differentiate unstable versus stable plaques. Many research

Cardiac Imaging
0.4 mm and gantry rotation time of 82 ms or lesser and it is no
longer mandatory to reduce the heart rate. As long as it is stable, projects are currently going on to help identify vulnerable
a heart rate of 90 beats per minute too can give reasonably unstable plaque.
accurate images of coronary arteries on dual source CT. Image
Functional assessment of ventricles and planimetry of the
acquisition lasts 8–10 seconds only and hence breath hold is
stenotic valves (Figure 20) can be done using cardiac CT images
easy.
acquired throughout the cardiac cycle.
Calcium scoring is used as screening tool in many countries in
outpatient department patients. It is done by ECG-gated non-
contrast single breath hold scans. A software then calculates
the Agatston calcium score taking into account the area and
density of calcification. A negative calcium score has a high
negative predictive value for ruling out atherosclerosis and
stenotic CAD. On the other hand, high calcium score indicates
high probability of future hard cardiac events due to CAD. If
calcium is concentrated in a single segment and overall score
is more than 1,000, the interpretation of underlying coronary
arteries becomes an issue and the contrast CT angiography
should not be done.
CT angiogram (Figures 16 to 19): Sixty to eighty millilitre of
non-ionic contrast is injected at the rate of 5-6 mL per second
through antecubital vein. ECG-gated images are acquired in
different phases of cardiac cycle and reconstructions are made
from phases showing least movement.
Pooled data from multiple studies on 64 slice and dual source
scanners have demonstrated high sensitivity (89%) and
specificity (96%) of coronary CT angiography for evaluation of
CAD. It is the modality of choice for evaluation of bypass grafts Figure 17: Volume rendered CT image showing Distal LAD Bridging (arrow).
after coronary artery bypass grafting. In stented arteries, in-stent RCA = Right coronary artery; D1 = First diagonal branch.
lumen can usually be well seen in stents greater than 2.5 mm
but may vary with stent architecture and design.
Plaque imaging is being done with high-resolution CT
angiography and Dual-energy (on Dual-source CT) to

Figure 16: Oblique MIP CT image showing mixed plaque with calcification in
mid left anterior descending artery (LAD). Figure 18: Oblique MIP-CT image showing patent stent in mid LAD.
603
 Figure 20: CT image of calcific aortic valve with thickened leaflets.

clinical situations, CT and MRI are complementary in terms of

the information that they can provide for optimal diagnosis,
treatment planning and surveillance after treatment.
Figure 19: CT angiogram of post-operative CABG patient. Volume rendered
image showing patent venous grafts to LAD and OM. A stump of occluded graft
to diagonal is also seen.
RECOMMENDED READINGS
1. American College of Cardiology Foundation Task Force on Expert
AO = Aorta; LAD = Left anterior descending artery; LV = Left ventricle; OM = Obtuse
Consensus Documents, et al. ACCF/ACR/AHA/NASCI/SCMR 2010 expert
marginal; RV = Right ventricle; SVG = Saphenous vein graft.
consensus document on cardiovascular magnetic resonance: a report
of the American College of Cardiology Foundation Task Force on Expert
Overall, optimised cardiac imaging requires an appropriate Consensus Documents. Circulation 2010; 121:2462-508.
patient selection. Both CT and MRI share advantages such as 2. Di Carli MF, Hachamovitch R. New technology for noninvasive evaluation
being multi-planar, out-patient based and gated acquisition of coronary artery disease. Circulation 2007;115: 1464-80.
among others. Factors including the speed of examination, 3. François CJ, Schiebler ML, Reeder SB. Cardiac MRI evaluation of non-
image resolution, motion artefacts, feasibility of functional ischemic cardiomyopathies. J Magn Reson Imag 2010; 31: 518-30.
information, radiation exposure and the need for iodinated 4. Kim RJ, Wu E, Rafael A, et al. The use of contrast-enhanced magnetic
resonance imaging to identify reversible myocardial dysfunction. N Engl J
contrast influence technique selection in a given patient. Med 2000; 343:1445-53.
Whereas claustrophobia, instability and pacemaker limit MRI; 5. Schroeder S, Achenbach S, Bengel F, et al. Cardiac computed tomography:
body habitus limits, pregnancy, contrast reactions limit use indications, applications, limitations, and training requirements. Eur Heart
of CT scan. Echocardiography and SPECT may be helpful. In most J 2008;29:531-56.

604
 12.7 Nuclear Cardiology

Vikram R Lele, Parag Aland

Nuclear cardiology involves use of radiopharmaceuticals to Diastolic function abnormality occurs much earlier than systolic
study the function of the heart (Table 1). Radiopharmaceuticals function abnormality in all cardiac disorders including coronary
which have affinity for the myocardium are injected intra- artery disease (CAD) and congestive cardiac failure. The earliest
venously and with the help of a gamma camera, functional change in CAD is reduction in PFR. With exercise, the expected
images of the heart are obtained. Two technologies are used: increment in PFR is blunted. LV function and ventricular volumes
single photon emission computed tomography (SPECT) which are powerful independent prognostic variables in cardiac
uses single, dual or triple headed gamma cameras and isotopes patients. An LV end systolic volume (ESV) of < 70 mL is related
of 99mTechnetium, and positron emission tomography (PET) to low mortality while ESV > 70 mL is related to high death rate.
which uses short-lived isotopes of 18F, 14O,13N, and 11C which In aortic and mitral regurgitation, preoperative ESV > 60 mL/m2
are produced in cyclotrons and imaged with special PET cameras. predicts a high-risk of peri-operative cardiac death.

Table 1: The Scope of Nuclear Cardiology Exercise induced regional wall motion abnormalities (RWMA)
may appear in CAD before development of ECG abnormalities
Myocardial function or symptoms of ischaemia. Normal subjects increase their LVEF
Myocardial perfusion generally by at least 5% from rest to peak exercise. Patients with
Myocardial metabolism significant CAD show no rise, or an actual fall compared to rest
Myocardial infarction LVEF.
Myocardial receptors
Atherosclerosis, apoptosis imaging The ‘gold standard’ for LVEF measurements is MRI of the heart
Gene therapy imaging due to its most accurate estimation of LV volumes on which
LVEF measurements are based. GBP and first-pass studies and
MYOCARDIAL FUNCTION myocardial perfusion studies are, however, reproducible, easier
to perform and less expensive. GBP are used in follow-up of
Nuclear medicine techniques are ideally suited for analysis of
patients on chemotherapy for detecting early cardiotoxicity and
myocardial function (Table 2). By labelling the patient’s red
in follow-up of cardiac transplant recipients.
blood cells with radiotracer, and using ECG triggered gating,
the blood pool in the heart is imaged.This study called the ‘gated MYOCARDIAL PERFUSION
blood pool’ (GBP) study helps to give accurate quantification
Myocardial perfusion imaging (MPI) is now a well-established
of left ventricular ejection fraction (LVEF) and also the wall
regularly used method in evaluation of a patient with ischaemic
motion of different walls of the left and right ventricle. Analysis
heart disease. The procedure involves injection of radio-
of the electrical conduction can also be made from special
pharmaceutical intravenously during exercise followed by
computer derived ‘phase images’ and asynchrony in conduction
acquisition of post exercise images with a gamma camera
can be mapped. Diastolic function can also be quantified by
(Tables 3 and 4). The patient is re-injected at rest followed by
analysis of the computer generated LV volume curve.
resting image acquisition. The stress and rest images are then
Diastolic function, estimated from the LV volume curve, gives compared. The radiopharmaceutical, usually Thallium or 99mTc
four parameters of ventricular relaxation and filling. These are methoxy isobutyl isonitrile (MIBI) is selectively picked up by the
peak filling rate (PFR), time to peak filling rate (TPFR), average myocardium in proportion to blood flow. Areas supplied by
filling rate (AFR) and atrial contribution to LV filling. stenosed coronary arteries do not get adequate supply of the

Table 2: The Nuclear Techniques for Evaluation of Myocardial Function

Study Name Isotope Used Information Obtained Importance

Gated blood pool and 99mTc-pertechnetate Left ventricular ejection fraction Robust parameter of left ventricular function.
first-pass studies 20 to 30 mL (LVEF) Altered in various cardiac disorders like
myocardial infarction, cardiomyopathy
Wall motion Exercise induced wall motion abnormalities
are sensitive and specific for ischaemia
Diastolic function Earliest to be affected in cardiac disorders
Gated myocardial 99mTc-MIBI/ LVEF/Wall motion, wall thickening, Single test combining perfusion and function
perfusion scan tetrofosmin diastolic function, perfusion,
(myocardial ischaemia, infarct)
82Rb, 13NH3 Absolute quantification of Most accurate method for myocardial flow
myocardial blood flow, coronary estimation. CFR is of great importance in
flow reserve (CFR) estimation management decisions
605
 radiopharmaceutical as compared to areas supplied by normal indicate <1% probability of cardiac events (myocardial infarct,
arteries. This is seen as a ‘perfusion defect’. If this defect death) in the following 2 years. Large defects (high-risk scans)
disappears on the resting study, ischaemia is diagnosed. If the indicate >8% probability of cardiac events.
defect persists, then infarction is likely to be present.
Table 5: The Scan Patterns
Coronary blood flow increases several fold during exercise or
following adenosine infusion, in the normal coronary vascular Scan patterns
bed due to coronary vasodilatation in response to metabolic Low-risk scan
demand. It fails to increase appreciably in the territory of an Normal perfusion, or
obstructed coronary artery or arteries or in arteries with diffuse Small perfusion defects <10% of myocardium
endothelial dysfunction. The ratio of resting flow to flow after Intermediate risk scan
maximal coronary dilatation is called the coronary flow reserve Medium defect 10% to 20% of the myocardium, or
(CFR). Measurement of CFR is being increasingly recognised as Small perfusion defect + LV dilatation or lung uptake of tracer
vital information for making management decisions about High-risk scan
intervention in CAD. Large defects >20% of myocardium, or
Medium perfusion defect + transient dilatation of LV or lung
Table 3: Radiopharmaceuticals Used in Myocardial Perfusion
Imaging uptake of tracer

SPECT Higher the quantity of ischaemic myocardium (>12.5% of total

201 Thallium myocardium), the better the results from interventional
99mTc-MIBI treatment strategies (CABG, angioplasty) rather than medical
99mTc-Tetrofosmin management.
99mTc-Teboroxime
Thus, MPI identifies patients who should be managed by
PET medical versus revascularisation strategies.
82 Rubidium
PET technology allows absolute quantification of myocardial
13N-Ammonia
blood flow in mL/g/min and also estimates the CFR.
Table 4: Indications for Performing Myocardial Perfusion
Coronary angiography is blind to vessels <400 microns in
Imaging diameter. A significant portion of disease involves these vessels.
The only way to assess these vessels is through the estimation
1. Patients with abnormal baseline ECG (LBBB, LVH, digitalis of CFR (Table 6).
therapy, WPW syndrome) where treadmill stress test
interpretation is difficult. Table 6: The Utility of Estimating CFR
2. Women: high rate of false positive stress test results.
Patients unable to perform treadmill stress test (severe arthritis, Potential clinical applications of PET MPI and CFR estimation
neurological disorders, lack of motivation. Pharmacological Impaired CFR in early coronary atherosclerosis
stress test with adenosine/dobutamine can be done). Hypertension
3. Asymptomatic or mildly symptomatic individuals with risk Hyperlipidaemia
factors for ischaemic heart disease. Diabetes
4. Patients with diagnosed coronary artery disease by Smoking
angiography; for risk stratification and for evaluation of
Impaired CFR in coronary stenosis and advanced coronary
physiological significance of coronary stenosis.
atherosclerosis
5. Post-angioplasty for evaluation of re-stenosis.
Evaluation of functional significance of coronary lesions
6. Post-coronary bypass surgery for patency of grafts.
(intermediate lesions)
7. Post-myocardial infarction for risk stratification and viability
Detection/delineation of multi-vessel CAD
assessment.
Track disease progression/regression
Based on the scan findings, the results are classified into high, Impaired CFR in non-atherosclerotic microvascular disease
intermediate and low-risk scans. Patients demonstrating ‘low- Syndrome X, cardiomyopathies (HCM, DCM), hypertensive heart
risk scan’ pattern can be managed medically even in presence disease
of abnormal coronary angiograms (Table 5).
CFR is found to be impaired in patients with hypertension,
Patients showing ‘high-risk scan’ pattern should be sent for hyperlipidaemia, diabetes, and in smokers long before they
coronary angiogram (if not already performed) and for develop manifest atherosclerosis and coronary disease.
revascularisation. Figures 1 to 3 demonstrate the low, inter- Corrective measures have shown normalisation or improvement
mediate and high-risk scan patterns. Myocardial perfusion in CFR.
imaging (MPI) thus performs ‘gatekeeper’ function in CAD
In some patients with so called ‘balanced triple vessel disease’
management.
where there is similar degree of stenosis in all three coronary
It has been demonstrated by large volume of data over last arteries, a SPECT myocardial perfusion scan will look spuriously
several years that the size and severity and reversibility of normal since the tracer will go equally badly in all stenosed
perfusion defects demonstrated on a myocardial perfusion territories and there will be no relative hypoperfusion in a
have significant prognostic value. Small defects (low-risk scan) particular territory. In this situation, an absolute quantification
606
 Nuclear Cardiology
Figure 1: Shows a normal myocardial perfusion scan. Top two rows show matched short axis slices from apex to base: upper row post-stress and lower row during
rest. The middle two rows show vertical long-axis slices from septum to lateral wall (upper post-stress, lower resting). The lower two rows show horizontal long axis
slice from inferior to anterior wall. Note the homogenous perfusion in all areas with no perfusion defects.

of blood flow will show low values in all territories and the CFR during stress, ischaemic areas would show increased uptake of
will show low reserve. the glucose tracer. The normal areas would show no uptake of
18F-FDG. Stress FDG imaging is undergoing clinical studies.
This underscores the importance of PET scans in evaluation of
Hence, in patients coming to hospital with acute chest pain, a
MPI and CFR. Limited at the moment due to its high cost and
fatty acid tracer would immediately identify if there is ongoing
limited availability, PET MPI and CFR will in future become the
ischaemia, showing reduced uptake of the tracer in ischaemic
main tests in evaluation of ischaemic heart disease.
areas.
MYOCARDIAL METABOLISM
Table 7: Available Techniques for Imaging Myocardial
The normal myocardium predominantly uses fatty acids for Metabolism
its metabolic needs, to produce energy for contraction. In
Evaluation of myocardial metabolism with SPECT and PET
ischaemic conditions, the metabolism switches to the use of
glucose in order to produce ATP. This is an inefficient way of SPECT tracers
producing energy, but the only way available for the myocardium Fatty acid metabolism
in times of ischaemia. 123I-BMIPP, IPPA, DMIPP
PET tracers
It is possible with SPECT and PET techniques to evaluate myocardial Fatty acid metabolism
metabolism of fatty acids as well as glucose (Table 7). 11C-Palmitate
Evaluation of glucose metabolism has become the mainstay in Glucose metabolism
detection of viable myocardium. 18F-FDG (Fluoro-deoxy-glucose)

The switch in metabolism from fatty acids to glucose Many times after a large myocardial infarction with a resultant
metabolism can be used to diagnose myocardial ischaemia. If a low left ventricular ejection fraction, it is necessary to know if
fatty acid tracer is injected during stress, ischaemic areas would there is viable myocardium in the infarct zone. It has been
show reduced uptake of fatty acid tracer. If 18F-FDG is injected conclusively shown that revascularisation provides better 607
 Figure 2: Shows an intermediate risk scan pattern showing medium sized perfusion defects in apex, and lateral wall.

clinical outcomes in terms of survival and symptomatic PET remains the ‘gold standard’ for detecting myocardial
improvement in patients with viable myocardium as compared viability. Viable myocytes retain capability of metabolising
to medical therapy. Therefore, identification of viable glucose. Dead myocytes or scar tissue cannot metabolise
myocardium is of great importance post myocardial infarction. glucose. Hence, if a resting myocardial perfusion shows a severe
Several techniques are available for this identification, namely perfusion defect and an FDG scan shows uptake of tracer in
low-dose dobutamine stress echocardiography, delayed the same area (perfusion-metabolism mismatch), then viability
608 enhanced MRI, and 18F-FDG myocardial PET. Currently, 18F-FDG is present.
 Nuclear Cardiology
available, it will become increasingly important to identify
markers predictive of drug efficacy for individual heart failure
patients, based on sympathetic nerve imaging.

APOPTOSIS IMAGING
Pathological insults can induce apoptosis in various cardio-
vascular disorders, e.g. infarction and reperfusion injury,
myocarditis, heart failure, heart transplant rejection.
Identification of apoptosis is possible by imaging with 99mTc-
annexin. The usefulness of serial imaging has been demon-
strated clinically in early detection of cardiac transplant
rejection by positive scans. Upon immunosuppressive
therapy with cyclosporine the scans become negative within
two days.

ATHEROSCLEROSIS AND GENE THERAPY IMAGING

For ensuring success of gene and cell based therapies, it is of
Figure 3: Shows a high-risk scan pattern with transient LV dilatation and large prime importance to develop technology for non-invasive
reversible defects in apical and anterior segments. monitoring of the location and duration of gene expression,
distribution and targeting of therapeutically engineered cells
MYOCARDIAL INFARCTION and vector particles in vivo. A number of advances have been
On standard MPI, an area of infarction is seen as a persistent achieved in high resolution, in vivo imaging methods, such as
perfusion defect on both the stress and rest images (fixed bioluminescence imaging, MRI, PET and various fluorescence
defect). Tracers have been developed which would be imaging techniques, including fluorescence-mediated
concentrated in infarcted tissue. tomography (FMT) and near infrared fluorescence (NIRF)
reflectance imaging.
Glucaric acid localises in necrotic (not normal or ischaemic)
tissue. Acute MI can be visualised within 1 to 2 hours of the onset Identifying patients at high-risk for an acute cardiovascular
of pain, in patients with or without thrombolytic therapy. Infarcts event such as myocardial infarction or stroke and assessing the
older than 2 to 3 days are not likely to show up on imaging. total atherosclerotic burden are clinically important. Currently
Tc-glucaric acid imaging will provide an important triage available imaging modalities can delineate vascular wall
function in the emergency room in the evaluation of acute anatomy and, with novel probes, target biologic processes
coronary syndromes. It will also detect peri-operative infarcts important in plaque evolution and plaque stability.
following CABG. CONCLUSION
MYOCARDIAL RECEPTORS Nuclear cardiology has established itself as a very important
Non-invasive assessment of cardiac pre-synaptic sympathetic diagnostic tool in the management of heart disease. By its
nerve activity is possible with 123I-MIBG SPECT and 11C meta unique ability to study physiological processes and their
hydroxyephedrine (HED) PET. Myocardial receptor imaging alteration in health and disease, it provides important diagnostic
has a potential diagnostic and prognostic role in patients with and prognostic information vital for making appropriate
heart failure and cardiomyopathies. Regional uptake and management decisions. Information from anatomical
washout of the radiotracer are expressed as heart to upper modalities should be combined with physiological information
mediastinum (H/M) ratio in the early and late images of 123I- from nuclear cardiology techniques for full understanding of
MIBG SPECT. A low H/M ratio strongly predicts poor outcome. disease pathophysiology and appropriate management.
Other applications include detection of diabetic autonomic RECOMMENDED READINGS
neuropathy, cardiac transplant, re-innervation and re-entrant
1. Al-Mallah MH, Sitek A, Moore SC. Assessment of myocardial perfusion
arrhythmias post-myocardial infarction. with PET and PET-CT. J Nucle Cardiol 2010;17: 498-513.
Regional heterogeneities in β-adrenergic receptor number 2. Beller G. Clinical value of myocardial perfusion imaging in coronary artery
disease. J Nucle Cardiol 2003; 10:529-42.
and reuptake occur in subjects with sudden cardiac death,
3. Jain D, Lesig H. Influence of 99mTc-Tetrofosmin SPECT myocardial
and may be predictive for future events. Genetic variations in perfusion imaging on the prediction of future adverse cardiac events. J
β-adrenergic receptors have major implications in terms of Nucle Cardiol 2009; 16: 4.
future development of CHF and early associated mortality. As 4. Zaret B, Beller G. Clinical Nuclear Cardiology: State of the Art and Future
newer third generation beta blockers like carvedilol become Directions; 4th Ed. Elsevier Mosby; 2010.

609
 12.8 Cardiac Catheterisation and
Angiocardiography
Lekha Adik Pathak, NO Bansal

INTRODUCTION Technique
The introduction of cardiac catheterisation ushered in the era of Cardiac catheterisation is performed in adults and older children
modern cardiology with marked improvement in the diagnostic under light sedation and local anaesthesia with xylocaine.
capabilities of cardiac ailments and followed in turn, with the key- However, in smaller children and infants, general anaesthesia is
hole approach to treatment of a large majority of the cardiac required. The portals of entry commonly employed are as under:
patients since the 1980s. Even today angiography is considered
‘gold standard’ in the diagnosis of coronary artery disease (CAD). Table 1: Indications of Cardiac Catheterisation
Diagnostic
HISTORY
To define cardiovascular anatomy in patients with congenital or
Cardiac catheterisation opened the way for the study of acquired heart diseases
anatomy and physiology of heart. The development of cardiac To define coronary artery anatomy
catheterisation has had profound impact on the diagnosis and To assess ventricular function
treatment of CAD and congenital and valvular heart diseases. To determine intracardiac/intravascular pressures and measure
The noted 19th century French physiologist Claude Bernard flow (cardiac output) for calculation of physiological parameters
catheterised and measured pressure in the various cardiac To determine transvalvular gradients across cardiac valves and
chambers and great vessels of the animal heart. The first to quantify valvular regurgitation when there is disparity between
catheterisation of the living human heart was performed by a clinical and echocardiographic findings
young surgeon, Werner Forssmann (on himself ) in 1929 in For electrophysiologic (EP) studies to localise the site of heart
Eberswald, Germany. Cardiac catheterisation paved the way for block and the nature and pathway of cardiac arrhythmias
coronary arteriography. The first coronary angiogram was To perform endomyocardial biopsies
performed by F. Mason Bones on October 30, 1958; since then Therapeutic
it has revolutionised our understanding and treatment of CAD. Percutaneous coronary interventions (PCI)
The coronary angiogram not only provided objective evidence Valvular dilations such as balloon mitral valvuloplasty (BMV),
to support or refute the clinical diagnosis of angina pectoris balloon pulmonary valvuloplasty (BPV), balloon aortic valvuloplasty
but, more importantly, led to first studies of the natural history Device closure of atrial septal defects (ASD), ventricular septal
of patients with CAD. The coronary angiogram provided the defects (VSD), patent ductus arteriosus (PDA) and other uncommon
road map necessary for the successful development of coronary congenital defects such as coiling or device closure of ruptured sinus
of Valsalva aneurysm (RSOV), and coiling of coronary artery fistulas
angioplasty. On 16 September 1977, Andreas Gruentzig
Balloon atrial septostomy as in patients with transposition of great
performed the first coronary angioplasty in an awake human, a
arteries (TGA)
37-year-old insurance salesperson with proximal LAD lesion and
Radiofrequency ablation (RFA) of foci of cardiac arrhythmias and
thus described a new way of achieving coronary revascularisation
pathways of aberrant conduction
by the endovascular dilation of an obstructing lesion, that he
Local thrombolysis in patients with pulmonary artery embolism
referred to as percutaneous transluminal coronary angioplasty
Alcohol septal ablation in HOCM
(PTCA).

CARDIAC CATHETERISATION PROCEDURE Table 2: Relative Contraindications of Cardiac Catheterisation

Cardiac catheterisation procedure involves: Uncontrolled ventricular irritability (increased risk of ventricular
1. Pressure measurements: To calculate pressure, gradients tachycardia/fibrillation)
and valve areas. Digitalis toxicity
2. Oximetry data: To measure oxygen saturation and for Electrolyte imbalance (e.g. uncontrolled hypokalaemia)
calculation and directions of shunts. Uncorrected hypertension
3. Contrast injections for opacification of cardiac chambers Concurrent febrile illness
and coronary angiograms. Decompensated heart failure
Indications Severe renal insufficiency, unless dialysis is planned
Severe allergy to radiographic contrast agent
The decision to perform cardiac catheterisation must be based
Prothrombin time >18 or INR >2 or bleeding diathesis
on a careful balance of the risk of procedure against the
anticipated benefit to the patient. Indications of cardiac
Femoral route
catheterisation are enumerated in Table 1.
The femoral artery and vein are the most commonly used vessels
Contraindications for cardiac catheterisation. It is important to puncture these
There is no absolute contraindication to cardiac catheterisation. vessels at correct level, i.e. 1 cm to 2 cm below the inguinal
610 Relative contraindications are given in Table 2. ligament (and not the inguinal skin crease) which runs from the
 Cardiac Catheterisation and Angiocardiography
anterior superior iliac spine to pubic tubercle. Though earlier Hovagim and validated by Gerard Barbeau) can also be done.
puncture was done using Seldinger technique with a Seldinger This method involves placing a pulse oximeter probe on
needle, nowadays most of the cardiac catheterisation the thumb while compressing the radial artery. Adequacy of
laboratories use a single wall puncture needle. Once the needle palmar arch blood flow is confirmed by the presence of an arterial
is in the vessel, it is stabilised with the left hand and a guide wire waveform (even if with reduced amplitude or delayed appearance)
(0.035 or 0.038 inch) with J tip is inserted via the needle into the and oxygen saturation of >90%. The patency of radial and ulnar
vessels, while making sure that there is no resistance felt during arteries is best confirmed by Doppler study. The major advantages
its advancement. The needle is then removed and a skin nick (if of radial artery approach are faster time to ambulation and rare
not already done) is made. An appropriate sized sheath is then access site bleeding complications. Limitations include smaller
threaded over the guide immediately after sheath insertion. artery size and inability to take venous access.
The catheters are then guided under fluoroscopic control to
Other sites
appropriate site, through the sheath (Figure 1).
Brachial artery can be approached over the antecubital fossa
by both percutaneous technique and surgical cut-down. Axillary
artery can be entered over the head of humerus. In the new
born, umbilical artery can be used for catheterisation.

GENERAL PRINCIPLES
Figure 2 outlines the hardware and machine used for cardiac
catheterisation.
Certain general principles should be followed during cardiac
catheterisation. Haemodynamic measurements should
precede angiographic studies, so that the pressure and flow
measurements are made as close as possible to the basal state.
Measurements of pressure and cardiac output should be made
as simultaneously as possible. Cardiac output can also be
measured using thermodilution techniques.
Limit total contrast volume for the study (in paediatric patients,
this should not exceed >5 mL/kg). Currently, most contrast
media used are non-ionic with low osmolality. Nowadays, 10%
to 30% of coronary angiograms and angioplasties are done via
radial route and it is increasing still further in view of great
patient comfort and less bleeding. The blood samples need to
be acquired with the patient breathing (or being ventilated
with) air or a gas mixture containing no more than a maximum
Figure 1: Regional anatomy relevant to percutaneous femoral arterial and venous
catheterisation. Schematic diagram showing the right femoral artery and vein of 30% oxygen.
coursing underneath the inguinal ligament, which runs from the anterior superior
iliac spine to the pubic tubercle. The arterial skin nick should be placed INTERPRETING TRACINGS
approximately 1 cm to 3 cm below the ligament and directly over the femoral
arterial pulsation, and the venous skin nick should be placed at the same level Atrial Tracings
but approximately one finger-breadth more medially. Although this level Atrial tracings have three positive waves namely ‘a’, ‘c’ and ‘v’ and
corresponds roughly to the skin crease in most patients, the anatomical
two descents namely ‘x’ and ‘y’. The ‘c’ wave is often missing. Left
localisation relative to the inguinal ligament provides a more constant landmark.
atrium (LA) tracings differ from those of right atrium (RA) in the
form that ‘v’ wave is taller than ‘a’ wave in the former (Figure 3)
Radial artery route
Also pressures are generally higher in the LA tracing. Tall ‘a’ waves
This approach is especially useful for those with peripheral arterial in the RA tracing suggest tricuspid stenosis (TS), pulmonary
disease and morbid obesity. The preferred site of puncture is stenosis (PS), and significant pulmonary hypertension (PH). Tall
approximately 1 cm to 2 cm proximal to the radial styloid. Radial ‘a’ waves in the LA tracing suggest mitral stenosis (MS) and left
artery cannulation is done using a micropuncture needle (21 ventricular hypertrophy (LVH) due to any cause.In atrial fibrillation
gauge). Using the technique as described above, an appropriate (AF), ‘a’ wave is absent. Tall ‘v’ waves in the RA tracing suggest
sized sheath (5 or 6 F) is inserted into the vessel. Anticoagulation tricuspid regurgitation (TR) and in the LA suggest mitral
(usually, heparin) and cocktail of vasodilators (NTG 100 mg to 200 regurgitation (MR). A well marked ‘y’ descent rules out significant
mg, verapamil 1.25 mg to 2.5 mg) is administered immediately stenosis of the respective AV valve. In cardiac tamponade, the ‘x’
after sheath insertion. As the risk of post-procedural radial artery descent is present but ‘y’ descent is absent. A rapid ‘x’ and ‘y’
occlusion is up to 3%, palmar arch patency must be assessed prior descent (M or W sign) is seen in constrictive pericarditis.
to the procedure. This is done by Allen’s test. Both the radial and
ulnar arteries are compressed while the patient is asked to make Ventricular Tracings
and open fist 3 to 4 times. Ulnar artery compression is then Left ventricular end-diastolic pressure (LVEDP) is somewhat
removed and the time taken for the palm to get flushed is noted. higher than right ventricular end-diastolic pressure (RVEDP)
Absent or delayed flushing suggests inadequate palmar arch reflecting the greater stiffness of LV. High right ventricular systolic
611
blood flow. A modification of Allen’s test (first developed by pressure (RVSP) is seen in PS and PH due to any cause. Raised
 Figure 2: Cineangiography equipment. The major components include a generator, X-ray tube, image intensifier attached to a positioner such as a C-arm, optical
system, video camera, videocassette recorder (VCR), analog to digital converter (ADC), and television monitors. The X-ray tube is the source of the X-ray beam,
which passes superiorly through the patient.

Figure 3: Normal right- and left-heart pressures recorded from fluid-filled catheter systems in a human.

left ventricular systolic pressure (LVSP) is seen in systemic With significant aortic stenosis (AS), there is decapitation of
hypertension and left ventricular outflow tract obstruction systolic pressure. Similar changes are seen in respective
(LVOTO) due to any cause (aortic stenosis, hypertrophic pulmonary artery tracings in those with PR or PS. Pulmonary
obstructive cardiomyopathy). Higher ventricular end-diastolic arterial wedge pressure obtained by wedging the right heart
pressures reflect ventricular dysfunction or restrictive physiology. catheter far out into a pulmonary artery branch reflects the
LA pressure in individuals without any vascular lung disease
Arterial Tracings or pulmonary venous obstruction. It is, thus, a measure of
In severe aortic regurgitation (AR), the arterial pulse pressure is LV diastolic pressure in those with normal functioning mitral
wide with a high systolic pressure and lower diastolic pressure. valve.
612
 Cardiac Catheterisation and Angiocardiography
Pressure recordings provide an important clue to the presence Shunt Detection
of valvular stenosis. With significant stenosis of semilunar valves, Cardiac catheterisation data are also used to detect, localise and
a systolic pressure gradient is present between the respective quantify left to right shunt or right to left shunts. For example, a
great artery and the ventricular chamber (Figure 4). Stenosis step-up in oxygen saturation from 65% in the RA to 80% in
across the AV valves results in pressure gradients in diastole pulmonary artery is indicative of large left to right shunt that may
between the respective atrial and ventricular chamber. (Table 3 be due to ventricular septal defect. Pulmonary to systemic flow
gives normal pressure values of chambers and across valves). ratio (Qp:Qs) can be calculated as it provides a simple and reliable
estimate of the extent to which pulmonary flow is increased or
Table 3: Haemodynamic Data
reduced and provides a useful insight into the severity of the
Chamber Normal Values haemodynamic disturbance in most cases. It is also very simple
RA pressure Mean 1 to 5 mm Hg to perform, employing the oxygen saturation data.The formula is:
RV systolic pressure (RVSP) 15 to 30 mm Hg Qp:Qs = Sat AO – Sat MV
RV end diastolic pressure (RVEDP) 1 to 7 mm Hg
Sat PV – Sat PA
PA systolic pressure (PASP) 15 to 30 mm Hg
PA diastolic pressure (PADP) 4 to 12 mm Hg where Sat AO is aortic saturation, Sat MV is mixed venous
PA mean 9 to 19 mm Hg saturation; Sat PV is pulmonary vein saturation, and Sat PA is
PCWP Mean 4 to 12 mm Hg pulmonary artery saturation.
LA pressure Mean 2 to 12 mm Hg
LV systolic pressure (LVSP) 90 to 140 mm Hg Calculation of pulmonary vascular resistance (PVR) and systemic
LV end diastolic pressure (LVEDP) 5 to 12 mm Hg vascular resistance (SVR) is very important in cases of shunts to
Aorta systolic pressure 90 to 140 mm Hg decide further treatment options.
Aorta diastolic pressure 60 to 90 mm Hg
Mean aortic pressure (MAP) 70 to 105 mm Hg ANGIOGRAPHY (CONTRAST INJECTION)
Systemic vascular resistance 1170 ± 270 dynes sec/cm–5
The goal of coronary angiogram is to examine the entire
Pulmonary vascular resistance 67 ± 30 dynes sec/cm–5
Oxygen consumption 125 mL/m2 coronary anatomy including the native vessels and bypass grafts,
AV oxygen difference 30 to 50 mL/L if any.The coronary artery can be delineated by opacifying it with
Cardiac output 4 to 8 L/min contrast material which is injected via a catheter that is engaged
to the respective coronary artery sinus. Images of the coronary
Valve Area artery are recorded by filming with digital cineangiography
Calculation of valve area is based on the hydraulic formula systems at 10 to 30 frames/s. Each coronary artery is visualised
usually referred to as the ‘Gorlin formula’. The calculation in several views and analysed for the anatomy, number and
depends on obtaining estimates for valve flow in mL/s during severity of stenosis (commonly expressed as % stenosis relative
the time that the valve is open. to normal segment) (Figures 5 to 7).
Normal mitral valve area in adults is 4 to 5 cm2. When it is less VENTRICULOGRAM
than 1 cm2, it becomes critical MS. In adults, the normal aortic
A ventriculogram can be performed by rapid injection of radio-
valve area is 3 to 4 cm2 and critical AS is said to be present when
opaque contrast agent into the chamber to be assessed. A
valve area is less than 0.8 cm2.
power injector injects the contrast agent at a pre-selected flow
rate, volume and pressure. The catheter used is usually an end-
hole catheter with multiple side-holes (pigtail catheter) as it can

Figure 4: Pressure gradient in a patient with mitral stenosis. The pressure in Figure 5: Left coronary angiogram in right anterior oblique (RAO) caudal view,
the left atrium (LA) exceeds the pressure in the left ventricle (LV) during diastole, showing left main trunk (LMT), left anterior descending (LAD) and left circumflex
producing a diastolic pressure gradient (green shaded area). arteries (LCX) and their branches. 613
 Figure 6: Left coronary angiogram in left anterior oblique (LAO) cranial view.
LMT = Left main trunk; LAD = Left anterior descending; LCX = Left circumflex artery. Figure 8: Balloon mitral valvuloplasty showing the inflated Inoue balloon across
the mitral valve.

COMPLICATIONS
Serious complications of cardiac catheterisation include death,
myocardial infarction (MI), or stroke. Their incidence is < 1%. The
risk of vascular injury requiring transfusion or surgical repair is
<2%. Perforation of heart or great vessels may occur, especially
when using the trans-septal technique. Vasovagal reactions are
common and respond well to atropine. Major arrhythmias occur
in 1% patients and include ventricular tachycardia/fibrillation and
bradyarrhythmias. Because cardiac catheterisation is inherently
a sterile procedure, infection is extremely unusual. Iodinated
contrast agents may trigger allergic reactions. At least 5% of
patients experience a transient rise in serum creatinine (contrast
induced nephropathy) following coronary angiography; however,
nowadays non-ionic low osmolar contrast agents are widely used
which have significantly lower incidence (1%) of allergic reaction.
Hypotension and heart failure may occur sometimes especially
Figure 7: Right coronary angiogram in right anterior oblique (RAO) view, in those with extensive CAD or depressed LV function.
showing right ventricular, posterior left ventricular (PLV) and posterior
descending (PDA) branches. RECOMMENDED READINGS
RCA = Right coronary artery. 1. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint
National Committee on Prevention, Detection, Evaluation, and Treatment
rapidly deliver a bolus of the contrast agent without recoil. of High Blood Pressure: The JNC 7 report. JAMA 2003; 289: 2560-72.
Ventricular wall contraction can be visually assessed by 2. Courtois M, Fattal PG, Kovács SJ, et al. Anatomically and Physiologically
Based Reference Level for Measurement of Intracardiac Pressures.
ventriculogram. Regional abnormalities of wall motion include Circulation1995; 92: 1994-2000.
diminished inward motion of myocardial segment (hypokinesia), 3. Duprez DA. Role of the rennin-angiotensin-aldosterone system in vascular
absence of movement of myocardial segment (akinesia) and remodelling and inflammation: A clinical review. J Hypertens 2006; 24: 983-91.
paradoxical systolic expansion of regional myocardial segment 4. Jacobs AK, Faxon DP, Hirshfeld JW, et al. Task force 3: Training in diagnostic
(dyskinesis). Also ventricular end-diastolic pressures can be cardiac catheterisation and interventional cardiology. Revision of the 1995
COCATS training statement. J Am Coll Cardiol 2002; 39: 1242-6.
determined. Ventricular systolic function can also be assessed
5. Jolly SS, Amlani S, Hamon M, et al. Radial versus femoral access for coronary
by calculating ejection fraction, dp/dt or stroke work.
angiography or intervention and the impact on major bleeding and
Besides aortography may be performed when indicated (as in ischaemic events: a systematic review and meta-analysis of randomised
trials. Am Heart J 2009; 157: 132-40.
quantification of aortic regurgitation, identification of aortic
6. Scanlon PJ, Faxon DP, Audet AM, et al. ACC/AHA guidelines for coronary
aneurysm and/or aortic dissection) to define the size of aortic angiography: A report of the American College of Cardiology/American
root and thoracic aorta. Heart Association Task Force on Practice Guidelines (Committee on Coronary
Angiography) developed in collaboration with the Society for Cardiac
Various procedures, like balloon valvuloplasties of AV valves can Angiography and Interventions. J Am Coll Cardiol 1999; 33: 1756-1824.1.
be easily done, by percutaneous route, with the help of contrast 7. Victor RG, Shafiq MM. Sympathetic neural mechanisms in human hyper
614 ventriculograms (Figure 8). tension. Curr Hypertens Rep 2008; 10: 241-7.
 12.9 Pharmacotherapy of Cardiovascular Disorders

J C Mohan, Vipul Mohan

INTRODUCTION between dosing is an effective means of overcoming the

It is well known that cardiovascular diseases are the number development of tolerance; although in some cases, a rebound
one cause of mortality in the world. Cardiovascular of symptoms may occur at this time. Eccentric dosing of oral
pharmacotherapy has been a tremendous success story. nitrates is a recognised way of reducing nitrate tolerance.
Underlying this success has been knowledge of the neuro- This can be obviated by the concomitant use of another class
endocrine signal transduction pathways, receptors, enzymes, of anti-anginal agents. Nitrates do not influence morbidity or
cytokines and ion channels involved in pathogenesis of disease mortality.
process.
Table 2: Major Classes of Anti-anginal Drugs
MANAGEMENT OF ANGINA AND MYOCARDIAL ISCHAEMIA Organic nitrates (reduce pre-load and increase coronary blood flow)
Angina results from an imbalance between myocardial Pure negative chronotropic agents (direct sinus node inhibitors, like
perfusion and myocardial metabolic demands. Heart rate (HR) ivabradine, cilobradine, etc.)
reduction can alter both elements of this imbalance beneficially. Negative chronotropic and negative inotropic agents (beta-
The resulting increase in diastolic filling time should improve adrenergic receptor blockers and phenylalkylamine and
myocardial perfusion; myocardial oxygen demand varies benzothiazepine calcium channel blockers, like verapamil,
diltiazem, etc.)
directly with HR. It is essentially due to demand-supply
mismatch of oxygen at mitochondrial level. There is, however, a Vasodilatory non-chronotropic calcium channel blockers (nifedipine,
nitrendipine, amlodipine, etc.)
weak relationship between severity of pain and degree of
oxygen deprivation in the heart muscles. Delayed sodium current (phase I sodium channel blockers)
modifiers, like ranolazine
About five million patients in India use anti-anginal drugs. Nitric oxide donors, like nicorandil and nebivolol
Anti-anginal efficacy is documented by improved exercise
Metabolic modulators (trimetazidine, perhexiline maleate,
tolerance, reduction in angina attack rate and short-acting diacetoacetate, etc.)
nitrate use, and anti-ischaemic efficacy by reduction in exercise-
induced electrocardiogram (ECG) ST-segment depression. Table 3: Different Types of Nitrates
Pharmacological Approach in Ischaemia/Angina Short-acting nitrates: Nitroglycerine, amyl nitrate
Pharmacological treatment of angina encompasses both the Intermediate-acting nitrates: Isosorbide dinitrate
prevention of the complications of coronary atherosclerosis Long-acting nitrates: Isosorbide mononitrate
and the relief of symptoms. Progress of atherosclerosis can be
retarded by statins, anti-RAAS agents and blood pressure Calcium antagonists
lowering drugs. Modes of relief of ischaemia are shown in Calcium antagonists cause coronary and peripheral vasodilation.
Table 1. Furthermore, smooth muscle relaxation and reduction of after-
load together with the negative inotropic effects of some of
Table 1: Modes of Relief of Ischaemia
the agents will reduce myocardial oxygen consumption. While
Reduce energy expenditure (mainstay) various formulations of the two prototype papaverine-like and
Increase oxygen delivery (increase myocardial blood flow) benzothiazepine-like calcium antagonists, verapamil and
Increase oxygen efficiency (complimentary) diltiazem are widely available, most current development
Combined involves analogues of the nifedipine-like dihydropyridine class.
The calcium antagonists are a structurally heterogeneous group
Drugs which reduce myocardial contractility, HR and/or of compounds with important differences in pharmacological
systolic blood pressure are the mainstay of anti-anginal therapy action.
(Table 2). These include beta-adrenergic receptor blockers,
calciumchannel blockers and direct sinus node inhibitors. Verapamil slows conduction through the atrioventricular node
and has important negative inotropic effects as well as causing
Nitrates smooth muscle relaxation which leads to an increase in
Sublingual nitrates work rapidly, i.e. within minutes, and the coronary blood flow and a reduction in after-load. The
effect lasts for about 30 to 45 minutes. Profound relief of dihydropyridines, such as nifedipine and amlodipine, also
symptoms is the result of venodilatation, after-load reduction cause smooth muscle relaxation but have no effect on cardiac
and coronary dilatation. Many nitrate delivery systems have pacemaker tissue which may result in a reflex increase in the
been developed for chronic prophylactic use (Table 3). It has HR. In common with other calcium antagonists, these drugs
become clear, however, that patients can develop at least have negative inotropic effects, which are, however, less
partial tolerance to this therapy. The use of nitrate-free interval marked than those of verapamil. The effect of diltiazem is 615
 similar to those of verapamil though it has a less potent effect oxygen efficient, and hence, switching from free fatty acids to
of left ventricular function. glucose will relieve ischaemia in a strained heart.
Beta-adrenergic receptor blockers Most commonly used metabolic modulator as an anti-
Catecholamines stimulate largely type 1 beta-receptors present ischaemic agent is trimetazidine in a maximum dose of 60 mg
in myocardium. Although this activation of beta-1 receptors per day. It is the mitochondrial enzyme long-chain 3-ketoacyl
provides inotropy, chronotropy and lusitropy which is extremely coenzyme A thiolase, inhibition of which triggers a balancing
useful in acute situations, chronic overstimulation creates a state increase in pyruvate oxidation and reduces the accumulation
of energy starvation, calcium overload, mechanical inefficiency, of lactate.
hypertrophy, inhibition of repair, extracellular matrix synthesis,
state of inflammation and hypokalaemia and aggravates angina MANAGEMENT OF ACUTE CORONARY SYNDROME
and ischaemia (Table 4). Beta-receptor antagonists counteract Besides the usual measures like bed rest, hospitalisation, oxygen
these deleterious effects by occupying the receptors and therapy, pain relief and use of above-mentioned anti-ischaemic
displacing catecholamines. drugs, it needs to be stratified into a risk category based upon
well-established scoring systems and algorithms. High-risk
Table 4: Mechanisms of Anti-Ischaemic Action of Beta-Blockers patients need a combination of pharmacotherapy with
Reduced energy expenditure by slowing the heart rate catheter-based interventions while non-high-risk patients are
Reduced energy expenditure by negative inotropy usually managed conservatively with potent anti-platelet and
anti-thrombotic drugs along with plaque stabilisers, like statins
Improved myocardial flow by prolonging diastolic filling period
and anti-RAAS agents. Drug therapy for acute coronary
Improvement in mechanoenergetics
syndrome is summarised in Table 5.
Reverse remodelling of the dysfunctional ventricular myocardium
Table 5: Drug Therapy for Acute Coronary Syndrome
Usually, beta-adrenergic receptor blocking agents are used
orally for chronic prophylaxis and can be administered once or Dual oral anti-platelet therapy
twice a day in progressively increasing doses till resting heart Anti-thrombotic therapy
rate reaches about 60 beats per minute or adverse effects Thrombolytic therapy for ST-elevation myocardial infarction
appear. Usual doses of atenolol (100 mg per day), metoprolol Anti-ischaemic therapy with emphasis on beta-blockers, calcium
(200 mg per day), bisoprolol (10 mg per day), nebivolol (5 to 10 channel blocking agents and nitroglycerine
mg per day), carvedilol (50 mg per day) are sufficient for this Plaque stabilising therapy like statins in high doses and beta-
purpose. Intravenous propranolol, atenolol and metoprolol have receptor blocking agents
been used during rest angina, especially when associated with Anti-RAAS agents after stabilisation
tachycardia (Figure 1). Potent intravenous anti-platelet agents for catheter-based
interventions

Aspirin has been thoroughly evaluated as an anti-platelet drug

and was found to prevent vascular death by approximately 15%
and non-fatal vascular events by about 30% in a meta-analysis
of more than 100 randomised trials in high-risk patients. The
best characterised mechanism of action of the drug is related
to its capacity to inactivate permanently the COX activity of
prostaglandin H-synthase-1 and -2 (also referred to as COX-1
and COX-2). The saturability of the anti-platelet effect of aspirin
at low doses, the lack of dose-response relationship in clinical
studies evaluating its anti-thrombotic effects, and the dose
dependence of its side effects all support the use of as low a
dose of aspirin as has been found to be effective in the
treatment of various thromboembolic disorders.
Figure 1: Classification of beta-adrenoreceptor blockers on the basis of cardio-
selectivity and intrinsic sympathomimetic activity (ISA). Dual anti-platelet therapy has become the standard of care
for all cases of acute coronary syndrome because of their
Metabolic modulators synergistic and additive benefits. Initially, it was used to be
aspirin (75 to 300 mg per day) along with ticlopidine but now
Metabolic modulators are the agents that may reduce
it is aspirin with clopidogrel (75 to 150 mg per day). Newer
symptoms without affecting haemodynamics, inotropy and/or
drugs like prasugrel and ticagrelor may replace clopidogrel
chronotropy. Glucose oxidation is the key step to be influenced
in near future at least in high-risk cases. Table 6 shows the
in a metabolic approach to the treatment of ischaemia/
anti-platelet drug therapy currently being used in patients
reperfusion diseases, such as angina. Free fatty acids are the
with acute coronary syndrome.
main fuel for the healthy heart, with a lesser contribution from
the oxidation of glucose and lactate. Myocardial ischaemia Dual anti-platelet treatment is required for at least one year
alters fuel metabolism, causing an accelerated rate of glucose after an episode of acute coronary syndrome or percutaneous
conversion to lactate and a switch from lactate uptake by the coronary intervention. Selected cases may, however, require
heart to lactate production. Metabolic modulators produce a longer treatment. Subsequent to one year, aspirin alone or
616
switch in substrate utilisation by the heart. Glucose is 16% more clopidogrel alone in aspirin-intolerant patients is sufficient.
 Pharmacotherapy of Cardiovascular Disorders
Table 6: Anti-Platelet Drugs fraction of heparin preparations is non-selective in its ability to
enhance anti-thrombin III-mediated inhibition of both thrombin
Cyclooxygenase-1 inhibitors and factor Xa, demonstrating equipotent activities in anti-factor
Aspirin IIa (thrombin)-specific and anti-factor Xa-specific assays.
Adenosine diphosphate receptor inhibitors
Clopidogrel Heparin is heavily sulphated, causing it to bind non-specifically
Elinogrel to various plasma and cellular proteins.This contributes to heparin’s
Prasugrel unfavourable pharmacokinetic properties, including a complex
Ticlopidine clearance mechanism and a relatively short, dose-dependent
Ticagrelor half-life. It also leads to reduced bioavailability and consequently,
Cangrelor (both oral and intravenous) an unpredictable anticoagulant response in different individuals,
Phosphodiesterase inhibitors which requires frequent laboratory monitoring of activated
Cilostazol partial thromboplastin time to ensure adequate anticoagulation
Glycoprotein IIB/IIIA inhibitors (intravenous use only) without enhanced bleeding risk. Heparin’s high degree of
Abciximab non-specific binding is directly responsible for a number of
Eptifibatide undesirable complications that represent major drawbacks to
Tirofiban
unfractionated heparin therapy; these complications include
Defibrotide
changes in platelet function that contribute to bleeding
Adenosine reuptake inhibitors
complications, heparin resistance, osteoporotic changes, and
Dipyridamole
most important, heparin-induced thrombocytopaenia.
Glycoprotein IIB/IIIA Inhibitors Low molecular weight heparin preparation
Platelet membrane glycoprotein (GP) IIb/IIIa receptors constitute Short chains containing the pentasaccharide sequence
the final common pathway of platelet aggregation, the integrin predominate, but longer chains that contain the pentasaccharide
GPIIb/IIIa antagonists prevent cross-linking of platelets. The sequence as well as thrombin-binding structures are included
inhibitors of GP-IIb/IIIa include monoclonal antibodies against in all low molecular weight heparin (LMWH) preparations to
the receptor (Abciximab), naturally occurring Arg-Gly-Asp varying degrees. Thus, LMWH that shares the same mechanism
sequence (RGD) containing peptides isolated from snake of anti-thrombin III-mediated inhibition as unfractionated
venoms, synthetic RGD- or Lys-Gly-Asp sequence (KGD) heparin, targets factor Xa preferentially but also exerts some
containing peptides, and peptidomimetic and non-peptide anti-factor IIa activity, based on the degree to which longer
RGD mimetics (eptifibatide and tirofiban) that compete with chains are present in different commercial LMWH preparations.
fibrinogen, von Willebrand factor, and/or perhaps other ligands
for occupancy of the platelet receptors. As a therapeutic agent, LMWH is rapidly absorbed into plasma
and has a longer half-life relative to that of unfractionated
Anti-thrombotic Agents heparin.The higher bioavailability of LMWH compared with that
Anti-thrombotic agents includes only those drugs which affect of unfractionated heparin leads to a more predictable dose
the coagulation cascade are described in Table 7. response and, therefore, a reduced need for routine laboratory
monitoring of haemostatic variables; this renders LMWH relatively
Table 7: Anti-Thrombotic Agents Used in Acute Coronary easy to use in clinical practice. Dalteparin, enoxaparin, tinzaparin,
Syndrome nadroparin, reviparin and certoparin are approved for use.
Non-selective indirect thrombin Inhibitors
Advantages of LMWH are subcutaneous twice daily
Unfractionated heparin
administration, no monitoring and somewhat better efficacy.
Low-molecular weight heparins
Usually, enoxaparin or dalteparin are used for 5 to 7 days. Classic
Direct thrombin inhibitors
indications are conservative management of acute coronary
Hirudin
Bivalirudin
syndrome, following thrombolysis and in a few selected cases
Argatroban after catheter-based interventions.
Dabigatran Thrombolytic Agents
Ximelagatran
Selective factor Xa inhibitors
Thrombolytic agents are used in patients with ST-elevation
myocardial infarction (MI) (other indications being submassive
Fondaparinux
Rivaroxaban pulmonary embolism, prosthetic valve thrombosis, selected
Apixaban cases of thrombotic stroke, proximal deep vein thrombosis,
etc.). Time to reperfusion remains a key modifiable deter-
Unfractionated heparin is still the most commonly used anti- minant of mortality in ST-elevation MI. Despite many years
thrombotic agent with a bolus dose of 50 to 100 units/kg of of medical advances, the time from symptom onset until the
weight followed by 10 to 15 units/kg per hour infusion for at start of pharmacological reperfusion treatment remains
least 48 hours and may be even longer. largely unchanged, with a median of approximately 2.5 to 3
hours.
Unfractionated heparin preparations contain molecules of
widely varying sizes (3,000-30,000 Daltons; mean 15,000 Thrombolytic drugs dissolve blood clots by activating
Daltons), but anticoagulant activity is limited to the relatively plasminogen, which forms a cleaved product called plasmin.
small proportion of molecules (approximately 30%) whose Plasmin is a proteolytic enzyme that is capable of breaking
617
structures include the pentasaccharide sequence. This active cross-links between fibrin molecules, that provide the structural
 integrity of blood clots. Due to these actions, thrombolytic drugs Diuretics, especially loop diuretics, are the most efficacious in
are also called ‘plasminogen activators’ and ‘fibrinolytic drugs’. relieving clinical symptoms of shortness of breath and signs
of peripheral oedema. The diuretic-induced reductions in
Streptokinase (1.5 M units over one hour) and urokinase are
ventricular filling pressures and ventricular cavity size,
inexpensive and used as infusion. Alteplase is used as bolus
decreases in mitral regurgitation and resulting increases in
followed by short infusion (100 mg dose). Reteplase (5 units
forward cardiac output, all may be favourable in HF. Digoxin
double bolus) and tenecteplase (50 to 60 mg rapid bolus) can
reduces hospitalisations for HF in patients with sinus rhythm.
be given as bolus and hence are of great use in pre-hospital
It maintains a role in those with advanced chronic HF and atrial
thrombolysis. Their efficacy is similar to or better than alteplase.
fibrillation, where rate control may improve symptoms.
Thrombolysis is always followed by 5 to 7 days of anti-
thrombotic therapy to prevent rebound thrombosis. Angiotensin-converting enzyme (ACE)-inhibitors are an
important component of standard HF therapy (Class I) in
MANAGEMENT OF SYSTEMIC ARTERIAL HYPERTENSION patients with current or prior symptoms of HF and depressed
See the chapter on Essential Hypertension left ventricular systolic function. The mechanism of action
consists of improvement in left ventricular geometry, ejection
MANAGEMENT OF HEART FAILURE
fraction and filling pressures. Randomised trials have
Over the last 20 years, enormous progress has been made shown that ACE-inhibitor therapy leads to symptomatic
in the pharmacotherapy of chronic heart failure. Large, improvement, reduced hospitalisation and enhanced survival
randomised, control trials of inhibition of the renin-angiotensin- in patients with HF and systolic dysfunction. Angiotensin
aldosterone system and sympathetic nervous system have led receptor blockers provide a unique pharmacological
to substantial improvements in both morbidity and mortality. mechanism for inhibiting the RAS and these are mostly used
The primary goal of drug therapy in heart failure (HF) is to in ACE-I intolerant patients.
improve cardiac function and to reduce the clinical symptoms Although seemingly paradoxical, beta-receptor blocking
associated with HF (e.g. oedema, shortness of breath, exercise drugs have been able to reduce HF mortality by about 35% in
intolerance). Improving cardiac function along with reducing various randomised trials. The strategy for administering all
blood volume can dramatically improve the clinical symptoms. β-blocking agents in the setting of chronic heart failure is to
The treatment of HF caused by systolic dysfunction follows clear start at extremely low doses and increase the dose gradually.
clinical guidelines based upon numerous clinical trials. Diastolic The pharmacological half-lives of metoprolol tartrate, carvedilol,
dysfunction, however, is more difficult to treat and there is no and bucindolol dictate twice-daily dosing, whereas bisoprolol
clear consensus regarding the best therapeutic options other and metoprolol succinate CR can be given once daily.
than targeting clinical symptoms related to fluid retention. In
addition, drugs that can adversely affect patients with HF due Aldosterone antagonists like spironolactone and eplerenone
to systolic dysfunction should be avoided or withdrawn. These have been used in HF with impressive mortality benefits.
include non-steroidal anti-inflammatory drugs, most anti-
arrhythmic drugs, and the non-dihydropyridine calcium MANAGEMENT OF CARDIAC ARRHYTHMIAS
channel blockers (i.e. diltiazem and verapamil). Drug therapy There are four main classes in the Vaughan-Williams
for systolic HF is grouped in four categories as shown Table 8. classification of anti-arrhythmic agents as described here:

Table 8: Drugs for the Prevention and Treatment for Chronic Heart Failure
Drug Initial Daily Dose(s) Maximum Total Daily Dosage
Angiotensin-converting enzyme inhibitor
Captopril 6.25 mg three times 50 mg three times
Enalapril 2.5 mg two times 10 mg two times
Lisinopril 2.5-5.0 mg once 20-35 mg once
Ramipril 1.25-2.5 mg two times 2.5-5 mg two times
Perindopril 2 mg once 8-16 mg once
Fosinopril 5-10 mg once 40 mg once
Angiotensin-receptor blocker
Trandolapril 0.5 mg once 4 mg once
Valsartan 40 mg two times 160 mg two times
Candesartan 4 mg once 32 mg once
Losartan 12.5 mg once 50 mg once
Beta-receptor blocker
Carvedilol 3.125 mg two times 25 mg two times
(50 mg two times if more than 85 kg)
Bisoprolol 1.25 mg two times 10 mg once
Metoprolol succinate CR/XL 12.5-25 mg once 200 mg once
Spironolactone 12.5-25 mg once 25-50 mg once
Eplerenone 25 mg once 50 mg once
Combination of hydralazine-isosorbide dinitrate 10-25 mg/10 mg three times 75 mg/40 mg three times
Fixed dose of hydralazine-isosorbide dinitrate 37.5 mg/20 mg (one tablet) 3 times 75 mg/40 mg (two tablets) 3 times
618 Digoxin 0.125 mg once 0.375 mg once
 Pharmacotherapy of Cardiovascular Disorders
Class I Agents 2. PDE-5 inhibitors (sildenafil, tadalafil)
The class I anti-arrhythmic agents interfere with the sodium (Na+) 3. Endothelin receptor antagonists (bosentan, ambrisentan,
channel. These are grouped by what effect they have on the Na+ sitaxentan)
channel and what effect they have on cardiac action potentials. 4. Prostaglandins (iloprost, epoprostenol, treprostinil)
These agents are also called membrane stabilising agents. 5. Oral anticoagulants
The ‘stabilising’ is the word used to describe the decrease of
excitogenicity of the plasma membrane which is brought about MANAGEMENT OF CARDIOGENIC SHOCK
by these agents (Also noteworthy is that a few class II agents Circulatory shock is a life-threatening emergency that results
like propranolol also have a membrane stabilising effect). in death in approximately half of all patients.
Class I agents are divided into three groups (1a, 1b and 1c) based Intravenous vasopressors provide inotropic support increasing
upon their effect on the length of the action potential. perfusion of the ischaemic myocardium and all body tissues.
1. 1a lengthens the action potential (right shift), e.g. quinidine, However, extreme heart rates should be avoided because they
procainamide, disopyramide. may increase myocardial oxygen consumption, increase infarct
size, and further impair the pumping ability of the heart. No
2. 1b shortens the action potential (left shift), e.g. lignocaine,
particular vasopressor has been shown to be superior to
bretylium, mexiletine.
another except recent data which suggest some superiority of
3. 1c does not significantly affect the action potential (no norepinephrine over dopamine. Carefully chosen combinations
shift), e.g. flecainide, encainide, ajmaline, propafenone. of vasopressors may be useful.
Class II Agents Dopamine may provide vasopressor support.With higher doses,
Class II agents are conventional beta-blockers. They act by it has the disadvantage of increasing the HR and myocardial
blocking the effects of catecholamines at the β1-adrenergic oxygen consumption. Intravenous (IV) continuous infusion of
receptors, thereby decreasing sympathetic activity on the 5 to 20 mcg/kg per minute; increase by 1 to 4 mcg/kg per minute
heart. These agents are particularly useful in the treatment of q 10 to 30 minutes to optimal response (>50% of patients have
supraventricular tachycardias. They decrease conduction satisfactory responses with doses <20 mcg/kg per minute).
through the AV node. Class II agents include atenolol, esmolol,
Dobutamine, inamrinone (formerly amrinone), or milrinone may
propranolol and metoprolol.
provide inotropic support. In addition to their positive inotropic
Class III Agents effects, inamrinone and milrinone have a beneficial vasodilator
Class III agents predominantly block the potassium (K+ ) effect, which reduces pre-load and after-load. Some of these
channels, thereby prolonging repolarisation. Since these drugs are described below:
agents do not affect the Na+ channel, conduction velocity is not Milrinone: Loading dose, 50 mcg/kg IV over 10 min; continuous
decreased. The prolongation of the action potential duration infusion: 0.375 to 0.75 mcg/kg per minute IV.
and refractory period, combined with the maintenance of
Norepinephrine: Norepinephrine infusion must be considered in
normal conduction velocity, prevent re-entrant arrhythmias.
refractory cardiogenic shock, though it significantly increases after-
Typical examples are amiodarone, sotalol, dofetilide and
load but is less arrhythmogenic (Dosage: 0.5 to 1 mcg/min IV
dronedarone.
infusion initially, titrated to effect; not to exceed 30 mcg/minute).
Class IV Agents
Levosimendan: Levosimendan, though not approved for use in
Class IV agents are slow calcium channel blockers. These the USA, can be considered in conjunction with vasopressors.
decrease conduction through the AV node and shorten phase It should be used with caution as it can cause hypotension.
two (the plateau) of the cardiac action potential. Thus, these When used with vasopressors, levosimendan may improve
reduce the contractility of the heart, so may be inappropriate haemodynamics and improve coronary blood flow. However,
in HF. However, in contrast to beta-blockers, these allow the there are no trials with this drug in patients with cardiogenic
body to retain adrenergic control of HR and contractility. Class shock.
IV agents include verapamil and diltiazem.
In summary, these are exciting times for cardiovascular
Others pharmacotherapy. Novel molecules are being developed. Older
These include the following: drugs are undergoing reappraisal. Polypharmacy-based one
1. Digoxin decreases conduction of electrical impulses type of system is being challenged. Combination therapy and
through the AV node and increases vagal activity via its fixed-drug combinations are gaining ground. Targets for drugs
central action on the central nervous system. are being redefined. It would not be long before many of today’s
dogma shall become obsolete.
2. Adenosine
3. Magnesium sulphate has been used for torsades de pointes. RECOMMENDED READINGS
1. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 Guidelines for
MANAGEMENT OF PULMONARY HYPERTENSION
the Management of Patients With Unstable Angina/Non-ST-Elevation
The drugs used for the management of pulmonary hyper- Myocardial Infarction: Executive Summary: A Report of the American Col-
tension are: lege of Cardiology/American Heart Association Task Force on Practice
Guidelines (Writing Committee to Revise the 2002 Guidelines for the Man-
1. Calcium channel blockers (only in patients with demonstrable agement of Patients With Unstable Angina/Non-ST-Elevation Myocardial
vaso-reactivity) Infarction): Developed in Collaboration with the American College of Emer- 619
 gency Physicians, the Society for Cardiovascular Angiography and Inter- Infarction (Updating the 2004 Guideline and 2007 Focused Update) and
ventions, and the Society of Thoracic Surgeons: Endorsed by the American ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention
Association of Cardiovascular and Pulmonary Rehabilitation and the Soci- (Updating the 2005 Guideline and 2007 Focused Update): A Report
ety for Academic Emergency Medicine. Circulation 2007; 116: e148-304. of the American College of Cardiology Foundation/American Heart
2. Fraker TD, Fihn SD, Gibbons RJ, et al. Chronic Angina Focused Update of Association Task Force on Practice Guidelines. Circulation 2009;120:
the ACC/AHA 2002 Guidelines for the Management of Patients With Chron- 2271-306.
ic Stable Angina: A Report of the American College of Cardiology/Ameri- 5. Mancia G, De Backer G, Dominiczak A, et al. ESH-ESC practice guidelines
can Heart Association Task Force on Practice Guidelines Writing Group to for the management of arterial hypertension. ESH-ESC task force on the
develop the focused update of the 2002 Guidelines for the management management of arterial hypertension. J Hypertens 2007; 25: 1751-62.
of patients with chronic stable angina. Circulation 2007;116: 2762-72. 6. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 Expert Con-
3. Jessup M, Abraham WT, Casey DE, et al. Focused Update: ACCF/AHA Guide- sensus Document on Pulmonary Hypertension: A Report of the American
lines for the Diagnosis and Management of Heart Failure in Adults: A Re- College of Cardiology Foundation Task Force on Expert Consensus Docu-
port of the American College of Cardiology Foundation/American Heart ments and the American Heart Association: Developed in Collaboration
Association Task Force on Practice Guidelines: Developed in Collaboration With the American College of Chest Physicians, American Thoracic Soci-
With the International Society for Heart and Lung Transplantation. Circu- ety, Inc., and the Pulmonary Hypertension Association. Circulation 2009;
lation 2009;119:1977-2016. 119: 2250-94.
4. Kushner FG, Hand M, Smith SC, et al. Focused Updates. ACC/AHA 7. Opie L, Gersh BJ. Drugs for the Heart, 7th Ed. Philadelphia: Saunders Elsevier;
Guidelines for the Management of Patients With ST-Elevation Myocardial 2009.

620
 12.10 Heart Failure

Donald Kikta, Veronica Franco

INTRODUCTION overload impairs ventricular ejection by significantly increasing

Heart failure (HF) is defined as the inability of the heart to pump resistance to flow. These conditions result in a reduced stroke
blood forward at a rate sufficient to meet the metabolic volume as systolic emptying ceases at a higher end-systolic
demands of the body, or the ability to do so only if the cardiac volume than normal. When normal pulmonary venous return is
filling pressures are abnormally high. It most commonly results added to the increased end-systolic volume that has remained
from myocardial or extra-myocardial abnormalities which in the ventricle because of incomplete emptying, the diastolic
interfere with normal left ventricular function. It may result from chamber volume increases resulting in a higher than normal end-
a sudden overwhelming cardiac load, as with an acute hyper- diastolic volume and pressure. Conditions resulting in excessive
tensive crisis, or a chronic cardiac stressor such as systemic afterload include uncontrolled systemic hypertension and
hypertension. Chronic HF that results predominantly from aortic stenosis. Although an increase in preload induces a
an abnormality of ventricular emptying, due to impaired compensatory rise in stroke volume via Frank-Starling mechanism,
contractility or excessive afterload, is often termed systolic HF. impaired contractility or increased afterload cause the end-
Heart failure that results from an abnormality of ventricular diastolic volume to remain elevated. During diastole, the
filling was previously referred to as diastolic HF. Heart failure persistently elevated left ventricular pressure is transmitted to
with preserved ejection fraction is now the preferred term, the left atrium through the open mitral valve and to the pulmonary
as the physiologic abnormalities in this condition are not veins and capillaries. An elevated pulmonary capillary hydrostatic
solely restricted to either diastole or systole. HF may be the final pressure results in transudation of fluid into the pulmonary
and most severe manifestation of nearly every form of interstitium and symptoms of pulmonary congestion.
cardiac disease including coronary atherosclerosis, valvular Heart failure with preserved ejection fraction results from
disease, hypertension, congenital heart disease and the impaired ventricular filling resultant from mechanical
cardiomyopathies. The mortality rate in patients with HF has obstruction or impaired diastolic relaxation. Left ventricular
remained unacceptably high despite improvements in therapy, hypertrophy, hypertrophic cardiomyopathy, restrictive cardio-
making early detection of susceptible persons, who would myopathy and myocardial ischaemia result in reduced chamber
benefit from preventive measures imperative. compliance and diastolic dysfunction. Mitral stenosis and
pericardial constriction obstruct normal ventricular filling
PATHOPHYSIOLOGY necessitating elevated diastolic pressures. Filling of the ventricle
The heart normally accepts blood at low filling pressures during occurs at higher than normal pressures and is transmitted
diastole and then propels it forward at higher pressures in retrograde to the pulmonary and systemic veins.
systole. In a healthy individual, the cardiac output is matched
Isolated right ventricular failure is less common and usually
to the body’s total metabolic need through adjustments in heart
reflects increased right ventricular afterload due to disease of
rate and ventricular stroke volume. Stroke volume is a function
the lung parenchyma or pulmonary vasculature. When the right
of ventricular preload, afterload and contractility. Within a
ventricle fails, the elevated diastolic pressure is transmitted
physiologic range, ventricular output increases in relation to the
retrograde to the right atrium with subsequent congestion of
preload or stretch on the myocardial fibres before contraction.
the systemic veins. The most common cause is actually left-sided
The ventricular wall stress that develops during systolic ejection,
HF, where elevated pulmonary vascular pressures resultant from
or afterload, reflects the resistance the ventricle must overcome
left ventricular dysfunction lead to excessive right ventricular
to empty its contents. This pressure determines the end-systolic
afterload.
volume of the left ventricle independent of the preload.
Myocardial contractility accounts for changes in the force of NEUROHORMONAL MODEL FOR HEART FAILURE
contraction independent of the preload and afterload, and can
Clinicians have used a variety of increasingly complex model
be augmented by increasing the cycling rate of actin-myosin
systems to describe the syndrome of HF. It was initially viewed
cross-bridge formation in the cardiac myocyte. Heart failure
as a problem of excessive salt and water retention caused by
aetiologies can be grouped into those with impaired
renal blood flow abnormalities. Later, haemodynamic studies
contractility, increased afterload or impaired ventricular filling.
revealed that HF is associated with a reduced cardiac output
Systolic HF results from diminished capacity of the affected and excessive peripheral vasoconstriction. Although the
ventricle to eject blood because of impaired myocardial cardiorenal and cardiocirculatory models for HF explain the
contractility or excessive afterload. Loss of contractility may result excessive salt and water retention that patients experience and
from destruction of myocytes, abnormal myocyte function or provide a rational basis for the therapeutic use of diuretics,
fibrosis. Conditions associated with impaired contractility include inotropes and vasodilators, neither of these models explain the
dilated cardiomyopathy, chronic volume overload due to valvular relentless disease progression that occurs in this syndrome. It
insufficiency and myocardial ischaemia or infarction. Pressure is increasingly apparent that HF can no longer be described in
621
 simple haemodynamic terms. Some experts suggest that HF The prevalence of HF increases exponentially with age. Data
should be viewed as a neurohormonal model, in which it suggest the lifetime risk in the United States of developing HF
progresses as a result of the overexpression of biologically active is 20%. Investigations using echocardiography estimate that
molecules that are capable of exerting deleterious effects on only 50% of patients with LV dysfunction are symptomatic. Half
the heart and circulation. of the patients who develop HF have a normal or preserved LV
ejection fraction. The Framingham Heart Study estimated the
Heart failure is a progressive disorder that is initiated after an
prevalence of symptomatic HF in the United States as 0.8% and
index event either damages the heart muscle, with a resultant
6.6% in the sixth and ninth decades of life.
loss of functioning cardiac myocytes, or alternatively disrupts
the ability of the myocardium to generate a force, thereby The population-attributable risk for HF was prospectively
preventing the heart from contracting normally. The index event estimated to be 62%, 17%, 10%, 8%, 3%, and 2% for coronary
may have an abrupt onset, as in the case of a myocardial artery disease, cigarette smoking, hypertension, obesity,
infarction; it may have a gradual or insidious onset, as in the diabetes mellitus and valvular heart disease respectively, in
case of haemodynamic pressure or volume overloading; the US. Ischaemic cardiomyopathy is the most common cause
or it may be hereditary, as in the case of the genetic of systolic HF in the western world, whereas hypertension and
cardiomyopathies. In most instances, patients will remain valvular heart disease have become less common due to
asymptomatic or minimally symptomatic for a prolonged improvements in detection and therapy. The exact cause cannot
period. This is likely due to a number of compensatory be determined in 20% to 30% of cases and is, therefore, classified
mechanisms which become activated in the setting of cardiac as idiopathic. Ageing, female gender, hypertension, diabetes
injury and appear to modulate left ventricular (LV) function mellitus, LV hypertrophy, coronary artery disease and infiltrative
within a physiological range such that the functional capacity cardiomyopathies are associated with diastolic dysfunction.
of the patient is preserved or only minimally depressed.
The prevalence or risk of developing HF in emerging nations
The principal neurohormonal systems involved in the response is less defined due to a lack of population-based studies.
to HF are the sympathetic nervous system, the renin-angiotensin- Hypertension has the greatest impact on the development of
aldosterone system, anti-diuretic hormone, endothelin, natriuretic this syndrome and is estimated to account for 39% of events in
peptides and nitric oxide. Neurohormonal activation is acutely men and 59% in women. A recent study at an urban African
beneficial in patients with HF since the elevations of cardiac hospital demonstrated that 88% of de novo presentations for HF
contractility, vascular resistance and renal sodium retention tend were attributed to uncontrolled hypertension, idiopathic dilated
to restore the cardiac output and tissue perfusion towards normal. cardiomyopathy or right-sided heart failure.Valvular heart disease
The deleterious effects, however, predominate over the long-term only accounts for 7% to 8% of cases. Pathologies associated with
leading to pulmonary and peripheral oedema, increased a high cardiac output, such as anaemia, are seldom responsible
afterload, pathologic myocardial remodelling and more for the development of HF in a normal heart. However, in the
rapid progression of myocardial dysfunction. The major presence of underlying structural heart disease, the additional
pathophysiologic process in the progression of HF appears to work required in high output conditions may contribute to
be cardiac remodelling, often referred to as progressive chamber overt congestive failure. Rheumatic heart disease remains a
enlargement over time and obligatory reduction in ejection major cause of HF in Africa and Asia. Chagas disease is still an
fraction.The ability of ACE inhibitors and beta-blockers to improve important aetiology in South America. As developing nations
survival and slow progression of this disease in clinical trials is undergo socio-economic development, the epidemiology
compatible with this hypothesis. Clinical studies have additionally of HF is becoming similar to that of Western Europe and North
shown that other medical and device therapies have favourable America.
effects on cardiac remodelling, resulting in stabilisation or reversal
of LV chamber mass and dilation. Although the precise cellular CLINICAL MANIFESTATIONS
and molecular mechanisms that are responsible for this “reverse Heart failure is a bedside diagnosis that is defined by clinical
remodelling”are not fully known,recent studies have demonstrated assessment. The clinical manifestations result from impaired
that improvement in ventricular function is associated with forward cardiac output and/or elevated venous pressures
favourable changes in myocardial gene expression. and relate to which of the ventricles has failed. The cardinal
EPIDEMIOLOGY symptoms of chronic LV failure are dyspnoea, exercise
intolerance and fatigue. Elevated pulmonary venous pressures
The magnitude of HF is difficult to assess with precision since
cause transudation of fluid into the lung parenchyma,
reliable, population-based estimates of its prevalence, incidence
increasing work of breathing due to reduced pulmonary
and prognosis are lacking. Large differences exist among studies
compliance, increased airway resistance and stimulation of
in their definition of the condition and the methods used to
juxtacapillary receptors. Accumulation of lactic acid due to low
establish its presence. HF affects nearly twenty-three million
cardiac output may contribute to this sensation.
people worldwide. There is an increase in prevalence due to
ageing of the population and improved survival of patients due As HF advances, dyspnoea occurs with progressively less
to modern therapeutic interventions.The worldwide prevalence strenuous activity and ultimately is present even at rest. The
and incidence rates of HF are approaching epidemic New York Heart Association (NYHA) functional classification,
proportions, as evidenced by the relentless increase in the although somewhat vague, remains the most commonly used
number of hospitalisations, the growing number of HF- standard to describe severity of signs and symptoms. Additional
attributable deaths and the spiralling costs associated with the common symptoms related to left ventricular congestion
622
care of HF patients. include orthopnoea, nocturnal cough and paroxysmal
 Heart Failure
nocturnal dyspnoea. Orthopnoea is the sensation of laboured important to note that a patient classified as Stage B has a better
breathing while lying flat and is relieved by sitting upright. prognosis than one with Stage C NYHA class I symptoms.
Orthopnoea and nocturnal cough result from redistribution of
A major challenge in the management of HF is the accurate
fluid from the splanchnic circulation and lower extremities into
identification of those patients who have a poor prognosis and
the central circulation during recumbency, with a resultant
would, therefore, be most likely to benefit from intensive
increase in pulmonary capillary pressures. Paroxysmal nocturnal
medical therapy. Although multiple variables have been
dyspnoea is severe, sudden nocturnal breathlessness which
identified as predictors of survival within a large population,
occurs hours after going to bed. It results from gradual
their ability to predict survival in individual patients is limited.
reabsorption of lower extremity interstitial oedema into the
Many factors affect patient outcomes including co-morbid
circulation with subsequent intravascular volume expansion
medical conditions, psycho-social factors and intensity of
and increased venous return to the heart and lungs. Common
medical care. The most frequently predictors of adverse
symptoms related to chronic right ventricular congestion
outcome directly or indirectly reflect the severity of cardiac
include abdominal discomfort, anorexia, nausea, peripheral
dysfunction. Prospective studies have demonstrated a one-year
oedema and weight gain. Elevated systemic venous pressures
mortality of 5% for patients in NYHA functional class I, 15% in
result in abdominal discomfort due to hepatic engorgement
classes II-III and 64% in class IV. Exercise variables such as
and capsular distention. Anorexia and nausea may result
maximal oxygen consumption and six-minute walk testing
from oedema within the gastrointestinal tract. Weight gain
provide the most objective assessment of functional capacity
and peripheral oedema result from the accumulation of
in patients with heart failure and are an important component
interstitial oedema within the dependent portions of the body.
in the evaluation of patients for advanced heart failure therapies.
Common symptoms related to low cardiac output include
fatigue, weakness, dulled mental status and nocturia. These Need for hospitalization is an important marker for poor
result from impaired skeletal muscle, cerebral and renal prognosis. In-hospital, 30-day and one-year mortality after index
perfusion. hospitalisation are estimated to be 6%, 11% and 30% in the US.
Additional univariate predictors of survival in systolic HF include
The physical signs of HF depend on the severity and chronicity
signs of congestion or reduced tissue perfusion on physical
of the condition and again can be divided into those due to
examination; severe LV systolic dysfunction; concomitant
left or right cardiac dysfunction. Common signs of left-sided
diastolic dysfunction or right ventricular dysfunction with
HF include pulmonary rales, wheezing, increased intensity
associated pulmonary hypertension; attenuated response to
of S2, S3 or S4 gallop and a mitral regurgitation murmur.
diuretics or lack of haemodynamic improvement with therapy;
Pulmonary rales result from the popping open of small airways
echocardiographic evidence of left ventricular remodelling;
which had been closed off by oedema fluid before inspiration,
ventricular dyssynchrony resulting from conduction system
while ‘cardiac asthma’ results from compression of larger
defect; severe ventricular ectopy after exercise; evidence of
airways. An early diastolic sound, or S3, signifies increased left
neurohormonal activation including hyponatraemia, elevated
ventricular end-diastolic pressure in patients with decreased
brain natriuretic peptide (BNP), reduced heart rate variability
left ventricular function. A late diastolic sound, or S4, may
and sinus tachycardia; ischaemic cardiomyopathy; concomitant
result from forceful atrial contraction into a stiffened LV. Left
paroxysmal atrial fibrillation, sleep-disordered breathing, renal
ventricular dilation can result in incomplete closure of the
insufficiency or anaemia; elevated serum troponin or markers
mitral valve during systole and functional mitral regurgitation.
of inflammation; low serum cholesterol or weight loss.
Common signs of right-sided HF include distention of the
jugular veins, hepatic enlargement, dependent oedema, The prognosis in HF patients with preserved ejection fraction
right ventricular heave or gallop and tricuspid regurgitation is less well-defined. Although once thought to be better than
murmur. Signs of impaired peripheral perfusion, cardiac those with systolic dysfunction, recent evidence suggests
cachexia, diaphoresis, tachycardia, tachypnoea and narrow similar mortality rates. The two main causes of death in patients
pulse pressures are often signs of advanced disease. with HF are sudden death due to arrhythmias and progressive
pump failure. It has been postulated that progressive pump
PROGNOSIS failure, sudden death due to arrhythmia and sudden death
Morbidity and mortality after the onset of symptomatic HF are during episodes of clinical worsening each account for one-
extremely high despite improvements in therapy. This is a third of cardiovascular mortality in this population.
progressive condition, beginning with predisposing factors and
leading to the development and worsening of clinical illness. RECOMMENDED READINGS
The latest American College of Cardiology and American Heart 1. Hunt SA, Abraham WT, Chin MH, et al. Focused update incorporated into
the ACC/AHA 2005 Guidelines for the Diagnosis and Management of
Association (ACC/AHA) guidelines have classified HF using Heart Failure in Adults: A Report of the American College of Cardiology
a new staging system that emphasizes the evolution and Foundation/American Heart Association Task Force on Practice Guidelines
progression across a continuum. Stage A patients are at high- Developed in Collaboration With the International Society for Heart and
risk for developing heart failure without structural heart disease. Lung Transplantation. J Am Coll Cardiol 2009; 53: e1-90.
Stage B patients have structural heart disease but have not yet 2. Leier CV, Chatterjee K. The physical examination in heart failure – Part II.
Congest Heart Fail 2007; 13: 99-104.
developed symptoms of HF (post-myocardial infarction,
3. Mendez GF, Cowie MR. The epidemiological features of heart failure in
hypertension, valvular disease or asymptomatic LV dysfunction). developing countries: A review of the literature. Int J Cardiol 2001; 80:
Stage C patients had past or current symptoms of HF associated 213-9.
with underlying structural heart disease. Stage D patients have 4. Pang PS, Komajda M, Gheorghiade M. The current and future management
end-stage disease requiring specialised advanced therapy. It is of acute heart failure syndromes. Eur Heart J 2010; 31: 784-93.
623
 12.11 Heart Failure Management

Veronica Franco, Ragavendra Baliga

Therapy for heart failure (HF) is divided into 2 distinct clinical 2. Oxygen supplementation is seldom needed in HF patients.
scenarios and approaches: acute decompensated HF and, If oxygen saturation is low, evaluation for pulmonary disease
chronic stable HF (Table 1). The goals of therapy are different: or residual pulmonary oedema is recommended.
in decompensated HF it is to stabilise the patient, improve organ 3. Treatment of depression with appropriate therapy is very
perfusion and filling pressures; in chronic stable HF, the aim is important. Selective serotonin re-uptake inhibitors (SSRIs)
to extend survival, good quality of life and delay disease are preferred.
progression. Approach therapy for patients with chronic HF is
based on their stage classification. Diuretics, vasodilators and Routine Healthcare
positive inotropic agents are used to improve symptoms. 1. Limit daily consumption of alcohol to less than 2 drinks
Neurohormonal inhibitors are used to reduce mortality and in men and less than 1 drink in women. In patients with
delay disease progression. alcoholic cardiomyopathy, total abstinence is recommended.
2. Pneumococcal and influenza vaccinations are indicated.
Table 1: Treatment of Heart Failure
3. Endocarditis prophylaxis is not recommended based on the
Decompensated Heart Failure Chronic Stable Heart Failure
diagnosis of HF alone.
Diuretics Diuretics
Loop diuretics (po)
4. Nonsteroidal anti-inflammatory drugs are not recommended
Loop diuretics (IV)
due to associated fluid, salt retention and acute renal
Thiazides (IV) Thiazides (po)
antagonists failure.
Vasodilators
Nitrovasodilators (IV) Vasodilators 5. Exercise training, with the goal of 30 minutes of moderate
Direct acting nitrates (po) Nitrovasodilators (po) exercise activity at least five times per week.
Calcium channel blockers (IV; in the Direct acting nitrates (po)
PHARMACOLOGICAL THERAPIES
setting of angina or hypertension) Positive inotropic agents
Natriuretic peptides (nesiritide) Digitalis Two classes of agents have become the cornerstone of therapy
Positive inotropic agents to delay or halt progression of cardiac dysfunction and improve
Neurohormonal inhibitors
Beta-adrenergic receptor agonists mortality: angiotensin converting enzyme (ACE) inhibitors and
Angiotensin converting
Phosphodiesterase inhibitors enzyme inhibitors beta-blockers.
Phosphodiesterase inhibitors Angiotensin receptor blockers ACE-Inhibitors
with calcium sensitizer action Beta-adrenergic blockers
They block the renin-angiotensin-aldosterone system (RAAS)
and should be used in all patients with HF and LVEF less than 40%.
NON-PHARMACOLOGICAL THERAPIES They block the conversion of angiotensin I into angiotenin II,
These therapies apply to patients with decompensated and as well as degradation of bradykinin. Kinins are responsible for
chronic HF, at all stages. the cough and angioedema present in 5% of patients. There
Diet has been evidence of ‘angiotensin II escape’, however this has
not been translated into clinical trials and ACE inhibitor remain
1. Dietary instruction regarding sodium intake is one of the
the prefer red medication, over angiotensin receptor blockers
cornerstones of HF treatment. It plays a very important role
(ARBs).
in the prevention of acute recurrent events.
2. Sodium restriction (2 to 3 g daily) is recommended for all Foetal angiotensin I receptors are growth stimulators, therefore
patients, regardless of their left ventricular ejection fraction should not be used in pregnant patients. They have an anti-
(LVEF). Further restriction (<2 g daily) is recommended for adrenergic effect secondary to decrease in norepinephrine
those with moderate to severe HF. production. Finally, angiotensin II produces efferent arteriolar
vasoconstriction to improve glomerular filtration rate (GFR) and
3. Fluid intake less than 2 litre daily is recommended for patients
after decrease in production of angiotensin II, renal function
with serum sodium less than 130 mEq/L and patients with
could worsen.
volume retention.
4. Prealbumin and caloric evaluation is recommended for ACE inhibitors have been shown in double-blind, placebo-
patients with cardiac cachexia and unintentional weight loss. controlled trials to produce clinical benefit, increase LVEF and
improve survival. Should be started at the lowest dose and
Other Therapies titrated as tolerated to doses used in clinical trials (Table 2),
1. Continuous positive airway pressure if there is a diagnosis during concomitant uptitration of beta-blockers. Patients
of sleep apnoea has been shown to improve symptoms of should not receive an ACE inhibitor if they have experienced
624 dyspnoea. life-threatening side effects (angioedema or anuric renal failure).
 Heart Failure Management
They should be used with extreme caution if the patient is optimization of volume status and successful discontinuation
hypotensive, have bilateral renal artery stenosis, potassium of IV diuretics/inotropes. If possible, beta-blockers should be
greater than 5.5 meq/L, or creatinine greater than 3 mg/dL. initiated in the hospital setting to evaluate tolerability. These
Renal function and potassium should be checked within 1 to 2 are indicated even in patients with diabetes mellitus, peripheral
weeks. vascular disease and/or asthma and chronic obstructive lung
disease. It should be used with caution if recurrent hypoglycaemic
Table 2: Medication Dosage in Chronic HF episodes or resting limb ischaemia is present. These are
Medication Usual Dosage Target Doses in HF contraindicated in active bronchospasm. Beta-blockers should
be initiated at low doses and titrated up to optimal doses every
Loop diuretics
2 weeks (Table 2). Beta-blockers should be continued in
Frusemide 10 to 360 mg/day
Bumetanide 0.5 to 20 mg/day
patients experiencing a symptomatic exacerbation, unless they
Torsemide 2.5 to 200 mg/day develop cardiogenic shock or refractory volume overload.
Thiazide diuretics Diuretics
Chlorothiazide 50 to 100 mg/day
Hydrochlorothiazide 25 to 50 mg/day
These drugs improve congestion, dyspnoea and retard adverse
Chlorthalidone 25 to 100 mg/day remodelling in the ventricle due to reduced wall stress. Diuretics
Metolazone 5 to 10 mg/day do not improve survival, except for aldosterone antagonists, and
K+ sparing diuretics should not be used as monotherapy.
Eplerenone 25 to 50 mg/day 50 mg/day
Diuretics are prescribed for patients with previous or current
Spironolactone 12.5 to 25 mg/day 25 mg/day
fluid retention. Intravenous formulations should be used if
ACE-inhibitors
Captopril 50 mg tid
significant volume overload. In patients with difficult to treat
Enalapril 10 mg bid HF, combination of diuretics acting by different mechanisms
Lisinopril 20 mg qd often works synergistically. Non-steroidal anti-inflammatory
Ramipril 10 mg qd drugs can inhibit the natriuretic effect of many diuretics and
Trandolapril 4 mg qd produce renal failure.
Fosinopril 80 mg qd
Quinapril 80 mg qd Loop diuretics
Angiotensin receptor blockers This class of diuretics includes: furosemide, bumetanide,
Candasartan 32 mg qd torsenide, ethacrynic acid and piretanide. The most commonly
Losartan 150 mg qd used is furosemide. Its half-life is 1.5 hours and total duration
Valsartan 160 mg bid of action 4 to 6 hours. The effect can be as fast as 10 minutes
Beta-blockers if given intravenously. Acutely (within minutes), they not
Bisoprolol 10 mg qd
only produce venodilation and decrease wedge pressure,
Carvedilol 25 mg bid
Metoprolol succinate (XL) 200 mg qd
but also cause neurohormonal activation. Side-effects include
hypochloraemic metabolic alkalosis, hypokalaemia,
Other vasodilators
Fixed dose of 75 mg hydralazine + hyponatraemia, hypocalcaemia, increased uric acid and higher
Hydralazine/nitrates 40 mg isosorbide risk of gout.
dinitrate, tid
Loop diuretics are the preferred therapy in HF, because of better
Hydralazine 75 mg qid
fluid clearance (20% to 25% increase in sodium excretion
Isosorbide dinitrate 40 mg qid
compared to 5% to 10% seen with thiazides) and effectiveness
despite renal insufficiency. The optimal doses are detailed
Alternative for ACE-inhibitors
in Table 2. Importantly, loop diuretics can induce a sulfa-
Angiotensin receptor blockers (ARBs) are recommended for like toxicity in those patients with a sulfa allergy (skin
those patients intolerant to ACE inhibitors. Both drugs have photosensitivity, blood dyscrasias, hepatitis, pancreatitis,
similar effect on renal function, potassium and blood pressure. interstitial nephritis and pneumonitis).
Angioedema has been reported very infrequently with ARBs
and patients that experience that side effect with ACE inhibitors, Thiazide diuretics
should have a trial with ARBs. If a patient is intolerant to ACE This class of diuretics includes chlorthalidone, hydro-
inhibitors and ARB, then the combination of hydralazine/ chlorothiazide and metolazone. The total duration of action is
nitrates could be used. There is no evidence to support the 16 to 24 hours. Side effects include hypokalaemia, hyponatraemia,
routine use of ARBs in combination with ACE inhibitors. mild metabolic alkalosis, hypercalcaemia and increase in uric
Beta-Blockers acid and higher risk of gout. Metolazone is the only thiazide
effective in patients with renal failure.
Beta-blockers interfere with the actions of the sympathetic
nervous system and have been shown to be effective in clinical Thiazide diuretics are the preferred therapy in hypertension,
trials in reducing morbidity and mortality. Only metoprolol because these are effective for almost 24 hours. High doses
succinate, bisoprolol and carvedilol are approved in HF therapy. of thiazide diuretics (50 to 200 mg daily) will be more helpful
They are recommended for all HF patients with reduced LVEF, in the treatment of HF and volume overload, however
with or without previous myocardial infarction. It can also be they produce more metabolic adverse effects like hyper-
used in patients with recent decompensation of HF, after glycaemia, high triglycerides and low-density lipoproteins (LDL).
625
 These effects are rarely seen with low-dose (12.5 mg or 25 mg despite optimal therapy. Digoxin does not improve mortality
daily). or is beneficial if preserved LVEF. The usual dose is 0.125 mg
daily with a goal level less than 1.0 ng/mL. The narrow safety
K+ sparing diuretics
profile and significant drug interactions are the main reasons
This includes triamterene, amiloride and mineralocorticoid why digoxin is utilized rarely. Side effects include cardiac
receptor antagonists (spironolactone and eplerenone). The arrhythmias, heart block, gastrointestinal symptoms,
main side effects is hyperkalaemia. These are weak diuretics neurological complaints (visual disturbances, disorientation
because in HF, the sodium retention occurs before the collecting and confusion). Digoxin toxicity could be precipitated
ducts and they not effective in achieving a negative sodium by hypokalaemia, hypomagnesaemia, renal failure or
balance if used alone. Spironolactone produces gynaecomastia, hypothyroidism.
impotence and menstrual irregularities in up to 10% of patients.
These effects have not been observed with eplerenone because Beta-adrenergic agonists
these are more selective. These diuretics are contraindicated if These have a positive inotropic and chronotropic effect (Table 4).
creatinine greater than 2.5 mg/dL, GFR less than 30 mL/min or They have a short half-life (minutes) and that is one of their
potassium greater than 5.0 mEq/L. advantages over phosphodiesterase (PDE) inhibitors.
Dobutamine is preferred over dopamine for most patients with
Vasodilators
decompensated HF who have not responded well to
Systemic vascular resistance (SVR) is increased in HF as a result intravenous diuretics. The limitations of dobutamine are: (1) It
of neurohormonal activation. Vasodilators increase cardiac does not work as well if patient has desensitisation of beta-
output and blood flow to organs (Table 3). Vasodilators receptors as happens with end-stage HF; (2) It cannot be
are more important in the treatment of acute decompensated effectively used with high levels of beta-blockers; (3) It only
HF and only hydralazine/nitrates combinations have modestly reduces elevated pulmonary arterial pressure and
been approved for chronic HF therapy. Importantly, pure pulmonary vascular resistance (PVR). Epinephrine is a
vasodilators (without a neurohormonal effect) have not vasodilator and vasoconstrictor, utilised in cases of concomitant
demonstrated a reduction in mortality and, in fact, powerful septic and cardiogenic shock. Norepinephrine is a powerful
vasodilators, like the prostacyclin epoprostenol, increase vasoconstrictor not recommended in HF.
mortality in HF.
Phosphodiesterase inhibitors (Milrinone)
Nitrovasodilators
They are good inotropes without the associated chronotropic
Nitroglycerin: These are powerful venodilators, mainly in effect. Their vasodilator properties are both a strength and
epicardial coronary flow (used in acute coronary syndromes). weakness of this medication. These work particularly well in
No effect on mortality. In acute decompensated HF, they lower patients with secondary pulmonary hypertension due to HF.
filling pressures and increase cardiac output.The main limitation Problems by its use are: (1) hypotension; (2) prolonged half-life
is the development of tolerance after 24 hours. Hydralazine can and (3) 80% of the medication is renally excreted and should
attenuate nitrate tolerance. be used with caution in patients of renal failure, (for detail
Nitroprusside: It has a very quick onset of action and, therefore, therapy see chapter pharmacotheraphy of cardiovascular
preferred in decompensated HF. Complications include cyanide disorders).
toxicity and coronary steal. It should be used only for a short
Table 4: Adrenergic Agonists.
period of time.
Medication β1 affinity β 2 affinity α affinity
Table 3: Vasodilators
Dobutamine +++++ +++ +
Medication Site of Action: Site of Action: Dopamine +++++ +++ +++++
Vein Arteriolar Epinephrine ++++ ++++ ++++++
Norepinephrine ++++ +++ ++++
Nitrates +++ +
Isoproterenol ++++ ++++ 0
Hydralazine + +++
Phenylephrine 0 0 ++++++
CCBs + +++
Minoxidil ++ +++
Prostacyclins +++ ++ ACUTE DECOMPENSATED HEART FAILURE
Nesiritide +++ + In acute HF, the aim of therapy is to provide immediate
ACE inhibitor, ARB ++ + symptomatic relief of pulmonary oedema and rescue patients
from imminent cardiorespiratory collapse by optimising the
Nesiritide haemodynamic status. The emphasis is on agents given
It is a vasodilator and has a direct natriuretic effect on the intravenously (Table 1). The hallmark of therapy is intravenous
kidneys. Nesiritide is less arrhythmogenic than dobutamine. loop diuretics. If the patient exhibits signs of normal cardiac
Titration or boluses are no longer recommended because of output, nitrates or nesiritide could be used to assist with
potential hypotension and acute renal failure. vasodilation. If there is low cardiac output and end-organ
damage, inotropic agents could be used, however, there is no
Positive Inotropic Agents
evidence that these give long-term benefit, and in fact, could
Digoxin cause more harm and increase mortality. Reduction of
Weak positive inotrope used to improve symptoms in patients hospitalisations for acute HF is important to reduce morbidity
626 LVEF ≤ 40% and recurrent admissions for HF exacerbation, and mortality.
 Heart Failure Management
CHRONIC HEART FAILURE: THERAPIES BY HEART FAILURE cases of rapidly progressive clinical HF with severe heart block
STAGE or arrhythmias. Also important is to identify any exacerbating
The objectives of therapy are: (1) to prevent progressive damage factors for HF, co-morbidities that could influence therapy and
to the myocardium (prevention); (2) to prevent or reverse further barriers to adherence. Treatment recommendations include
enlargement of the heart (reverse remodeling); (3) to improve smoking cessation, optimal blood pressure control, avoiding
the quality of life by relief of symptoms; and (4) to prolong life. deconditioning and alcohol abstinence if previous history of
While the era of device therapy for HF is currently expanding excessive alcohol intake is present. Pharmacological therapies
at a tremendous rate, the clinician should be aware of the for asymptomatic patients with LVEF less than 40% include: ACE-
importance of achieving specific pharmacologic goals in their inhibitors and beta-blockers.
HF patients. The pathophysiology of symptoms in chronic HF Stage C
is not well understood, but in contrast to acute HF is not directly
This category includes patients with structural changes that
related to high left atrial pressure. have developed symptoms. All recommendations for Stage B
Stage A—Preventive Therapy HF patients apply to patients with symptoms. The New York
Recognition that many risk factors can be modified and Heart Association (NYHA) functional classification, determines
that treating HF is difficult and costly has focused attention the pharmacological and device therapy in HF patients. The
on preventive strategies for HF. Treatment of systemic hyper- degree of volume excess is a key consideration in the treatment
tension, with or without hypertrophy, reduces the development of HF. ACE-inhibitors and beta-blockers are recommended for
all patients, aldosterone antagonist and digoxin should be
of HF. Myocardial infarction confers an 8- to 10-fold increased
reserved for those with NYHA class III-IV.
risk for subsequent HF. Early identification and treatment of risk
factors is the most significant step in limiting the public health The utilisation of implantable cardioverter defibrillatory (ICD)
impact of HF. See previous chapter for more details as well as for primary prevention of sudden cardiac death in HF patients
Tables 5 and 6. Routine evaluation of B-type natriuretic peptide improves survival significantly. The recommendations for ICD
(BNP) for asymptomatic patient evaluation is not recommended. are: (1) patients with LVEF ≤ 35% and NYHA class II-III symptoms
ACE-inhibitors are recommended for prevention of HF in (ischaemic and non-ischaemic cardiomyopathies); (2) patients
patients at risk. undergoing cardiac resynchronisation therapy (CRT )
implantation; (3) survivors of cardiac arrest from ventricular
Table 5: Indications to Suspect Heart Failure (Perform History fibrillation or haemodynamically unstable ventricular
and Physical) tachycardia that is not due to a reversible aetiology like acute
Conditions Test findings myocardial infarction. If there is severe refractory HF and the
Hypertension Arrythmias life expectancy is less than 1 year, an ICD is not recommended.
Diabetes mellitus Abnormal ECG (LBBB, LVH, Biventricular pacing seeks to improve and synchronize
Elevated BMI Q waves) ventricular contraction, which results in less mitral regurgitation
Coronary artery disease Cardiomegaly in chest X-ray and increase diastolic filling time. Cardiac resynchronization
Atherosclerotic disease therapy is indicated in: (1) patient with LVEF ≤35%, QRS ≥120 ms
(peripheral vascular disease or plus NYHA class III symptoms despite optimal medical therapy;
cerebrovascular disease)
(2) selected ambulatory NYHA IV patients in sinus rhythm, with
Valvular heart disease LV dysfunction and QRS ≥120 ms; (3) may be considered in
First degree relative with HF patients with NYHA class I or II symptoms, LV dysfunction and
Cardiac toxins exposure QRS ≥150 ms; and 4) may be considered in patients with LV
Obstructive sleep apnoea dysfunction in whom frequent chronic pacing is expected (i.e.
complete heart block).
Table 6: Indications to Assess Cardiac Structure by
Echocardiogram Stage D
Coronary artery disease While there has been a significant positive impact on HF
Valvular heart disease outcomes with the advent of new pharmacologic approaches
First degree relative with HF to treatment, the disease remains burdensome. End-stage HF
Supraventricular tachycardia: Atrial fibrillation or flutter patients have poor quality of life, frequent hospitalisations, and
Abnormal ECG (LVH, LBBB, Q waves) higher mortality, despite optimal medical management. They
Ventricular tachycardia or fibrillation
also produce major economic stress on the healthcare system.
The possibility of salvage by medical therapy at this stage is
Cardiomegaly on chest X-ray
remote.
Stage B The goals of therapy differ from those in stages A, B and C and
These patients will have cardiac structural changes but have will include palliation of symptoms and hospice, reducing rates
not developed HF symptoms yet. It is important to determine of hospitalisations, and in subjects that are eligible, cardiac
the aetiology of HF, with particular attention to reversible causes transplantation and/or left ventricular assist devices (LVADs). In
including coronary ischaemia. Coronary angiography should be patients with recurrent admissions, inotropic therapy should
considered when pre-test probability is high. Laboratory testing be considered as a bridge to transplantation/LVAD or as part of
for unusual aetiologies of HF is recommended if no cause is the hospice period. The indications for transplantation are listed
identified. Endomyocardial biopsy is only recommended in on Table 7. 627
 Table 7: Indications for Heart Transplantation or LVAD Evaluation Heart failure has worse prognosis than many cancers and
premature death from progressive acute decompensated
Absolute indications
HF or sudden cardiac death is common. Hospice services
For haemodynamic compromise due to HF
should be implemented after the patient has been evaluated
Refractory cardiogenic shock
Inotrope dependent at a specialised centre and determination that LVAD or
Peak VO2 <10 mg/kg/min with achievement of ventilator threshold transplantation is ill-advised. It is important to allow adequate
Severe symptoms of ischaemia and refractory angina, not time (weeks to months) for medications and other therapies to
amenable to revascularisation exert a beneficial effect before considering these advance
Recurrent symptomatic ventricular arrythmia therapies.
Relative indications
Peak VO2 11 to 14 mg/kg/min (or 55% predicted) and major RECOMMENDED READINGS
limitation in performance of daily activities 1. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail 2010;
Recurrent instability of fluid balance/renal function not due to 16: e1-e194.
patient non-compliance with medical regimen 2. Jessup M, Abraham WT, Casey DE, et al. 2009 Focused Update: ACCF/AHA
Not appropriate indications guidelines for the diagnosis and management of heart failure in adults.
Low left ventricular ejection fraction Circulation 2009; 119: 1977-2016.
Functional class III or IV heart failure 3. Opie LH, Gersh BJ. Drugs for the heart. Elsevier Saunders 2005.
Peak VO2 >15 mg/kg/min (and >55% predicted) and no other 4. Zipes DP, Libby P, Bonow RO, et al. Braunwald’s Heart Disease: A textbook
indications of cardiovascular medicine. Elsevier Saunders 2005.

628
 12.12 Acute Rheumatic Fever

R Krishna Kumar

INTRODUCTION occurred in industrialised nations all over the world with

Acute rheumatic fever (RF) is an immune-mediated non- improving living standards and with introduction of penicillin.
suppurative consequence of pharyngitis due to group-A beta- Industrialised nations now have an average annual RF
haemolytic Streptococcus (GABHS). The morbidity resulting incidence of less than 0.5 per 100,000 and RHD prevalence of
from an episode can be considerable and rarely, an episode less than 0.05 per 1,000. Improved living standards translate
of RF may result in death. However, the major concern relating into reduction in overcrowding, better access to healthcare
to RF is often not the episode itself but the long-term and more widespread use of antibiotics, all of which allow
consequences of damage to heart valves, rheumatic heart prompt treatment of streptococcal infections and help abort
disease (RHD) that often results from recurrence of RF. For this epidemics. However, the small but significant resurgence of
reason, RF and RHD are often clubbed together in discussions the RF in parts of the US during the mid-eighties suggested
on epidemiology. RF-RHD continues to be a major public that additional factors also contribute to occurrence of RF,
health problem in many parts of India. The impact of the albeit in a small way. Selected populations in Australia, New
disease through disability, premature deaths and economic Zealand and the Pacific islands also appear to have a very high
losses is substantial at all levels. It is important for physicians occurrence of RF and RHD that is perhaps in part explained
to be thoroughly familiar with the diagnosis and management by a genetic predisposition.
of RF as well as preventive strategies both for the individual A number of studies have attempted to document RF incidence
as well as for the population. and RHD prevalence in India. School surveys are traditionally
In the past four to five decades, there have been modest considered useful for this purpose because the denominator is
advances in our understanding of the disease process. There clear. However, school surveys will miss older patients with RHD.
have been minor changes in the diagnostic criteria and In areas where RF and RHD are on the decline most patients
management practices for RF have also largely remained with RHD tend to be older. Population-based registries have the
unchanged for the last 20 to 30 years. However, there have been potential to capture all age groups but are heavily dependent
important changes in the epidemiology both in India and the on referral mechanisms. Hospital-based statistics have serious
rest of the world. There appears to have been a sharp decline in limitations because only the most seriously affected are
RF and RHD in parts of India that have shown improving indices represented.
of human development. Physicians living in these parts of India It is important to recognise, however, that data from these highly
need to be mindful of the prospect of over-diagnosis of RF. selected regions are not representative of the country as a
For most of India, however, the disease is still quite common whole. The parts of the country with the highest prevalence
and it is important to not miss the initial episode of RF because today are also those regions with the poorest healthcare
secondary penicillin prophylaxis still remains the most effective infrastructure. Most comparative studies have reported a
way of preventing RHD. substantially higher prevalence in rural regions. Because of
In this chapter, the existing information on aetiopathogenesis, serious limitations in the healthcare delivery systems, the
diagnosis and management of RF will be summarised. There magnitude of the problem remains unrecognised in many
will be additional emphasis on the epidemiology of the disease poorly-served regions. Very few systematic surveys are available
and an effort will be made to focus on data from India over the from rural populations with a poor healthcare infrastructure,
last several years. urban slums and tribal colonies. Given the extraordinary
variations in indices of human development across the country
EPIDEMIOLOGY and even within regions, it is difficult to make generalisations
There is an undeniable relationship between the incidence for the entire country. Table 1 summarises the results of selected
of RF and of living standards. A sharp decline in RF and RHD studies from India over the last 50 years.

Table 1: Rheumatic Fever/Rheumatic Heart Disease Status in India

Authors Place Year Age Population RHD Prevalence RF Incidence
(yrs) Studied (per 1000) (per 1000/yr)
Padmavati Delhi (urban) 1984-94 5 to 10 40,000 3·90 0·38
Lalchandani et al Kanpur 2000 7 to 15 3,963 4·54 0·75
Jose et al Vellore 2001-02 5 to 18 2,29,829 0.68* —
Soman et al** Ernakulam 2002-04 5 to 16 25,033 0.12* 0.08
RHD = Rheumatic heart disease; RF = Rheumatic fever.
* These studies used strict diagnostic criteria (echocardiogram confirmation of diagnosis).
** Unpublished data of the Jaivigyan ICMR rheumatic fever and rheumatic heart disease in Ernakulam district. 629
 AETIOLOGY a variety of genes in the HLA-DR loci and B-cell alloantigens.
Rheumatic fever is an excellent example of a condition where Loose associations have been identified for different racial-
all three components of the classic epidemiologic triad: agent, ethnic groups. The available information seems to indicate that
host and environment interact to result in the development of heredity plays a small role, if at all, in the development of RF.
the disease. Environmental Factors
The Agent Trends in RF and RHD over the last one-and-a-half centuries,
The role of preceding group-A beta-haemolytic streptococcal in both the developed and developing countries, all point
pharyngeal infection in the development of RF was suspected towards environmental factors such as poor living conditions,
and firmly proven in the early 1930s and this association overcrowding and access to healthcare as the most significant
remains undisputed to this day. The clearest evidence of determinants of disease distribution. Indeed, global, and to a
causality was provided by the demonstration of efficacy of substantial extent regional, distributions of RF and RHD are
penicillin prophylaxis dramatically reducing recurrences of RF. still largely influenced by socio-economic indices. Parts of India
Further, mass penicillin prophylaxis terminated epidemics of RF that have good human development indices (HDI), such as
in closed populations and in civilian populations as well. Kerala, have a much lower incidence of RF when compared to
Streptococcal pharyngeal infections also result from other parts of India with low HDI, such as Chhattisgarh or Orissa. It
streptococci (groups B, C, G and F), but these do not result in RF. is generally believed that crowded living conditions, with
close interpersonal contacts, contribute to the rapid spread and
Notwithstanding the clear demonstration of the association
persistence of virulent streptococcal strains. However,
between GABHS and RF some aspects of this association that are
population density does not correlate well with RF incidence.
unclear.The occurrence of group-A beta-haemolytic streptococcal
Variations within India are best explained by education and
pharyngeal infection has remained unchanged in various parts of
the world including developed nations.Yet in most of these nations access to health care including perhaps antibiotic usage.
RF fever has declined substantially. Certain aspects of the Seasonal variations in the incidence of RF (i.e. high incidences
association between GABHS and RF have been defined: in early autumn, late winter and early spring) closely mimic
variations in streptococcal infections in temperate climates.
Epidemics of streptococcal infection are far more likely to cause Such variations are not significant in the tropics.
RF than endemic streptococcal infections. The frequently
quoted figure of 3% for epidemics and 0.3% for endemic PATHOGENESIS AND PATHOLOGY
infections are derived from studies in the 1950s on adult military The fact that RF represents an immunologic consequence of
recruits and civilian medical practice respectively. The risk of RF GABHS infection is largely uncontested. However, significant
increases dramatically in recurrent attacks of GABHS infections gaps remain in our understanding of many of the specific
in children and adults with a previous episode of RF. pathways involved. This together with the absence of a reliable
The intensity of antigenic stimulus as suggested by the anti and consistently reproducible animal model has come in the
streptolysin-O (ASO) antibody titres correlate with attack rates way of developing a suitable vaccine for the disease.
of RF. Pathology of Rheumatic Carditis
There is a carrier state for GABHS infections. This refers to the All components of the cardiac tissue are affected. Acute
isolation of GABHS from asymptomatic patients. This does not pericarditis occurs in 18% of cases and results in adhesions
translate into a risk of development of RF and does not require because of its fibrinous nature. Small-to-moderate effusions are
treatment. also common. However, large effusions and tamponade is
The molecular basis of rheumatogenic potential of GABHS is distinctly rare. Pericarditis is self-limiting and does not result in
unclear. There is also no clear relationship between specific constriction unlike tuberculous or pyogenic pericarditis. Acute
serotypes and the propensity to produce RF. The virulence of endocardial and valvular inflammation is characterised by tiny
streptococcus is closely linked to its rheumatogenic potential. vegetations that neither embolise nor are infected.
The M protein is responsible for the ability of GABHS to resist Valvular involvement alone has long-term consequences. The
phagocytosis. However, there appears to be no consistent valve heals with fibrosis and results in incompetence or stenosis.
relation between specific M protein serotypes and the incidence Not uncommonly, during acute RF one or more chordae of the
of RF after GABHS infection. mitral valve may rupture resulting in a flail leaflet and severe
Host Factors mitral regurgitation. Myocardial involvement is typically
The first attack of RF typically occurs between 5 and 15 years confined to the interstitium and does not result in myocardial
with a peak at 8 years. Attacks are uncommon below 5 years damage or dysfunction.
and rare below 3 years. Virulent GABHS epidemics can result in The histological hallmark of rheumatic carditis is the Aschoff
RF occurring for the first time in young adults. There are body. This is a granulomatous lesion, less than 1 mm in size,
anecdotal reports of initial attacks in the fourth or fifth decades. found in the endocardium, subendocardium and in the
While both sexes are equally predisposed to develop RF, chorea perivascular regions of the interstitium. It consists of a central
is strikingly uncommon in post-pubertal males. Interestingly, area of fibrinoid necrosis surrounded by cardiac histiocytes
selected large community surveys from India on RHD have (Aschoff cells or Anitschkow myocytes).
shown a striking female preponderance. Pathology of Arthritis and Chorea
Genetically-programmed determinants of host susceptibility to Synovial thickening and fibrinous exudates without any pannus
630 RF have been studied extensively. These determinants include formation are typical of rheumatic arthritis. Joint lesions heal
 Acute Rheumatic Fever
without any permanent damage. The pathologic basis of chorea For the diagnosis of a primary episode of RF, it is recommended
is unclear. A variety of changes have been described in the that the major and minor clinical manifestations of RF, the
cortex, cerebellum and basal ganglia (especially the caudate laboratory manifestations, and evidence of a preceding
nucleus). The specificity of these changes is not established. streptococcal infection should all continue according to the
1988 WHO recommendations. In the context of a preceding
Pathogenesis of Rheumatic Heart Disease following
streptococcal infection, two major manifestations, or a
Rheumatic Fever
combination of one major and two minor manifestations,
Among the tissues affected during an episode of RF, only heart provide reasonable evidence for a diagnosis of RF. The WHO
valves suffer permanent damage. All other affected tissues has continued to maintain that a diagnosis of a recurrence of
typically heal with no residual sequelae. Thus, pericarditis RF in a patient with established RHD should be permitted on
resolves completely without constriction, chorea resolves the basis of two minor manifestations plus evidence of a recent
without long-term neurologic consequences and arthritis streptococcal infection.
does not leave behind any disability. The reasons why heart
valves are permanently damaged by one or more episodes of INDIVIDUAL MANIFESTATIONS OF RHEUMATIC FEVER
RF have not been fully understood. The following hypothesis Major Manifestations
appears most plausible.
Carditis
Histopathological findings indicate widespread vascular Valvulitis is always seen in patients with carditis and is often
disease throughout the body during an acute episode of RF. clinically evident. Rheumatic pericarditis and myocarditis do not
The immunological findings suggest that RF predominantly occur without accompanying valvulitis.
damages the vascular endothelium and mesothelium. The
adjacent subendothelial and submesothelial tissues are The initial symptom of carditis is often the pain of pericarditis
affected to a very limited depth. Despite the diffuse collagen or symptoms of heart failure typically manifesting about 2 to 3
– vascular involvement, one of the mysteries of the pathology, weeks after the onset of RF. Symptoms may be subtle in children
of RF is the remarkable tendency for the disease to heal rather with nausea and vomiting resulting from gastric congestion,
than to scar the tissues it affects, with the exception of cardiac right upper quadrant pain because of hepatic capsule
valves. The damaged endothelium gets replaced by a new distension or non-productive cough from pulmonary
endothelium within days after injury without significant congestion. Carditis may be present particularly with insidious
scarring. The valves are structurally unfortunate in having a onset in young children under the age of 6 years. This is
small core of connective tissue covered by two layers of identified as a separate category (insidious or chronic carditis)
endothelium. and is typically not accompanied by arthritis.
It is likely that the endothelium suffers initial damage due to a Signs and symptoms of carditis can be classified depending on
humoral immune response, the damage resulting in VCAM-1 the pathology.
being expressed on the endothelium. This is followed
Pericarditis
by activation of cellular immune response. As a result, CD4+,
CD8+, T lymphocytes and macrophages get attached to the Pericarditis results in chest pain and is identified through
valvar endothelium and migrate to the connective tissue core. auscultation of a friction rub.This may or may not be accompanied
This sets up an inflammatory response. The inflammation is by a small pericardial effusion that is identified by echocardio-
accompanied by neovascularisation of the valve substance. graphy. In presence of mitral and/or aortic valve lesions, a
The endothelium of the newly formed vessels may serve as pericardial friction rub strongly suggests acute RF. Pericarditis
a substrate for additional inflammation and perhaps setup is equally diagnostic in primary episode or a recurrence of RF.
a vicious cycle of inflammation, neovascularisation and Myocarditis
further damage resulting eventually in a permanently scarred
valve. Left ventricular function is rarely affected in acute rheumatic fever
and heart failure is almost always the result of acute valvular
DIAGNOSIS AND CLINICAL MANIFESTATIONS OF ACUTE regurgitation. Disproportionate tachycardia and a soft first heart
RHEUMATIC FEVER sound are accompanying features of rheumatic carditis.
Jones Criteria Endocarditis/Valvulitis
Duckett Jones introduced specific criteria in 1944 as a set of For patients who do not have a history of RHD, the presence of
clinical guidelines for the diagnosis of rheumatic fever (RF) and apical holosystolic murmur of mitral regurgitation (with or
carditis. The clinical features of RF were divided into major and without apical mid-diastolic murmur, Carey Coomb’s) or basal
minor categories, based on the prevalence and specificity of early diastolic murmur strongly supports the diagnosis of acute
manifestations. The criteria needed to be sensitive enough to RF. For patients with previous RHD, a definite change in the
limit under-diagnosis and specific enough to limit over- character of any of the murmurs or the appearance of a new
diagnosis. Over the years, there have been modifications and significant murmur suggests the presence of carditis. Mitral
revisions proposed by the American Heart Association (AHA) regurgitation may disappear (58% to 74%) in time but aortic
to improve the specificity of these criteria largely dictated by involvement is usually permanent.
the declining incidence of RF in industrialised nations. In 1988
and subsequently in 2002-2003, WHO introduced specific Arthritis
modifications to the Jones criteria to allow wider application in Arthritis is the most frequent major manifestation of RF,
today’s developing world. occurring in up to 75% of patients in the first attack of RF. It 631
 occurs early in the course of the disease, as the presenting laboratory test for establishing a diagnosis of Sydenham’s
complaint. Arthritis is often the only major manifestation in chorea, and the diagnosis is largely clinical.
adolescents as well as in adults. The articular manifestations in
Subcutaneous Nodules and Erythema Marginatum
RF typically present as migratory polyarthritis, most often in the
larger joints (commonly in the knees and ankles); the wrists, Subcutaneous nodules and erythema marginatum are rare;
elbows, shoulders and hips are less frequently involved; and the usually, present in fewer than 10% of cases. Because the skin
small joints of the hands, feet, cervical and thoracic or lumbar over them is not inflamed, they may easily be missed if not
spine are rarely affected. Inflamed joints are characteristically carefully sought on physical examination. Subcutaneous
warm, red and swollen, and an aspirated sample of synovial fluid nodules are found over extensor surfaces of joints, are seen most
may reveal a high average leucocyte count. Tenderness in often in patients with long-standing rheumatic heart disease
rheumatic arthritis may be out of proportion to the objective and are rare in patients experiencing an initial attack. They are
findings and severe enough to result in excruciating pain on invariably associated with carditis and typically occur six weeks
touch. The term ‘migratory’ reflects the sequential involvement after the initial attack (Figure 1).
of joints with each completing a cycle of inflammation and
resolution, so that some joint inflammation may be resolving
while others are beginning. Many cases of rheumatic arthritis
do not conform to this characteristic description. Monoarthritis
may occur, for example, typically when anti-inflammatory
therapy is initiated before RF is fully expressed. Frequently,
several joints may be affected simultaneously, or the arthritis
may be additive rather than migratory. Inflammation in a
particular joint usually resolves within two weeks and the entire
bout of polyarthritis in about a month if untreated.
Chorea
Sydenham’s chorea occurs in fewer than 10% patients with
rheumatic fever.
Chorea occurs primarily in children and is rare after the age of
20 years. It occurs primarily in females and almost never occurs
in postpubertal males. Sydenham’s chorea is characterised by
emotional lability, uncoordinated movements, and muscular
weakness. The onset may often be difficult to determine, as
initially the child may become fretful, irritable, inattentive to
schoolwork, fidgety or even severely disturbed. Physical
incoordination soon becomes apparent, perhaps manifested
as clumsiness and a tendency to drop objects, which progresses
to spasmodic, uncoordinated movements. On physical
examination, the movements are abrupt and erratic. All muscle
groups may be affected, but erratic movements of the hands,
During acute rheumatic fever 6 weeks later
feet and face are most evident. Facial movements include
grimaces, grins and frowns. When the tongue is protruded, it Figure 1: Subcutaneous nodules in rheumatic fever: These pictures have been
resembles a ‘bag of worms’ and speech is jerky and staccato. obtained from an 8-year-old boy who had characteristic subcutaneous nodules
in a number of locations including the back and dorsum of the hand as shown
Handwriting becomes illegible and the patient may stumble
in the figure. Six weeks after presentation, following administration of anti-
when attempting to walk. When the hands are extended, the inflammatory medications that included a course of steroids, the nodules
dorsum assumes a ‘spoon’ or ‘dish’ configuration due to flexion disappeared completely.
of the wrist and hyperextension of the metacarpophalangeal
joints. When raising the hands above the head, the patient may Erythema marginatum is an extremely uncommon manifest-
pronate one or both hands (‘pronator sign’). Patients with ation. It is a macular eruption with rounded borders – usually
chorea are unable to sustain a titanic contraction; therefore, concentrated on the trunk with serpiginous margins. It is only
when asked to grip the examiner’s hand, their irregular, noticeable in fair-skinned individuals and tends to be very
repetitive squeezes have been termed ‘milkmaid grip’. Although evanescent.
the choreiform movements are usually bilateral, they may be
unilateral (hemichorea). The choreiform movements disappear Minor Criteria
during sleep, decrease with rest and sedation, and can be briefly The minor criteria are non-specific and may be present in
suppressed by volition.They may be accentuated by asking the many clinical conditions. Fever occurs in almost all rheumatic
patient to perform several voluntary movements at once. attacks at the onset, usually ranging from 101°F to 104°F (38.4°C
Neither sensory deficits nor pyramidal tract involvement are to 40.0°C). Diurnal variations are common, but there is no
present. The latent period between the onset of the initiating characteristic fever pattern. Arthralgia without objective
streptococcal infection and the onset of Sydenham’s chorea findings is common in RF. The pain usually involves large joints,
may be as long as several months. There is no definitive may be mild or incapacitating and may be present for days to
632
 Acute Rheumatic Fever
weeks, often varying in severity. Abdominal pain and epistaxis Acute phase reactants
may occur in only about 5% of patients with RF. Both C-reactive protein (CRP) and erythrocyte sedimentation
Interpretation of Jones Criteria rate (ESR) are widely available. Unlike ESR, CRP levels are not
increased in presence of anaemia and not diminished in the
To fulfil the Jones criteria, two major criteria, or one major
presence of heart failure.
criterion and two minor criteria, plus evidence of an
antecedent streptococcal infection (see below) are required. Electrocardiogram
The latter may be provided by recovery of the organism on Prolonged PR interval is accepted as a minor criterion and is
culture or by evidence of an immune response to one of not a sign of carditis. Accelerated junctional rhythm is well
the commonly measured group A streptococcal antigens (e.g. described in children. Higher grades of heart block (2nd degree
antistreptolysin O, antideoxyribonuclease B, and anti- or complete heart block) have also been described.
hyaluronidase). Insidious or chronic carditis and chorea can
occur several weeks after GABHS infection, and therefore, do The WHO 2002-2003 criteria for the diagnosis of RF are shown
not require the essential criteria of evidence of streptococcal in Table 2.
infection for the diagnosis of RF. Role of Echocardiography for the Diagnosis of Rheumatic
Interpretation of Laboratory Data Fever
Antistreptolysin O test According to the WHO recommendations, clinical examination
remains the basis of diagnosis of RF and carditis, and the role
Although widely used, ASO test has important limitations that
of echocardiography should be considered supportive.
need to be understood. ASO is positive in 85% of RF patients.
However, an echo-Doppler examination should be performed
The antibody levels in the normal population are influenced
if the facilities are available. Echocardiography offers several
by several variables such as age, geographic location, socio-
clues to support the diagnosis of rheumatic fever (Table 3).
economic status, season of the year and genetic factors.
Echocardiogram has several additional benefits in guiding
Attempts to define normal values in Indian children indicate
appropriate therapy and in prognostication. However, strict
considerable variability. Several normal children had strikingly
echocardiographic criteria should be used to diagnose valve
high titres.
regurgitation. It is important not to label small colour Doppler
In the absence of normative data for a given geographic region, jets of physiologic mitral regurgitation as significant. If mild
ASO in excess of 240 for adults and 320 for children are mitral regurgitation is identified in absence of a murmur, the
considered to be abnormal. However, ASO titres have to be features suggestive of RF is a discrete posteriorly directed jet
interpreted with caution in patients with suspected RF. Mere that often reaches the left atrial wall.
elevation of ASO in the presence of non-specific symptoms
should not be labelled as RF. Penicillin prophylaxis should not MANAGEMENT
be initiated on this basis. If necessary, a repeat titre should be The management algorithm for rheumatic fever is shown in
obtained after a week. ASO antibodies appear after 7 to 10 days, Figure 2.
peak at 2 to 3 weeks following GABHS infection and drop
General Measures
steadily thereafter.
Hospitalisation is recommended for confirmation of diagnosis,
Other streptococcal antibody tests treatment initiation, patient and family education. A throat
Other antibodies to extra-cellular streptococcal antigens culture should be obtained; blood should be drawn for ASO, ESR,
(AntiDNAse B, antihyaluronidase, antistreptokinase and CRP and blood culture (if infective endocarditis needs to be ruled-
antistreptococcal esterase) can be used to improve sensitivity. out). A chest X-ray and an echocardiogram should also be done.
If some of these tests are combined with ASO, the overall Rest is recommended for 4 weeks for patients with carditis.
sensitivity can be improved to more than 95%. However, these
Eradication of Pharyngeal Streptococcal Infection
tests are not generally available, particularly in smaller clinics
in the developing world. Eradication of the pharyngeal streptococcal infection is
mandatory to limit repetitive exposure to streptococcal
Throat culture antigens. A single dose of benzathine penicillin (1.2 million
Throat swabs should be obtained carefully and inoculated units) is ideal. Alternatives include penicillin V (250 mg qid for
within 5 hours of being obtained or should be transferred using 10 days) or erythromycin (250 mg qid for 10 days) for those with
appropriate transport methods. Throat swab culture does not penicillin allergy.
differentiate between carrier and an active infection. Delays in
Suppression of the Inflammation
obtaining throat swabs are common in the field setting and
many patients receive antibiotics before samples can be Anti-inflammatory treatment with salicylates or steroids does
obtained. not appear to influence the long-term outcome of RF or
progression of heart valve lesions. Salicylates or steroids should
Rapid antigen detection be initiated only after a diagnosis of RF is confirmed. Aspirin,
Rapid detection of streptococcal antigens from throat swabs 100 mg/kg/day divided into 4 to 5 doses, is generally adequate
using latex agglutination or enzyme immunoassay is a practical for achieving a clinical response. The optimal aspirin dose
alternative to the throat swab. It has a sensitivity of 60% to 90% should ensure an adequate response but avoid toxicity. After 2
and a specificity of 95%. weeks, the dose can be decreased to 60 to 70 mg/kg per day
633
 Table 2: 2002-2003 WHO Criteria for the Diagnosis of Rheumatic Fever and Rheumatic Heart Disease (Based on the Revised Jones
Criteria)
Major manifestations Two major or one major and two minor manifestations plus evidence of a preceding
group A streptococcal infection
Minor manifestations Two major or one major and two minor manifestations plus evidence of
a preceding group A streptococcal infection
Supporting evidence of a preceding streptococcal Two minor manifestations plus evidence of a preceding group A
infection within the last 45 days streptococcal infection
Other major manifestations or evidence of group A streptococcal infection not
required
Patients do not require any other criteria to be present for the first time with patient
diagnosed as having rheumatic heart mitral stenosis or mixed mitral valve disease
and/or aortic valve disease
Primary episode of RF Carditis
Polyarthritis
Chorea
Erythema marginatum
Subcutaneous nodules
Recurrent attack of RF in a patient without Clinical: fever, polyarthralgia
established rheumatic heart disease Laboratory: elevated acute phase reactants (erythrocyte sedimentation rate or
Recurrent attack of RF in a patient with leucocyte count)
established rheumatic heart disease
Rheumatic chorea, insidious onset rheumatic carditis Electrocardiogram: prolonged P-R interval
Chronic valve lesions of RHD Elevated or rising antistreptolysin-O or other streptococcal antibody, or a positive
throat culture, or rapid antigen test for group A streptococci, or recent scarlet fever
1. Patients may present with polyarthritis (or with only polyarthralgia or monoarthritis) and with several (3 or more) other minor manifestations, together with evidence
of recent group A streptococcal infection. Some of these cases may later turn out to be rheumatic fever. It is prudent to consider them as cases of ‘probable rheumatic
fever’ (once other diagnoses are excluded) and advise regular secondary prophylaxis. Such patients require close follow up and regular examination of the heart.
2. This cautious approach is particularly suitable for patients in vulnerable age groups in high incidence settings.
3. Infective endocarditis should be excluded.
4. Some patients with recurrent attacks may not fulfil these criteria.
5. Congenital heart disease should be excluded.

Table 3: Echocardiographic Findings Suggestive of Rheumatic Fever

Structure Modality Findings
Mitral valve Two-dimensional imaging Thickened leaflets
Limited mobility of posterior mitral leaflet
Nodules on leaflet margins (25%)
Flail anterior or posterior (rare) leaflet
Evidence of chronic RHD
Thickened chordal apparatus
Varying degrees of stenosis
Limited mobility of AML
Colour Doppler Posteriorly directed jet of mitral regurgitation
Aortic valve 2D colour Doppler Thick leaflet margins
Varying grades of aortic regurgitation
Evidence of RHD
Aortic stenosis
Reduced leaflet mobility
Tricuspid valve 2D and colour Doppler Rarely affected in the initial episode; chronic RHD is associated with organic
tricuspid valve involvement in up to 30% with leaflet thickening, and varying
degrees of TR; tricuspid stenosis is relatively uncommon but well-described
Atria M-mode and 2D Left atrial enlargement is an inevitable consequence of significant mitral
regurgitation
Ventricles M-mode and 2D Left ventricle enlargement is a result of mitral regurgitation. LV function tends to
be well-preserved except in the presence of acute severe MR. LV dysfunction is,
therefore, rare in the absence of significant MR.

634
 Acute Rheumatic Fever
Figure 2: Algorithm for management of acute rheumatic fever.

for an additional 3 to 6 weeks. Any other non-steroidal anti- Management of Chorea

inflammatory drug (NSAID) can be used as an alternative for Chorea has traditionally been considered to be a self-limiting
those allergic to aspirin. benign disease, requiring no therapy. However, there are recent
Patients with carditis and heart failure should receive steroids reports that a protracted course can lead to disability and/or
to facilitate early recovery. Steroids rapidly relieve symptoms social isolation. The signs and symptoms of chorea do not
and shorten duration of hospitalisation. Steroids are also respond well to anti-inflammatory agents or steroids. Supportive
advisable in patients who do not respond to salicylates and who measures such as rest in a quiet room together with medications
continue to worsen and develop heart failure despite anti- such as haloperidol, diazepam, and carbamazepine have all
inflammatory therapy. Prednisone (1 to 2 mg/kg-day, to a been reported to be effective. Pimozide is a new drug that is
maximum of 80 mg/day given once daily, or in divided doses) believed to be effective in rheumatic chorea.
is usually the drug of choice. In life-threatening circumstances, Role of Surgery in Refractory Heart Failure
therapy may be initiated with intravenous methylprednisolone.
After 2 to 3 weeks of therapy, the dosage may be decreased by Under exceptional circumstances, valve replacement operation
25% each week. While reducing the steroid dosage, a period of may be advised to help manage refractory heart failure from
overlap with aspirin is recommended to prevent rebound. severe mitral (or rarely aortic) valve leakage. Typically, the valve
Duration of treatment is dictated by the clinical recovery. leaflets are flail. Mitral valve repair can be considered for patients
Typically 4 to 6 weeks of total treatment is advisable. However, after the acute inflammation subsides because of the possibility
prolonged treatment is sometimes necessary for the small of recurrence of mitral regurgitation from ongoing inflamm-
proportion of patients (5%). ation. Exceptionally, valve repair has been undertaken during
the acute phase.
Management of Heart Failure
Although heart failure in RF generally responds to bed rest and NATURAL HISTORY OF VALVE LESIONS
steroids, diuretics, angiotensin converting enzyme inhibitors Mitral regurgitation associated with acute RF has a tendency
and digoxin are often initiated early. This allows greater patient to decline over the next several weeks or months once the
comfort and may help shorten the duration of hospitalisation. acute inflammation subsides. Rarely, it may disappear
The role of ACE inhibitors in acute mitral or aortic valve altogether. There are also instances where stenosis develops
regurgitation is controversial. with time. 635
 PREVENTION Table 4: Secondary Prophylaxis Following an Episode of
Primary Prevention Rheumatic Fever
This refers to prevention of occurrence of RF for the first time Antibiotic Mode of Administration Dose
following an episode of streptococcal sore throat infection. The
Benzathine Single intramuscular 12,00,000 units for
antibiotic regimens are essentially identical listed for eliminating penicillin injection every patients ≥30 kg;
Streptococci from the throat during an acute episode of RF. 3 to 4 weeks* 600,000 units for
Secondary Prophylaxis (Prevention of Recurrences of RF) patients <30 kg**

One of the most important aspects of management of acute Penicillin V Oral 250 mg twice daily
RF is the prevention of its recurrence through continuous Sulphonamide Oral 1 gm daily for
antibiotic prophylaxis regimes. Table 4 lists prophylactic (sulphadiazine, patients ≥ 30 kg and
regimes recommended by WHO. sulphadoxine, 500 mg daily for
sulphisoxazole) patients <30 kg
Duration of secondary prophylaxis Erythromycin Oral 250 mg twice daily
The following WHO recommendations are widely accepted: (for those allergic
to penicillin)
Patient without proven carditis
* 3 weekly injections are recommended for RF prophylaxis in high prevalence
For 5 years after the last attack, or until 18 years of age (whichever regions.
is longer). **For patients <30 kg in high prevalence regions, 600,000 units can be
administered every 2 weeks.
Patient with carditis mild mitral regurgitation or healed carditis
For 10 years after the last attack, or at least until 25 years of age
RECOMMENDED READINGS
(whichever is longer).
1. Narula J, Reddy KS, Tandon R, et al. Rheumatic fever. In: Narula J, Reddy KS,
Patients with established rheumatic heart valve disease or Tandon R, et al. American Registry of Pathology. Washington DC: 1999; pp
following valve surgery or balloon mitral valvotomy 41-68.
2. Padmavati S. Rheumatic fever and rheumatic heart disease in India at the
Life-long prophylaxis is usually recommended. However, some turn of the century. Indian Heart J 2001; 53: 35-7.
cardiologists do recommend discontinuation of prophylaxis 3. Rheumatic fever and rheumatic heart disease. Report of a WHO Study
after the age of 40 years because the likelihood of recurrence Group. World Health Organization, Geneva, 2004 (Technical Report Series
of RF beyond this age is considered minimal. No. 923).

636
 12.13 Valvular Heart Disease (I)

CN Manjunath

Rheumatic heart disease (RHD) constitutes the most common across the mitral valve. When the mitral valve orifice area (MVOA)
form of valvular heart disease in India. The reported prevalence is reduced to < 2.0 cm2, the LA pressure has to increase to propel
of RHD is 1.0 to 5.4 per 1,000 school children in our country. the blood from LA to LV. In severe MS, the mean LA pressure
Only 50% of patients with established RHD give a past history may become as high as 25 mm Hg to maintain antegrade flow
of rheumatic fever. This may be attributed to subclinical carditis across the mitral valve. This diastolic transmitral pressure
or the difficulty encountered in diagnosis. gradient is the haemodynamic hallmark of MS. During
tachycardia, the diastolic phase shortens and the time available
Rheumatic valvulitis most commonly affects the mitral valve
for blood flow from LA to LV is reduced. In such situations, the
(70% to 75%) followed by combined mitral and aortic
LA pressure raises abruptly and dramatically to maintain
involvement (20% to 25%), with isolated aortic disease being
adequate transmitral blood flow. The elevated LA pressure is
uncommon (5% to 8%). Though pathological involvement
transmitted backwards into the pulmonary veins resulting in
of tricuspid valve is seen in 30% to 50% of patients, clinical
pulmonary venous hypertension which causes dyspnoea.When
manifestations are rare. The mitral valve is most commonly
the mean LA pressure exceeds 25 mm Hg pulmonary oedema
affected in RHD because it withstands a high left ventricular
occurs. Hence conditions that cause tachycardia like exercise,
(LV) pressure of about 120 mm Hg during systole (aortic valve
anaemia, fever, pregnancy and atrial fibrillation worsen the
is subjected to about 80 mm Hg during diastole).
symptoms of MS. On the other hand, treatment with beta-
MITRAL STENOSIS blocker lowers the heart rate and increases the diastolic filling
period and produces symptomatic relief.
Mitral stenosis (MS) is a condition characterised by structural
abnormality of the mitral valve apparatus that results in Table 1: Assessment of Severity of Mitral Stenosis
obstruction to left ventricular inflow. The most common cause
of MS is rheumatic carditis. Other causes are extremely MVOA Mean Gradient PASP
(cm2) (mm Hg) (mm Hg)
uncommon and include congenital MS, mitral annular
calcification (MAC), carcinoid syndrome, mucopolysaccharidosis, Mild MS >1.5 to 2.0 <5 <30
Fabry’s disease, Whipple’s disease, amyloidosis and methysergide Moderate MS 1.0 to 1.5 5 to 10 30 to 50
therapy. Severe MS <1.0 to 0.5 10 to 20 >50
Critical MS <0.5 >20
Isolated MS occurs in 25% of all RHD patients and about 40%
have combined MS and mitral regurgitation (MR). The female MVOA = Mitral valve orifice area; PASP = Pulmonary artery systolic pressure.
to male ratio is 2:1. Long standing MS eventually leads to pulmonary arterial
Pathology hypertension (PH), the mechanism of which is explained by
The mitral valve apparatus is composed of the annulus, anterior Jordan’s hypothesis. According to this hypothesis, when the
and posterior mitral leaflets which are attached to the pulmonary venous pressure increases, fluid passes into alveolar
anterolateral and posteromedial papillary muscles via the walls and promotes thickening and fibrosis of the wall resulting
chordae tendinae (about 120 in number). The normal mitral in hypoxaemia. This hypoxaemia is sensed by chemoreceptors
valve orifice area is 4-6 cm2. The mechanism by which the initial that lead to reflex pulmonary arterial vasoconstriction.This triad
episode of rheumatic fever progresses onto MS, has been of passive pressure transmission, reflex vasoconstriction and
explained by two theories, namely the smoldering process of obliterative changes in the vascular bed causes PH. When
rheumatic carditis and ‘Selzer and Cohn’ hypothesis. According pulmonary artery pressure exceeds 60 mm Hg, right ventricular
to this hypothesis, the initial mitral valvulitis leads to abnormal (RV) dysfunction with tricuspid regurgitation (TR) occurs. When
flow patterns across the mitral leaflets that promote thickening, PH is severe, the chance of developing pulmonary oedema
fibrosis and calcification of leaflets. The thickened leaflets fuse decreases and symptoms of right heart failure dominates the
clinical picture.
along their edges, i.e. commissures, resulting in a stenosed mitral
valve which has a ‘Fish mouth’ or ‘Buttonhole’ appearance. This LA enlargement is a consequence of MS and fibrosis of atrial
commissural fusion may be associated with cuspal or chordal wall due to rheumatic carditis. The disorganisation of atrial
fusion or both. The severity of MS is determined by several muscle bundles coupled with in homogenous refractory
parameters as enumerated in Table 1. periods culminates in atrial fibrillation (AF). Initially, AF tends to
be paroxysmal and later on becomes permanent. Incidence of
Pathophysiology
AF in symptomatic MS is 30% to 40%.
In normal individuals, the mean pressure in the left atrium (LA)
is 2 to 12 mm Hg, whereas the LV end-diastolic pressure ranges Clinical Features
from 5 to 12 mm Hg. During diastole, the mitral valve opens The age of presentation of MS in Western countries is third or
and blood flows from LA to LV and no pressure gradient exists fourth decade. We, in India, often seen them in second decade. 637
 Those presenting in teens are called as juvenile mitral stenosis. A presystolic murmur (accentuation of MDM) occurs due to LA
The most common symptom of MS is exertional dyspnoea. It is contraction which increases flow in presystolic phase
accompanied with history of orthopnoea and paroxysmal augmenting MDM in sinus rhythm. It is absent in AF although it
nocturnal dyspnoea (PND) which distinguish dyspnoea to be can occur in AF during beats with short cycle length (Crile’s
due to pulmonary venous hypertension (PVH). Patients have hypothesis). The other causes of MDM at apex are a Carey Comb
history of dyspnoea, orthopnoea, PND for a long duration. murmur (acute rheumatic fever valvulitis), Austin Flint murmur
Second important symptom is haemoptysis. It can occur due in aortic regurgitation and MDM due to left atrial myxoma. The
to various causes as shown in Table 2. other murmur often heard is a pansystolic murmur of TR that
increases in intensity with inspiration and is best heard in the
Table 2: Causes of Haemoptysis in Mitral Stenosis lower left sternal border.
Pulmonary apoplexy (rupture of thin walled bronchial veins) Two factors help in assessing severity of MS, clinically. The
Acute pulmonary oedema shorter the A2-OS interval more severe is the stenosis. The
Pulmonary infarction duration of MDM is directly proportional to severity of MS. A
Winter bronchitis MDM that occupies the entire diastole denotes severe stenosis.
Pulmonary haemosiderosis The pliability of the valve is assessed by the intensity and
History of palpitations is prominent in these patients specially sharpness of S1 and presence of OS.
when they develop atrial fibrillation (AF). Patients symptoms Complications and Natural History
worsen after the onset of AF. They also complain of fatigue due The complication unrelated to severity of stenosis includes AF,
to low cardiac output at this stage. Pedal oedema occurs later embolism and infective endocarditis. Incidence of systemic
when right heart failure sets in and patients have pain in right embolism is 20% and risk factors include age, size of LA and AF.
hypochondrium due to hepatomegaly. Hoarseness of voice Other complication includes pulmonary hypertension and
(Ortner’s syndrome or cardiovocal syndrome) can occur due to heart failure.
compression of left recurrent laryngeal nerve by dilated LA or
pulmonary artery. Chest pain is a rare symptom and can occur The time interval from rheumatic fever to development of MS
due to pulmonary hypertension, RV ischaemia or associated is 15 to 20 years. It further takes 5 to 10 years to progress from
coronary artery disease. NYHA class II to III or IV. In India, the latent period is short and
severe symptomatic stenosis occurs as early as 6 to 12 years of
The clinical findings in MS are characterised by mitral facies - age. MS occurring before 18 years is termed as juvenile MS. The
pinkish purple patches on cheeks (due to low cardiac output MVOA decreases by 0.09 cm2/year. Five-year survival rate is 64%
and peripheral vasoconstriction). Patients are often weak and in NYHA class III patient and only 15% in class IV.
cachexic. The pulse is of normal volume and regular in sinus
rhythm. It is irregular when AF occurs. Absent peripheral pulse Investigations
denotes possible embolic occlusion. The blood pressure is ECG and radiographic findings are shown in Tables 3 and 4.
normal. In AF, average of three values of BP should be taken.
The JVP shows prominent ‘a’ wave in sinus rhythm. ‘a’ wave is Table 3: ECG Findings
absent in AF. ECG shows evidence of LA enlargement in the form of bifid ‘P’ waves
in lead II and ‘P’ terminal force in V1 >0.04 mms (Morris index)
On cardiac examination, the apical impulse is normal in position
Rhythm may be sinus or atrial fibrillation
and tapping (due to loud S1) in character. Apex displaced down
An R/S ratio >1 in V1 denotes right ventricular hypertrophy (RVH)
and out (LV apex) denotes associated MR or AR. In gross, RV
When QRS axis is >60°, MVOA is usually <1.3 cm 2 and extreme right
enlargement apex is shifted out but not downward. The left
axis denotes severe PH
parasternal impulse heave his present due to RVH. In second
space, P2 is palpable and PA pulsations can be felt denoting
pulmonary artery hypertension. On auscultation, the first heart Table 4: Radiological Abnormalities
sound is loud S1 in sinus rhythm. LA pressure is high and this LA enlargement: Double density, splaying of carina, straightening
causes mitral leaflets to be well recessed into LV cavity. With of left heart border
onset of systole, the LV pressure rises rapidly and the valve closes Pulmonary venous hypertension
with wide closing excursion causing loud S1. S1 is varying in Grade 1 – Prominent upper lobe veins
intensity in AF. A soft S1 denotes calcific MS or associated MR or Grade 2 – Kerley B, A and C lines
AR. The second heart sound is normally split and loud P2 Grade 3 – Bat wing appearance of pulmonary oedema
denotes PH. An opening snap (OS) is snappy, high frequency Pulmonary arterial hypertension: Dilated PA (>17 mm in men,
sound heard 40 to 120 ms after S2. During early diastole, the high >16 mm in women)
LA pressure causes rapid, excursion of anterior mitral leaflet to Pulmonary haemosiderosis
fully open position. The tensing of leaflets in this open position
Cardiomegaly suggests associated MR or AR or tricuspid disease
causes OS. Absent OS denotes calcific or fibrosed non pliable
MS.The murmur due to diastolic flow cross stenosed mitral valve
is a mid diastolic murmur (MDM). It is a rough, rumbling, low- Echocardiography
pitched murmur best appreciated at apex in expiration, with Echocardiography is the investigation of choice to diagnose
bell of stethoscope with patient in left lateral position.The MDM MS. The salient findings are described in Table 5. Out of 98,302
is accentuated by exercise, coughing, squatting, amyl nitrite echocardiogram done between 1st January, 2009 and 31st
638 inhalation and decreased by strain phase of Valsalva manoeuvre. December 2009 at Sri Jayadeva Institute of Cardiovascular
 Valvular Heart Disease (I)
Sciences and Research, Bangalore, 8.6% (8,512) were BMV is contraindicated in patients with (i) bicommisural
diagnosed with RHD. Of these, 8,512 echocardiograms calcification; (ii) densely calcified valve; (iii) more than moderate
predominant MS constituted 55%, predominant MR 22% and MR; (iv) specific types of LA clot; and (v) lack of expertise.
combined MS and MR about 18%.
Complications of BMV include MR (15%, of which 2% require
Table 5: Echocardiographic Findings in MS emergency surgery), cardiac tamponade (1% to 3%), stroke (1%)
and residual ASD (5%). The overall mortality is about (0.5% to
Diastolic doming of mitral valve with thickened leaflets and 1%). Data from national interventional council registry shows
commissural fusion, resulting in fish mouth appearance
that in the year 2006; total of 7,221 BMVs were performed in
Reduced EF slope
India with a procedural success of 96%.
Determine severity of MS by:
MVOA by planimetry and pressure half time Mitral valve replacement
Mean gradient by pulsed wave Doppler across mitral valve Mitral valve replacement is indicated in:
Calculation of PA pressure by TR jet gradient 1. Symptomatic (NYHA class III or IV) patients with moderate
Calcification, submitral fusion to severe MS when BMV is contraindicated
LA enlargement (Manjunath et al)
2. Symptomatic (NYHA class I or II) with severe MS when PA
Site and size of LA clot can be assessed pressure is > 60 mmHg if BMV is contraindicated
Assess other valvular lesion and ventricular function
3. Other value requiring surgery.
Assess suitability for balloon mitral valvotomy (BMV) using Wilkin’s
score or Cormier classification Open mitral valvotomy is currently done only when the chest
is opened for some other surgery, presence of left atrial clot or
Treatment
in Lutembacher’s syndrome. Closed mitral valvotomy (CMV)
Medical was performed earlier. This has been replaced now with BMV.
Penicillin prophylaxis is indicated in all rheumatic MS patients
atleast up to 40 years. Asymptomatic patients with mild to MITRAL REGURGITATION
moderate MS require only regular follow-up. But symptomatic RHD is the commonest cause of mitral regurgitation (MR).
patients require the following: Incidence of isolated rheumatic MR is 10%. MR may be acute or
1. Diuretics to reduce pulmonary venous hypertension. chronic based on the mode of onset.
Frusemide (20 to 40 mg) in combination with spironolactone Chronic Mitral Regurgitation
(25 to 50 mg) is the preferred combination. The aetiopathogenesis of chronic MR is listed in Table 6.
2. Beta-blocker in low dose is indicated even in sinus rhythm,
as it prevents tachycardia and hence sudden surge in LA Table 6: Aetiopathogenesis of Chronic MR
pressure and provides symptomatic relief. Digoxin has no RHD: Fibrosis, shortening and retraction of leaflets and subvalvular
role in MS in sinus rhythm. structures leads to non-coaptaton of leaflets
3. Oral anticoagulation in presence of AF. MVP: Redundant leaflets with interchordal hooding
4. Patients should avoid sport activities and heavy exertion. Degenerative: Calcification causes loss of sphincteric action of
annulus
Restoration to sinus rhythm is possible in patients with AF, DCM: Annular dilation
only when LA size is <5.5 cms. Patient should be optimally HCM: SAM of mitral valve and intrinsic abnormalities of valve
anticoagulated for a period of 4 weeks and clot should be ruled- Connective tissue disorders: Valvulitis and vegetation
out before cardioversion. All AF patients require rate control Congenital: Cleft AML in AV canal defect
with beta-blockers, calcium channel blockers and digoxin. The
DCM = Dilated cardiomyopathy; HCM = Hypertrophic cardiomyopathy;
target heart rate is 60 to 80 beats/min at rest and <100 beats/ SAM = Systolic anterior motion.
min with mild exercise. Anticoagulation to achieve an INR of
2.0 to 3.0 is warranted. Mitral regurgitation may be primary (valve disease) or secondary
(functional). Secondary MR occurs in dilated cardiomyopathy
Balloon mitral valvotomy
or ischaemic heart disease.
Balloon mitral valvotomy (BMV) in the procedure of choice
when indicated. The indications are as under. BMV is indicated Mitral valve prolapse (floppy mitral valve) is one of the more
in patients with suitable valve morphology, when they are: (i) common causes of mild mitral regurgitation often seen in
symptomatic (NYHA class II, III or IV) with moderate to severe young women. It may be associated with Marfan’s syndrome or
MS; (ii) asymptomatic with severe MS with PA pressure > 50 connective tissue disorders. It may present with some benign
mmHg at rest or > 60 mm Hg on exercise or new onset AF; (iii) arrhythmias (VPC’s), atypical chest pain or small increased risk
MR less than moderate; and (iv) absence of LA thrombus of stroke. It is characterised by mid systolic click and late systolic
murmur. In some patients, chordal rupture can occur resulting
Mitral stenosis in pregnancy shows worsening of symptoms in severe MR. These patients benefit from β-blockers.
specially in second trimester due to fluid overload. These
patients may need semi-urgent corrective BMV during Pathophysiology
pregnancy. Mitral restenosis occurs often (~60% to 70%) after During systole, the LV end-diastolic volume is ejected into aorta
8 to 12 years. These patients require repeat procedures like BMV, and LA. In chronic MR, LA is compliant; hence it accommodates
CMV or valve replacement. the regurgitant volume without increase in LA pressure. As the
639
 LA receives blood from both pulmonary veins and LV during Natural History
systole, there is volume overload of LA. This increased volume Mild-to-moderate MR remain asymptomatic for several years.
of blood in LA is emptied into LV resulting in LV volume overload. Asymptomatic severe MR invariably progresses to symptoms
As LV volume increases, LV dilation occurs. This, in turn, leads to or LV dysfunction within 10 years. The 5 and 10 year survival of
mitral annular dilation and worsening of MR.Thus, a vicious cycle symptomatic, severe MR is 30% and 10% respectively, without
is established wherein ‘MR begets MR’. intervention. Annual mortality is about 6.3%.
The increased LV preload (increased volume of blood from LA) Investigations
and reduced afterload (decreased forward flow into aorta)
Electrocardiography and radiographic findings of MR are
coupled with eccentric hypertrophy of LV leads to supranormal
indicated in Tables 7 and 8.
ejection fraction (EF) (>60%) and normal cardiac output is
maintained. This constitutes the compensated phase and Table 7: ECG Findings of MR
patient may be asymptomatic for many years despite severe
Normal
MR. Even a fall in EF to low normal levels (50% to 60%) denotes
LA enlargement
onset of LV dysfunction. This constitutes the decompensated
phase and leads to progressive LV dysfunction and heart failure. Atrial fibrillation (AF)
LV hypertrophy (LVH) with volume overload pattern
Giant LA (>65 mm) is a feature of chronic MR and it predisposes Q waves in V5, V6
to AF. LA thrombus is less likely as compared to MS. Other
complications of MR include infective endocarditis (IE), Table 8: CXR in MR
pulmonary arterial hypertension and heart failure.
Cardiomegaly of LV type
Clinical Features LA enlargement (can be aneurysmal)
The predominant symptom of MR is chronic fatigue due to low Evidence of pulmonary venous hypertension is rare. However, with
cardiac output. Palpitations may be due to LV volume overload onset of LV dysfunction, it is evident.
or AF. Unlike MS, dyspnoea is a late symptom of MR and denotes
Echocardiography
LV dysfunction, pulmonary hypertension or noncompliant LA.
Echocardiography is the investigation of choice to diagnose,
The clinical findings are: the pulse is usually normal but may assess severity and determine treatment options. Findings in
show a pseudo collapsing character (due to LV volume overload, MR are described in Table 9.
increased volume of blood is pumped rapidly into aorta, giving
a rapid upstroke to the pulse). It is generally regular since AF Table 9: Echocardiography in MR
is less common in MR than in MS although these patients Dilated LA and LV
have larger LA. The blood pressure is usually normal. The JVP is Assess mitral apparatus for cause of MR
unremarkable. On cardiac examination, the apical impulse is MR is severe when:
hyperdynamic and is shifted downwards and laterally. The MR jet area to LA area >50%
parasternal impulse shows rocking motion of the precordium Dense spectral pattern on Doppler
(LA enlargement causes late systolic pulsation in lower left
Vena contracta >6 mm
sternal border). On palpation, LV apex and S3 may be there.
Large PISA (Proximal isovelocity surface area)
Features of PAH are late and less prominent than in MS. On
Systolic flow reversal in pulmonary vein
auscultation, S1 is soft (reduced leaflet excursion due to
Assess PA pressure and ventricular function
abnormal leaflets) and S2 widely split (due to early occurrence
EF <60% denotes LV dysfunction
of A2, as LV systole is completed earlier). S3 is audible due to
increased flow rate across mitral valve (denotes severe MR). A Treatment
pansystolic, blowing, high-pitched murmur of uniform intensity
is best heard at the apex and radiates to axilla (radiates to Medical
sternum if MR is due to posterior leaflet abnormality). The Penicillin prophylaxis is indicated up to 40 years of age. Infective
murmur does not vary in intensity following an ectopic beat endocarditis prophylaxis is not required. Asymptomatic patient
because regurgitant volume is unchanged due to reduced with MR requires only regular follow-up. But symptomatic
regurgitant orifice area and increased regurgitant fraction. This patient requires the following:
helps in differentiating from aortic stenosis (AS) murmur. In 1. Diuretics, if pulmonary venous hypertension is present.
dynamic auscultation, squatting and handgrip increase
2. ACE-inhibitors are indicated, when EF is <60%.
intensity of murmur and standing, Valsalva, exercise and amyl
nitrite decrease the intensity of murmur. In some cases with 3. AF requires cardioversion or rate control and anticoagulation.
severe MR, a soft MDM may be heard due to early rapid filling. Medical management has very little to offer for MR patients and
Clinically MR is considered severe, when: surgery is the treatment of choice when warranted.
1. Apex is hyperdynamic and shifted down and out Surgery
2. Presence of S3 Mitral valve repair is preferred over mitral valve replacement
3. Flow MDM at apex (MVR) when feasible. MVR is possible in: MVP MR, ischaemic MR,
annular dilation, chordal rupture, leaflet perforation, and
4. Wide split S2
children with pliable valves. Rheumatic MR usually requires MVR
640 Intensity of PSM is not related to severity of MR. rather than repair.
 Valvular Heart Disease (I)
Indications of MVR/repair mean diastolic pressure gradient is the haemodynamic
1. NYHA class II, III or IV symptoms with severe MR hallmark of TS.
2. Asymptomatic patient with severe MR, when: Organic tricuspid valve disease should be suspected when right
 EF <60% heart symptoms and signs dominate the clinical picture. Most
common symptom of TS is fatigue due to reduced cardiac
 LV end systolic dimension >40 mm
output. Symptoms of MS like dyspnoea and orthopnoea are
 PASP >50 at rest or >60 mm Hg on exercise characteristically absent. Gross ascites and pedal oedema are
 New onset AF invariably present. JVP reveals prominent ‘a’ waves and slow ‘y’
descent. Absent parasternal heave with presystolic pulsatile,
Two types of valves are used for replacement. Metallic valves
tender hepatomegaly suggests RV inflow obstruction. In
and bioprosthetic valves. Metallic valves (bi-leaflet, e.g. St. Jude
addition to the auscultatory findings of mitral valve disease,
valve) require anticoagulation for lifelong, to keep INR between
an opening snap and a crescendo-decrescendo mid-diastolic
2.5 and 3.0. These have longer life. The bioprosthetic valve do
murmur at lower left sternal border, which increases on
not require anticoagulation, however, these valves show
inspiration, are present.
dehiscence after 8 to 10 years. Choice of valve depends on age,
education level and choice of patient. ECG and radiograph reveal RA enlargement. Radiographic
findings of pulmonary venous hypertension are rare. The
MVR is not indicated in severe symptomatic MR when EF
echocardiograph shows diastolic doming of tricuspid valve. A
<30%, as the perioperative mortality exceeds conservative
mean tricuspid gradient of >2 mm Hg confirms the diagnosis
management.
of TS and a gradient >5 mm Hg denotes severe TS.
Percutaneous mitral valve repair (PMVR) using MitraClip is a
Judicious use of two or more diuretics that have different
promising therapy for select subset of MR.
mechanism of action with intensive salt restriction is required
Acute Mitral Regurgitation to treat the pedal oedema and ascites. Percutaneous
Acute MR is a cardiac emergency. The causes of acute MR are transvenous tricuspid commisurotomy can be done where
listed in Table 10. feasible. Alternatively, open valvotomy can be done at the time
of surgery for the other valvular lesions. Rarely, valve
Table 10: Aetiology of Acute MR replacement with bioprosthetic valve may be required for
Acute coronary syndrome (papillary muscle dysfunction/rupture) optimal outcomes.
Infective endocarditis
TRICUSPID REGURGITATION
Acute rheumatic carditis
Post-BMV
Tricuspid regurgitation (TR) may be classified as: primary TR –
Trauma
intrinsic abnormality of valve, and secondary TR – dilation of
Prosthetic valve dysfunction
RV and tricuspid annulus causes TR.
Chordal rupture Secondary or functional TR is the most common type and is
usually due to left heart disease. Most common cause of primary
Ischaemia of papillary muscles can cause acute MR. The TR is RHD. Other causes include IE, carcinoid syndrome, Ebstein’s
anterolateral papillary muscle has dual blood supply from anomaly, tricuspid valve prolapse or drugs. Staphylococcus
diagonal and obtuse marginal coronary branches and is less aureus endocarditis and IE in intravenous drug abusers are
prone for ischaemia. The posteromedial papillary muscle is notorious for developing TR.
supplied only by PDA branch and is prone for ischaemia.
Clinically, patients present with fatigue, ascites and pedal
In acute MR, the LA is small, noncompliant and is unable to oedema. JVP is elevated with prominent ‘C-V’ waves. Tender
accommodate the regurgitant blood. So the LA pressure rises systolic pulsations of liver may be appreciated. In secondary
sharply and abruptly, resulting in acute pulmonary oedema and TR, a PSM that increases in intensity with inspiration is heard in
even cardiogenic shock. Most common symptom of acute MR lower left sternal border, whereas, in organic TR, the murmur is
is sudden onset of breathlessness. Unlike chronic MR, apical low in intensity and occupies only first half of systole. Other
impulse is normal in character and the systolic MR murmur is corroborative evidence of pulmonary hypertension like
shorter and ends well before A2. Normal LA and LV dimensions parasternal heave, loud P2, pulmonary ejection systolic murmur,
with severe MR on Doppler echocardiography suggest the ejection click or Graham Steell murmur may be present in
diagnosis of acute MR. secondary TR.
Haemodynamic stabilisation is achieved with nitroprusside,
ECG shows RA enlargement. Radiograph shows RV type of
inotropic support and intra-aortic balloon pump. Emergency
cardiomegaly with gross RA enlargement. Echocardiography
mitral valve repair or replacement is the treatment of choice.
is useful to assess the severity and aetiology of TR. If the
TRICUSPID STENOSIS pulmonary artery systolic pressure exceeds 55 mm Hg, then TR
is likely to be secondary.
Tricuspid stenosis (TS) always occurs along with rheumatic MS.
Rare cause of TS includes carcinod syndrome, IE, tumour and Aggressive diuretic therapy is needed to reduce oedema.
endomyocardial fibrosis. Clinically significant TS occur only in Secondary TR requires appropriate treatment for underlying
5% of patients. Pathology of the valve is similar to MS except disease. If the tricuspid annulus exceeds 21 mm/m2, then
that calcification is uncommon. Presence of transtricuspid tricuspid annuloplasty (Ring or De Vegas annuloplasty) is a must
641
 to relieve symptoms and this can be done during surgery for 3. Khandenahally SR, Dwarakaprasad R, Karur S, et al. Balloon mitral valvotomy
other valves. for calcific mitral stenosis. JACC Cardiovasc Interv 2009; 2:263-4.
4. Manjunath CN, Srinivasa KH, Ravindranath KS, et al. Balloon mitral
RECOMMENDED READINGS valvotomy in patients with mitral stenosis and left atrial thrombus. Catheter
Cardiovasc Interv 2009;74: 653-61.
1. Ahmed MI, McGiffin DC, O’Rourke RA, et al. Mitral regurgitation. Curr Probl
5. Manjunath C, Srinivas KH, Dattatreya P, et al. The 7th report of the non-
Cardiol 2009; 34: 93-136.
coronary cardiac interventions registry of India. Indian Heart J 2008; 60:73-8.
2. Bonow RO, et al. American College of Cardiology/American Heart
6. Padmavati S. Rheumatic Fever and Rheumatic Heart Disease in India at
Association Task Force on Practice Guidelines. 2008 focused update
the Turn of the Century. Indian Heart J 2001; 53: 35-7.
incorporated into the ACC/AHA 2006 guidelines for the management of
patients with valvular heart disease: a report of the American College of 7. Rheumatic fever and rheumatic heart disease. World Health Organisation
Cardiology/American Heart Association Task Force on Practice Guidelines. Tech Rep Ser 2004; 923:1-122.
J Am Coll Cardiol 2008; 52: e1-142. 8. Shah PM, Raney AA. Tricuspid valve disease. Curr Probl Cardiol 2008; 33: 47-84.

642
 12.14 Valvular Heart Disease (II)

VK Bahl, Ishwar Chandra Malav

AORTIC STENOSIS
Aetiology
The three common causes of aortic stenosis (AS) are congenital,
rheumatic and degenerative. It is seen in patients who are 35
years or older and results from calcification of a congenital or
rheumatic valve or of a normal valve that has undergone
‘degenerative’ changes. Rare causes of AS include obstructive
infective vegetations, homozygous type II hyperlipo-
proteinaemia, Paget’s disease of bone, rheumatoid disease,
ochronosis, and irradiation.
Pathophysiology
AS can be mild, moderate or severe depending on the
constriction and calcification of aortic valve. This causes pressure
overload on the left ventricle leading to concentric LV
hypertrophy, keeping the cardiac output in the normal range
(Table 1).
Table 1: Severity of Aortic Stenosis According to Valve Area and
Consequent Gradient Across Valve and Echo Doppler Jet
Velocity
Valve Area Gradient Doppler Jet
(cm2) (mm Hg) Velocity (m/sec) Figure 1: Pathophysiology of aortic stenosis.
Mild >1.5 <25 <3
Moderate 1 to 1.5 25 to 40 3 to 4 gastrointestinal haemorrhage and anaemia. Bleeding can be
Severe <1.0 >40 >4 caused by an acquired defect in the structure of von Willebrand
factor. Calcific systemic embolism may occur.
As the severity of AS increases, cardiac output remains within
the normal range at rest but fails to increase in proportion to Physical examination
the amount of exercise performed or does not increase at all. The arterial pulse is slow rising and late peaking (parvus et
Eventually left ventricular failure occurs giving rise to pulmonary tardus). A systolic thrill may be felt in the carotid arteries. The
hypertension and right-sided heart failure (Figure 1). jugular venous pulse and the heart size are normal in absence
of heart failure. The cardiac impulse is heaving and sustained in
Clinical Features
character with the presence of palpable S4.The S2 may be single
History since A2 and P2 are superimposed or A2 is absent or soft. It
Most patients with valvular AS are asymptomatic.The symptoms may be paradoxically split because of late A2. A systolic ejection
of AS are angina pectoris, syncope, exertional presyncope, sound is often present in young patients with valvular AS and
dyspnoea (on exertion, orthopnoea, paroxysmal nocturnal patients with bicuspid AV.
dyspnoea, pulmonary oedema), and the symptoms of heart
An aortic systolic thrill is often present at the base of the heart.
failure. Sudden cardiac death is stated to occur in 5% of patients
The turbulent flow across stenotic aortic valve causes a mid-
with AS. It occurs only in those with severe valve stenosis. Typical
systolic ejection murmur that peaks late in systole. In older
angina pectoris occurs with or without associated CAD.
patients, the systolic ejection murmur may be heard only at the
Exertional syncope occurring on effort is caused by either
apex of the heart (Gallavardin phenomenon). The intensity of
systemic vasodilatation in the presence of a fixed or inadequate
the systolic murmur varies from beat to beat. This characteristic
cardiac output, an arrhythmia, or both. Dyspnoea on exertion,
is helpful in differentiating AS from MR, in which the murmur is
orthopnoea, paroxysmal nocturnal dyspnoea, and pulmonary
usually unaffected. The murmur of valvular AS is augmented
oedema result from varying degrees of pulmonary venous
by squatting, which increases stroke volume. It is reduced in
hypertension. Systemic venous congestion is rather a late
intensity during the strain of the Valsalva manoeuvre and when
phenomenon with enlargement of the liver and peripheral
standing.
oedema results from increased systemic venous pressure and
salt and water retention. There is an increased incidence of Severe AS is indicated by slow rising pulse, presence of S4,
gastrointestinal arteriovenous malformations, also known as paradoxical splitting of S2 and late peaking systolic ejection
Heyde syndrome. As a result, these patients are susceptible to murmur. In the presence of heart failure, the jugular venous 643
 pressure is often increased, the LV is dilated, a third heart sound seen by measuring simultaneous LV and ascending aortic
is present, and the systolic murmur may be very soft or absent. pressures. Cardiac output can be measured by either the Fick
Physical findings are summarised according to severity in Table 2. principle or the indicator dilution technique.

Table 2: Physical Findings with Varying Severity of Aortic Valve Stenosis

Mild AS Moderate AS Severe AS + Normal Severe AS + LV Severe AS + Heart
LV Function Dysfunction Failurea
Arterial pulse Normal Slowly rising Parvus et tardus Parvus et tardus Small volume
Jugular venous pulse Normal Normal Normal Normal ±
Carotid thrill ± ± ± ± ±
Cardiac impulse Normal Heaving Heaving, sustained Heaving Heaving or reduced
palpable ‘a’ wave
Precordial thrill ± ± Usually ++ ± –
Auscultation
S4 – ± + + –
S3 – – – ± +
ESS + ± – – –
Peak of ESM Early systole Mid systole Late systole Late to midsystole, soft Mid systole, soft or absent
S2 Normal Normal or single Single or paradoxical Single Single

Investigations Natural History

The ECG, chest radiograph and echocardiography are baseline The natural history of AS in the adult consists of a prolonged
investigations required before these patients management latent period. Once moderate stenosis is present (jet velocity
plan can be made. The salient features of these investigations >3 m/s), the average rate of progression is an increase in jet
in aortic stenosis are shown in Tables 3 to 5. velocity of 0.3 m/s per year, an increase in mean pressure
gradient of 7 mm Hg per year, and a decrease in valve area of
Table 3: ECG Findings
0.1 cm2 per year. Eventually, symptoms of angina, syncope, or
Left ventricular hypertrophy with or without secondary ST-T wave heart failure develop and the outlook changes dramatically.
changes. (Pressure overload pattern – ST depression and T wave After the onset of symptoms, average survival is 2 to 3 years,
inversion in lateral leads) with a high-risk of sudden death.
LA enlargement/hypertrophy
Sometimes shows conduction delay, left bundle branch block. Management
Heart blocks (calcification) can occur rarely Medical treatment
Atrial fibrillation indicates associated mitral disease or heart failure Patients with severe AS should be cautioned to avoid vigorous
athletic and physical activity. Exercise stress testing should be
Table 4: Radiological Abnormalities absolutely avoided in symptomatic patients. Symptomatic
Normal sized heart patients with severe AS are usually operative candidates
Dilated proximal ascending aorta (post-stenotic dilation) because medical therapy has little to offer. However, medical
Calcification of aortic valve (better seen on fluoroscopy). Calcification therapy may be necessary in patients who are considered to
does not mean severe AS be inoperable (usually because of comorbid conditions that
Late stages heart size large with pulmonary venous hypertension preclude surgery). Diuretics must be used with caution because
hypovolaemia may reduce the elevated LV end-diastolic
Table 5: Echocardiography pressure, lower cardiac output, and produce orthostatic
Valve thickening and doming on 2D and gradient across valve on hypotension. ACE inhibitors should be used with caution but
CW Doppler are beneficial in treating patients with symptomatic LV systolic
All severe AS in adults will be calcified dysfunction who are not candidates for surgery. Beta-adrenergic
Allows definition of valve anatomy, cause of AS, calcification and blockers can depress myocardial function and induce LV failure
assessment of severity of AS and should be avoided in patients with AS. AF should be treated
Left ventricular hypertrophy, systolic functions (ejection fraction) promptly (Table 6).
can be evaluated
Assessment of aortic root dilatation and associated mitral valve Surgical treatment
disease Children: In the adolescent or young adult with severe
congenital AS, balloon aortic valvotomy is recommended in all
Chest X-ray symptomatic patients and in asymptomatic patients with a
Cardiac catheterisation and angiography transvalvular gradient greater than 60 mm Hg or in those with
The main indication for cardiac catheterisation and angiography ECG showing ST changes at rest or with exercise. The same
is to look for associated CAD in these patients before surgery. indications are appropriate for surgical intervention, although
Otherwise, the lesion can be assessed and followed-up with balloon valvotomy is probably preferable at experienced
644 echocardiography. The gradient on cardiac catheterisation is centres.
 Valvular Heart Disease (II)
Adults: Aortic valve replacement (AVR) is the treatment of choice and LA pressures are increased markedly. There is a fall in cardiac
for patients of severe AS. AVR is indicated for symptomatic output due to decrease in stroke volume.
patients with severe AS, patients with severe AS undergoing In contrast, in cases of chronic aortic regurgitation eccentric
coronary artery bypass graft surgery (CABG), patients with cardiac hypertrophy with the increased preload allows a large
severe AS undergoing surgery on the aorta or other heart valves, increase in LV end-diastolic volume. The large total stroke
and patients with severe AS and LV systolic dysfunction volume allows forward stroke volume to be normal despite a
(ejection fraction less than 0.50). large regurgitant volume. The large total stroke volume along
with the wide pulse pressure produces most of the physical
Table 6: Medical Treatment of Patients with Aortic Valve signs of aortic regurgitation.The combined pressure and volume
Stenosis
overload stimulates the development of both concentric
Antibiotic prophylaxis and eccentric hypertrophy. After many years, LV dysfunction
Infective endocarditis eventually develops, with further LV dilation, elevation of LV
Recurrent rheumatic carditis filling pressure, decreased EF, and reduced total and forward
Restriction of activities stroke volume.
Severe exercise Natural History
Competitive sports
The rate of progression to symptoms and/or LV systolic
Arrhythmias dysfunction is about 4.3% per year in asymptomatic patients
Prevent and/or control of severe AR. Sudden death occurs at the rate of less than
Restore sinus rhythm, if possible 0.2% per year in this subgroup of patients. The average rate
Cardiac medications (only if essential) of symptom onset in patients with depressed LV function
Avoid negative inotropic and proarrhythmic agents if possible is greater than 25% per year. Mortality rates of greater than
Diuretics – use cautiously 10% per year have been reported in patients with angina
Arteriolar and venodilators – use cautiously pectoris and greater than 20% per year in those with heart
Follow-up of asymptomatic patients failure.
Mild aortic stenosis: every 2 to 5 years Clinical Features
Moderate aortic stenosis: every 6 to 12 months
History
Develop symptoms: immediate
Patients with aortic regurgitation in the chronic compensated
phase are often entirely asymptomatic. As LV decompensation
AORTIC REGURGITATION
proceeds, symptoms of dyspnoea, palpitations, orthopnoea,
Aetiology and in advanced cases, paroxysmal nocturnal dyspnoea and
Aortic regurgitation (AR) can result from disease of the aortic peripheral oedema occur. Nocturnal angina occurs due to
valve (aortic cusp) and due to dilatation of aortic root. Physical bradycardia and increased AR with reduced aortic diastolic
findings can help differentiate between these although pressure leading to diminished coronary perfusion.
echocardiography is required for this. Generally, AR is chronic
Physical examination
in most conditions. However, acute AR can be seen in infective
endocarditis, aortic dissection and during acute rheumatic fever In patients with chronic, severe AR, the head frequently bobs
(Table 7). with each heartbeat (de Musset sign), and the pulses are of
the ‘water-hammer’ or collapsing type with abrupt distention
Table 7: Aetiology of Chronic Aortic Valve Regurgitation
and quick collapse (Corrigan pulse). A bisferiens pulse may be
present and is more readily recognised in the brachial and
Aortic root dilatation femoral arteries than in the carotid arteries. Traube sign (also
Hypertension with aortic root dilatation, atherosclerosis known as ‘pistol shot sounds’) refers to booming systolic and
Various forms of aortitis and arteritis, e.g. giant cell arteritis and diastolic sounds heard over the femoral artery; Müller sign
Takayasu disease, syphilis consists of systolic pulsations of the uvulal; and Duroziez sign
Connective tissue disease, e.g. Marfan syndrome, osteogenesis consists of a systolic murmur heard over the femoral artery
imperfecta, and Ehlers-Danlos syndrome when it is compressed proximally and a diastolic murmur
Autoimmune diseases, e.g. ankylosing spondylitis, rheumatoid when it is compressed distally. Capillary pulsations (i.e.
arthritis, and systemic lupus erythematosus Quincke sign) can be detected by pressing a glass slide on
Congenital lesions, e.g. supravalvular or discrete subvalvular aortic the patient’s lip, by transmitting a light through the patient’s
stenosis, ventricular septal defect, and aneurysm of the sinus of
fingertips, or by exerting gentle pressure on the tip of a
Valsalva
fingernail.
Aortic valve diseases
Congenital bicuspid valve Systolic arterial pressure is elevated, and diastolic pressure is
Rheumatic heart disease abnormally low. Hill sign refers to popliteal cuff systolic pressure
Previous infective endocarditis exceeding brachial cuff pressure by more than 60 mm Hg.
Korotkoff sounds often persist to zero even though intraarterial
Pathophysiology pressure rarely falls below 30 mm Hg. The point of change in
Acute AR results in severe volume overload of left ventricle with Korotkoff sounds (i.e. the muffling of these sounds in phase IV)
resultant pulmonary congestion as LV chamber is small and LV correlates with the diastolic pressure.
645
 The apical impulse is diffuse and hyperdynamic and is displaced created by rapid antegrade flow across a mitral orifice that is
laterally and inferiorly. The augmented stroke volume may narrowed by the rapidly rising LV diastolic pressure caused by
create a systolic thrill at the base of the heart or suprasternal severe aortic reflux impinging on the anterior leaflet of the mitral
notch, and over the carotid arteries. The PR interval may be valve. The Austin Flint murmur may be difficult to differentiate
prolonged, causing a soft S1. A2 may be normal or accentuated from that caused by mitral stenosis (MS), but the presence of an
when AR is due to disease of the aortic root but is soft or absent opening snap and a loud S1 in MS and the absence of these
when the valve is causing AR. P2 may be obscured by the early findings in AR are helpful clues. As the LV end-diastolic pressure
diastolic murmur. Thus, S2 may be absent or single or exhibit rises, the Austin Flint murmur commences and terminates earlier.
narrow or paradoxical splitting. A systolic ejection sound,
The diastolic murmur of AR may be accentuated when the
presumably related to abrupt distention of the aorta by the
patient sits up and leans forward or by interventions that raise
augmented stroke volume, is frequently audible. S3 gallop
the arterial pressure, such as squatting or isometric exercise. The
correlates with an increased LV end-diastolic volume. Its
intensity of the murmur is reduced by interventions that lower
development may be a sign of impaired LV function, which is
the systolic pressure, such as inhalation of amyl nitrite or the
useful in identifying patients with severe AR who are candidates
strain of the Valsalva manoeuvre. The Austin Flint murmur, like
for surgical treatment.
the murmur of AR, is augmented by isometric exercise and
The aortic regurgitant murmur, the principal physical finding administration of vasopressors and is reduced by amyl nitrite
of AR, is one of high frequency that begins immediately after inhalation.
A2. The murmur is heard best with the diaphragm of the
stethoscope while the patient is sitting up and leaning forward, In sharp contrast to the patients with chronic AR patients with
acute, severe AR appear gravely ill, with tachycardia, severe
with the breath held in deep exhalation. The severity of AR
peripheral vasoconstriction and cyanosis, and sometimes with
correlates better with the duration than with the intensity of
pulmonary congestion and oedema. The peripheral signs of AR
the murmur. When the murmur is musical (‘cooing dove’
are often not impressive and certainly not as dramatic as in
murmur), it usually signifies eversion or perforation of an aortic
patients with chronic AR. The normal or only slightly widened
cusp. In patients with severe AR and LV decompensation,
pulse pressure may lead to serious underestimation of the
equilibration of aortic and LV pressures in late diastole abolishes
severity of the valvular lesion. The LV impulse is normal. S1 may
the late diastolic component of the regurgitant murmur.
be soft or absent because of premature closure of the mitral
When regurgitation is caused by primary valvular disease, the
valve. Closure of the mitral valve may be incomplete, and
diastolic murmur is heard best along the left sternal border in
diastolic MR may occur. Evidence of pulmonary hypertension,
the 3rd and 4th intercostal spaces. However, when it is caused
with an accentuated P2, S3, and S4, is frequently present.
mainly by dilation of the ascending aorta, the murmur is often
more readily audible along the right sternal border. Many The early diastolic murmur of acute AR is lower pitched and
patients with chronic AR have a harsh systolic outflow murmur shorter than that of chronic AR.The Austin Flint murmur is often
caused by the increased total LV stroke volume and ejection present, but is brief and ceases when LV pressure exceeds left
rate. A mid-diastolic and late diastolic apical rumble, the Austin atrial pressure in diastole. With premature diastolic closure of
Flint murmur, is common in severe AR and may occur in the the mitral valve, the presystolic portion of the Austin Flint
presence of a normal mitral valve. This murmur appears to be murmur is eliminated (Table 8).

Table 8: Physical Findings with Varying Severity of Chronic Aortic Valve Regurgitation
Mild AR Moderate AR Severe AR Severe AR + Left Severe AR + Heart Failure
Ventricular Systolic + Left Ventricular
Dysfunction Systolic Dysfunction
Arterial pulse Normal Corrigan + to ++ Corrigan +++ Corrigan ++ Corrigan +
Arterial pressure
Systolic Normal Increased + to ++ Increased +++ Increased ++ Normal +
Diastolic Normal Decreased + to ++ Decreased +++ to ++++ Decreased ++ to +++ Decreased +
Pulse pressure Often normal Increased + to ++ Increased +++ to ++++ Increased ++ to +++ Increased +
Cardiac impulse Often normal Hyperdynamic Very hyperdynamic Hyperdynamic May be hypodynamic
visible ± chest may rock
Precordial thrill
Systolic – ± ± ± –
Diastolic – – ± ± –
Auscultation
S4 – – – – –
S1 Normal Often soft Soft Soft Soft
S2 Normal Normal or single Often single Often single Often single
S3 – + ++ to +++ +++ +++
ESM ± + + to ++ + to ++ +
AoDM + ++ +++ to ++++ ++ to +++ + to ++
Austin Flint murmur – – ± – –
646
 Valvular Heart Disease (II)
Investigations bradyarrhythmias are poorly tolerated and should be
ECG, chest radiograph and echocardiography are baseline prevented, if possible.
investigations (Tables 9 to 11). These reveal features of LV Vasodilator therapy
dilatation and volume overload which are the hallmark of
There is considerable uncertainty regarding vasodilator
chronic aortic regurgitation.
therapy. Short-term studies spanning 6 months to 2 years have
Table 9: ECG Findings demonstrated beneficial haemodynamic effects of oral
hydralazine, nifedipine, felodipine, and ACE-inhibitors. But, in
Left axis deviation with left ventricular hypertrophy of volume view of conflicting data, definitive recommendations regarding
overload, pattern (prominent Q waves in leads I, aVL, and V3
the indications for long-acting nifedipine or ACE-inhibitors are
through V6)
not possible.
Tall and upright T-waves. Later on inverted T-wave, with ST-segment
depressions Surgery: Indications
Intraventricular conduction defects occur late in the course and are AVR is the treatment of choice in symptomatic patients. Chronic
usually associated with LV dysfunction
medical therapy may be necessary in some patients who refuse
surgery or are considered to be inoperable because of co-morbid
Table 10: Radiological Abnormalities conditions. These patients should receive an aggressive heart
Marked enlargement of cardiac shadow failure regimen with ACE-inhibitors (and perhaps nitrates),
Calcification of the aortic valve uncommon digoxin, diuretics, and salt restriction, but beta-blockers should
Dilation of the ascending aorta (more than in AS) be avoided. In patients who are candidates for surgery but who
Severe aneurysmal dilation of the aorta suggests aortic root have severely decompensated LV function, vasodilator therapy
disease (Marfan syndrome, cystic medial necrosis, or annuloaortic may be particularly helpful in stabilising patients while
ectasia) preparing for operation. Such patients also respond, at least
Linear calcifications in the wall of the ascending aorta – syphilitic temporarily, to treatment with digitalis glycosides, salt
aortitis restriction, and diuretics.
Acute AR: less cardiac dilatation and more pulmonary venous
AVR is indicated for following patients with AR:
hypertension
1. Symptomatic patients with severe AR.
Table 11: Echocardiography 2. Asymptomatic patients with chronic severe AR and LV
systolic dysfunction (ejection fraction 0.50 or less) at rest.
Transthoracic echocardiography: measurement of LV end-diastolic
and end-systolic dimensions and volumes, ejection fraction, and 3. Patients with chronic severe AR while undergoing CABG or
mass. Serial measurements for follow-up surgery on the aorta or other heart valves.
High-frequency fluttering of the anterior leaflet of the mitral valve 4. Asymptomatic patients with severe AR with normal LV
during diastole systolic function (ejection fraction greater than 0.50)
Doppler echocardiography and colour flow Doppler imaging are but with severe LV dilatation (end-diastolic dimension
the most sensitive and accurate non-invasive techniques in the
greater than 75 mm Hg or end-systolic dimension greater
diagnosis and evaluation of AR
than 55 mm Hg).
AR can be quantified into mild, moderate, and severe AR on above
basis PULMONARY VALVE DISEASE: VALVULAR PULMONIC
LV size and ejection fraction are normal STENOSIS
Aetiology
Cardiac catheterisation and angiography Diseases of pulmonary valve (PV) are more often congenital in
Cardiac catheterisation is undertaken when the severity of AR origin. There are 3 morphological types of congenital
is not clear on non-invasive evaluation. The indications for pulmonary stenosis (PS): (i) typical dome-shaped PV; (ii)
selective coronary angiography are the same as for aortic dysplastic PV; and (iii) unicuspid or bicuspid PV.
stenosis. Pulmonary valve disease as an acquired condition in the adult
Management is extremely rare and may be seen in rheumatic fever, bacterial
endocarditis, carcinoid heart disease, etc.
Medical treatment
Majority of patients with AR are not candidates for prophylaxis. Pathophysiology
Patients with mild or moderate AR should be followed PS increases RV afterload and causes right ventricular
clinically and by echocardiography. Asymptomatic patients hypertrophy. Right ventricular hypertrophy under usual
with chronic, severe AR and normal LV function should be circumstances maintains normal pulmonary blood flow. When
examined at intervals of approximately 6 months. Patients the normal output is not maintained, right ventricular failure
with AR who have limitations of cardiac reserve and/or ensues. This occurs in two instances: in neonates with critical
evidence of declining LV function should avoid heavy exertion. PS and in patients with severe PS later in childhood or
Systemic arterial diastolic hypertension should be treated adulthood. With increased right ventricular systolic pressure,
because it increases the regurgitant flow; vasodilating agents RV compliance decreases and resulting increased right atrial
such as nifedipine or ACE-inhibitors are preferred and beta- pressure may cause right to left shunt through patent foramen
blocking agents should be used with great caution. AF and ovale. 647
 Natural History beyond A2. An ejection click seldom occurs with dysplastic
Adult patients with mild valvular PS do not progress. Moderate pulmonary stenosis. Signs of right heart failure are present in
PS can progress in 20% of unoperated patients and may require advanced stages (Table 12).
intervention. Patients with severe PS will have had balloon or Investigations
surgical valvotomy to survive to adult life. Long-term survival
Electrocardiogram
in patients with repaired pulmonary valve stenosis is similar to
that of the general population, with excellent to good functional With pulmonary valve stenosis, the electrocardiogram reflects
class at long-term follow-up in most patients. the haemodynamic severity of the lesion.With severe pulmonary
stenosis, the electrocardiogram shows right axis deviation and
Clinical Features right ventricular hypertrophy with a qR wave in the V1 lead. With
History moderately severe pulmonary stenosis, there is an rSR’ in the V1
Many patients with PS are asymptomatic when first seen. lead. With severe right ventricular hypertrophy, peaked P waves
With severe PS, RV hypertrophy develops, and symptoms of in the II, III, and aVF leads reflect right atrial abnormality.
dyspnoea, fatigue, chest pain, palpitations, presyncope, and Chest radiograph
decreased exercise tolerance may occur. If the right atrial (RA) With severe pulmonary stenosis, right ventricular hypertrophy
pressure increases, features of right heart failure are present and is manifested by lifting of the apex off the left hemidiaphragm
the opening of a patent foramen ovale may occur along with and filling in of the retrosternal space in the lateral chest
cyanosis. radiograph.The heart size on chest radiograph is usually normal
Physical examination unless there is RV failure or an associated cardiac lesion.
Dilatation of the main and left pulmonary artery is common in
Most adult patients with PV or other RVOT obstructive lesions
doming but not in dysplastic PS or in subpulmonic stenosis.
are normal in appearance, although certain phenotypical
Calcification may be seen in older patients. The RA and RV may
syndromes occur that include valvular, branch, or peripheral PS.
These include the rubella syndrome, Noonan syndrome (60% be enlarged if there is RV decompensation.
have a dysplastic valve), Alagille syndrome, Williams syndrome Echocardiography
and Keutel syndrome. The echocardiogram is generally definitive. A Doppler gradient
Physical examination may reveal a prominent jugular A wave, a is evident, the valve mobility can be assessed along with
right ventricular lift, and possibly a thrill in the 2nd left intercostal subpulmonic or supravalvular stenosis, the size and function of
space. Auscultation reveals a normal S1, a single or split S2 with a the RV can be determined and any vegetation on pulmonary
diminished P2 (unless the obstruction is supravalvular, in which valve can be assessed. Continuous, pulsed, and colour-flow
case the intensity of the P2 is normal or increased), and a systolic Doppler confirm any pulmonary regurgitation, tricuspid
ejection murmur best heard in the 2nd left intercostal space. regurgitation, or right-to-left shunting. Saline microcavitations
When the pulmonary valve is thin and pliable, a systolic ejection can also confirm a right-to-left shunt. When the PS is severe,
click will be heard which decreases on inspiration. As the severity interventricular septal flattening may occur. In patients with a
of the pulmonary stenosis progresses, the interval between S1 dysplastic valve, the valve is thickened and immobile, and there
and the systolic ejection click becomes shorter, S2 becomes is lack of a dilated pulmonary main trunk. With carcinoid
widely split, P2 diminishes or disappears, and the systolic ejection involvement of the pulmonary valve, thickening and lack of
murmur lengthens and peaks later in systole, often extending flexibility can be seen.

Table 12: Parameters for Severity of Pulmonary Stenosis

Haemodynamic Haemodynamic Evaluation: Haemodynamic Physical Examination
Evaluation: Degree Peak Systolic Doppler Evaluation: RV Systolic
of Obstruction Gradient (mm Hg) Pressure (mm Hg)
Trivial <25 <50 —
Mild 25 to 49 50 to 74 Jugular venous pressure: Normal except mildly increased
‘a’ wave
RV palpation: No RV lift
Auscultation: Ejection sound present (decreases with
inspiration: systolic ejection murmur increases with
inspiration and ends in midsystole) generally grade 3/6
or less
Moderate 50 to 79 75 to 100 Jugular venous pressure: Elevated;‘c-v’ wave if present
Severe >80 >100 Increased ‘a’ wave
RV palpation: RV lift; generally no impulse over PA; thrill
may be present
Auscultation: No ejection sound; prolonged RV outflow
tract systolic ejection murmur with no P2 or wide split of
second sound if P2 present; murmur often 3-6/6 in
intensity; right-sided S4
648
 Valvular Heart Disease (II)
Cardiac catheterisation and angiography is not entirely benign, because right ventricular dysfunction and
Cardiac catheterisation is rarely necessary for diagnosis. right heart failure can occur.
Gradients above, at, and below the PV should be obtained. A With pulmonary hypertension, the patient has right ventricular
peak RV systolic value of <35 mm Hg and a systolic PV gradient hypertrophy, and pulmonary regurgitation occurs with
of <10 mm Hg are the upper limits of normal. RV function can dilatation of the pulmonary valve annulus. The degree of
be assessed, and shunting through any patent foramen ovale pulmonary regurgitation is usually not severe and is rarely
can be defined. RV angiography helps to define contractile haemodynamically significant. Right ventricular dilatation and
function, the presence of infundibular obstruction, and the dysfunction leading to right ventricular failure are more
mobility of the PV. Pulmonary angiography assesses the degree frequent in these patients as a result of the right ventricular
of PR and any stenotic lesions in the main, branch, or peripheral systolic overload rather than as a result of the pulmonary
pulmonary arteries. regurgitation.
Management Clinical Features
No intervention is required in mild PS. With severe PS, right History
ventricular failure most commonly occurs after the fourth
Patients with pulmonary hypertension have symptoms related
decade of life. With severe pulmonary valve stenosis, surgical
to the cause of the pulmonary hypertension. Patients with PR
repair in the past has given good long-term results. At present,
owing to endocarditis have symptoms related to the infection
balloon valvotomy is the treatment of choice, even in the adult
such as fever, left heart failure if the mitral or aortic valve is
with congenital pulmonary valve stenosis. Immediate and
infected, or septic pulmonary emboli with an infected tricuspid
intermediate results are similar to those of surgery. Following
valve. When the patient has PR due to carcinoid tumour, the
are the recommendations regarding percutaneous or surgical
symptoms are dominated by those seen with metastatic
intervention in patients with valvular pulmonary stenosis:
carcinoid tumour.
1. Balloon valvotomy is recommended for asymptomatic
patients with a domed pulmonary valve and a peak Isolated PR causes RV volume overload and may be tolerated
gradient greater than 60 mm Hg or a mean gradient greater for many years without difficulty unless it complicates, or is
than 40 mm Hg (in association with less than moderate complicated by, pulmonary hypertension.
pulmonic valve regurgitation). Physical examination
2. Balloon valvotomy is recommended for symptomatic The physical findings in isolated PR are those of a prominent
patients with a domed pulmonary valve and a peak right ventricular anterior precordial lift, frequently with a lift
gradient greater than 50 mm Hg or a mean gradient greater in the second left interspace that is caused by the dilated
than 30 mm Hg (in association with less than moderate pulmonary artery.There is also a diastolic murmur along the left
pulmonic regurgitation). sternal border in the second and third interspaces. With isolated
pulmonary valve regurgitation, this murmur starts 0.04 to 0.06
3. Surgical therapy is recommended for patients with severe
seconds after the aortic second sound and is characteristically
PS and an associated hypoplastic pulmonary annulus,
short and low-pitched.
severe pulmonary regurgitation, subvalvular PS, or
supravalvular PS. If pulmonary hypertension is present, the second heart sound
is single and accentuated, and the diastolic murmur starts with
PULMONARY REGURGITATION P2 and is high-pitched and decrescendo in character. This is
Aetiology called the Graham-Steell murmur.
By far, the most common cause of pulmonic regurgitation (PR) If the pulmonary regurgitant volume is large, an early peaking
is dilation of the valve ring secondary to pulmonary systolic ejection murmur ending before the second heart sound
hypertension (of any aetiology) or to dilation of the pulmonary may be heard and can be grade 3 to 4/6 in loudness.
artery, either idiopathic or consequent to a connective tissue
disorder such as the Marfan’s syndrome. The second most Investigation
common cause of PR is infective endocarditis. Less frequently, Electrocardiogram
PR is iatrogenic and is induced at the time of surgical treatment In the absence of pulmonary hypertension, PR often results
of congenital PS or tetralogy of Fallot. Less common causes in an ECG that reflects RV diastolic overload, i.e. an rSr (or rsR)
include trauma, carcinoid syndrome, rheumatic involvement, configuration in the right precordial leads. PR secondary to
injury produced by a pulmonary artery flow-directed catheter, pulmonary hypertension is usually associated with ECG
syphilis, and chest trauma. evidence of RV hypertrophy.
Pathophysiology Chest radiograph
In pulmonary valve regurgitation, there is a volume overload of Both the pulmonary artery and the right ventricle are usually
the right ventricle, resulting in dilatation of the right ventricle enlarged, but these signs are nonspecific.
and, eventually, eccentric right ventricular hypertrophy. With the
increased right ventricular stroke volume, there is dilatation of Echocardiography
the proximal pulmonary arteries. In the absence of pulmonary Two-dimensional echocardiography shows RV dilation and in
hypertension, even severe volume overload of the right patients with pulmonary hypertension, RV hypertrophy as well.
ventricle is well-tolerated for many years; however, the prognosis RV function can be evaluated. Abnormal motion of the septum
649
 characteristic of volume overload of the right ventricle in Doppler echocardiography, is of decisive value in detecting
diastole and/or septal flutter may be evident. The motion of the MS and MR.
pulmonic valve may point to the cause of the PR. Doppler
Since double-valve replacement is associated with increased
echocardiography is extremely accurate in detecting PR and in
short-term and long-term risk, balloon mitral valvotomy can be
helping to estimate its severity.
the first procedure. If this causes LV dilation, AVR can follow.
Management Alternatively, open mitral valvotomy and AVR can be performed
PR alone is seldom severe enough to require specific treatment. at the same time.
Treatment of the primary condition, such as infective Aortic Stenosis and Mitral Stenosis
endocarditis, or the lesion responsible for the pulmonary
This combination is most commonly caused by rheumatic heart
hypertension, such as surgery for mitral valvular disease, often
disease. The murmur of MS may not be easily discerned in
ameliorates the PR. Surgical treatment directed specifically at
presence of severe aortic valve stenosis. The loud systolic
the pulmonic valve, such as patients with severe PR caused by
murmur of AS is also heard at the apex and hypertrophied left
surgical correction of tetralogy of Fallot, is required only
ventricle may mask the diastolic rumble of MS. Similarly, the low
occasionally because of intractable right heart failure. Under
cardiac output resulting from severe MS may result in
such circumstances, valve replacement may be carried out,
underestimation of the severity of AS as the resulting gradient
preferably with a porcine bioprosthesis or a pulmonary
is low. The echocardiogram exhibits pathology in both valves,
allograft.
and the severity of MS based on pressure half time is unaffected
MULTIVALVULAR DISEASE by AS. The peak and mean gradients are underestimated
because of reduced cardiac output.
Multivalvular involvement is caused frequently by rheumatic
fever, myxomatous heart disease, Marfan’s syndrome and other Percutaneous balloon valvotomy for MS may result in increased
connective tissue disorders. Degenerative calcification of the cardiac output and acute LV failure may develop when the
aortic valve may be associated with degenerative mitral annular severity of AS has not been recognised. The appropriate
calcification and cause AS and MR. Different pathological treatment consists of aortic valve replacement and mitral valve
conditions may affect two valves in the same patient, such as repair or replacement.
infective endocarditis on the aortic valve causing AR and
Aortic Stenosis and Mitral Regurgitation
ischaemia causing MR.
This combination of lesions is usually caused by rheumatic
In patients with multivalvular disease, the clinical manifestations heart disease. The combination of severe AS and mitral
depend on the relative severities of each of the lesions. Usually, regurgitation (MR) is a hazardous one. AS augments the volume
the proximal lesion tends to mask the distal lesion. of MR flow, whereas the presence of MR diminishes the
It is important to recognise multivalvular involvement ventricular pre-load necessary for maintenance of the LV stroke
preoperatively because failure to correct all significant volume in patients with AS. The result is a reduced forward
valvular disease at the time of operation increases mortality cardiac output and marked left atrial and pulmonary venous
considerably. In patients with multivalvular disease, the relative hypertension. The development of AF (due to left atrial
severity of each lesion may be difficult to estimate by clinical enlargement) has an adverse haemodynamic effect in the
examination and noninvasive techniques because one lesion presence of AS. The physical findings may be confusing. In
may mask the manifestations of the other. For this reason, patients with severe AS and MR, both valves must usually be
patients suspected of having multivalvular involvement and treated surgically by AVR and, if possible, by MV repair or MVR.
who are being considered for surgical treatment should Aortic Regurgitation and Mitral Regurgitation
undergo careful clinical evaluation and both full Doppler This relatively frequent combination of lesions may be caused
echocardiographic evaluation and right- and left-cardiac by rheumatic heart disease, myxomatous degeneration, or
catheterisation and angiography. by dilation of both annuli in patients with connective tissue
Mitral Stenosis and Aortic Regurgitation disorders. The left ventricle is usually greatly dilated. The clinical
Approximately 10% of patients with mitral stenosis (MS) have features of AR usually predominate. When both valvular leaks are
severe rheumatic AR. In keeping with the general observation severe, this combination of lesions is poorly tolerated.The normal
that a proximal lesion may mask a distal lesion, significant AR mitral valve ordinarily serves as a ‘backup’ to the aortic valve,
may be missed in patients with severe MS. On the other hand, and premature (diastolic) closure of the mitral valve limits the
MS may be missed or, conversely, may be falsely diagnosed volume of reflux that occurs in patients with acute AR.With severe
on clinical examination of patients with obvious AR. An combined regurgitant lesions, regardless of the cause of the mitral
accentuated S1 and an opening snap in a patient with AR lesion, blood may reflux from the aorta through both chambers
should suggest the possibility of mitral valvular disease. of the left-side of the heart into the pulmonary veins. Physical
However, an Austin Flint murmur is often inappropriately and laboratory examinations usually show evidence of both
considered to be the diastolic rumbling murmur of MS. These lesions. An S3 and a brisk arterial pulse are frequently present.
two murmurs may be distinguished at the bedside by means The relative severity of each lesion can be assessed best by
Doppler echocardiography and contrast angiography. This
of amyl nitrite inhalation, which diminishes the Austin Flint
murmur but augments the murmur of MS; isometric handgrip combination of lesions leads to severe LV dilation.
and squatting augment both the diastolic murmur of AR and MR that occurs in patients with AR secondary to LV dilation often
650 the Austin Flint murmur. Echocardiography, particularly pulsed regresses following AVR alone. If severe, the MR may be
 Valvular Heart Disease (II)
corrected by annuloplasty at the time of AVR. An intrinsically trivalvular disease may present in advanced heart failure with
normal mitral valve that is regurgitant because of a dilated marked cardiomegaly, and surgical correction of all three
annulus should not be replaced. valvular lesions is imperative. However, triple-valve replacement
is a long and complex operation. It should be avoided, if possible.
Mitral Stenosis and Tricuspid Regurgitation
In many patients with trivalvular disease, it is possible to replace
If pulmonary hypertension is severe and the tricuspid valve the aortic valve, repair the mitral valve, and perform a tricuspid
anatomy is not grossly distorted, improvement in tricuspid annuloplasty or valvuloplasty.
regurgitation (TR) can be expected after correction of MS. On
the other hand, if there is severe rheumatic deformity of the When multiple prosthetic valves must be inserted, it is logical
tricuspid valve, dilatation of the tricuspid annulus, or severe TR, to select either two bioprostheses or two mechanical
competence is likely to be restored only by surgery. prostheses for the left side of the heart. If the patient is
to be exposed to the hazards of anticoagulants for one
If the mitral valve anatomy is favourable for percutaneous mechanical prosthesis, it seems unreasonable to add the
balloon valvotomy and there is concomitant pulmonary potential risks of early failure of a bioprosthesis. However, if
hypertension, valvotomy should be performed regardless of two mechanical prostheses are selected for the left side of the
symptom status. After successful mitral valvotomy, pulmonary heart, the use of a bioprosthesis in the tricuspid position is
hypertension and TR almost always diminish. suggested.
If mitral valve surgery is performed, concomitant tricuspid
annuloplasty should be considered, especially if there are RECOMMENDED READINGS
preoperative signs or symptoms of right-sided heart failure, 1. Bonow RO, et al. American College of Cardiology/American Heart
Association Task Force on Practice Guidelines. 2008 focused update
rather than risking severe persistent TR, which may necessitate
incorporated into the ACC/AHA 2006 guidelines for the management of
a second operation. Annuloplasty of the tricuspid valve based patients with valvular heart disease: a report of the American College of
on tricuspid dilatation (tricuspid annulus diameter >35 mm) Cardiology/American Heart Association Task Force on Practice Guidelines.
improves functional status independent of degree of TR. J Am Coll Cardiol 2008; 52: e1-142.
2. Coats L, Bonhoeffer P. New percutaneous treatments for valve disease. Heart
Triple-Valve Disease 2007; 93: 639-44.
Haemodynamically significant disease involving the mitral, 3. Otto CM. Valvular aortic stenosis: Disease severity and timing of
aortic and tricuspid valves is uncommon. Patients with intervention. J Am Coll Cardiol 2006; 47: 2141-51.

651
 12.15 Infective Endocarditis

Shyam S Kothari

Infective endocarditis (IE), an endovascular microbiological affected by IE, perhaps depending on the strength of the
infection of cardiovascular structures, remains a serious illness. abnormal haemodynamic jets. For example, IE is very
The various considerations in the diagnosis and management uncommon in atrial septal defect where the blood flows from
of IE provide such a challenge that it can be said that ‘know IE left to right atrium with low pressure difference compared to
and you know medicine.‘ In this chapter, salient aspects of IE ventricular septal defects with high pressure gradients between
are recapitulated with an emphasis on Indian experience. the ventricles. It is also uncommon in patients with Eisenmenger’s
syndrome where the difference in pressures between the
EPIDEMIOLOGY
chambers is abolished and there are no high velocity
Despite several advances in the field of medicine, the incidence jets. Further, in mitral valve lesions also, IE is uncommon in
of IE has not reduced significantly over last 50 years, but the patients of mitral stenosis compared to patients with mitral
pattern of the disease has changed. IE occurs in 1-6/100,000 regurgitations. The general risks are shown in Table 2.
patient years in the Western world. There are no systematic
population based data from India, but the incidence may be It is clinically useful to consider IE (1) in terms of the tempo of
higher due to large number of rheumatic heart disease (RHD) the disease (acute or subacute); (2) in terms of the valve involved
and untreated congenital heart disease (CHD) patients in India. (diseased native, normal native or prosthetic valve); and (3) in
Hospital-based studies show a higher, prevalence of underlying terms of the causative organism (common organism like
RHD, lower pick up of vegetations and blood cultures and Streptococcus viridans, or virulent like methicilin resistant
greater mortality in the Indian series as compared to the Staphylococcus aureus or fungi, or unknown organisms). The
western data. These trends are shown in Table 1. major differences between acute and sub acute bacterial

Table 1: A Comparison of Indian and Western Series of Infective Endocarditis

Characteristics Indian Series Western Series
Choudhury, et al Garg, et al Meta-analysis EHS
Duration 1981–91 1992–2001 1993–2003 April–July
Episodes 190 198 3,784 159
Age (years) 25±1.2 27.6±12.7 36-69 56±17
Identifiable preceding event (portal of entry) (%) 15 16.6 NA 41-48
Predisposing condition RHD (%) 42 46.9 NA NA
CHD (%) 33 28.6 NA NA
PVE (%) 1 10.4 7-25 26
IV drug abuse 0.5 0 15 NA
Echocardiogram positive (%) 64 89.9 NA 82
Blood culture positive (%) 47 67.7 90 86
Surgery for IE (%) in-hospital 1 23 25-40 52
Mortality (%) 25 21 16 12.6
EHS = European heart survey; RHD = Rheumatic heart disease; CHD = Congenital heart disease; PVE = Prosthetic valve endocarditis; IV = Intravenous; IE = Infective endocarditis.

IE is uncommon in infants and children and the incidence

Table 2: Risk of IE in Various Cardiac Lesions
increases with age. Males outnumber females (M:F = 1.7:1 in
general, but up to 7:1 in patients above 70 years of age in some High Risk Moderate Risk Low Risk
series). About 75% of episodes occur in diseased native valves, Prosthetic heart Mitral valve prolapse Mitral valve prolapse
whereas infection on a normal native valve is increasingly seen valves with MR without MR
as nosocomial infection in immunocompromised, elderly, Previous IE Degenerative valvular Isolated ASD
Tetralogy of Fallot disease in elderly Cardiac pacemaker
diabetics, and in intravenous drug users. The relative
Especially with BT patients Prior CABG
proportions of valves involved in IE is interesting and possibly shunt Tricuspid regurgitation Prior Kawasaki’s disease
result from the difference in the pressure gradients across the PDA Pure mitral stenosis Rheumatic fever without
valves. In an autopsy series of 1,024 patients in the pre-antibiotic Aortic regurgitation Tricuspid stenosis valvular dysfunction
era, the proportions of involved valves were mitral valve in 86 %, Mitral regurgitation Pulmonary stenosis
aortic 55%, tricuspid valve 19% and pulmonary valve in 1.1%. Mitral stenosis with Hypertrophic obstructive
regurgitation cardiomyopathy
Nowadays higher proportion of aortic valve involvement may
VSD
be seen in elderly and tricuspid valve in drug addicts. The Coarctation of aorta
652 different underlying lesions have different risks of being
 Infective Endocarditis
endocarditis are shown in Table 3. These considerations
influence the treatment and prognosis.Thus, subacute IE caused
by Streptococcus viridans in a RHD patient is viewed differently
from staphylococcal endocarditis on a native mitral valve in a
patient on maintenance haemodialysis.

Table 3: Salient Features of Acute and Sub-acute Bacterial

Endocarditis (Significant Overlap is Seen)
Acute Sub-acute
Onset (from bacteraemia) Within 2 weeks Within 2 months
Progression Days to weeks Weeks to months
Organism Virulent Less virulent
(i.e. Staphylococcus (i.e. Streptococcus
aureus) viridans)
Structural heart disease Absent Present

Figure 1: Echocardiogram (parasternal long axis view) showing vegetations on

PATHOGENESIS aortic and mitral valves (arrows).
The hallmark of IE is the presence of vegetation in the LA = Left atrium; LV = Left ventricle.
endocardium of the heart. Normal endocardium is resistant to
infection, but a traumatised endocardial surface is exposed to infection, local destruction in the heart, embolism, and immune
platelets and fibrin. Local trauma from an abnormal blood jet activation.
or systemic factors may result in unhealthy endocardium. A
coagulum of platelet and fibrin is formed on the endocardial THE ORGANISMS
surface resulting in non-bacterial thrombotic endocarditis It is good to remember that while many micro-organisms may
(NBTE). Any subsequent bacteraemia may colonise such cause IE, most episodes are caused by only a few bacterial species
vegetation. The vegetation are avascular and the fibrin layer of streptococci and staphylococci. The organism causing IE have
possibly provide a barrier from leucocytes, thus bacteria rapidly certain peculiarities, viz. ability to adhere to the endothelial
grow within these vegetations. Early treatment may eradicate surface, or the ability to penetrate normal endothelial barrier. It
infection from vegetation but after 3 days it is not possible to is hypothesised that factors such as fibronectin binding proteins
get rid of the bacteria from vegetations due to high density on S. aureus, clumping factors or glucans on S. viridans are
and other dynamics of bacterial growth, thus underlying the important in this regard. Despite frequent occurrence of Gram-
need for long-term bactericidal antibiotics therapy for IE. The negative bacteraemia, organisms such as Klebsiella, or Salmonella
micro-organisms grow within vegetation and shed bacteria in rarely cause IE. Generally speaking, nearly 75% to 80% of the
circulation frequently; some of the colonies become episodes are caused by streptococcal and staphylococcus sp., 5%
metabolically inactive and hence difficult to eradicate. The Gram-negative bacilli (of HACEK groups mainly,and Pseudomonas),
infection can spread locally, or systemically. 5% fungi, and rest by other uncommon organisms including
coxiella, legionella, anaerobes (<1%), and others. The other
The vegetation may occur at the valves, on mural endocardium organism must be considered in the clinical context. For example,
(e.g. in front of the VSD jet), in aorta (beyond coarctation site), fungal IE in patients who have received broad spectrum
in pulmonary arteries (at the ductus arteriosus insertion site) antibiotics for long time for some systemic infection, Brucella or
or in aneurysms. In the valves typically, vegetation occur on the Q fever in a dairy worker or a veterinarian who has chronic IE
atrial surface in mitral valve in a patient with mitral regurgitation with large vegetations and negative blood cultures. Bartonella
and ventricular surface of aortic valves in patients with aortic in a HIV positive homeless destitute, but such association or
regurgitation respectively. These observations are consistent background is not enough to establish the diagnosis. A brief
with Rod Board's hypothesis of bacterial colonisation resulting discussion about the common organisms is in order.
from venturi effects of jet lesions. In Libman-Sacks endocarditis,
Streptococci
and in marantic IE, the vegetation occur at the ventricular
surface of MR, on chordae tendineae, etc. In a patient of aortic Streptococcus viridans species (S. mitis, S. salivarius, S. sanguinis)
regurgitation due to IE, mitral valve may become infected and is a normal commensal organism of the oropharynx and still
the vegetation are seen at the chordae where the jet of aortic remains the commonest cause of native valve IE in the average
regurgitation strikes the mitral valve (Figure 1). The vegetation community setting. Most Streptococcus viridans are penicillin
of IE may grow from few millimetres to as large as few sensitive although some strains may require higher minimum
centimetres and may obstruct the valve. These may regress with inhibitory concentration (MIC). Some strains of streptococci (e.g.
treatment or may disappear due to embolisation. Increasing size abiotrophia) are fastidious and require special culture medium
of vegetation during treatment usually, but not always, indicate and also higher MIC for cure.
persistent infection and treatment failure. Large vegetations are Streptococcus bovis has emerged as a common cause of IE in
seen in fungal endocarditis, and also with Gram-negative IE but elderly. Isolation of this organism in blood culture in a patient
size of vegetation is not a reliable criterion for the diagnosis of mandates the evaluation of gastrointestinal tract for colonic
the organism. The clinical features of the disease result from cancer or polyps. 653
 Streptococcus faecalis (enterococci) is a commensal of genitourinary change in murmur may not be appreciable. Changing
tract and is an uncommon cause of community acquired IE. The murmurs or new murmur may occur with valve destruction,
microbe has a high order of resistance to antibiotics. It causes a chordal rupture, paravalvular leaks or fistulae formation.
recalcitrant form of IE needs special considerations for Local invasion and destruction occur rapidly in acute IE but
treatment. Occasionally, it can cause acute form of IE. may occur with all IE, albeit, slowly and uncommonly with
usual Streptococcus viridans IE. Staphylococcus aureus, S.
B streptococcus may cause IE in neonates or in the post-partum
lugdunensis, beta-haemolytic streptococci and pseudomonas
setting. β haemolytic streptococci, the cause of acute rheumatic
fever, causes a destructive IE but is a very rare occurrence. cause rapidly destructive IE. Extension beyond valve ring
resulting in annular abscess, myocardial abscesses,
Staphylococci pericardial extension and tamponade or coronary artery
Staphylococcus aureus has been increasingly seen now and has embolism may all lead to worsening cardiac status, but the
become the commonest cause of IE in some series. Typically, it valve lesions are the most significant amongst all of these
causes acute IE with local destruction, CNS embolism and as the cause of heart failure. Mechanical complication may
metastatic septic foci. S. epidermidis, a coagulase negative occur even after bacteriological cure of IE. Congestive heart
Staphylococcus is a normal commensal of skin flora and is the failure is the commonest cause of death from IE.
commonest cause of early prosthetic valve IE . It may also cause
3. Embolism
destructive IE. S. lugdunensis, another coagulase negative
Staphylococcus has emerged as cause of destructive IE. S. aureus Embolisms to organs is often clinically silent, although
can also cause subacute IE. detected in autopsy in 60%. Any organ may be involved by
embolism of the vegetations from IE, but brain, spleen,
Other Organisms kidneys, bowels, limbs, or lungs (in right-side IE)
Gram-negative organism of HACEK group cause IE in <5% cases. predominate. Embolism occurs in nearly 50% of patients
(HACEK include Haemophilus, Actinobacter, Cardiobacter, with IE and is the presenting feature in many patients
Eikenella, Kingella). Pseudomonas aeruginosa rarely cause IE, but because it often occurs early in the disease. The incidence
may be an important cause in drug addicts, in HIV positives, of embolism is high in the first 2 weeks of illness and falls
and in nosocomially acquired IE. Fungi are dreaded cause of IE rapidly with treatment even though it may occur after full
(candida or aspergillosis) and typically occur in a settings for treatment in some patients. It occurs at a rate of 12 per 1,000
fungal sepsis like post-operative prosthetic valve IE. Anaerobes patient days in the initial 2 weeks, but decrease to 1.2 per
cause <1% IE. Other interesting causes of IE include brucella, 1,000 patient days after 2 weeks of treatment. It is difficult
chlamydia, psittacosis, legionella, mycobacterium, tropheryma to predict embolism. Various features such as size, shape,
whippelei, bartonella, etc. mobility, location of vegetations, causative organism and
other characteristics of patients have been studied to
CLINICAL FEATURES predict embolisation. Vegetations more than 10 mm,
IE has protean manifestations and is not uncommon for patients vegetations on anterior mitral leaflet (which moves twice
to remain undiagnosed for months as PUO. With the advent of during diastole), and that caused by S. aureus, fungi, or Gram-
echocardiography, the diagnosis is facilitated very significantly, negative bacilli are more likely to embolise. Mobility of
still patients may present to neurology, nephrology or vegetation is difficult to quantify and some studies suggest
haematology departments with different complaints. that mobility is only a matter of size of vegetation and not
The clinical manifestation of IE can be grouped into four independent predictor of embolism. Increasing size of
headings: vegetation during treatment is associated with higher risks
1. Constitutional Features of embolism. In one study, presence of anti-phospholipid
antibodies predicted embolism, but in general, predicting
Anorexia, fatigue, night sweats and feeling unwell are
embolisation in an individual patient is not possible.
universal. Weight loss can be quite significant and is
attributed to cytokine activation. Aches, pains, arthralgia Embolism occurs at branch point of arteries. In CNS, 90%
and backache are common and may be the presenting of embolism occurs in middle cerebral artery territory
features confusing the primary diagnosis. leading to serious neurological deficits. Embolism to
splenic artery is common but clinically may not be apparent
Fever is almost always present in IE, and has no typical
or may cause splenic infarct. Pain in left hypochondrium
pattern. Recurrent chills at onset favours a bacteraemic
referred to left shoulder in a patient of IE is suggestive of
illness, though frank rigors are uncommon. The usual
splenic infarct. Similarly, renal infarct may cause loin pain,
temperature varies from 100 °F to 103 °F, but hectic fever
hypertension, and haematuria. Mesenteric ischaemia, and
with rigors may be seen in acute IE. Fever is sometimes
not reported by the patient and may not be conspicuous limb threatening ischaemia may also occur with embolism.
in nearly 5% of patients such as frail elderly, renal failure, Bacteria or fungi can be grown from materials recovered at
due to prior antibiotic use or in immunosuppressed surgery. Embolism of IE is not influenced by anticoagulant
patients. or antiplatelet treatment. Right-sided IE is regularly
accompanied by pulmonary embolism leading to lung
2. Cardiac Involvement infiltrate, consolidation, infarct, abscess or pulmonary artery
A heart murmur is present in the majority of patients, but pseudoaneurysms. Mycotic aneurysms result from
may be faint or absent in right-sided endocarditis. The embolisation to vasa vasorum of the vessels and
654 patient may have a murmur from a previous lesion and subsequent weakness of the wall or from direct arterial wall
 Infective Endocarditis
infection. These are most commonly seen in the brain and staphylococcal sepsis. Serum ferritin, acute phase reactant may
may result in catastrophic haemorrhage. Mycotic aneurysm be elevated early in the course, but in chronic phase it is more
are more common with S. viridans than staphylococcal IE. often elevated in malignancy and Still‘s disease.
4. Immunological Manifestation Urine
IE results in intense humoral and cellular immune Microscopic haematuria is common. Gross haematuria suggests
stimulation. Peripheral stigmata of IE are supposed to result renal infarct. Proteinuria, casts may occur in patients with
from immune complex deposition although septic glomerulonephritis. Rapidly progressive crescentic glomerulo-
embolism may account for some of these. nephritis sometimes occurs in IE and it resolves with antibiotics
treatment, and/or with plasmapheresis.
Osler’s Nodes
Typically, 2 to 15 mm pea-shaped, painful reddish nodules in Blood Culture
the pulp of fingers and toes are seen in classical IE. These are Blood culture must be carefully obtained with antiseptic
uncommonly seen in acute IE, and possibly result from vasculitis. precautions. It is recommended to take three sets of cultures
Sometimes, bacteria have been recovered from these lesions. (at least 1 hour apart), and from two separate venipunctures,
Similar lesions may occur in gonococcal infection, haemolytic (10 mL blood in adults) in each bottle is required, in sicker
anaemia, SLE, marantic endocarditis, and in extremities with patients, empirical treatment may be started after taking culture;
cannulated infected arterial lines. Lesions are transient, multiple but in stable patients who have received prior antibiotics
and do not ulcerate. waiting for 48 hours before taking cultures should be practised.
Janeway’s Lesion Addition of polysulphonates or resins to culture bottles may
be helpful. Better culture medium like BACTEC improve the
Flat macular erythematous non-painful lesion in palms and positivity rates and yield results early but are not widely available.
soles, often seen in acute Staphylococcus IE. Bacteria may be If there is no growth after 5 to 7 days and IE is suspected,
isolated from these. subcultures on special media should be done. But chances of
Petechiae and Purpura contaminant growth also increase after 5 to 6 days. Fastidious
Petechiae are common, may occur in crops, seen after few weeks organisms like nutritional variant S. viridans, or HACEK organisms
of infection and usually identified in sublingual, subconjunctival need special culture media techniques.
areas, but can occur anywhere in the skin. They represent Help of microbiologist should be sought early in the disease
vasculitis, thrombocytopaenia, or sepsis. Streaky lines in nails and since each laboratory may have local protocols, this should
are not characteristic of IE and may occur from trauma or other be discussed. Acridine dye test is sometimes useful in identifying
causes in many hospitalised patients. organism even with obviously negative cultures.
Roth’s Spots Isolation of a microbe typically known to cause IE is highly likely
Retinal haemorrhages with white centres are Roth’s spots. These to be the significant, but sometimes it is difficult to distinguish
lesions are seen in number of conditions and represent capillary contaminant from the culprit, or simple bacteraemia from IE.
haemorrhages, not bacterial infection. These are also seen in Staphylococcal bacteraemia is associated with IE in nearly
anaemia, leukaemia, vasculitis, diabetes, carbon monoxide a quarter but enterococcal bacteraemia have IE in only 10%
poisoning and rarely in HIV.These lesions undergo changes quickly. of patients. Community acquired bacteraemia, persistent
bacteraemia in the absence of obvious focus favour the
INVESTIGATIONS diagnosis of IE. Diphtheroids, acinetobacter are common
Haematological commensals and contaminants but isolation from multiple
cultures may be significant. Polymicrobial IE is uncommon
Normocytic normochromic anaemia of chronic disease is the
except in drug addicts.
rule in IE. Leucocytosis is not common and normal counts are
seen in 70% to 80%. Acute IE (staphylococcal and others), and Several bacteria do not grow in the culture medium and
fungal infection cause leucocytosis. Shift to left and toxic serological tests or histological confirmation is required for the
granulations may occur. ESR is very useful, though non-specific diagnosis. Example includes Brucella, Q fever, bartonella,
test, and should not be omitted. Mean ESR in IE is in the range legionella. More recently PCR techniques are utilised for the
of 50 to 60 mm in first hour. (High ESR as minor criteria is >30 diagnosis of some of these, and in future wider availability of
mm in patients less than 60 years, and >50 for older patients). PCR probes for usual IE will make the diagnosis quick for routine
CRP (>100 mg/L) is faster to resolve than ESR. A very high ESR cases as well. Identification of bacterial 16SrRNA and specific
helps in narrowing differential diagnosis in patient of PUO. DNA after amplification can identify responsible agent from
tissues obtained at operation in culture negative cases. However,
Other haematological tests are sometimes useful. Rheumatoid
PCR may remain positive in treated old IE as well. Similarly,
factor is positive in half of the cases, specially with longer clinical
histological demonstration of micro-organism from valves,
course. Circulating immune complex are seen in majority of
sometimes, may represent dead bacteria.
patients but have no major additional value. Cryoglobulinaemia
may occur. Non-specific elevation of gamma globulin is Antibiotic sensitivity of the organism is a vital information for
common. Serum complement is reduced in patients with selection of antibiotics, though sometimes in vivo sensitivity
glomerulonephritis and IE. Anti-streptolysin O (ASLO) is not may be different. Finding the minimum inhibitory concentration
elevated (except in the rare β haemolytic streptococcal IE). (MIC) to antibiotic like penicillin is useful in the treatment of IE,
Elevated procalcitonin is seen with sepsis, more so in but is not widely practised. 655
 ECHOCARDIOGRAPHY of vegetation is a risk marker for embolism or poor prognosis.
Echocardiography is the cornerstone of the diagnosis of IE Echocardiography should not be done as a screening test for
and has revolutionised the management of IE. Presence of patients with fever in whom IE is not likely.
vegetations, new onset valve regurgitation, annular abscess
DIAGNOSIS
or valve dehiscence are diagnostic of IE. Of these, vegetations
are most important. Typical vegetation of IE is seen as The diagnosis of IE is a clinical diagnosis. Although modified
oscillating mass few mm to cm(s) in size attached to valve or Duke‘s criteria (Tables 4A and 4B) are widely recognised as
mural endocardium having an independent mobility. important in the diagnosis of IE, it cannot be overemphasised
Vegetations more than 2 mm are identifiable by echo- that the comprehensive picture of the patient should be taken
cardiogram, but the identification of vegetation is dependent into account. Bacteraemia with typical organisms known to
on the experience of operator. Vegetations may be confused cause IE and vegetations on echocardiogram combined make
with some normal tissues like Chiari malformations in right the diagnosis of IE definite. These are considered major criteria
atrium, parts of normal chordae, surgical stitch. Vegetations for the diagnosis in Duke’s criteria. In the absence of one of these
may also occur in other disease like marantic and Libman- major criteria, minor criteria need to be looked into. Since, we
Sacks endocarditis or anti-phospholipid antibody syndrome have large number of culture negative cases, the modified
and in acute rheumatic fever. Sometimes, the vegetations may Dukes criteria that involve the minor criteria are important for
be too small or sessile, or represent previous treated IE. Further, us. As such, performance of Dukes scheme has not been
up to 20% patients may have limited echocardiographic rigorously evaluated in Indian setting, but the basic principles
windows. Thus, possibilities of misdiagnosis and missed are useful for uniformity. The diagnosis of IE is considered
diagnosis of IE remain even with echocardiography. In rejected if alternative diagnosis is firmly established or if fever
general, transthoracic echocardiography has a sensitivity disappears before 4 days of treatment without recurrence.
of 65% to 70% for the diagnosis of IE. Transoesophageal The differential diagnosis of PUO is long, but tuberculosis,
echo-cardiography (TEE) is preferred in doubtful cases, in poor autoimmune diseases, malignancy like lymphoma pose major
echo-cardiographic window, or prosthetic valve IE, and for problems.
monitoring the complications of IE. Practically, the most difficult differential diagnosis in a known
Echocardiography is required to monitor the course of the RHD patient involve the consideration of rheumatic activity
illness and is extremely useful for therapeutic decisions as it versus IE as both can cause fever, raised ESR, arthralgia,
also gives haemodynamic information and idea about worsening failure and even vegetations. In rheumatic fever,
therapeutic response. Severity of regurgitation, ventricular the symmetrical small vegetations are different, ASO is
function, extension of infection, and size of vegetation are easily raised, nodules may be present, and fever is not long-lasting.
evaluated by echocardiogram repeatedly. With effective However, a careful appraisal of entire clinical picture is always
treatment, vegetation size generally decreases. Increase in size required.

Table 4A: Original Duke Criteria for the Diagnosis and Classification of Infective Endocarditis
Major Criteria Minor Criteria Diagnosis
Positive blood culture Predisposition Definite
Typical organism in >2 blood cultures Heart condition 2 Major
in the absence of a primary focus 1 Major and 3 minor
Drug abuse
(Staphylococcus aureus, enterococci, 5 Minor
Streptococcus viridans, Fever >38°C Pathologic/histologic findings
Streptococcus bovis, HACEK) Vascular phenomena Possible
Persistently positive blood culture drawn Major arterial emboli Findings fell short of the definite but
more than 12 hour apart or all ¾ drawn at least Janeway’s lesions not rejected categories
1 hour apart between first and last
Septic pulmonary infarcts Rejected
Evidence of endocardial involvement Alternate diagnosis
Immunologic phenomena
Positive echocardiogram (TEE) Resolution of the infection with
Osler’s nodes
Oscillating intracardiac mass on valve, antibiotic therapy for less than 4 days
Roth’s spots No pathologic evidence after
implanted material or supporting structures
in path of regurgitant jets Rheumatoid factor antibiotic therapy
Abscess Glomerulonephritis
New partial dehiscence of prosthetic valve Microbiologic evidence
New valvular regurgitation Positive blood culture
Positive serologic finding
Echocardiographic evidence
consistent with infective
endocarditis but not meeting
the major criteria

656
 Infective Endocarditis
Table 4B: Suggested Modifications of Duke‘s Criteria organism, 4 weeks duration is required with careful
attention to renal and vestibular functions.
Major criteria: consider the following as major criteria
9. Enterococci do not respond to methicillin, cephalosporin
Staphylococcal bacteraemia (irrespective of community or
nosocomially acquired, or with or without a focus) and often have resistance to aminoglycosides as well.
Positive serology for coxiella, chlamydia, bartonella
Combination therapy is preferred.
Positive molecular diagnosis for specific gene targets of bacteria 10. Linezolid, daptomycin are increasingly used for vancomycin
and fungi resistant enterococci or Staphylococcus aureus, and others.
Minor criteria: add the following as minor criteria 11. A consultation from infectious disease specialist should be
Raised CRP (>100 mg/L), obtained in difficult circumstances.
Raised ESR (>30 for <60 yrs, and >50 for older) 12. Culture negative endocarditis can be treated with
Newly diagnosed clubbing vancomycin, ceftriaxone and gentamicin pending further
Splinter haemorrhages insight into the possible organism (some prefer only
Microscopic haematuria vancomycin and gentamicin).
Splenomegaly 13. Ideally trough drug levels should be measured, but is not
Petechiae, or purpura possible in most circumstances.
Delete the following from minor criteria
14. Surgery should be considered early, rather than late, in some
Echocardiogram consistent with IE but not meeting major criteria
situations.
Diagnosis
Treatment of common organisms is shown in the Table 5.
Possible IE can be diagnosed either with one major and one minor,
or three minor criteria alone Therapy of atypical organisms need special considerations
and consultations with infectious disease specialists. Therapy
TREATMENT for brucella include doxycycline with streptomycin, (with
or without rifampicin), and in children trimethoprim-sulphame-
The treatment of IE entails long course of bactericidal antibiotics
thoxazole and rifampicin, Q fever needs doxycycline with
intravenously, monitoring for response, decision for surgical
hydroxychloroquine (possibly with fluoroquinolones),
treatment if required, attention to portal of entry if possible,
bartonella can be treated with amoxicillin with gentamicin or
and ancillary measures for patients well-being including anti-
tetracyclines/macrolides antibiotics. These are not detailed here.
cipatory guidance for preventing recurrence. Recommended
antibiotic treatment charts are available in all standard texts, Surgery for Infective Endocarditis
the principles of drug therapy are summarised. Surgical treatment during IE may be required because of (1)
1. Therapy has to be of sufficient dose and duration to severe congestive heart failure from mechanical complications,
eradicate bacteria, prevent mortality, and relapse. Usually (2) uncontrolled infection, and (3) repeated embolism. While
4 weeks therapy is required. All patients should be complications of surgery is higher during IE than without IE, but
hospitalised for at least 2 weeks initially. the mortality without surgery in such patients is very high and
2. Longer-term treatment (6 to 8 weeks) is recommended if surgery is preferred and should be done early without waiting
the symptoms have been present for >3 months, if IE is for infection to subside. Although, mortality despite operation in
these circumstances may be as high as 20% to 40%, mortality
complicated by embolism, poor response, likely resistant
without operation is in the range of 60% to 90%. The chances of
bacteria, atypical organisms, or for prosthetic valve
postoperative IE in the replaced valves are not higher than 2% to
endocarditis (8 weeks).
3%. Early prosthetic valve endocarditis, paravalvular leak, annular
3. In penicillin sensitive organism, penicillin is better than abscesses, fungal endocarditis, persistent fever >2 weeks despite
vancomycin. The dose of penicillin to be used in a patient antibiotics in the absence of other causes, and embolisms are
(12-24 million units in 4-6 divided doses) depends on the typical indications for consideration of operative treatment.
available or perceived sensitivity of the organism, or clinical
IE. Various types of operative procedures may be required.
Thorough debridement, patch repairs, vegetectomy and valve
4. Intermittent bolus or continuous infusion are probably
repair may be done, usually valve replacement is needed. The
equally effective, boluses are usually preferred. Attention
choice of valve is individual preference and outcomes are not
to planning of veins to be used, changing intravenous lines different between mechanical or biological valves. Some may
48 hourly, use of central lines and aseptic precautions are prefer homografts. If the patient has suffered a CNS event, it is
customary details. better to postpone surgery, if possible. Open heart surgery
5. Therapy for staphylococcal sp. is based on methicillin should be postponed by 3 to 4 weeks after a haemorrhage
sensitivity and not coagulase status. Almost all Staphylococcus in the brain and at least a few days to weeks after an infarct
are penicillin resistant, methicillin sensitive strain respond because of the use of anticoagulation during open heart
better to methicillin congeners. surgery and the risks of adverse neurological outcomes.
6. Rifampicin is utilised in patients with prosthetic valves, or Anticoagulation in Infective Endocarditis
foreign materials and staphylococcal IE.
Anticoagulation increase the chances of CNS bleed and should
7. Fluoroquinolones can be substituted for Staphylococcus be avoided. In a patient with mechanical prosthetic valve, careful
resistant to aminoglycosides as additional therapy. titration of minimal possible anticoagulation should be used. It
8. Aminoglycosides are added carefully and therapy is only is preferable to stop oral anticoagulant and rely on heparin for
for few days in Staphylococcus, or for 2 weeks. In some the duration of therapy. 657
 Table 5: Treatment of Infective Endocarditis (Common Organisms)
Microorganism Antibiotics Dose (Per Day) Duration
1
Streptococcus viridans Penicillin G 12 to 24 MU/6 doses 4 weeks2
Streptococcus bovis Amoxicillin or 100 to 200 mg/kg 4 weeks2
Ceftriaxone 2g in (100 mg/Kg) single dose 4 weeks2
If penicillin allergy-vancomycin 30 mg/kg in 2 doses 4 weeks2
Enterococcus Amoxicillin or ampicillin with 200 mg/kg in 4 to 6 dosage 4 to 6 weeks
gentamicin 3 mg/kg in 2 to 3 doses
If penicillin allergic vancomycin with gentamicin3 30 mg/kg in 2 to 3 doses
Staphylococcus Flucloxacillin or oxacillin 12 g/d in 4 to 6 doses 4 to 6 weeks
If penicillin – allergic vancomycin 30 mg/kg in 2 doses 4 to 6 weeks
Optional gentamicin 3 mg/kg 5 days
Prosthetic valve IE Vancomycin with 30 mg/kg in 2 dose ≥ 6 weeks
Or MRSA rifampicin with 1,200 mg in 2 dose ≥ 6 weeks
gentamicin 3 mg/kg in 2 dose 2 weeks
Fungal endocarditis Amphotericin 1 to 1.5 mg/kg4 6 to 8 week or more
Flucytosine 100 to 150 mg/kg in 4 doses
or fluconazole (second line only) 600 to 800 mg or 10 to 12 mg/kg
oral or IV in 2 doses
Culture negative Vancomycin with 30 mg/kg in 2 dose 4 to 6 weeks
Gentamicin and 3 mg/kg in 2 dose
Ceftrioxone5 2 g in single dose
IE HACEK Ceftriaxone or 2g single dose 4 to 6 weeks
Ampicillin-sulbactam 12 gm (2 g Ampicillin and 1 g Sulbactam)
If allergic, ciprofloxacillin in 4 doses or 300 mg/kg ampicillin 6 hourly,
800 mg IV or 1,000 mg oral in 2 doses
1 = Dose of penicillin depends on the MIC for the organism, in the absence of that data, empirically decided; 2 = The duration of therapy should be 6 weeks if the
symptoms have lasted for more than 3 months. For uncomplicated and responsive endocarditis, some authors have reported cure with 2 weeks therapy of ceftriaxone;
3 = for uncommon vancomycin resistant or multidrug resistant enterococci, Linezolid 600 mg IV or oral BD has been used; 4 = Amphotericin has to be built up slowly to
this dose after initial test dosages, lipid soluble formulations may be better tolerated. Newer antifungals like caspofungin and newer azoles are being tried;
5 = Treatment of culture negative endocarditis varies with the clinical background. Some authors recommend adding ceftriaxone to cover Gram-negative organisms.

Monitoring During Therapy being should be evaluated routinely and thorough physical
Monitoring the patient during long course of treatment is vitally examination daily is mandatory. Echocardiography should be
important. Most patients start showing clinical improvement repeated weekly. Blood cultures, haemogram, ESR, chest
and become afebrile within a week. Some may respond slowly. radiographs, renal parameters, are monitored frequently.
The diagnosis is doubted if the patient becomes afebrile in less Recurrence of fever after initial response may occur (Table 6)
than 4 days of therapy. Appetite, body weight, sense of well due to several reasons. Drug fever may occur without rash and

Table 6: Fever During the Treatment

Cause Indicators Treatment
Uncontrolled infection Continuing ill-health, metastatic foci, extension of infection in heart Review choice or dosages of antibiotics
Annular abscess Conduction disturbance on ECG, pericarditis suggest the diagnosis, Consider change in antibiotics, surgery
often missed, TEE useful
Organ infarcts Renal, pulmonary or spleen, may become infected Splenic abscess may need precutane-
Splenic common, ultrasound/CT required ous drainage or splenectomy
Mycotic aneurysms Common in CNS, may cause cerebral haemorrhage, not routinely Aneurysm can decrease with
searched antibiotics, surgery may be required
Thrombophlebitis Minor phlebitis more often incriminated as cause than actual, may Change IV lines frequently, if peripheral
miss more serious cause
Drug fever Common with penicillin after 3rd week, rash, eosinophilia may not Require to change antibiotics, total
be present duration of treatment should count
Patient appear less toxic despite high fever
Super infection May be nosocomial fungal or Gram-negative infection Addition of appropriate therapy
required
Reflects poor hospital practices, broad index of suspicious required
Immunologic For example, a patient with glomerulonephritis, or immune mediated Glomerulonephritis may remit after
phenomenon phenomena in otherwise responding patient surgical removal of infection
Wrong diagnosis or SLE, lymphoma, tuberculosis may masquerade, double disease Treat according to the diagnosis
double disease diagnosis is against the law parsimony (i.e. diagnose one condition in a
658 patient), but very rarely does occur
 Infective Endocarditis
can be high grade. Other investigations like abdominal
ultrasound and CT are utilised as required. Splenic infarct or
abscess can be diagnosed with both. Mycotic aneurysms are
not routinely searched in the absence of symptoms. MR
angiography can detect CNS aneurysms if suspected.

SPECIAL SITUATIONS
Prosthetic Valve Endocarditis
IE in patients with prosthetic valve occurs nearly in 1% in the
first year and 0.5% per year afterwards. Early prosthetic valve
endocarditis (PVE) occurring within 2 months of operation
results from contamination in the operative or post-operative
period and carry very high mortality. Organisms like coagulase
negative Staphylococcus or S. aureus, Pseudomonas, Candida
predominate. Some authors consider early PVE till 1 year
period. Surgical treatment is the rule for early PVE and
antibiotics are required for 6 to 8 weeks. IE later is due to the Figure 2: Echocardiogram in four chamber view showing vegetations
usual organisms but carries a higher-risk. PVE is essentially an (arrow) on tricuspid valve in a patient of small ventricle septal defect (not seen).
annular infection, and therefore, chances of annular abscess LV = Left ventricle; RV = Right ventricle.
are higher.
Culture Negative Endocarditis
Culture negative endocarditis, although thought of as a group,
actually encompass different entities. Culture could be negative
because of (1) prior antibiotic therapy in otherwise a usual
endocarditis, the commonest cause, (2) poor culture techniques,
inadequate sample, media, transport, etc., (3) fastidious
organisms needing special media like abiotrophia, HACEK,
etc., and (4) organism that do not grow in blood culture like
aspergillus, tropheryma whipplei, coxiella. The approach to
these groups should be different. As discussed above, serological
tests are useful in the diagnosis of brucella, Q fever, etc., and
PCR is being utilised for many bacteria and improves the
positive yield. In the absence of any clinical clues, suggested
broad-spectrum cover include vancomycin with gentamicin
and ampicillin or ceftriaxone.
Infective Endocarditis in Children
IE is uncommon before 2 years of age, except as nosocomial
infection in neonates in presence of intravenous cannula and
central lines. Staphylococcus aureus and candida dominate.
Tricuspid valve endocarditis may present with unexplained
dyspnoea due to unanticipated pulmonary embolism. Most Figure 3: Chest radiograph of a patient of tetralogy of Fallot having right-sided
infective endocarditis. Note the shadow in right lower chest from a pulmonary
other IE in children occur in the presence of a CHD or RHD. IE in infarct.
the VSD or tetralogy of Fallot patients occurs as right-sided
endocarditis (Figures 2 and 3). Systemic embolism does not pentazocine have high chances of pseudomonas, and heroine
occur unless there is a right to left shunt or IE occur in the left- addicts injecting brown heroine in lemon juice frequently have
sided structures also. Pulmonary complications like infiltrate, candida.
infarct, abscess, pulmonary artery pseudo-aneurysm occur.
In Elderly
Response to therapy can be satisfactory. Surgery might have
to be resorted to in the presence of active infection in IE in elderly is increasingly seen and is more common in males.The
unsatisfactory responders. Ligation of ductus arteriosus is underlying predisposing lesion often is mitral valve prolapse
frequently followed by response to therapy in patients with with mitral regurgitation or degenerative valvular aortic stenosis.
ductus arteriosus and pulmonary valve endocarditis. Co-morbidities decide the clinical course. Drug therapy will need
extra care and dose adjustments with attention to renal and
Infective Endocarditis in Drug Addicts hepatic functions.
IE in drug addicts usually affects normal tricuspid valve, but may
also occur on aortic, and mitral valves. Right-sided IE responds MORTALITY
well to therapy. Some may have HIV, but IE in them also responds Without treatment IE is invariably fatal. Rare case reports of
well, unless CD4 counts drop low. Polymicrobial IE or IE due to recovery in the pre-antibiotic era may be misdiagnosis.
unusual organisms like bartonella may occur. Addicts using Antibiotics reduced the mortality but IE has a mortality of 20% 659
 Table 7: Prevention of Infective Endocarditis
Underlying Lesions Procedures Antibiotics
Rheumatic heart disease Dental procedure Oral amoxicillin 2 g (50 mg/kg), or
Prosthetic valves Involving periapical region of Intravenous/intramuscularly ampicillin 2 g,
Previous infective endocarditis teeth or perforation of the oral cefazolin, ceftriaxone 1 g (50 mg/kg)
Congenital heart disease mucosa or gingival tissues In allergic to penicillin:
Unrepaired cyanotic CHD including Respiratory procedures Oral cephalexin 2 g (50 mg/kg), or
palliative shunts and conduits Respiratory tract that involves incision azithromycin/clarithromycin 500 mg
Within 6 months of repair, devices or biopsy of the respiratory mucosa, such (15 mg/kg), or intravenous clindamycin
Residual lesions near patches, or prosthesis as tonsillectomy and adenoidectomy, 600 mg
Valve disease after cardiac transplant (none for bronchoscopy)
Skin and soft tissue
Surgical procedure that involves
infected skin, skin structure,
or musculoskeletal tissue
Genitourinary or Gastrointestinal
procedures
None

to 40% even in current era. Further reduction in mortality is CONCLUSIONS

expected with more frequent surgical treatment. Mortality The following parameters recapitulate important aspects of
rates depend on several factors, but large size vegetations, management of infective endocarditis.
heart failure portends poorer prognosis. Some subsets have
particularly high mortality. Prosthetic valve IE has a mortality of Do’s and Don‘ts of Infective Endocarditis
30% to 55% with surgery and 60% to 90% without surgery. 1. Prevent IE by anticipatory guidance on oral hygiene in RHD,
The mortality in fungal IE is 60% to 90% despite treatment. CHD and other at risk patients.
With concerted efforts, protocol driven management and 2. Think of IE in all susceptible patients with fever, anaemia,
teamwork of cardiologist, microbiologists, surgeons and weight loss, or heart failure.
infectious disease specialist, the mortality of Streptococcus
3. Do not rely overly on any test including echocardiogram
viridans IE can be as low as 7% to 10%, but enterococci and
as false positive and false negatives are not uncommon.
Staphylococcus mortality remains about 10% and 10% to 20%
respectively. Right sided IE in drug addicts have a better 4. Think of plausible portal of entry/organism before deciding
response and lower mortality. on therapy.
5. Do not jump to the latest antibiotics, nor slavishly follow
PREVENTION the regimens, think critically.
In experimental settings, antibiotics administration before 6. Monitor trends carefully, anticipate the complications but
inoculating bacteria prevented colonisation and IE, and hence do not change antibiotics frequently with any minor
for years, elaborate recommendations were made for drugs alterations including 1 to 2 days fever.
to be given before procedures expected to cause bacteraemia.
7. Keep the surgeon in the loop for decision regarding early
With time, it became clear that bacteraemia occur in daily living
surgery, if required.
activities (like brushing, chewing, etc.) far more frequently than
procedure induced, and that very few episodes of IE, if at all, 8. Prevent recurrence, relapse by appropriate advice and
could be prevented by such administration as previously management.
advised. Further, costs and adverse effects of antibiotics use RECOMMENDED READINGS
(including development of resistance) are not negligible.
1. Anderson JL, Sande MA, Kartalija M, et al. Infective endocarditis. In: Fuster
Therefore, it is prudent to advise all patients on maintaining V, et al, editors, Hurst‘s the Heart; 11th Ed. McGraw Hill Publication; 2004: pp
good oral health and routine dental visits. Such is not the routine 2001-36.
in India, but that can help reducing IE burden more than any 2. Mylonakis EM, Calderwood SB. Infective endocarditis in adults. N Engl J
antibiotic prophylaxis. Antibiotics before procedures are Med 2001;345:1318-30.
recommended only to patients in whom risks of occurrence and 3. Prevention of infective endocarditis. Guidelines from the American Heart
consequences of IE (if it occurs) are considered high (Table 7). Association: A Guideline From the American Heart Association Rheumatic
Fever, Endocarditis, and Kawasaki Disease Committee, Council on
No IE prophylaxis is recommended for gastrointestinal or Cardiovascular Disease in the Young, and the Council on Clinical Cardiology,
genitourinary procedures in the American Heart Association Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care
recommendations. Dental procedures which may cause gum and Outcomes Research Interdisciplinary Working Group. Circulation 2007;
bleeding or apical tissue handling would cause bacteraemia are 116:1736-54.
specified. Only single dose 2 gm amoxicillin is recommended 4. The Task Force on the Prevention, Diagnosis, and Treatment of Infective
Endocarditis of the European Society of Cardiology (ESC). Guidelines on
where required. the prevention, diagnosis, and treatment of infective endocarditis (new
version 2009); Eur Heart J 2009; 30: 2369-413.
There have been no new data about RHD, and these patients
5. Wilson WR, Karchmer AW, Dajani AS, et al. Antibiotic treatment of adults
could have poor oral hygiene. Individual judgement should still
with infective endocarditis due to streptococci, enterococci, staphylococci,
be used in advising prophylaxis. No prophylaxis is required for and HACEK micro-organisms. American Heart Association. JAMA 1995; 274:
660 vaginal delivery, tattooing, ear piercing, or TEE. 1706-13.
 12.16 Atherosclerosis

KK Sethi, S Lahiri

INTRODUCTION
Atherosclerosis is multi-focal, multi-factorial smouldering
inflammatory disease that affects the intima of medium sized
and large arteries, resulting in intimal thickening that may lead
to luminal narrowing and inadequate blood supply. Athero-
sclerosis derives its name from the Greek word ‘adhere’—means
gruel or porridge, and ‘sclerosis’ means hardening, i.e. hardening
of gruel-like material inside the blood vessels.
According to the original concept, atherosclerosis was thought
to be just a bland proliferative process. The advent of cell biology
era of atherosclerosis modified the earlier view and implicated Figure 1: Formation of fatty streak.
inflammatory mechanism in disease development. According Source: Weissberg, Heart 2000; 83: 247-52.
to that concept, endothelial denudation resulted in platelet
are responsible for the extracellular accumulation of lipids.
aggregation and release of platelet-derived growth factor
Blood-derived atherogenic lipoprotein particles may be
(PDGF) which led to the proliferation of smooth muscle cells in
trapped directly within the proteoglycan-rich extracellular
the arterial intima. Current evidence integrates inflammation
matrix and/or lipid may be released from the macrophage foam
as a key regulatory process with multiple other risk factors in
cells after their death by apoptosis. Within a lipid-rich core,
atherosclerosis.
erythrocytes and their lipid-rich membranes may contribute to
PATHOGENESIS the expansion of the core (plaque rupture and haemorrhage).
Early Atherosclerotic Lesions There is accumulation of smooth muscle cells which gives
The earliest lesions of atherosclerosis, i.e. fatty streaks, are rise to a heterogeneous spectrum of plaques ranging from
present in the aorta from early childhood and may even begin fibro-fatty plaques (abundant smooth muscle cells) to thin-
to develop early in foetal life.They are highly cellular inflammatory cap fibroatheroma (scanty smooth muscle cells with rich lipid
lesions consisting of macrophage foam cells (intracellular lipid) core). With the passage of time endothelial denudation
and T-lymphocytes (immune reaction). Fatty streaks do not takes place and adherent platelets can be seen over mature
plaques. Growth factors released from the adherent
protrude into the lumen and hence are not symptomatic. Fatty
platelets and micro thrombi may stimulate the smooth muscle
streaks develop under an intact but activated, dysfunctioning
cells within the plaque to produce more connective tissue
endothelium particularly atherosclerosis prone areas with pre-
matrix.
existing intimal thickening. Hypercholesterolaemia is associated
with increased endothelial permeability, increased transcytosis Neovascularisation
and intimal retention of lipoproteins and endothelial activation Neovascularisation is frequently present at the base of
with focal expression of vascular cell adhesion molecule 1 advanced atherosclerotic plaques and is thought to be derived
(VCAM-1) leading to monocyte and T-lymphocyte adhesion. It from vasa vasorum derived new vessels. Vasa vasorum
is thought that inflammatory cells are recruited by adhesion developing from the adventitial layer of vessel wall also serve
molecules and chemokines such as monocyte chemo- the purpose of transit of leukocytes and other growth factors
attractant protein-1 (M-CSF) and activated in the intima by inside the plaque.
factors such as oxidised lipids and cytokines. Within the intima,
Vulnerable Plaque and Plaque Instability
the monocyte-derived macrophages engulf the blood derived
low-density lipoprotein (LDL), possibly through their scavenger Pathological studies indicate that certain plaques are more
receptors after oxidative modification and become lipid-filled prone to develop acute myocardial infarction (MI) than others.
foam cells. These inflammatory cells constitute the major part These are called vulnerable plaques, i.e. plaques which are at
of the early fatty streak lesions (Figure 1). high risk of for disruption or thrombosis leading to symptomatic
cascade of acute coronary events. Vulnerable plaques are
Fate of Fatty Streaks characterised by the following:
Fatty streaks can progress to more advanced lesions because they  A thin fibrous cap (thin cap fibroatheroma or TCFA),
occur at the same anatomic sites. A smaller fraction of fatty streaks  A large lipid pool of cholesterol esters,
appears to progress to more advanced symptomatic lesions.
 Heightened inflammation,
Advanced Atherosclerotic Lesions  Positive remodelling of the vessel (outward expansion of
When lipids begin to accumulate, extracellular atherogenesis the opposite wall of the vessel), and
has passed beyond the fatty streak stage.Two different processes  Extensive neovascularisation. 661
 Vulnerable plaque ruptures due to uneven thinning of the fibrous Recent data suggest that CIII, a constituent of certain triglyceride-
cap. Rupture usually occurs often at the shoulders of the lesion rich lipoproteins incites inflammation by binding to TLR2. The
where macrophages enter, accumulate and are activated. activation of platelets results in secretions of proinflammatory
Degradation of the fibrous cap results from elaboration of cytokines such as CD40-ligand and also myeloid-related protein
matrix metalloproteinases such as collagenases, elastases and (MRP) 8/14. The MRP serves as a biomarker for adverse cardio-
stromelysins. The metalloproteinases are stimulated by activated vascular events and can promote endothelial cell apoptosis, a
T-cells which promote plaque instability and rupture (Figure 2). process thought to be vital in plaque thrombosis.
Adaptive immunity requires antigen presenting cells, such as
dendritic cells. The dendritic cells populate atherosclerotic
plaques and present antigens to T-lymphocytes, thus forming
the key limb of adaptive immunity. These antigens in relation
to atherosclerosis are heat shock proteins (HSP), components
of plasma proteins and some microbial structures. T-cells
proliferate and produce cytokines that amplify inflammation.
There are several types of T-cells. Helper T-cells (Th1) response
appears to aggravate atherosclerosis as it amplifies proinflam-
matory pathway by gamma interferon production. The Th2
cells produce cytokines that modulate inflammation. These
cytokines such as interleukin (IL)-4 can promote humoral
immunity. Regulatory T-cells can, however, dampen athero-
sclerotic response. There is also a role of CD8 marker T-cells or
Figure 2: Vulnerable (instable) plaque formation.
cytotoxic T-cells or CD8 cells. CD8 T-cells are capable of killing
smooth muscle cells and macrophages and cause lesion growth
VSMC = Vascular smooth muscle cell; INF-γ = Interferon-gamma.
and complications.
Source: Weissberg, Heart 2000; 83: 247-52.
Humoral immunity is mediated by B-lymphocytes. B-lymphocytes
secrete antibodies which attenuate rather than aggravate
Role of Innate and Adaptive Immunity atherosclerosis. Splenectomy aggravates athero-sclerosis by
Innate immunity is the primitive arm of inflammation and eliminating some population of B-cells. Humoral immunity
constitutes immune response that is elicited without ‘education’ against oxidised LDL might protect against atherosclerosis and
of the immune system. This response is very rapid and combats may be a potential target of vaccine therapy.
perceived foreign invaders. Natural antibodies, certain
complement proteins and families of cell surface receptors RISK FACTORS FOR ATHEROSCLEROSIS
recognise microbial products and provide primordial host Classic risk factors of atherosclerosis are also known as traditional
defence responses. These receptors include scavenger receptors risk factors.These risk factors can predict atherosclerotic coronary
which cause uptake of modified lipoproteins, and are toll-like events to a certain extent.The NCEP ATP- III is based on traditional
receptors (TLR) that recognise microbial structures and products. (old) risk factors of age, sex, total cholesterol, HDL cholesterol,
These receptors trigger a complex intracellular signalling cascade systolic BP and smoking. In a more recent scoring system
that stimulates the production of pro-inflammatory cytokines (PROCAM), eight risk variables are identified: age, LDL
and other inflammatory mediators. The cellular recruitment seen cholesterol, diabetes, smoking, HDL cholesterol, triglycerides
very early in atherosclerosis is an example of innate immunity. (TG), systolic BP, family history of premature coronary artery
The mononuclear phagocytes get attached to activated disease. Table 1 presents risk factors for atherosclerosis.
endothelial cells by leucocyte adhesion molecules. Maturation
of monocytes into macrophages, their multiplication and Hypertension
production of mediators ensues. Recent evidence suggests Hypertension is considered to be one of the traditional risk factors
that mononuclear recruitment is a continuous process which of atherosclerosis. Concentrations of angiotensin-II, the principal
is also seen in established lesions and could be a therapeutic product of renin-angiotensin system are often elevated in patients
target for targeting monocytes for treatment. In the presence of with hypertension. Angiotensin-II is a potent vasoconstrictor. In
hyperlipidaemia, there is an enrichment of proinflammatory addition to cause hypertension, it can contribute to atherogenesis
subset of monocytes. Apart from monocytes, there is now firm by stimulating the growth of smooth muscle cells. Angiotensin
evidence that mast cells release vasoactive small molecules such binds to specific receptors in smooth muscle cells resulting in
as histamine and leukotrienes, serine proteinases and heparin activation of phospholipase C, which can lead to increase in
— a cofactor in growth factor action and angiogenesis. Certain intracellular calcium and smooth muscle contractions, increased
pharmacological agents can modulate mast cell function and this protein synthesis and smooth muscle hypertrophy. It also increases
can have therapeutic implications. There are links between smooth muscle lipooxygenase activity which can increase
lipoproteins and innate immunity. Modified lipoproteins such as inflammation and oxidation of LDL. Hypertension also has
oxidised lipoproteins and oxidised phospholipids may drive proinflammatory actions such as increasing the formation of
inflammation. A lipoprotein-associated phospholipase-A2 hydrogen peroxides and free radicals such as superoxide anions
(Lp-PLA2) currently targeted in clinical trials may generate and hydroxyl radicals in plasma. These substances reduce the
proinflammatory derivatives of oxidatively modified lipoproteins formation of nitric oxide (NO) by endothelium, increase leucocyte
662 (apolipoproteins). adhesion and increase peripheral resistance.
 Atherosclerosis
Table 1: Old, Old/New, and New Risk Factors for Atherosclerosis Metabolic Syndrome
Metabolic syndrome encompasses a range of cardiovascular risk
Old Old/New New
factors such as elevated TG (> 150 mg/dL), low HDL cholesterol
Sex (men > women) High-normal Apolipoprotein B; (men < 40 mg/dL; women < 50 mg/dL), impaired fasting glucose
blood pressure Apolipoprotein A-1 (≥ 110 mg/dL), high blood pressure (≥ 130/85 mm Hg) and
Age Metabolic Triglycerides; increased waist circumference (men > 90 cm, women > 80 cm
syndrome triglyceride-rich in Asians) is believed to increase the risk for CHD at any level of
lipoprotein remnants
LDL cholesterol. Further, the presence of metabolic syndrome
Family history of Diabetes Small, dense LDL; has a greater impact on the incidence of CHD in women than
premature cardiovas- mellitus; oxidised LDL; anti-
men. Leptin is a protein that plays a role in fat metabolism and
cular disease impaired glucose bodies against
closely correlates with insulin resistance and is an independent
tolerance; oxidised LDL
impaired risk factor for CHD.
fasting glucose
Lipid Risk Factors
Total cholesterol; Lipoprotein(a)
LDL cholesterol; Triglycerides and triglyceride-rich remnant lipoproteins
HDL cholesterol Though there was some initial debate on the role of
(negative risk factor) hypertriglyceridaemia as an independent CHD risk factor,
Hypertension Homocysteine data from the PROCAM study showed a significant relation
Smoking High-sensitivity between hypertriglyceridaemia and CHD risk independent
C-reactive protein of LDL cholesterol and/or HDL cholesterol. Triglyceride-rich
Overweight/obesity lipoproteins comprise a great variety of nascent and
metabolically modified lipoprotein particles. The capacity to
LDL = Low-density lipoprotein; HDL = High-density lipoprotein.
enter the subintimal area of the vasculature is inversely related
Smoking to the size of the lipid particles. Whereas chylomicrons and large
very low-density lipoprotein (VLDL) particles are unable to pass
Smoking increases the risk of atherosclerosis by several
mechanisms. Cigarette smoking is associated with increased through the endothelial layers, smaller VLDL, IDL and LDL
levels of lipoproteins and the effects of oxidants in cigarette particles can enter the suboptimal space. In the Framingham
smoke renders LDL more susceptible to peroxidative Offspring Study, both remnant lipoprotein (RLP)-cholesterol and
modification by cellular elements such as macrophages and RLP-TG were significantly increased in diabetic men and women
vascular smooth muscle cells. The inflammatory cells recruited compared to non-diabetes. Remnant lipoproteins were
in the atherosclerotic plaques are increased in smokers. Nicotine independent risk factors for atherosclerosis. Lipoprotein (a) [Lp
activates the complement system as well, which causes increased (a)] is formed by joining a lipoprotein that is structurally similar
inflammation in the vessel wall. Certain chemicals in tobacco to LDL in protein and lipid composition to a carbohydrate-rich
smoke tend to activate factor XII and favour thrombus formation. hydrophilic protein Apo (a). The Lp (a) particles contain Apo (a)
The risk associated with smoking diminishes slowly after smoking and Apo (B) in a 1: 1 molar ratio. Most of the data on Lp (a) comes
cessation and equals to non-smokers after 3 years of cessation. from retrospective studies. Prospective studies, however, have
mixed results. However, plasma Lp (a) is indeed an independent
Diabetes Mellitus risk factor for CHD in both men and women. The Lp (a) levels
In the first 20 years of the Framingham Heart Study, the incidence above 33 mg/dL and high LDL cholesterol (>163 mg/dL was
of cardiovascular disease among men with diabetes mellitus associated with increased cardiovascular risk compared with
was twice than that among men without diabetes. Among Lp (a) levels below 33 mg/dL.
women with diabetes, the incidence of cardiovascular disease
was three times than that among women without diabetes. Homocysteine
Microalbuminuria and silent myocardial ischaemia at baseline Homocysteine is formed during demethylation of methionine,
has predictive value for future coronary heart disease (CHD) in whereas its degradation takes place via remethylation and/or
asymptomatic patients with type II diabetes. Subjects with trans-sulphuration). Impaired homocysteine metabolism has
impaired glucose tolerance and those with insulin resistance been implicated as a risk factor in atherosclerosis, cerebrovascular
are more likely to have subclinical atherosclerosis (Framingham disease and peripheral vascular disease. Hyperhomocy-
Offspring Study) and it is no wonder that NCEP considers steinaemia results from genetic cause (enzyme deficiencies),
diabetes as a CHD risk equivalent. Type II diabetes is associated vitamin deficiency (folic acid, B12, B6), use of certain medications
with insulin resistance. Insulin resistance reduces the ability of and impaired renal function. Direct relations between
adipose tissue to clear/store circulating lipids, in part because homocysteine, cigarette smoking, diabetes, obesity and
of reduced lipoprotein lipase activity. This results in paradoxical hypertension have been suggested. The exact mechanism by
elevation in serum TG and free fatty acids (FFA). There is also which hyperhomocysteinaemia may translate into increased
elevation in the apoB due to increased lipogenesis by the CHD and/or thrombotic risk remains speculative. Both direct
liver. Insulin resistance is characterised by the formation of toxic effects on endothelial cells, in part due to oxidative stress
more atherogenic (small dense) LDL. It can also stimulate as well as more indirect mechanisms have been postulated.
inflammation. The secretion of proinflammatory mediators However, treating hyerhomocysteinaemia with vitamins has not
initiated by systemic insulin resistance stimulates several shown to be beneficial in large studies both in terms of stroke
intracellular cascades of nuclear factor kappa beta pathway. and cardiovascular event reduction. 663
 Thrombogenic/Haemostatic Factors Technology has now made it possible to image atherosclerosis
Elevated plasma fibrinogen and factor VII are potential risk and the day is not far when it will be routinely used in identifying
factors for CHD. Other thrombogenic/haemostatic factors that vulnerable plaques which are prone to rupture. It is yet
have been investigated in their potential role in atherogenesis unproven that therapies directed at sealing such plaques are
and/or thrombosis include von Willebrand factor and beneficial. Techniques to image “vulnerable” plaque is given in
plasminogen activator inhibitor-1. Table 2.

High-Sensitivity C-Reactive Protein and Other Inflammatory Table 2: Techniques to Image “Vulnerable Plaque”
Markers Angioscopy
Since atherosclerosis represents a chronic inflammatory state, Intravascular ultrasound
inflammatory parameters (e.g. IL-6, tumour necrosis factor-alpha) Palpography
have predictive value for future cardiovascular events. Data shows Virtual histology
that CRP has additive value for predicting CHD risk on top of Near-infrared/Raman spectroscopy
traditional risk factors. hs-CRP is associated with subclinical
Ocular coherence tomography/ocular frequency domain imaging
pericardial coronary calcification in men and women and is
Thermography
significantly elevated in patients suddenly dying of severe
Vasa vasorum imaging
coronary artery disease. Elevated hs-CRP constitutes an
independent predictor of advanced plaques in dyslipidaemic Magnetic resonance imaging (invasive and non-invasive)
subjects and early onset carotid atherosclerosis with increased Positron emission tomography/computed tomography
intima-media thickness and elevated serum levels of inflammatory Molecular imaging
markers. Matrix-metalloproteinase 9 concentration has been
identified as a novel predictor of cardiovascular mortality in TREATMENT/PREVENTION
patients with coronary artery disease. Elevated IL-10 has a more Systemic pharmacotherapy is the cornerstone of plaque
favourable prognosis in patients with acute coronary syndrome stabilisation, with reductions in lipid content, inflammation and
(ACS) and elevated CRP levels. vasa vasorum neovascularisation. Statin therapy in high-dose
has been documented to be beneficial in atherosclerotic plaque
Though there is no definite hard evidence of a causal relation
regression. In the A study to evaluate the effect of Ultrasound
between infection and atherosclerosis, studies are accumulating
rosuvastatin an Intravascular derived coronary Atheroma
that indicate a possible role of infection. Viral agents such as
Burden trial, rosuvastatin 40 mg per day led to an absolute
cytomegalovirus (CMV), enterovirus, influenza virus, human
regression in atheroma volume. Increasing HDL levels have been
parvovirus B19, herpes simplex viruses and bacterial agents
found to be antiatherogenic. However, even with the best
such as Chlamydia have been studied extensively. Other
combination consisting of high dose statins, ACE-inhibitors and
potential agents such as Helicobacter pylori and periodontitis
aspirin, there is still a 22% recurrent coronary event rate in 2
have been implicated. In a recent meta-analysis, it has been
years. Regional therapy such as photodynamic therapy and
shown that influenza vaccination in patients with CHD can lower
cryotherapy as intravascular treatment of coronary segments
the risk of acute myocardial infarction.
may be beneficial in near future. Plaque sealing with balloon
Periodontitis is associated with atherosclerotic cardiovascular expandable stents may tackle the vulnerable plaque.
disease, though direct causal relation is not yet established. The
Vaccine development for atherosclerosis
incidence of atherosclerotic cardiovascular events increase in
patients with chronic inflammatory diseases such as rheumatoid Historically, vaccines have been proven to be safe and
arthritis, systemic lupus erythematosus (SLE) and psoriasis. efficient for protection against infectious diseases. Several
antigen targets have been proposed for vaccine design,
Biomarkers such as hs-CRP, IL- 6, IL- 8, soluble CD40 ligand are implementation and efficacy for atherosclerosis. Ideal vaccines
all markers of widespread inflammatory process in the vessel for atherosclerosis should provide protective immunity against
wall and can be identified by laboratory assays to detect infection-derived pro-atherogenic antigens and also immune
subclinical atherosclerosis. There was an association between tolerance for auto-immunogenic selfantigens. LDL was the
CRP and carotid atherosclerosis as assessed by ultrasono-graphy earliest target for vaccine therapy as it is a major mediator of
among 3,173 men and women enrolled in the Framingham atherosclerosis. Studies focusing on a knockdown of Ox-LDL
Offspring Study. Overall, they found that increasing levels of CRP showed a decrease in atherosclerotic lesion size. Immunisation
were predictive of carotid artery disease. Elevated levels of CRP with phosphatidylcholine (PC) containing Streptococcus
may reflect the presence of vulnerable plaque that is at high- pneumoniae generated vaccine which showed reduced
risk of rupture, as opposed to solely reflecting the burden of atherosclerosis. However, the major problem with Ox-LDL is the
atherosclerosis. Emerging data, however, suggest that CRP may chance of cross-reactivity. For greater OX-LDL specificity, more
be a mediator as well as marker of atherosclerosis. CRP induces recent studies have targeted ApoB-100 peptide fragments.
expression of cellular adhesion molecules, IL-6 and endothelin- Studies to target the potential antigenicity of heat shock protein
1 by endothelial cells. Recently, interest has focused on the (HSP) mycobacterial HSP 65 elicit a pro-atherogenic response.
measurement of a circulating soluble form CD40 L (sCD40) for Immunisation of patients with HSP 70 also showed decreased
risk stratification of patients with or at risk of developing atherosclerosis. Following the idea that molecular mimicry is
coronary artery disease. However, in a large multiethnic the mechanism responsible for cross-reactivity with foreign HSP,
population-based sample, sCD40L was not associated with most vaccination against infectious agents like influenza virus has
664 atherosclerotic risk factors or subclinical atherosclerosis. been examined in the context of atherosclerosis. Vaccines
 Atherosclerosis
against more risk factors and proteins like nicotine, angiotensin- 2. Fuster V, Topol EJ, Nabel EJ. Atherothrombosis and Coronary Artery Disease.
2005; 2: 15-1575.
1, gherkin and periodontitis have also been examined with
some interesting results. Thus, vaccine development for 3. Hansson GK. Inflammation, atherosclerosis and coronary artery disease. N
Engl J Med 2005; 352: 1685-95.
atherosclerosis is already underway and showing promising
4. Libby P, Ridker MP, Hansson GK. Inflammation in atherosclerosis: From
results. physiology to practice. J Am Coll Cardiol 2009; 54: 2129-38.
5. McGill HC, McMahon CA, Gidding SS. Preventing heart disease in the 21st
RECOMMENDED READINGS century: Implications of the pathological determinants of atherosclerosis
1. Fruchart JC, Niermann MC, Stroes ESG, et al. New risk factors for in the youth (PDAY) study. Circulation 2008; 117: 1216-27.
atherosclerosis and patient risk assessment. Circulation 2004;109: 6. Moreno PR. Vulnerable plaque: Definition, diagnosis and treatment.
15-9. Cardiol Clin 2010; 28:1-30.

665
 12.17 Ischaemic Heart Disease

Inder S Anand, Shibba Takkar Chhabra

Ischaemic heart disease (IHD) is characterised by myocardial

impairment due to imbalance between coronary blood flow
and myocardial requirement. The commonest cause of IHD
is atherosclerotic coronary artery disease (CAD). Non-
atherosclerotic causes of myocardial ischaemia are rare and
include coronary spasm (Prinzmetal’s angina), coronary artery
embolism, coronary arteritis (polyarteritis nodosa, Takayasu’s
disease, systemic lupus erythematosus), cocaine abuse or
spontaneous dissection of coronary arteries.
CORONARY CIRCULATION
The left main and right coronary arteries arise from the left and
right coronary sinuses of the aortic root, distal to the aortic valve.
Within 2.5 cm of its origin, the left main coronary artery divides
into the left anterior descending artery (LAD), which runs in the
anterior interventricular groove, and the left circumflex artery
(LCX), which runs in the atrioventricular groove. The LAD gives
branches to supply the anterior part of the septum (septal
perforators) and the anterior, lateral and apical walls of the left
ventricle (diagonals). The LCX gives obtuse marginal branches Figure 1: The coronary arteries of the heart. Diagram of the anterior view.
that supply the lateral, posterior and inferior segments of the
left ventricular (LV). mediated by reduction in coronary arteriolar resistance. The
left coronary artery fills only in diastole while the RCA shows
The right coronary artery (RCA), runs in the right atrio-
both systolic and diastolic coronary flow.
ventricular groove, giving acute marginal branches that supply
the RA, RV and inferoposterior aspects of the LV. The posterior MAGNITUDE OF THE PROBLEM
descending artery runs in the posterior interventricular
Cardiovascular disease accounts for approximately 12 million
groove and supplies the inferior part of the interventricular
deaths annually and is the commonest cause of death globally.
septum. It arises from the RCA in approximately 85% of
Previously considered a disease of the affluent, the past
people (dominant right system) and from the LCX in the
three decades have seen considerable decline in the incidence
remainder (dominant left system). The coronary anatomy
and prevalence of atherosclerotic CAD in the industrialised
varies greatly from person to person and there are many
western world; whereas at the same time, this problem is
normal variants.
assuming epidemic proportions in the developing world. Asian
The RCA supplies the sino-atrial (SA) node in about 60% of Indians, whether living in their own country or elsewhere, have
individuals and in the remaining 40% SA node is supplied much higher incidence of CAD as compared to all other ethnic
by LCX. The AV node is supplied by a small AV nodal artery groups.
which arises from the dominant coronary artery (RCA in 85%)
(Figure 1). Proximal occlusion of the RCA, therefore, often While the incidence of coronary artery disease has reduced by
results in sinus bradycardia and may also cause AV nodal 50% in the west, in India it has doubled in the last 25 years. The
block. Abrupt occlusions in the RCA, due to coronary prevalence of coronary artery disease in the years 1960, 1980,
thrombosis, result in infarction of the inferior part of the LV 1990 and 2000 progressively increased (2%, 4% to 6%, 9.5% and
and often the RV. Abrupt occlusion of the LAD leads to 10% to 15% respectively). In the rural India, the CAD prevalence
anterior wall or anteroseptal myocardial infarction (MI). LCX increased two-fold from 2% to 4%. In urban India, the increase
causes infarction in the anterolateral territory of the LV. Acute was three-fold from 3.45% to 9.45%. In 1990, 25% deaths in India
occlusion of the left main coronary artery is usually fatal. were attributable to cardiovascular disease compared to 9% due
to diarrhoeal disease, 12% due to respiratory infections and 5%
PHYSIOLOGY due to tuberculosis.
The myocardium relies almost exclusively on oxidative
metabolism for its energy needs. Even at rest the RISK FACTORS
transmyocardial oxygen extraction is near maximal with a The National Heart Lung and Blood Institute of USA initiated
coronary venous O 2 saturation that is lowest in the body (25% the Framingham Heart Study in 1949 and by 1961, the concept
to 35%). Any increase in myocardial O2 demand can only be of risk factors for CHD was established with hypertension and
666 met by proportional increase in myocardial blood flow, chiefly hypercholesterolaemia being identified for intervention.
 Ischaemic Heart Disease
The classically defined eight risk factors for CAD are sudden cardiac death (Table 3). The understanding of the
hypertension, dyslipidaemia, diabetes, physical in activity conversion of a stable atherosclerotic lesion to a plaque rupture
and sedentary lifestyle, central obesity, stress and type A with thrombosis has provoked a unifying hypothesis for the
personality, family history of CAD and smoking. Of these, aetiology of acute coronary syndromes.
smoking, diabetes, hypertension and family history of
premature CAD are particularly important. Table 1 enlists the Table 3: Nomenclature of Myocardial Ischaemia
modifiable and non-modifiable risk factors for CAD. Old Present

Table 1: Risk Factors for Clinical Atherosclerosis Asymptomatic Asymptomatic

Stable effort angina Stable effort angina
Non-Modifiable Modifiable Unstable angina Acute coronary syndromes, unstable
Age Dyslipidaemia angina without necrosis
Male gender Hypertension Non-Q wave MI Non-ST elevation MI (NSTEMI)
Family history of CHD Diabetes (evidence of myocardial necrosis)
Presence of CHD Abdominal obesity Q wave MI ST elevation MI (STEMI)
Menopause Smoking Sudden death Sudden death
Physical inactivity Diet Silent ischaemia Ischaemic cardiomyopathy

Asian Indians have the highest ethnic risk of CAD despite CLINICAL PRESENTATION
lower rates of smoking, hypertension, obesity and higher vegeta- Symptoms
rianism. The insulin resistance syndrome (metabolic syndrome
X), lipoprotein(a), atherogenic dyslipidaemic phenotype and The typical clinical presentation of angina refers to poorly
some newer emerging risk factors [homocysteine, tissue localised retrosternal discomfort with radiation to neck,
plasminogen activaetor (tPA), plasminogen activator inhibitor shoulders, arms, jaws, epigastrium or back; usually, not above
(PAI-1), fibrinogen, infections and inflammation] may be more the jaw and not below the umbilicus. Angina is typically
relevant as underlying genetic susceptibility associated with a triggered by physical activity, emotional stress, exposure to cold,
modest abnormality in lipid and lifestyle factors makes CAD consuming a heavy meal or smoking.
assume an aggressive course in Asian Indians. Important risk Pain is poorly localised, vague chest discomfort which may be
factors in Asian Indians have been listed in Table 2.The INTERHEART described as squeezing, burning, tightness, choking, heaviness,
study (2004) on 25,000 myocardial infarction patients confirmed hot or cold sensation, dyspnoea, fatigue, weakness, light-
nine risk factors attributing to CAD—ApoB/ApoA-1, smoking, headedness, nausea, diaphoresis, altered sensorium and
diabetes, hypertension, abdominal obesity, psychosocial, fruits syncope. These symptoms have been called angina equivalents.
and vegetable intake, exercise and alcohol. Of these ApoB/
Pain lasts for 2 to 8 minutes. Ischaemia seldom lasts more than 30
ApoA-1 and smoking were especially associated with increased
minutes without causing acute myocardial infarction (AMI). Pain is
incidence of myocardial infarction in younger patients.
relieved with rest or sublingual nitroglycerine in 2 to 5 minutes.
Table 2: Coronary Risk Factors for Asian Indians It is less likely to be angina if it is localised (finger pointing),
Fixed less than 30 s, or more than 30 min without AMI, exclusively at
Male age >35 years rest (except unstable/Prinzmetal), pricking or jabbing and
Female age >45 years changing sites of pain (Figure 2).
Family history of premature CAD (at age <55 years)
Modifiable: Non-lipid
Hypertension
Cigarette smoking/tobacco abuse
Diabetes mellitus/insulin resistance syndrome
Apple obesity or body mass index >23
Homocysteine >10 mmol/L
High PAI – 1
Modifiable: Lipid
Total cholesterol >150 mg/dL
Triglycerides >150 mg/dL
LDL cholesterol >100 mg/dL
ApoA lipoproteins <100 mg/dL
HDL <40 mg/dL males, <50 mg/dL females
Modifiable: Lipoprotein ratios
TC/HDLc >4.5
LDLc/HDLc >3.5
ApoA/ApoB <1.2

SPECTRUM OF MYOCARDIAL ISCHAEMIA

The ischaemic heart disease can present as stable effort angina,
Figure 2: Identifying ischaemic versus non-cardiac chest pain.
unstable angina, non-Q wave MI, Q wave MI, heart failure and 667
 The location of pain and its relation with exertion are two DIAGNOSTIC TESTING
important factors in patient’s history for determination of cause For a patient with stable CAD, investigations are aimed at
of chest pain. In presence of both factors (diffuse retrosternal excluding non-cardiac cause of chest pain, assessment of risk
pain and aggravation with exertion; relief on rest), chest pain factors for modification, risk stratification, stress testing to
is likely to be due to underlying CAD in 90% of patients. In evaluate inducible ischaemia, LV function assessment,
presence either of one factor (atypical chest pain), underlying assessment for silent myocardial ischaemia and assessment of
CAD is likely in 50% of patients. If both the factors are absent, coronary anatomy where indicated.
the cause of pain is most likely non-cardiac.
Risk Factors
A few patients have walk-through angina (pain gets relieved
while the patient continues to walk). Decubitus angina is The patient should be evaluated for presence of underlying
believed to be caused by blood volume shifts towards the lungs, diabetes mellitus (Fasting and post-prandial blood sugar
resulting in rise in LV end-diastolic pressure. Nocturnal angina levels, HbA1C), dyslipidaemia (raised total cholesterol,
may be associated with nightmares. LDL-C, VLDL-C, triglycerides, ApoB and reduced HDL-C). The
presence of markers like hs-CRP, lipoprotein (a), homocysteine,
Prinzmetal’s angina attributable to intense coronary vasospasm tPA, PAI-I, fibrinogen, etc. can be indicators of underlying
was described first in 1959 by Prinzmetal with a consistent yet atherosclerosis.
atypical pattern of angina at rest (non-threshold angina) precipitated
by cold, emotional stress and smoking which was associated with Baseline Electrocardiogram
ST-segment elevation. Paradoxic responses consistent with This is likely to be normal in over 90% cases and only helps to
endothelial dysfunction have been described. Intense vasospasm recognise LVH, bundle branch block, old MI or pre-excitation. A
is also seen in subjects who abuse cocaine and amphetamine. normal ECG does not exclude ischaemia as being a cardiac
Provocative testing by inducing hyperventilation or administering cause.
intracoronary acetylcholine or ergonovine typically precipitate an
Stress Testing
attack of variant angina associated with focal spasm.
Exercise is a common physiological stress used to elicit
Grading of angina is based on NYHA classification, specific cardiovascular abnormalities not present at rest and to determine
activity scale index and Duke activity status index. Table 4 lists the adequacy of cardiac function. As exercise progresses, in
the conditions to be considered in differential diagnosis of individuals with underlying CAD, there occurs a mismatch
coronary pain.

Table 4: Common Causes of Chest Pain Mimicking Chronic Stable Angina

System Syndrome Clinical Description Key Distinguishing Features
Cardiac Angina Retrosternal chest pressure, burning, or Precipitated by exercise, cold weather, or
heaviness; radiating occasionally to neck, emotional stress; duration < 2 to10 minutes
jaw, epigastrium, shoulders, or left arm
Oesophageal Acid peptic disease, History of retrosternal burning, bloating Association with meals and posture, may be
gastro-oesophageal reflux sensation and reflux (linked angina) relieved by S/L nitrates
Musculoskeletal Costochondritis Sudden onset of intense fleeting pain May be reproduced by pressure over affected
joint; occasional patients have swelling and
inflammation over costochondral joint
Cervical disc disease Sudden onset of fleeting pain May be reproduced with movement of neck
Trauma or strain Constant pain Reproduced by palpation or movement of
chest wall or arms
Infections Herpes zoster Prolonged burning pain in Vesicular rash, dermatomal distribution
dermatomal distribution
Psychological Panic disorder Chest tightness or aching, often Patient may have other evidence of emotional
accompanied by dyspnoea and lasting disorder
30 minutes or more, unrelated to exertion
or movement

Physical Findings between oxygen supply and demand which may manifest with
The physical finding may reveal risk factors of CAD. These electrocardiographic, regional wall motion or myocardial perfusion
abnormalities. The commonly used exercise stress tests to
include elevated BP, corneal arcus, xanthelasma, retinal arteriolar
diagnose underlying CAD are—treadmill stress test, dobutamine
changes, diagonal earlobe crease, etc.The cardiovascular system
stress echocardiography and stress perfusion imagining.
(CVS) examination is normal (except for audible S4) in most
individuals with stable angina. The presence of systolic murmur Treadmill stress test
may suggest underlying aortic stenosis, mitral valve prolapse Treadmill stress test remains a cornerstone of cardiovascular
(MVP) or hypertrophic obstructive cardiomyopathy (HOCM) as evaluation. It is a simple, safe and cost-effective test in the
cause of angina. diagnosis of coronary artery disease. The average present
668
 Ischaemic Heart Disease
sensitivity and specificity of exercise testing in diagnosing comparison of systolic thickening before and after
coronary artery disease in 68% and 77%. In single vessel disease, administration of dobutamine is performed using recorded
the sensitivity ranges from 25% to 71% while that for left main images. Low-dose dobutamine inducing increased systolic
and triple vessel disease is 86%. The results are less specific with thickening at low dose that deteriorates at high dose (‘biphasic
more false positive outcomes in patients with marked resting response’) is most specific for predicting response to
ST-segment depression, digitalis effect, valvular heart disease, revascularisation. The greater the number of viable segments,
hypokalaemia and young female subjects with non specific the greater is the chance of survival after revascularisation.
T wave changes. Stress echocardiography and thallium stress
There are thus several techniques for identification of viability.
testing increase the diagnostic yield especially in the above
PET is the ‘gold standard’ but dobutamine echocardiography
subsets.
may be the most specific for prediction of improvement
Prognostic yield of exercise testing results should not be following revascularisation. However, cardiac MRI probably
considered in isolation. Exercise parameters associated with identifies scar tissue the best with excellent reproducibility and
adverse prognosis include duration of symptom limiting will probably be used more extensively to make decisions about
exercise, more than 5 METs, exercise-induced ST-elevation, intervention in the future.
sustained ventricular tachycardia, down-sloping ST-segment
Ambulatory Electrocardiographic Monitoring
depression involving more than 5 leads and 5 minutes into
recovery. On the other hand, excellent exercise tolerance more Silent myocardial ischaemia is defined as documented episodes
than 10 METs generally indicates good prognosis regardless of of ischaemia not associated with any typical or atypical
anatomical disease. symptoms that occur among patients with obstructive coronary
artery disease. Holter monitoring is required to identify these
Stress perfusion imaging and myocardial cellular clinically asymptomatic events. The asymptomatic MI and
metabolism assessment ischaemic episodes are common in diabetics.
See chapter 7 of this section.
Coronary Angiography
Echocardiography and stress echocardiography in CAD The coronary arteries can be visualised by either invasive or
Use of ultrasound for analysing the structure and function of computed tomography (CT) coronary angiography. While
the heart provides useful non-invasive information in the overall CT coronary angiography presently cannot be considered a
assessment of a patient of CAD. Global LV systolic function routine replacement for invasive coronary angiography,
frequently guides the choice of therapy. Segmental wall motion clinical application, especially to rule-out coronary stenoses in
abnormalities are useful and specific. These wall motion patients who do not have a high pretest likelihood of disease,
abnormalities can be segmentally scored. Various complications is conceivable.
of CAD such as dyssynergic areas, aneurysm, intramural clot, free
The major epicardial branches and their second- and third-order
wall rupture, pseudoaneurysm formation, pericardial effusion,
branches can be visualised using coronary arteriography. CAD
mitral filling patterns, assessment of aetiology and severity of
is considered to be significant when more than 70% stenosis of
mitral regurgitation, assessment of tricuspid regurgitation,
arterial diameter is seen in one or more of these vessels or more
deduction of PA pressure and LVEDP can be performed.
than 50% of left main coronary artery is involved. Stenoses of
Myocardial viability assessment can be performed using
less than 50% has major prognostic implications because these
dobutamine stress echocardiography in patients with CAD and
lesions most commonly lead to plaque rupture and acute MI.
LV dysfunction. Stunned myocardium is a transient myocardial
Subcritical stenoses of less than 50% are best characterised as
dysfunction that occurs after an acute episode of ischaemia and
non-obstructive CAD; obstructive CAD is classified as one-, two-
may occur despite the restoration of normal blood flow.This may
or three-vessel disease.
last several days to weeks. Contrast echocardiography and cardiac
MRI are techniques that reliably identify ‘stunned myocardium’. Cardiac Biomarkers
Impaired regional myocardial energy production, calcium See chapter 18 and 19 of this section.
overload, free radical injury and ischaemic damage to extra-
cellular matrix may be underlying mechanisms for stunning. Multislice CT Coronary Angiogram
CT scan in CAD has multiple potential uses: assessment of
Hibernating myocardium refers to persistently dysfunctional
ventricular function, visualisation of coronary arteries and
myocardial segments in chronic low flow state who have
evaluation of coronary artery calcification. Coronary calcium is a
potential for recovery of function with restoration of flow.
surrogate marker for coronary atherosclerotic plaque but only
Positron emission tomography comparing a perfusion tracer
non-linear correlations exist between amount of coronary
rubidium and metabolism tracer, flurodeoxy glucose (FDG),
calcium and angiographic severity of CAD. Therefore, the
cardiac MRI and dobutamine stress echocardiography are
detection of even large amounts of coronary calcium does not
techniques developed to identify hibernating myocardium.
imply the presence of significant stenosis, but the complete
Dobutamine stress echocardio-graphy has been found to be
absence of coronary calcium rules out significant CAD. Thus,
the best predictor of improvement following revascularisation
multislice CT, in experienced hands is a modality that can rule-
(‘contractile reserve’) although cardiac MRI may be more
out significant CAD in low-risk population non-invasively.
specific for diagnosis of viability.
Applications beyond this are still subject to validation but the
Dobutamine echocardiography is an established technique for non-invasive nature of this investigation makes it an attractive
the identification of hibernating myocardium. A segmental application for intense scrutiny.
669
 THERAPY OF CORONARY ARTERY DISEASE Risk Factor Modification
Goals of treatment are to improve quality of life, reduce incidence Control of hypertension
of unstable angina and MI, decrease frequency and severity of Patients of angina and hypertension benefit with control of
anginal episodes and to improve the longevity. The modalities BP to less than 140/90 mm Hg (more aggressive reduction
of treatment are risk factor modification, lifestyle modification, in diabetics). A meta-analysis of nine major trials of
pharmacological measures and revascularisation shown in antihypertensive treatment of elderly patients showed 12%
Table 5 and Figure 3. reduction in all-cause mortality, 25% reduction in CAD mortality
and 30% reduction in stroke mortality. The totality of available
Table 5: Methods of Treatment of CAD
data suggests that BP control favourably influences outcome.
Lifestyle modification There is a debate about the best agent for BP control in
Pharmacologic uncomplicated hypertension, but beta-blockers have a definite
Anti-platelets role in symptomatic CAD. ACE-inhibitors and calcium channel
Lipid lowering agents blockers can be used in patients with CAD for effective BP
Nitrates control.
Beta-blockers
Calcium channel blockers Diabetes mellitus and insulin resistance
Adjunctive treatments Strict control of diabetes has beneficial effects in reducing the
Metabolic modulation: Trimetazidine incidence of microvascular complications such as retinopathy
LV Dysfunction and renal disease. The effect on macrovascular complications
ACE-inhibitors is less established. Diabetes is considered a CAD equivalent
Aldosterone antagonists and patients should be started on treatment for secondary
Gene therapy prevention of CAD. Diabetes accelerates atherosclerotic process
Stem cell therapy and leads to more severe, extensive diffuse disease with higher
Percutaneous coronary intervention left main disease and less collaterals. The major risk factors are
Surgical revascularisation amplified in diabetics with diabetic dyslipidaemia (high TG
and small dense LDL and low HDL), increased prevalence of
hypertension and insulin resistance syndrome. Efforts to target
all risk factors among diabetics must be undertaken with
exercise, control of body weight and blood sugar, smoking
cessation, lipid lowering and aggressive control of blood
pressure.
Dyslipidaemia
Dyslipidaemia, especially hypercholesterolaemia, elevated
LDL and decreased HDL levels are strongly associated with
increased risk for CAD. 1% reduction in cholesterol causes a
2% to 3% reduction in CHD risk. NCEP ATP-III guidelines
recommend different therapeutic targets depending on a
patient’s overall risk. Patients with existing CHD (or a CHD
risk equivalent, such as diabetes or peripheral vascular
disease) are at the highest risk for a cardiovascular event and
thus have the lowest LDL target (less than 100 mg/dL), with
the option of setting the goal at less than 70 mg/dL for those
who have had a recent acute coronary event or who have
CVD combined with either diabetes or severe or poorly
controlled risk factors.
Lipoprotein(a) is an LDL-like particle with apolipoprotein(a)
attached to apolipoprotein B. A large body of literature links
Lp(a) to CAD especially among Asian Indians. Cardiovascular
risk appears to increase incrementally with Lp(a) but more with
Lp(a) greater than 30 mg/dL.
Lifestyle Modification
Smoking cessation, a healthy diet and regular exercise,
maintaining ideal body weight, improving fitness levels can only
Figure 3: Approach for management of patient with stable angina. be achieved by lifestyle modification, dietary advice and
CABG= Coronary artery bypass grafting; PTCA= Percutaneous transluminal counselling. These may forestall the need for pharmacologic
coronary angioplasty.
measures to reduce coronary risk.

670
 Ischaemic Heart Disease
Cigarette smoking may be the single-most preventable cause option of treatment strategy is based on risk stratification
of death and its cessation reduces risk of CAD mortality by 50% with stress testing and LV systolic function assessment. Low-
in 1 year. After 10 years, the coronary mortality risk is reduced risk patients (small perfusion defects, small wall motion
to that of non-smokers. Exposure to second-hand smoke abnormalities on echo, high ischaemic threshold, normal LV
increase risk to death due to CAD by 30%. Cigarette smoking function) can be managed medically. Persistence of symptoms
activates platelets, increase circulating fibrinogen, increases despite optimal anti-anginal therapy, presence of multiple
heart rate and blood pressure. segment perfusion defects, low ischaemic threshold and
moderate LV dysfunction warrant coronary angiography (CAG).
Exercise In patients with single vessel disease, medical management
Exercise conditions the skeletal muscles, which decreases can be the treatment option in low-risk patients. In case of
oxygen consumption for the same workload. It also lowers heart persistent symptoms and high-risk patients (e.g. proximal LAD
rate for any level of exertion. It is recommended that aerobic involvement), double vessel disease, PTCA is recommended.
isotonic exercises with a goal of 85% age predicted maximal Surgical revascularisation is the treatment of choice for
heart rate for 20 to 30 minutes be achieved 3 to 4 times a week significant left main disease and triple vessel disease with
for secondary prevention. diminished LV function. Registry based data suggests that
multivessel stenting may be as efficacious in the short term as
Diet
CABG. Diabetics often have small-sized vessels with diffuse
Vegetarian diets with less than 10% fat and no dairy products disease and are poor candidates for PCI-based therapies. In
have been shown to be beneficial. It is recommended to limit insulin-requiring diabetics, CABG is definitely better. The grafts
saturated fat intake to less than 7% of calories, keep trans fatty used in CABG patients include venous (reversed saphenous vein
acids as low as possible and use dietary adjuncts to improve grafts harvested from legs) and arterial grafts [left internal
the likelihood of attaining LDL-C goals like dietary fibre, dietary mammary artery (LIMA) and radial artery grafts]. The arterial
plant stanol/sterol esters, etc. grafts (LIMA) have better patency and long-term outcomes
Obesity (especially in diabetics).
Obesity especially central obesity is associated with increased Acute complications of PTCA include death (<1.0%),
risk of developing CAD. Obese patients have higher all cause periprocedural MI (0.4%), abrupt closures due to dissections and
mortality rates and are more likely to be diabetic. Hence, regular thrombus, etc. A 15% to 20% restenosis rate has been reported
exercise is recommended in obese patients for adequate weight with the bare metal stents. The advent of DES has reduced
loss and risk reduction. restenosis rates to 8% to 12%. However, subacute and late stent
thrombosis have emerged as a small but definite risk in patients
Stress and type A personality who undergo intervention with a DES.
In patients with stress and type A personality, biofeedback
relaxation techniques and yoga can help modify anger, hostility Percutaneous intervention and medical therapy should be
and stress. viewed as complimentary rather than opposing strategies.
While PTCA improves coronary blood flow considerably more
Pharmacological Measures than lipid lowering, its effects are restricted to the target vessel
Patients with chronic stable angina need to be treated with and need to be followed with lipid lowering and medical
anti-anginal medications. The three conventional anti-anginal management.
class of drugs are nitrates, beta-blockers and calcium channel
Compared to medical treatment CABG improves survival
blockers. Beta-blockers are the preferred agents and should be
among high-risk patients with stable angina such as left main
used in all unless contraindicated. Target resting heart rate of
disease, three vessel disease with impaired LV function and two
60 and post-activity heart rate of less than 100 is to be achieved vessel disease including proximal LAD stenosis associated with
with adequate beta-blocker doses. Cardioselective agents LV dysfunction. The greater use of arterial conduits, minimal
like metoprolol and bisoprolol are preferred. Nitrates—short- access surgery and surgery without cardio-pulmonary bypass
acting (isosorbide dinitrate) and long-acting are used 3 times has improved surgical results.
and 2 times a day, respectively. Nitrates are good agents for
acute relief of angina for which amyl nitrate and isosorbide Newer Approaches
dinitrate are used. In patients with class III and IV angina, Therapy with direct infusion of vascular endothelial growth
polytherapy with all three class of agents is used. All these factor (VEGF) and basic fibroblast growth factor (bFGF) have
patients need to be on aspirin. Statins (simvastatin, atorvastatin, been shown to increase collaterals flow. Approaches using
rosuvastatin, etc.) should be used to achieve LDL goals of gene therapy to overexpress endogenous growth factors to
less than 70 mg/dL. ACE-inhibitors (preferably ramipril) improve development of collaterals have been proposed.
retard the progress of atherosclerosis in patients with CAD However, initial optimism was not supported by trial-based
and have mortality reducing effects as documented in HOPE evidence.
study.
Stem cell therapy has been used in all situations in CAD and
Revascularisation currently is under intense scrutiny in the immediate post-MI
The modalities available for revascularisation in patients situation. There are conflicting data in this situation and the
with CAD are coronary artery bypass grafting (CABG) and verdict is still not out. Currently, stem cell therapy is only being
percutaneous transluminal coronary angioplasty (PTCA). The used in clinical trial situations.
671
 CORONARY ARTERY DISEASE IN WOMEN RECOMMENDED READINGS
Women with CAD may present differently than men, have 1. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or
different pathophysiologies and risk profiles and are often without PCI for stable coronary disease. N Engl J Med 2007;356:1503.
significantly older and thus often have poorer outcomes. Plaque 2. Budoff MJ, Achenbach S, Blumenthal RS, et al. Assessment of coronary artery
compositions are different (more cellular and fibrous), more disease by cardiac computed tomography. A scientific statement from the
American Heart Association Committee on Cardiovascular Imaging and
endothelial dysfunction, more plaque erosion compared to Intervention, Council on Cardiovascular Radiology and Intervention, and
rupture and more thrombogenesis (higher fibrinogen).They also Committee on Cardiac Imaging, Council on Clinical Cardiology. Circulation
have worse outcomes after CABG (more LVH, smaller coronary 2006;114:1761.
size).Women also have higher incidence of microvascular angina, 3. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint
vasospastic angina and abnormal coronary vasodilator reserve. National Committee on Prevention, Detection, Evaluation, and Treatment
However, they also have a higher incidence of atypical chest pain, of High Blood Pressure: The JNC 7 report. JAMA 2003;289:2560.
a fact that often complicates evaluation of chest pain in women. 4. Gersh BJ, Frye RL. Methods of coronary revascularisation — things may
Non-invasive diagnostic testing is more often false-positive in not be as they seem. N Engl J Med 2005;352:2235.
women and mortality after MI is worse in women after 60 years 5. Gibbons RJ, Balady GJ, Bricker JT, et al. ACC/AHA 2002 Guideline update for
as compared to men. Diabetes eliminates the ‘female advantage’ exercise testing: summary article: A report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines
of women. Obesity and fat distribution appear to be more
(Committee to Update the 1997 Exercise Testing Guidelines). Circulation
independent risk factors than in men. The premenopausal 2002;106:1883.
female has a relative protection against CAD and a multitude
6. Katritsis DG, Ioannidis JP. Percutaneous coronary intervention versus
of observational studies have suggested that oestrogen conservative therapy in nonacute coronary artery disease: A meta-analysis.
replacement therapy reduces risk. The recently reported heart Circulation 2005;111:2906.
and oestrogen/progestin replacement study (HERS) showed no 7. Smith Jr SC, Milani RV, Arnett DK, et al. Atherosclerotic Vascular Disease
reduction in recurrent coronary events in the active treatment Conference: Writing Group II: Risk factors. Circulation 2004;109:2613.
arm in postmenopausal female survivors of AMI. 8. Smith SC Jr, Allen J, Blair SN, et al. AHA/ACC Guidelines for secondary
prevention for patients with coronary and other atherosclerotic vascular
CONCLUSION disease: 2006 update: Endorsed by the National Heart, Lung, and Blood
In summary, the treatment of coronary artery disease is Institute. Circulation 2006;113:2363.
continuously evolving. Current treatment involves constant 9. Third Report of the National Cholesterol Education Program (NCEP)
risk stratification, modification of risk factors, optimising anti- Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation
platelet therapy, controlling blood pressure and blood sugar, 2002;106:3143.
symptomatic relief and revascularisation. Prevention of CAD
10. Yusuf S, Hawken S, Ounpuu S. On behalf of the INTERHEART Study
should be an important part of health education as it may be Investigators. Effect of potentially modifiable risk factors associated with
the most cost-effective measure towards reducing the disease myocardial infarction in 52 countries (the INTERHEART study): case-control
burden of this modern epidemic. study. Lancet 2004; 364: 937-52.

672
 12.18 Acute Coronary Syndrome

Gurpreet Singh Wander, Naveen Kumar Gupta

The term acute coronary syndrome (ACS) refers to any group are frequently superimposed on white clots, and cause total
of clinical symptoms compatible with acute myocardial occlusion resulting in STEMI. When occlusion is subtotal, UA/
ischaemia and covers the spectrum of clinical conditions NSTEMI are usually the result (Figure 2).
ranging from unstable angina (UA) to non-ST-segment
elevation myocardial infarction (NSTEMI) to ST-segment
elevation myocardial infarction (STEMI). Unstable angina was
the term used earlier and now NSTEMI is used more commonly.
The present chapter deals with UA and NSTEMI which are closely
related conditions but they differ in severity. STEMI (acute
myocardial infarction) is discussed in next chapter.

EPIDEMIOLOGY
According to OASIS registry, Indian patients are 7 to 8 years
younger than Western patients with mean age of 57 years as
against 65 years in Western population. Also, our patients are Figure 2: The spectrum of acute coronary syndromes.
more often diabetic. A large registry – CREATE registry was done
in 2008, involving 20,000 patients admitted in multiple centres The high-risk or vulnerable plaques are characterised by a large
in India. Thirty three per cent of these patients were less than lipid core, thin fibrous caps, a high density of macrophages and T
50 years of age. Patients of NSTEMI/STEMI reached hospital later lymphocytes, a relative paucity of smooth muscle cells, locally
as compared to the Western patients. In young patients coming increased expression of matrix metalloproteinases that degrade
from poorer socio-economic strata, smoking was the risk factor collagen, eccentric outward remodelling, and increases in plaque
in 50% of the patients. In older individuals from rich areas, neovascularity and intraplaque haemorrhage. Inflammation, an
diabetes and hypertension were more important risk factors. important determinant of the ‘vulnerability’ of plaques, is related
The mortality rate of NSTEMI in CREATE registry was 4% which to an increase in the activity of macrophages at the site of plaque.
is 1% more than in Western registries. Seventy per cent of lesions on coronary angiography that cause
ACS are less than 50 per cent stenosis of arterial diameter. So
PATHOPHYSIOLOGY most ACS episodes are due to rupture of non-obstructive plaques.
Atherosclerosis is the ongoing process of plaque formation The plaque usually ruptures at shoulder point.
that involves primarily the intima of large and medium-sized
arteries; the condition progresses overtime, before manifesting CLINICAL FEATURES
itself as an ACS. The pathogenesis of ACS involves an inter- History
play among the endothelium, the inflammatory cells, and the ACS occurs more commonly in males. As compared to stable
thrombogenicity of the blood. After plaque rupture (or angina, the discomfort associated with UA is more severe,
endothelial erosion), the subendothelial matrix (which is occurs at rest, lasts longer and is usually described as frank
rich in tissue factor, a potent procoagulant) is exposed to the pain (Figure 3). It is located in the substernal region (sometimes,
circulating blood; this exposure leads to platelet adhesion
followed by platelet activation and aggregation and the
subsequent formation of a thrombus (Figure 1). Two types of
thrombi can form: a platelet-rich clot (a white clot) that forms
in areas of high shear stress and partially occludes the artery, or
a fibrin-rich clot (a red clot) that is the result of an activated
coagulation cascade and decreased flow in the artery. Red clots

Figure 3: Clinical features and risk assessment of patients with stable or unstable
Figures 1A and B: (A) Atheromatous plaque; (B) Ruptured plaque with thrombus. angina.
673
 the epigastric area), radiates to the neck, jaw, left shoulder, and
left arm. The discomfort is often accompanied by burping and
eructations and is at time mistaken as ‘gas’ by the patients.
Some patients may present with symptoms other than chest
discomfort; such ‘angina equivalents’ symptoms include
dyspnaea (most common), nausea and vomiting, diaphoresis,
and unexplained fatigue. Atypical presentations are more
common among women, elderly people and in diabetics.
Rarely, syncope may be the presenting symptom of ACS.
Besides characteristics of pain other factors that help to
identify pain of CAD are older age, male sex, a history of CAD
and number of traditional risk factors present.
Unstable angina was sub classified by Dr. Eugene Braunwald as
class I, II, III according to severity and prognostic significance. It
is also sub classified as A,B, C according to clinical circumstances
(Table 1).
A diagnosis of NSTEMI can be made when the ischaemia is
sufficiently severe to cause myocardial damage that results in
the release of a biomarker of myocardial necrosis into the
circulation (cardiac-specific troponins T or I, or muscle and brain
fraction of creatine kinase [CK-MB]).

Table 1: Braunwald Clinical Classification of Unstable Angina

Secondary Primary Post-MI
UA (A) UA (B) Angina (C)
New onset angina (I) IA IB IC
Angina at rest not within II A II B II C
preceding 48 hours (II) Figures 4A and B: Electrocardiographic changes in ACS. (A) Normal or non-
diagnostic ECG; (B) ST depression or dynamic T wave inversions.
Angina at rest within III A III B-T Positive III C
48 hours (III) III B-T Negative →
troponin-T/troponin-I.They are used for the diagnosis of NSTEMI
Arrow indicates that with increasing severity prognosis worsens.
and for prognostication.Troponins are more sensitive and specific
Clinical Examination than any other biomarker. Both qualitative as well as quantitative
measurements are available. There is a direct relationship
The cardiovascular examination is mostly normal.The findings that
between the degree of troponin elevation and mortality. Patients
indicate a large area of ischaemia and high-risk include diaphoresis;
with elevated Troponin levels have 25% risk of death or MI at 6
pale, cool skin; sinus tachycardia; a third or fourth heart sound;
months as compared to less than 5% risk in patients with normal
basilar rales; and hypotension. The physical examination may also
Troponin levels. Troponins are not released before 4 to 5 hours of
provide clues that can help in determining the differential
symptoms, so these should be measured after 4 to 5 hours of
diagnosis. For example, unequal pulses or a murmur of aortic
symptom onset and if results are negative, these are measured
regurgitation indicates possible aortic dissection, whereas a
after 8 to 12 hours of symptom onset.Troponins remain elevated
pericardial friction rub suggests acute pericarditis.
up to 10 to 14 days of symptom onset. Levels of CK-MB start
INVESTIGATIONS increasing after 10 to 12 hours of symptom onset and remain
elevated for 24 to 36 hours. It is rapid, cost- efficient and detects
Electrocardiography
early reinfarction but lacks specificity in setting of skeletal muscle
Findings on ECG associated with UA include ST-segment disease or injury, including surgery.
depression, transient ST-segment elevation, T-wave inversion, or
some combination of these changes. Depending on the severity Other Laboratory Tests
of the clinical presentation, these findings are present in 30% to A chest X-ray is usually obtained at the time of admission. A full
50% of the patients. New ST-segment deviation, even of only 0.05 lipid profile should be obtained within 24 hours of the onset of
mV, is an important and specific measure of ischaemia and prognosis. ACS. Elevated CRP levels relate to an increased risk of mortality.
T wave inversion is sensitive for ischaemia but is less specific. B-type natriuretic peptide (BNP) provides useful prognostic
Patients with no ECG changes are at a lower risk of complications information across the entire spectrum of patients with ACS as
than those with ECG changes. Myocardial ischaemia is dynamic a marker of heart failure which may be associated in some high-
and patients hospitalised for UA/NSTEMI should undergo serial risk patients.
ECG tracings or continuous ST segment monitoring (Figure 4).
Echocardiography
Cardiac Biomarkers Echocardiography is the rapid bed side tool for assessment of
Markers of myocardial necrosis should be measured in all regional wall motion abnormalities (RWMA), LV functions and
674 patients of acute coronary syndromes and include CK-MB and mitral regurgitation. It also helps to rule out conditions like aortic
 Acute Coronary Syndrome
stenosis (AS), hypertrophic obstructive cardiomyopathy (HOCM) UA/NSTEMI show significant coronary lesions on coronary
and mitral valve prolapse (MVP) which may have similar angiography.
presentations.
Table 3: The TIMI Risk Score
Risk Stratification
TIMI Risk Score Risk of Death, MI, or Urgent
Patients of ACS have variable prognosis. At one end of spectrum (No. of Risk Factors)* Revascularisation (%)
are young patients with new onset angina, no ECG changes,
0 or 1 ~ 5%
non-elevated biomarkers and no haemodynamic instability.
These patients are managed pharmacologically and they should 2 ~ 10%
undergo non-invasive testing (TMT, stress echocardiography) 3 ~ 15%
after 10 days of symptom onset. At the other end are patients 4 ~ 20%
with history of recurrent/rest angina, fresh ECG changes, 5 ~ 25%
elevated biomarkers and, haemodynamically unstable patients 6 ~ 40%
who need early invasive treatment strategy in the form of PCI. * Risk factors include: Age ≥ 65 years; ≥ 3 CAD risk factors; Known CAD (>50%
stenosis); Prior aspirin therapy; ≥ 2 anginal episodes in last 24 hours; ST deviation
Patients with ACS are risk stratified on the basis of certain ≥ 0.5 mm; Elevated Troponins.
criteria, to assess which of them would benefit from early
invasive therapy (percutaneous coronary intervention) and MANAGEMENT
who will be managed conservatively (Table 2). Many risk
The principles of management are general measures,
profile models like TIMI (Table 3), GRACE have been proposed
pharmacological therapy and revascularisation.
for triage assessment. The TIMI risk score is determined by
seven variables, each of which is assigned one point. Patients General Measures
with scores of five or more have been shown to have a higher Patients with definite ACS are admitted to the hospital for
risk of adverse events and a higher mortality and these further treatment. Admission to the coronary care unit (CCU) is
patients should be considered for early coronary angiography recommended if there is an evidence of active, ongoing
and revascularisation. ischaemia or haemodynamic or electrical instability. The other
Forty per cent of rich and 8.5% of the poor patients had coronary measures include bed rest till patient is pain free for at least 24
angiography done in the CREATE registry. So besides above hours, mild sedation, quiet environment, morphine or pethidine
listed factors, socio-economic status also effects the decision if pain is not substantially relieved by nitrates and beta-blockers
for invasive strategy. and stool softeners to avoid straining.
Pharmacological Therapy
Table 2: Selection of Initial Treatment Strategy: Invasive versus
Conservative In general, all patients should receive dual anti-platelet agent
therapy (aspirin and clopidogrel), antithrombotic therapy
Invasive Recurrent angina or ischaemia at rest or with low-
(unfractionated heparin or low molecular weight heparin), beta-
level activities despite intensive medical therapy
blockers, statins and ACE-inhibitors.
Elevated cardiac biomarkers (TnT or TnI)
New or presumably new ST-segment depression Dual anti-platelet therapy includes aspirin and clopidogrel.
Signs or symptoms of HF or new or worsening Aspirin blocks the synthesis of thromboxane A2 by
mitral regurgitation irreversibly inhibiting cyclooxygenase 1, thereby diminishing
High-risk findings from non-invasive testing platelet aggregation. Randomised trials demonstrate that,
Haemodynamic instability compared with placebo, aspirin reduces the risk of death
Sustained ventricular tachycardia or MI by more than 50% for patients presenting with
PCI within 6 month UA/NSTEMI.
Prior CABG
Clopidogrel is a thienopyridine derivative that blocks the P2Y12
High-risk score (e.g. TIMI, GRACE) adenosine diphosphate (ADP) receptor on platelets. This action
Reduced left ventricular function (LVEF < 40%) decreases platelet activation and aggregation, increases
Conservative Low-risk score (e.g. TIMI, GRACE) bleeding time, and reduces blood viscosity. Therapy with
Patient or physician preference in the absence of clopidogrel and aspirin is recommended for essentially all
high-risk features patients with UA/NSTEMI.
CABG = Coronary artery bypass grafting; GRACE = Global registry of acute
coronary events; HF = Heart failure; LVEF = Left ventricular ejection fraction; The platelet GP IIb/IIIa inhibitors are potent and specific
PCI = Percutaneous coronary intervention; TIMI = Thrombolysis in myocardial inhibitors of platelet aggregation. They act by interrupting
infarction; TnI = Troponin I; TnT = Troponin T. the final common pathway of fibrinogen-mediated cross-
linkage of platelets. Several large trials involving patients
Coronary Angiography with UA/NSTEMI have shown that the GP IIb/IIIa inhibitors
Coronary angiography is done in all patients who are stratified are of substantial benefit for patients at high-risk, those
as high-risk by risk profile models as described above. undergoing PCI, or both. Three agents are currently
Angiography is the key in diagnosing the extent, location available for use: abciximab, eptifibatide, and tirofiban. The
and severity of lesions and in planning revascularisation main risk associated with GP IIb/IIIa inhibitors is an
[percutaneous coronary intervention (PCI) or coronary increased rate of haemorrhage, usually at the site of
artery bypass grafting (CABG)]. More than 80% patients with vascular intervention. 675
 Low molecular weight heparins (LMWH) have several advantages intervention (PCI), i.e. percutaneous transluminal coronary
over conventional heparins, including ease of administration angioplasty (PTCA) or coronary artery bypass grafting (CABG).
(twice a day), a lower rate of thrombocytopaenia, more
The choice of the revascularisation procedure depends on
bioavailability, and less binding to plasma proteins, a factor that
several factors, including the patient’s age, clinical status,
renders monitoring the level of anticoagulation unnecessary.
location and extent of lesions and especially, in the Indian
The factor Xa inhibitor fondaparinux is equivalent for efficacy setting—financial status. In CREATE registry, 6.7% of the patients
compared with enoxaparin with a lower risk of major bleeding of NSTEMI get PCI as compared to 30% patients in Western
and have the better benefit risk ratio besides once daily dosing. registries. This major difference is due to cost factor. In general,
patients with significant triple vessel disease, left main coronary
Direct thrombin inhibitors have several potential advantages
artery lesions and with lesions that are anatomically difficult to
over indirect thrombin inhibitors (such as UFH or LMWH): do
stent, are candidates for CABG.
not require a cofactor such as anti-thrombin for their action and
directly inhibit clot-bound thrombin, no interaction with plasma In the field of PCI, many advances have been made. Earlier, it
proteins and no thrombocytopaenia. Bivalirudin is used for the involved simple balloon dilatation of lesions (with consequent
treatment of patients with UA/NSTEMI selected for an early high restenosis rates). With the availability of bare metal stents
invasive strategy. (BMS), restenosis rates were significantly reduced across the
coronary lesions. The development of special stents coated with
Nitrates act as vasodilator, thereby reducing myocardial oxygen drugs like sirolimus and paclitaxel [drug-eluting stents(DES)],
demand via venodilatation and enhance myocardial oxygen further reduced restenosis rates to single digit percentages.
delivery by dilating large coronary arteries and improving These drugs have an anti-mitotic effect, whereby they inhibit
collateral flow to ischaemic areas. Nitrates relieve chest pain but neointimal proliferation, which is considered the major
do not reduce mortality in ACS. mechanism of in stent restenosis. To prevent the rate of
Beta-blockers can be used IV initially, if there is ongoing progression of late restenosis, newer polymer free stents are
ischaemia and pain, followed by oral therapy. Beta-blockers under investigation.
inhibit β-1 adrenergic receptors in the myocardium and
SUGGESTED READINGS
decrease myocardial contractility and heart rate, thereby
reducing myocardial oxygen demand. They reduce the 1. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for
the management of patients with unstable angina/non-ST-elevation
incidence of subsequent MI, recurrent ischaemia, or both. myocardial infarction: a report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines. J Am Coll
Calcium channel blockers are used in patients with resistant
Cardiol 2007; 50 (7): e1-157.
ischaemia despite beta-blocker therapy and in those with
2. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of
contraindications to beta-blockers. Calcium channel blockers randomised trials of antiplatelet therapy for prevention of death,
inhibit the contraction of both the myocardium (thereby myocardial infarction, and stroke in high-risk patients. BMJ 2002; 324 (7329):
reducing myocardial oxygen demand) and the vascular 71-86.
smooth muscle (thereby causing coronary vasodilatation and 3. Craig J, Bradbury I, Collinson P, et al. Organisation of Troponin Testing Services
improving myocardial blood flow). These agents should not in Acute Coronary Syndromes. Edinburgh: NHS quality Improvement
Scotland: (Health Technology Assessment Advice 4); 2004. [cited 2 October
be administered to patients with severe LV dysfunction or
2006].
pulmonary oedema.
4. Fox KA, Poole-Wilson P, Clayton TC, et al. 5-year outcome of an interventional
In the absence of contraindications, lipid-lowering therapy strategy in non-ST-elevation acute coronary syndrome: the British
with statins should be initiated for all patients with UA/NSTEMI, Heart Foundation RITA 3 randomised trial. Lancet 2005; 366 (9489): 914-
20.
regardless of baseline LDL cholesterol levels.
5. Mehta SR, Granger CB, Boden WE, et al. Early versus delayed invasive
Revascularisation intervention in acute coronary syndromes. N Engl J Med 2009;360 (21):
2165-75.
Revascularisation consists of measures to open the culprit vessel/(s)
6. Theroux P, Welsh RC. Meta-analysis of randomised trials comparing
to improve the perfusion to the ischaemic myocardium, after enoxaparin versus unfractionated heparin as adjunctive therapy to
identification of the location and extent of the lesions on coronary fibrinolysis in ST-elevation acute myocardial infarction. Am J Cardiol 2003;
angiography (CAG). It can be done by percutaneous coronary 91(7): 860-4.

676
 12.19 Acute Myocardial Infarction

Gurpreet Singh Wander, Naved Aslam

Acute myocardial infarction (AMI) is a clinical syndrome that of myocardial perfusion in the infarct zone when flow is restored
results from occlusion of a coronary artery with resultant death in the occluded epicardial coronary artery.
of cardiac myocytes in the region supplied by that artery. When
these patients present in emergency, they have ST elevation in CLINICAL PRESENTATION
ECG and so are referred as ST elevation myocardial infarction A precipitating factor is present before AMI in ~15% cases, such
(STEMI). Depending on the distribution of the affected coronary as vigorous physical exercise, emotional stress, or a medical or
artery, AMI can produce a wide range of clinical sequelae, surgical illness. Circadian and seasonal variations have been
varying from a small, clinical silent region of necrosis to a large reported with increased incidence in the morning within a few
area of infarcted tissue resulting in cardiogenic shock and death. hours of awakening and during winter months.
AMI is the leading cause of death in the developed and The most common presentation for AMI is abrupt onset chest,
developing countries, including India. The true incidence of AMI neck or jaw discomfort, which is usually described as pressure,
is difficult to judge because of varied reporting pattern. Moreover, burning or squeezing in character. Pain in AMI is usually very
up to 1/3rd cases die at home before they reach hospital or are severe, persistent and is relieved only with opiates. The pain of
examined by qualified practitioner. The risk of having an AMI AMI may radiate up to the jaw and to the umbilicus. AMI can be
increases with age, male gender, smoking, dyslipidaemia, the first presentation of CAD or it can occur in a patient with
diabetes, hypertension, abdominal obesity, a lack of physical known angina pectoris. Symptoms typically last more than 20
activity, low daily fruit and vegetable consumption and minutes. It is often accompanied by weakness, sweating,
psychosocial factors. As much as 90% of risk of AMI has been nausea, vomiting, anxiety, and a sense of impending doom. In
attributed to these modifiable risk factors in the INTERHEART about quarter of patients, the infarction may not be recognised
study. because of atypical symptoms. About 20% patients have silent
infarction, usually in diabetics and elderly.
PATHOPHYSIOLOGY
AMI usually occurs when coronary blood flow decreases Physical Findings
abruptly after a thrombotic occlusion of a coronary artery Most patients are anxious and restless, attempting un-
(vascular injury) previously affected by atherosclerosis. As successfully to relieve the pain by moving about in bed,
discussed in previous chapter, acute coronary syndrome occurs altering their position, and stretching. Pallor associated with
due to rupture of atheromatous plaque and subsequent perspiration and cold extremities occurs commonly. Usually,
formation of thrombus over it. STEMI and AMI occur when this patients have sinus tachycardia due to pain and anxiety.
thrombus causes complete occlusion of coronary artery, thus Patients are often tachypnoeic. About one-fourth of patients
resulting in myocardial necrosis. Myocardial necrosis starts early with anterior infarction have manifestations of sympathetic
within 15 to 20 minutes of occlusion and is complete by 6 to 9 nervous system hyperactivity (tachycardia and/or hyper-
hours depending on collateral circulation and recanalisation. It tension), and up to one-half with inferior infarction show
is for this reason that first 6 hours are most risky (time for primary evidence of parasympathetic hyperactivity (bradycardia and/
ventricular fibrillation) and also any reperfusion therapy has to or hypotension). The jugular venous pulse should be carefully
be done within this period. The central area of myocardial examined, its elevation in the setting of inferior myocardial
necrosis is surrounded by area of myocardial injury which is infarction (MI) without left heart failure suggests right ventricular
surrounded by area of myocardial ischaemia. Initially, myocardial infarction (MI). Detection of right ventricular MI is
inflammatory cells reach the site of myocardial necrosis and vital because it portends a much worse prognosis than isolated
endocardium becomes eroded. Over period of 2 to 6 weeks, inferior MI and the management strategy is different than
scarring occurs and results in myocardial scars which isolated inferior MI.
subsequently, remodels over months in the form of dilatation
The praecordium is usually quiet, and the apical impulse may
of infarcted segment and latera also of the non-infarcted
be difficult to palpate. In patients with anterior wall infarction,
segment in case the size of infarct is large.
an abnormal systolic pulsation caused by dyskinetic bulging of
In rare cases, AMI may be due to coronary artery occlusion infarcted myocardium may develop in the periapical area within
caused by coronary emboli, congenital abnormalities and the first days of the illness and then may resolve. Other physical
coronary spasm. The amount of myocardial damage caused by signs of ventricular dysfunction include fourth and third heart
coronary occlusion depends on the territory supplied by the sounds. A transient mid-systolic or late systolic apical systolic
affected vessel, the duration of coronary occlusion, the quantity murmur due to dysfunction of the mitral valve apparatus may
of blood supplied by collateral vessels to the affected tissue, be present. A pericardial friction rub is heard in many patients
the demand for oxygen of the myocardium whose blood supply with transmural AMI at some time in the course of the disease,
has been suddenly limited, native factors that can produce early if they are examined frequently. The carotid pulse is often
spontaneous lysis of the occlusive thrombus, and the adequacy decreased in volume, reflecting reduced stroke volume. 677
 Temperature elevations up to 38°C may be observed during the
first week after AMI.

DIFFERENTIAL DIAGNOSIS
The pain of AMI can simulate pain from acute pericarditis,
pulmonary embolism,acute aortic dissection, costochondritis, and
oesophageal rupture, café coronary. Pain of aortic dissection
radiates to back and can be suspected in presence of unequal
peripheral pulses.Acute pericarditic pain increases with inspiration.
Laboratory Findings
Myocardial infarction progresses through the following
temporal stages: acute (first few hours to seven days), healing
(7 days to 30 days), and healed (>29 days). When evaluating the
Figure 2: Inferior wall myocardial infarction.
results of diagnostic tests for AMI, the temporal phase of the
infarction must be considered. The laboratory tests of value in
confirming the diagnosis may be divided into four groups: (1)
ECG, (2) serum cardiac biomarkers, (3) cardiac imaging, and (4)
coronary angiography.
Electrocardiogram
During the initial stage, total occlusion of an epicardial coronary
artery produces ST segment elevation. Most patients initially
presenting with ST segment elevation ultimately evolve Q
waves on the ECG. The most rapid and helpful test in assessing
patient with suspected AMI is the 12-lead, ECG. It should be
performed as soon as possible, after the patient’s arrival in the Figure 3: Anterolateral wall myocardial infarction.
emergency, since the presence or absence of ST elevation
determines the preferred management strategy.Tall T wave and (reciprocal of Q waves) in the anterior leads. The ECG pattern
ST elevation is first sign and occur within minutes. ST elevation should prompt the use of posterior ECG leads V7 to V9 which
changes from concave upwards to coving (convex upwards) may show ST elevation. Sometimes determining whether ECG
within few hours and is then accompanied with T wave changes are new or old may be difficult, serial ECGs are
inversion. Q waves are formed in 6 to 12 hours. The central area necessary to diagnose dynamic changes.
of necrosis is represented by Q waves, surrounding area of injury
by ST segment changes and outer area of ischaemia by T wave Cardiac Biomarkers
changes. The Q wave persists for whole life. ST and T wave Cardiac biomarkers become detectable in the peripheral
changes revert to normal by 6 weeks to 3 months. For a blood once the capacity of the cardiac lymphatics to clear the
diagnosis of ST elevation MI (AMI), ST elevation must be present interstitium of the infarct zone is exceeded and spill over into
in at least two contiguous leads. For anterior MI, the precordial the venous circulation occurs. CPK-MB is used most commonly.
(V1 to V6) leads demonstrate ST elevation and if there is lateral Myoglobin is the first to rise but since it is non specific, it is
wall involvement, lead I and aVL may also show ST elevation. not used clinically. Troponins are also useful. The use of these
In inferior MI leads II-III and aVF are affected (Figures 1 to 3). In markers is shown in Tables 1 and 2.
addition to standard ECG leads, right ventricular leads should
be recorded in all patients with inferior MI. In posterior MI, The nonspecific reaction to myocardial injury is associated with
usually due to circumflex artery occlusion, changes seen on a polymorphonuclear leucocytosis, which appears within a few
standard ECG may be reciprocal ST depression and R waves hours after the onset of pain and persists for 3 to 7 days; the white
blood cell count often reaches levels of 12,000/mL to 15,000/mL.
The erythrocyte sedimentation rate rises more slowly than
the white blood cell count, peaking during the first week and
sometimes remaining elevated for 1 or 2 weeks.
Cardiac Imaging
Abnormalities of wall motion on two-dimensional echo-
cardiography are almost universally present. Early detection of
the presence or absence of wall motion abnormalities by
bedside echocardiography can aid in management decisions.
Echocardiography may also identify the presence of right
ventricular (RV) infarction, ventricular aneurysm, pericardial
effusion, and LV thrombus. In addition, Doppler echocardio-
graphy is useful in the detection and quantitation of a
ventricular septal defect and mitral regurgitation, two serious
Figure 1: Anterior wall myocardial infarction.
678 complications of AMI.
 Acute Myocardial Infarction
Table 1: Various Cardiac Markers in AMI
CK-MB Myoglobin Cardiac Troponins
Description High energy transfer cytoplasmic O2 binding haem protein, Regulatory proteins for calcium –
protein rapidly released dependent interactions between actin
myocyte injury and myosin
Origin Cardiac and skeletal muscle Cardiac and skeletal muscle Cardiac muscle
Release kinetics 2 to 3 hours; sensitivity 94% at 8 hours 1.5 to 2 hours 3 to 4 hours
peak rise and <50% at 2 hours
Return to normal 24 to 48 hours 8 to 12 hours 10 to 14 days
Advantages Able to detect early reinfarction Marker to detect very More sensitive and specific than CK-MB
early MI best marker for MI with skeletal muscle
injury, small MI or late MI (>2 to 3 days)
Disadvantages Low sensitivity for detection of very Low sensitivity for detection Low sensitivity for detection of early (<6 hr)
early (<6 hr) MI small MI; false positive of late MI with skeletal muscle MI or late reinfarction
with skeletal muscle trauma, CPR, trauma, CPR and renal failure
cardioversion, cardiac surgery

Table 2: Use of Serum Cardiac Markers in Relation to Time

Subset Total CK CK-MB Myoglobin Cardiac Troponins
MI < 4 hours – – + –
MI 4 to 12 hours + + + +
MI >2 to 10 days – – – ≥
Early reinfarction + + ≥ –
Small MI – – – +
MI after operation of trauma – ≥ – +
+ Useful, ≥ some value, – not useful.

Myocardial perfusion imaging can be useful in some cases with The biggest delay usually occurs not during transportation to
doubtful diagnosis. the hospital but rather between the onset of pain and the
patient’s decision to call for help which can be best reduced by
Coronary Angiography
health care professionals educating the public concerning the
Coronary angiography is done either at admission prior to significance of chest discomfort and the importance of seeking
primary PCI or pre discharge for assessment of disease. In a early medical attention.
conservative approach, patients of MI are subjected to non-
invasive stress evaluation (TMT, stress echocardiography, Management in the Emergency Department
myocardial perfusion imaging) and those with inducible Many aspects of the treatment of AMI are initiated in the
ischaemia are taken-up for coronary angiography while those Emergency Department and then continued during the in-
with no inducible ischaemia are treated medically. hospital phase of management.

INITIAL MANAGEMENT Aspirin is essential in the management of patients with

suspected AMI. Rapid inhibition of cyclooxygenase-1 in platelets
Pre-Hospital Care followed by a reduction of thromboxane A2 levels is achieved
The prognosis in AMI is largely related to the occurrence of two by buccal absorption of a chewed 160 to 325 milligram tablet
general classes of complications: (1) electrical complications in the emergency department. Six hundred mg of loading dose
(arrhythmias) and (2) mechanical complications (‘pump failure’). of clopidogrel followed by 60 mg once daily should be given to
Most out-of-hospital deaths from AMI are due to the sudden all patients of AMI (dual anti-platelet therapy).
development of ventricular fibrillation. The vast majority of
When hypoxaemia is present, oxygen should be administered
deaths due to ventricular fibrillation occur within the first 24
by nasal prongs or face mask (2 to 4 L/min) for the first 6 to 12
hours of the onset of symptoms, and of these, over half occur in
hours after infarction; the patient should then be reassessed to
the first hour. Therefore, the major elements of pre-hospital care
determine if there is a continued need for such treatment.
of patients with suspected AMI include:
1. Recognition of symptoms and seeking of medical attention. Sublingual nitroglycerin can be given safely to most patients
with AMI. Up to three doses of 0.4 mg should be administered
2. Emergency medical team for resuscitative manoeuvres and
at about 5-minute intervals. Therapy with nitrates should be
defibrillation.
avoided in patients who present with low systolic arterial
3. Transportation to hospital for managing arrhythmias and pressure (< 90 mm Hg) or in whom there is clinical suspicion of
providing advanced cardiac life support. right ventricular infarction (inferior infarction on ECG, elevated
4. Reperfusion therapy. jugular venous pressure, clear lungs, and hypotension). 679
 Morphine is a very effective analgesic for the pain associated Tissue-type Plasminogen Activator (tPA): Tissue-type plasminogen
with AMI. Morphine is routinely administered by repetitive activator (tPA) is the major intrinsic (physiologic) plasminogen
(every 15 min) intravenous injection of small doses (2 to 4 mg) activator. The short half-life has necessitated bolus/infusion
rather than by the subcutaneous administration of a larger regimens (over 1 to 3 hours). tPA is given as 15 mg bolus, then
quantity, because absorption may be unpredictable by the latter 0.75 mg/kg over 30 min (maximum 50 mg), then 0.50 mg/kg
route. over 60 min (maximum 35 mg).

MANAGEMENT STRATEGIES Reteplase: It is a non-glycosylated, single chain deletion variant

of human tPA. It is given in two bolus injections 30 minutes
The primary tool for screening patients and making triage
apart.
decisions is the initial 12-lead ECG. When ST-segment elevation
of at least 2 mm in two contiguous precordial leads and 1 mm Tenecteplase: Tenecteplase (TNK) is a triple mutant and is given
in two adjacent limb leads is present, a patient should be as single bolus dose (30 to 50 mg) over 1 to 2 minutes. The ease
considered a candidate for reperfusion therapy. of administration of TNK, together with its reduced transfusion
requirements, has led to its general acceptance and favoured
Reperfusion, either pharmacologically (by fibrinolysis) or by PCI,
status. Lower rates of dosing errors with bolus fibrinolytics such
accelerates the opening of infarct-related arteries in those
as TNK also contribute to superior clinical outcomes. TNK is
patients. Timely restoration of flow in the epicardial infarct–
dosed by weight (supplied in 5 mg/mL vials): 60 kg = 6 mL;
related artery, combined with improved perfusion of the
61–70 kg = 7 mL; 71–80 Kg = 8 mL; 81–90 kg = 9 mL; 90 kg = 10 mL.
downstream zone of infarcted myocardium, results in a
limitation of infarct size. The absolute and relative contraindications to fibrinolytic
therapy are summarised in Table 4.
Pharmacologic or Mechanical Reperfusion
Primary angioplasty
Although primary PCI is considered the reperfusion strategy of
choice, it is clear that this advantage is time dependent and Primary percutaneous coronary intervention (PCI) has been very
limited to specific patient populations. Most patients in India successful in accomplishing mechanical reperfusion of the
are given thrombolytic therapy due to cost factor and also since coronary artery in patients presenting with AMI (Figures 4A to C).
cardiac catheterisation lab facilities are not available widely. In Mechanical reperfusion has the potential to overcome many
the CREATE registry almost ~8% patients of AMI get primary of the limitations of fibrinolytics. The overall risk of intracranial
PCI in our country for this reason. In 2008, 55% of the patients bleeding is significantly lower with PCI. There is a significant
of AMI got thrombolysed as against 30% in 1990s since patients superiority of primary PCI, especially among patients in which
are now reaching hospitals early. it was logistically feasible to accomplish reperfusion within 90
Fibrinolytic therapy of STEMI significantly improves mortality minutes of presentation. Primary PCI is preferred modality of
rates; treatment within six hours of the onset of symptoms leads reperfusion over fibrinolytic therapy. However, this is available
to a reduction in mortality between 26 and 65 per 1,000 patients to small percentage of patients in India and also in Western
treated which has been extensively documented. world: 10% and 35% respectively.
When performing primary PCI for patients presenting with
Fibrinolytic agents STEMI, coronary stents, either Bare metal stent (BMS) or Drug
The fibrinolytic agents differ in several properties, as eluting stent (DES), should be used whenever technically
summarised in the text and Table 3. feasible. Significant clot burden may complicate acute STEMI,
management.
Streptokinase: Streptokinase (SK) is a bacterial protein with half-
life of 23 minutes. SK is antigenic, has less fibrin specificity, and Bypass surgery may be required owing to anatomic
causes systemic lytic effects in clinical doses. It is least expensive considerations, such as left main disease or coronary disease
of fibrinolytics and still widely used globally. SK is administered not suitable for immediate PCI, or mechanical complications
by short-term (1 hour) infusions. This is the agent of choice of from the MI such as acute severe mitral regurgitation, ventricular
our country. septal defect or a failed PCI.

Table 3: Comparison of Fibrinolytic Agents Approved by the US FDA for Intravenous Use
SK (Streptokinase) tPA (Alteplase) tPA (Reteplase) TNK (Tenecteplase)
Dose 1.5 million units 100 mg in 10 u + 10 u 30 to 50 mg
(MU) in 30 to 60 min 90 min 30 min apart Over 5 seconds
Circulating half life (min) 20 6 18 20
Antigenic Yes No No No
Allergic reactions Yes No No No
Systemic fibrinogen depletion Severe Mild moderate Moderate Minimal
Intracerebral haemorrhage 0.4% 0.7% 0.8% 0.7%
Patency (TIMI-2/3) rate, 90 min 51% 73% to 85% 83% 77% to 88%
Lives saved per 100 treated 3 4 4 4
Based on the finding from the GUSTO trial that tPA saves 1 more additional life per 100 treated than dose SK.
680
 Acute Myocardial Infarction
Adjuvant therapy COMPLICATIONS
All patients should be treated with ASA and a thienopyridine Complications following AMI are enumerated below.
(currently clopidogrel) as soon as possible following diagnosis. 1. Arrhythmias
The choice of anticoagulant therapy, in part, is dictated by 2. Heart failure
the method of reperfusion undertaken. Following fibrinolytic 3. Cardiogenic shock
therapy, both fondaparinux and LWWHs improve clinical
4. Sudden death
outcomes compared with UFH. Direct thrombin inhibitors
(Bivalirudin) appear to be a reasonable alternative to UFH, and 5. Reinfarction, extension and expansion of infarction
preferred in settings of thrombocytopaenia or prior heparin- 6. Infarction of papillary muscle of mitral valve – mitral
induced thrombocytopaenia. regurgitation (MR)
7. Rupture of interventricular septum leading to ventricular
Table 4: Contraindications and Cautions for Fibrinolysis in septal defect (VSD)
STEMI 8. Thrombus in LV causing peripheral embolism
Absolute contraindications 9. Cardiac rupture
Any prior ICH 10. Deep vein thrombosis in legs causing pulmonary embolism
Known structural cerebral vascular lesion (e.g. arteriovenous 11. Pericarditis during massive infarction
malformation)
Known malignant intracranial neoplasm (primary or metastatic) 12. Aneurysm of ventricle with thrombosis and thrombo-
Ischemic stroke within 3 months EXCEPT acute ischemic stroke embolic phenomenon
within 3 hours 13. Dressler’s syndrome (post-myocardial infarction syndrome)
Suspected aortic dissection
Active bleeding or bleeding diathesis (excluding menses) Arrhythmias
Significant closed head or facial trauma within 3 months Various types of arrhythmias that can follow AMI are listed in
Relative contraindications Table 5.
History of chronic, severe, poorly controlled hypertension
Severe uncontrolled hypertension on presentation (SBP greater Table 5: Important Arrhythmias in Acute Myocardial Infarction
than 180 mm Hg or DBP greater than 110 mm Hg) Ventricular premature beats
History of prior ischaemic stroke greater than 3 months,
Ventricular tachycardia
dementia, or known intracranial pathology not covered in
Ventricular fibrillation
contraindications
Traumatic or prolonged (greater than 10 minutes) CPR or major Accelerated idioventricular rhythm
surgery less than 3 weeks) Atrial premature beats
Recent (within 2 to 4 weeks) internal bleeding Atrial tachycardia
Non-compressible vascular punctures Atrial fibrillation
For streptokinase: prior exposure (more than 5 days ago) or prior
allergic reaction Premature ventricular complexes are the commonest and can
Pregnancy be forerunners of lethal ventricular arrhythmia viz ventricular
Active peptic ulcer tachycardia or fibrillation.Ventricular fibrillation is the major cause
Current use of anticoagulants: the higher the INR, the higher of death in those who die before receiving medical attention.
the risk of bleeding
Bradyarrhythmias and conduction disturbances may also occur
in the form of sinus node dysfunction, AV nodal block or distal
conduction disturbances (bundle branch block or complete
heart block). The details of arrhythmias are outlined in the
respective chapter on Tachyarrhythmias and Bradyarrhythmias
Chapters 23 and 24 of section 12.
Heart Failure
The extent of LV dysfunction is a strong predictor of short-
Figures 4A to C: Primary angioplasty of right coronary artery (RCA). (A) Coronary
angogram showing RCA filled with thrombus. (B) Partial flow in RCA after and long-term prognosis after MI. The Killip and Kimball
thrombus aspiration. (C) TIMI grade III flow after stenting. classification stratifies MI patients from low to very high risk
based upon clinical signs of heart failure (Table 6). It remains a
In patients undergoing primary PCI, UFH has traditionally reasonably accurate predictor of short-term survival.
been administered, based primarily on theoretical grounds
and the experience of experts. There is evidence that the Table 6: Killip and Kimball Classification
addition of a GP Ilb/IIIa receptor antagonist improves outcomes Class Clinical Features Mortality
(abciximab, eptifibatide, tirofiban). There is now evidence
from a single, moderately sized trial that bivalirudin is as Killip I MI with no HF 6%
efficacious as the combination of UFH plus a GP IIb/IIIa Killip II MI with mild HF (basal rales) 17%
receptor antagonist. Killip III MI with severe HF (rales ≥50% of lung fields) 38%
Killip IV Cardiogenic shock 81%
Bleeding complications in patients with AMI remain relatively
common and may be as important to long-term outcome as The presence of clinical signs of left ventricular failure is a strong
ischaemic events. indicator of a poor long-term prognosis. It is manifested by 681
 breathlessness, cough, haemoptysis, perspiration, S3, S4 gallop Reinfarction, Extension and Expansion of Infarction
and pulmonary rales in some, the symptoms may be minor in In STEMI treated with fibrinolysis, reinfarction can occur in 4%
others. Measurements of left ventricular function and diastolic to 8% of the patients. The reinfarction rate is significantly lower
volume predict short-term and long-term prognosis after STEMI. when primary percutaneous coronary intervention (PCI) is the
Severe forms of LV failure need haemodynamic monitoring initial treatment.
with a balloon-tipped, flow-guided Swan-Ganz catheter Acute Mitral Regurgitation
placed in the pulmonary artery. Cardiac output is estimated by
Mitral regurgitation (MR) complicating acute myocardial infarction
thermodilution technique. In the absence of mitral valve disease,
(Figure 5) ranges from mild papillary muscle dysfunction (no
pulmonary artery diastolic pressure reflects LV filling pressure
haemodynamic compromise) to severe form (ruptured papillary
(normal value 0 to 14 mm Hg) and is high in LV failure. An arterial
muscle) leading to heart failure or cardiogenic shock and is more
line to monitor systemic blood pressure is also required. Medical
common in females with inferior posterior infarction.
management involves intravenous nitroglycerine infusion. If
low, then the infusion of vasopressor like dopamine can be started The diagnosis is made clinically with pansystolic murmur,
along with nitroglycerine. Recently eplerenone, aldosterone maximal at the apex, and radiation to the axilla. Echocardio-
inhibitor in doses of 25 to 50 mg is used to treat LVF in AMI. graphic examination is invaluable in confirming the diagnosis.
The persistence of cardiogenic shock or severe failure with
Intra-aortic balloon counterpulsation can be a life-saving
preserved LV function usually indicates that an important
measure. The balloon is placed in the aorta distal to the left
mechanical complication is present.
subclavian artery. It is inflated during diastole, thus improving
the flow of blood into the coronaries, and deflated in systole Ventricular Septal Rupture
thereby reducing ventricular after load. Rupture of the interventricular septum occurs in approximately
ACE-inhibitors unequivocally reduce mortality overall, and the 2% of the female patients with large anterior wall MI (Figure 6).
benefit appears to be greatest among patients with depressed Early diagnosis may offer some hope of early repair. Most
LV function, overt heart failure or anterior infarction.
The initiation of ACE-inhibitor therapy early in the course of
infarction results in greater improvement in ejection fraction.
All patients with post-MI LV dysfunction should be administered
ACE-inhibitors unless contraindicated or not tolerated.
Cardiogenic Shock
Cardiogenic shock is a syndrome characterised by hypotension
and peripheral hypoperfusion, usually accompanied by high LV
filling pressures. The common clinical manifestations of these
haemodynamic derangements include mental obtundation
or confusion, cold and clammy skin, and oliguria or anuria.
Cardiogenic shock is the most common cause of in-hospital
mortality after MI. When cardiogenic shock is not secondary to a
correctable cause such as arrhythmia, bradycardia, hypovolaemia
or mechanical defect, short-term mortality is 80%.
Inotropic drugs (dopamine, dobutamine, epinephrine, nor- Figure 5: Colour Doppler showing lateral jet of acute mitral regurgitation due
to papillary muscle dysfunction.
epinephrine) have been subjected to detailed study and
widespread use in cardiogenic shock, but no benefit on
mortality has been demonstrated.
One important cause of hypotension which responds to
treatment is hypovolaemia. This may be caused by vomiting,
diuretics or inadequate fluid intake and is treated by adequate
fluid replacement. The pulmonary end-diastolic pressure
(PAEDP) must be kept around 15 to 18 mm Hg since the
infarcted ventricle needs a higher filling pressure to maintain
its cardiac output. If PAEDP is low, colloids must be infused to
increase it until the cardiac output is maximised. Raising it
beyond 20 mm Hg will aggravate pulmonary oedema.
An aggressive approach with reperfusion therapy and intra
aortic balloon pulsation treatment of patients in cardiogenic
shock due to predominant LV failure is associated with lower
in-hospital mortality rates than standard medical therapy.
Fibrinolysis could be considered for the patient with cardiogenic
Figure 6: Echocardiogram showing rupture of septum.
682 shock if access to PCI is not readily available.
 Acute Myocardial Infarction
patients with septal rupture develop signs of acute right- and palpated as a dyskinetic region adjacent to the apical impulse.
left-sided heart failure and a loud pan systolic murmur at the left A third heart sound and signs of heart failure may also be
sternal border along with systolic thrill. Echocardiography with detected. It is recognised by persistent ST elevation in the ECG
Doppler colour flow mapping localises the defect accurately. and dyskinesia seen on echocardiography and radionuclide or
contrast ventriculography. It may result in persistent LV failure,
Early closure is now recognised to yield better results. Although
arrhythmias and systemic embolism.
early surgical intervention may increase operative mortality,
overall mortality is reduced. Transcathethter closure is a feasible A pseudoaneurysm is a rare complication of MI that develops
alternative to surgical closure of post-MI septal rupture. when a myocardial rupture is sealed off by surrounding adherent
pericardium. The aneurysmal sac may progressively enlarge
Cardiac Thromboembolism
but maintains a narrow neck, in contrast to a true ventricular
The risk of thromboembolism (Figure 7) is more in patients with aneurysm. Differentiation of left ventricular pseudoaneurysm
large anterior infarctions and patients with atrial fibrillation. from true aneurysms is made with echocardiography or magnetic
Emboli are more common within the first few months after
resonance imaging.
infarction than later, and with large, irregular shaped thrombi,
particularly those with frond-like appendages. Surgery should be considered in all patients with LV pseudo-
aneurysms.
Dressler’s Syndrome
A form of post infarction pericarditis, occurring 7 days to 6 weeks
after the acute event characterised by prolonged or recurrent
pleuritic chest pain, a pericardial friction rub, fever, pulmonary
infiltrates or a small pulmonary effusion, and an increased
sedimentation rate. The incidence has reduced after the
introduction of reperfusion into clinical practice.
Non-steroidal anti-inflammatory drugs and steroids may be
required for control of Dressler’s syndrome.
Right Ventricular Infarction and Failure
Right ventricular (RV) infarction typically occurs in association
with inferior or posterior MI. Patients with RV infarction
complicating inferior MI have three times the risk of death of
patients without RV infarction.
Figure 7: Echocardiogram showing apical aneurysm with formation of thrombus.
The clinical features of RV infarction complicating inferior MI
Anticoagulation with heparin followed by Warfarin for six include hypotension, jugular venous distension on inspiration
months has been shown to reduce the incidence of thrombo- (Kussmaul’s sign) and clear lung fields, ST elevation of more than
embolism in patients with documented intra cavitary thrombus. 1 mm in V4R.

Free Wall Rupture Echocardiography commonly reveals wall motion abnormalities

of the right ventricle and interventricular septum.
Rupture of the free wall of the left ventricle is an almost uniformly
fatal, commonly under recognised complication. It occurs most Early reperfusion may improve the prognosis in patients who
frequently in elderly women with large anterior wall MI who have have primary PCI for treatment of their cardiogenic shock, those
been given late fibrinolytic therapy. The usual presentation is with right ventricular infarction fared better than patients with
sudden collapse associated electrical mechanical dissociation, cardiogenic shock due to left ventricular infarction.
and failure to respond to cardio pulmonary resuscitation. Urgent
Volume loading can normalise blood pressure and increase
echocardiography is invaluable in the assessment of a patient
cardiac output. It is the vital step in management of patients
who develops the above clinical features.
with right ventricular MI.
Pericarditis
Use of inotropic agents and maintenance of atrioventricular
Pericarditis occurs in approximately 25% of patients with Q wave synchrony with atrioventricular pacing is often critical to
infarctions within the first week. A pericardial friction rub may be the maintenance of a satisfactory cardiac output. Successful
present with or without symptoms. High-dose aspirin and non- reperfusion with fibrinolysis or PCI appears to reduce the
steroidal anti-inflammatory drugs (NSAIDs) are recommended incidence of RV infarction and is associated with dramatic
to treat the symptoms of post-infarction pericarditis. recovery of right ventricular function and reduced
A pericardial effusion can be detected by echocardiography in mortality.
some of these patients. Cardiac tamponade is a rare
Psychosocial Complications
complication of fibrinolytic therapy for acute MI.
An estimated 20% to 50% of post-infarction patients have high
Left Ventricular Aneurysm (Figure 7) levels of psychosocial stress, including anxiety, depression,
Left ventricular aneurysms develop most commonly after large denial, hostility, and social isolation and have a significantly
transmural anterior MIs. A ventricular aneurysm can often be adverse effect on outcome. 683
 Cardiac rehabilitation programmes provide psychologic and PROGNOSIS
social support to patients after MI, in addition to education In almost 25% of all cases of MI, death occurs within a few minutes
about risk factors and their modification. without medical care, half the deaths occur within 24 hours of
the onset of symptoms and about 40% of all affected patients
POST-MYOCARDIAL INFARCTION MANAGEMENT (TABLE 7)
die within the first month. A 30 days survival is of more than 85%
Most patients after MI, if they can afford, should have coronary of patients who are admitted in hospital. Early death is usually due
angiography done before discharge. Those with left main to an arrhythmia and is independent of the extent of MI. Late
and triple vessel disease with LV dysfunction and or proximal outcomes are determined by extent of myocardial damage; AV
LAD disease need coronary artery bypass graft (CABG). block and ventricular arrhythmias. Old age, depression and social
Those with single vessel disease with significant viable isolation are also associated with a higher mortality. Of those who
myocardium need PCI. Others can be managed medically survive an acute attack, more than 80% live for a further year,
with statins, aspirin, beta-blockers and ACE-inhibitors. about 75% for 5 years, 50% for 10 years and 25% for 20 years.
Revascularihsation of infarcted territory has not been shown
to be useful. RECOMMENDED READINGS
1. Antman EM, et al. ACC/AHA guidelines for the management of patients
Table 7: Late Management of MI with ST-elevation myocardial infarction: a report of the American College
of Cardiology/American Heart Association Task Force on Practice
Risk stratification and further investigation Guidelines (Committee to Revise the 1999 Guidelines for the Management
Life style modification of Patients with Acute Myocardial Infarction). Circulation 2004;110:82.
Cessation of smoking 2. Boersma E, et al. Acute myocardial infarction. Lancet 2003;361:847.
Diet (weight control, lipid lowering) 3. Keeley EC, et al. Primary angioplasty versus intravenous thrombolytic
Regular exercise therapy for acute myocardial infarction: A quantitative review of 23
Secondary prevention drug therapy randomised trials. Lancet 2003;361:13.
Anti-platelet therapy (aspirin and/or clopidogrel) 4. Morrow DA, et al. TIMI risk score for ST-elevation myocardial infarction: A
Additional therapy for control of diabetes and hypertension convenient, bedside, clinical score for risk assessment at presentation.
β-blocker Circulation 2000;102:2031.
Aldosterone receptor antagonist 5. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics —
ACE-inhibitor/ARB 2007 update: a report from the American Heart Association Statistics
Statin Committee and Stroke Statistics Subcommittee [erratum appears in
Circulation 2007; 115 (5): e172]. Circulation 2007; 115: e69-171.
Rehabilitation devices
Implantable cardiac defibrillator (high-risk patients) 6. Zimetbaum PJ, Josephson ME. Use of the electrocardiogram in acute
myocardial infarction. N Engl J Med 2003;348:933.

684
 12.20 Hypertension

M Paul Anand

INTRODUCTION AND EPIDEMIOLOGY Weight Gain

Hypertension is a very strong risk factor for cardiovascular Increased weight appears to be a major controllable risk factor
diseases (CVDs). It is estimated that it increases the risk at least for new onset of hypertension. The Framingham Study showed
two-fold for CVDs including coronary artery disease (CAD), approximately 1 mm Hg rise of SBP for every 1.25 Kg of weight
congestive heart failure (CHF)/stroke (ischaemic and gain. Abdominal obesity as evidenced by waist circumference
haemorrhagic), renal failure and peripheral arterial disease. of 80 cm in women and 90 cm in men has also been found to
Usually other risk factors like diabetes are also commonly be associated with the risk for hypertension. Abdominal obesity
associated with hypertension. may well be the most dangerous. It appears that 70% of
hypertension in men and 60% in women could be attributed
Hypertension is present globally but its prevalence varies
to abdominal obesity.
amongst countries and sub populations. The prevalence of
diabetes increases with growing age and it is estimated that Salt Intake
starting from around 15% to 20% in the early age it increases Several communities whose intake of sodium chloride is 3 g
to 75% to 80% in individuals above 70 years of age. or less per day have low average BP. The Intersalt Study of
There are no well-coordinated national surveys of the 10,079 men and women from 32 countries projected that a 100
prevalence of hypertension available from the Indian mmol/day lower sodium intake over a lifetime would result in a
subcontinent. Several regional small surveys in the last two 9 mm Hg smaller rise in SBP from 25 to 55 years age. The Intersalt
decades with varying protocols have reported a prevalence Study demonstrated a clear relationship between the salt intake
which varies from 6.15% to 36.36% in men and 2% to 39.4% in and the level of BP among communities.
women in urban areas and from 3% to 36% in men and 5.80% Alcohol Intake
to 37.2% in women in rural areas.
Excessive alcohol intake is an important risk factor for
More recent surveys in urban population have reported higher hypertension. Excess consumption accounts for 5% to 30% of
prevalence. All these surveys with one exception were based all hypertension. Several studies including the Intersalt Study
on a casual reading taken only on one occasion. have shown a strong and independent positive relationship
between alcohol intake and increase in BP.
In the survey in Mumbai, diagnosis of hypertension [systolic
blood pressure (SBP) 140 mm Hg and/or diastolic blood pressure Physical Activity
(DBP) 90 mm Hg] was based on the average of 3 initial readings Sedentary individuals have a 20% to 50% increased risk of
and confirmed on 2 subsequent occasions in those found to developing hypertension. Observational and experimental
have high blood pressure on the first visit. The overall studies have revealed the role of physical inactivity and its
prevalence based on readings at the time of the first visit was association with high BP.
34.12% and the prevalence based on the average of three
readings on the third occasion was 26.9%. Smoking
Tobacco smoking has been reported to cause acute rise of BP,
DETERMINANTS whether prolonged smoking leads to sustained hypertension
A strong familial and genetic predisposition exists and a has not been established.
number of modifiable predisposing factors have been
identified. DEFINITION OF HYPERTENSION
There is a continuous relationship between the level of BP and
Role of Genetics the risk of its complications. All definitions of hypertension,
Epidemiological studies suggest that 20% to 60% of essential including those issued by Joint National Committee (JNC) in
hypertension is inherited and the remainder is acquired or prevention, detection, evaluation and treatment of high blood
environmental. pressure (seventh report) (JNC-7) and World Health Organization
Age and Sex (WHO)/International society of hypertension (ISH) are arbitrary.
Almost all surveys show that blood pressure (BP) rises with age At present, hypertension in adults aged 18 years and older who
in both men and women. In adult women, BP is lower than in are not acutely ill, is defined as “SBP of 140 mm Hg or greater
men of comparable age, but the rise is more steep thereafter and/or DBP of 90 mm Hg or greater or any level of BP in patients
and around middle-age BP is about the same; in later life it is taking antihypertensive medication”. BP is classified into various
higher in women. stages as shown in Table 1.
685
 Table 1: Classification of Blood Pressure for Adults Aged 18 ISOLATED SYSTOLIC HYPERTENSION
Years or Older* Isolated systolic hypertension (ISH) is defined as SBP of
(JNC VI Category) (JNC VII Category) 140 mm Hg or greater and DBP below 90 mm Hg and staged
Category Systolic Diastolic appropriately (e.g. 170/82 mm Hg is defined as Stage 2 ISH).
(mm Hg) (mm Hg) ISH is present in two-thirds of all hypertensives 60 years of
Optimal <120 And <80 Normal
age.
Normal 120 to 129 Or 80 to 84 Prehypertension In older patients aged 60 years and above, in diabetic subjects
High normal 130 to 139 Or 85 to 89
and patients on antihypertensive medication, the BP should be
Hypertension** 140 Or 90 Hypertension
measured in supine, sitting and in standing positions to detect
Stage 1 140 to 159 Or 90 to 99 Stage 1
Stage 2 160 to 179 Or 100 to 109 Stage 2 postural hypotension.
Stage 3 180 Or 110 If atrial fibrillation is present, additional readings may be
* Not taking antihypertensive drugs and not acutely ill. When SBP and DBP fall required to estimate the average SBP and DBP.
into different categories, the higher category should be selected to classify the
individual’s blood pressure status. For example, 160 to 192 mm Hg should be In young obese persons with hypertension, high BP should be
classified as Stage 2 hypertension, and 174/120 mm Hg should be classified as measured with an appropriately large cuff.
Stage 3 hypertension.
** Based on the average of two or more readings taken at each of two or more HOME MEASUREMENT
visits after an intial screening.
JNC = Joint national committee; SBP = Systolic blood pressure; DBP = Diastolic Home measurement has the advantage that it distinguishes
blood pressure. sustained hypertension from “white-coat hypertension”, a
condition noted in patients whose BP is elevated in the
PRE-HYPERTENSION physician’s clinic but normal at other times. There is no
universally agreed upper limit of normal home BP, but readings
The designation pre-hypertension is intended to identify those
of 135/85 mm Hg or greater should be considered elevated.
individuals in whom early intervention by adoption of healthy
lifestyle could reduce BP, decreasing the rate of progression of
AMBULATORY BLOOD PRESSURE MEASUREMENT
BP to hypertensive levels with age, or prevent hypertension
entirely. Individuals who are pre-hypertensive are not Twenty-four hour ambulatory BP measurements have shown
candidates for drug therapy on the basis of their level of BP marked fluctuations of BP in the same individual. A close
and should firmly and unambiguously be advised to practice correlation has been demonstrated between ambulatory BP
lifestyle modification in order to reduce their risk of developing levels and the extent of target organ damage.
hypertension in the future. Moreover, individuals with pre- Ambulatory BP measurements has been found to be useful to
hypertension who also have diabetes or kidney disease should identify white coat hypertension, evaluate drug-resistant
be considered for appropriate drug therapy if a trial of lifestyle hypertension, episodic hypertension, hypotensive episodes while
medication fails to reduce their BP to 130/80 mm Hg or less. on medication and to evaluate antihypertensive drugs. One of
Apart from being at twice the risk of developing hypertension, the recommended definitions of normal BP and hypertension
compared to persons with normotension, the total morbidity, using ambulatory BP measurements is given in Table 2.
mortality and economic loss caused by cardiovascular events
Table 2: Blood Pressure Thresholds (mm Hg) for Definition of
amongst high normal blood pressure (pre-hypertension)
Hypertension with Different Types of Measurement
population far exceeds that caused by hypertensive population.
The new name suggests that it is urgent for the person so SBP (mm Hg) DBP (mm Hg)
diagnosed to invest time and effort to implement lifestyle changes. Office or Clinic 140 90
Ambulatory BP measurement
SYSTOLIC BLOOD PRESSURE
(24-hour average) 125 80
In persons older than 50 years, SBP of more than 140 mm Hg is
much more important cardiovascular disease (CVD) risk factor COMPLICATIONS OF HYPERTENSION
than DBP. Hypertension is a major risk factor for the development of CVD.
A large body of epidemiologic data indicates that SBP is far Its impact for stroke and end-stage renal failure is greatest.
more important than DBP as a determinant of cardiovascular Hypertensives when compared to normotensive, develop twice
risk, except in younger age groups. Epidemiologically, systolic as much coronary heart disease (CHD), four times as much
hypertension is the most common form of hypertension and congestive heart failure (CHF) and seven times as much stroke.
far easier to measure correctly. While there is no critical level, the risk of CVD rises progressively
with the level of SBP and DBP.
The National Health and Nutrition Examination Survey
(NHANES) has shown that Isolated systolic hypertension (ISH) Cardiovascular risks in hypertensives are also markedly affected
(SBP 140 mm Hg with DBP 90 mm Hg) was present in 65% of all by other co-existing risk factors.
hypertensives 60 years age in both men and women. Recent
data from Framingham Study has further reinforced the PATHOPHYSIOLOGY OF HYPERTENSION
prognostic significance of raised SBP. The importance of SBP in BP is defined as the product of cardiac output and peripheral
risk prediction has been convincingly shown in 12 years data resistance. Hypertension is, therefore, said to be caused by
from 316,000 men screened from the multiple risk factors increased cardiac output and/or increased peripheral
686 intervention trial (MRFIT) study. resistance.
 Hypertension
Each of these primary factors is determined by a complex series but not in all individuals. Sodium sensitivity of some individuals
of interactions (Figure 1). Increased cardiac output, though may play a pivotal role. Some investigators have also identified
involved in the initiation of hypertension, does not persists. The a sodium pump inhibitor as being responsible for volume
typical haemodynamic finding in established hypertension is expansion in hypertension.
an elevated peripheral resistance and normal cardiac output.
What causes the resistance to go up is not fully understood. Renal sodium retention
Excessive sodium retention by the kidney has also been
It is also suspected that heredity plays a role as a background proposed as an important factor. One reason for this could be
to most of these abnormalities, especially along with varying decreased filtration surface area (FSA) due to decreased
contributions of three environmental factors—sodium, stress nephron number or FSA per glomerulus.
and obesity.
Resetting of pressure-natriuresis
Factors Involved in Increased Cardiac Output
A resetting of the pressure-natriuresis relationship wherein a
Increased circulating fluid volume
rise in SBP evokes further sodium retention has been proposed
Excess sodium intake can cause hypertension by increasing fluid as a possible renal mechanism.
volume and preload, thus, increasing cardiac output, as well as
by its effects on vascular reactivity and contractility. Many Renin-angiotensin system
studies, such as the Intersalt Study, have verified the ability of The renin-angiotensin system (RAS) plays an important role in
dietary salt to elevate BP in some populations (salt-sensitive), salt and water homeostasis and BP control (Figure 2).

Figure 1: Factors involved in the pathogenesis of hypertension.

Figure 2: Role of renin-angiotensin system in the pathogenesis of hypertension. Note the effect of drugs at various steps in the pathway.
687
 Inappropriate release of renin culminating in the formation of The initial physical examination should include the following:
angiotensin II (which causes vasoconstriction) is also a possible (a) record three BP readings separated by 2 minutes each, with
mechanism for hypertension. the patient in either supine or sitting position and after standing
for at least 2 minutes; (b) record height, weight and waist-hip
Sympathetic nervous over-activity
ratio; (c) examine the pulse and the extremities for delayed or
The sympathetic nervous system (SNS) directly or indirectly absent femoral and peripheral arterial pulsations, bruits and
dictates the state of cardiac output and systemic vascular pedal oedema; (d) look for arcus senilis, xanthelesma and
resistance. Thus, excessive activity of SNS may increase the BP. xanthomas; (e) examine the heart for evidence of LVH, CAD, CHF
Sympathetic over-activity may also augment renin release. and record rate and rhythm; (f) neurological examination for
Increased peripheral resistance evidence of past or ongoing cerebrovascular disease; (g)
examine the optic fundus to detect hypertensive retinopathy
The final common feature of established hypertension is a
(Table 3); (h) examine the lungs for rales and rhonchi; (i) examine
raised peripheral resistance, that can be associated with both
the abdomen for bruits, enlarged kidneys, masses, and abnormal
functional constriction and structural vascular remodelling and
aortic pulsation.
hypertrophy. Direct mediation and interaction of numerous
factors such as increased intracellular calcium, growth factors Table 3: Keith and Wagner’s Grading of Hypertensive
such as angiotensin II and insulin like growth factor, Retinopathy
endothelium-derived relaxing factor (EDRF), prostaglandins and
Grade 1 Thickening and tortuosity of arteries showing ‘silver wire’
endothelin may also be involved.
appearance
EVALUATION Grade 2 Grade 1 changes plus arteriovenous nipping
Grade 3 Grade 2 changes plus flame-shaped (superficial)
Evaluation of patients with documented hypertension has three
haemorrhages and cotton wool exudates
objectives. These are to identify known causes of high BP, to
Grade 4 Grade 3 changes plus papilloedema
assess the presence or absence of target organ damage and to
identify other cardiovascular risk factors or concomitant
disorders that may define prognosis and guide treatment. LABORATORY INVESTIGATIONS
Data for evaluation acquired through medical history, physical Important laboratory investigations to be carried out in a
examination, laboratory tests and other special diagnostic hypertensive patient are given in Table 4.
procedures.
Table 4: Laboratory Investigations
MEDICAL HISTORY For most hypertensive patients
Hypertension is largely asymptomatic and is often diagnosed Urine for protein, glucose and microscopic (red blood cells/
on routine examination. Early morning headache, often other sediments)
localised to the occipital region as a symptom is usually a feature Haemoglobin, fasting blood glucose, serum creatinine,
of severe hypertension. Other symptoms, though uncommon, potassium and total cholesterol
may be dizziness, fatigue and palpitation. In addition, symptoms Electrocardiogram
related to organ damage involving the heart, brain, kidneys and Additional investigations when cost is not a constraint
eyes may be present in severe hypertension.
Lipid profile, uric acid
Medical history should include the following: (a) duration Chest radiography
and level of elevated BP, symptoms of CAD, heart failure, Echocardiogram
cerebrovascular disease, peripheral vascular disease and renal Tests for secondary hypertension
disease; (b) symptoms of diabetes mellitus, dyslipidaemia, gout, (see chapter 22 Secondary hypertension in this section)
sexual dysfunction or other co-morbid conditions; (c) family
history of high BP, premature CAD, stroke, dyslipidaemia and
diabetes; (d) symptoms suggesting secondary causes of FACTORS INFLUENCING RISK AND RISK STRATIFICATION
hypertension (see chapter on secondary hypertension); (e) history Before initiating therapy, patient’s overall risk should be
of smoking or tobacco use, physical activity, dietary assessment assessed taking into consideration presence of additional risk
including intake of sodium, alcohol, saturated fat and caffeine; (f) factors, extent of target organ damage and other associated
history of use of all prescribed and over-the-counter medications clinical conditions (Table 5).
which may raise BP or interfere with the effectiveness of
Prognosis of these patients, choice of drugs and need for
antihypertensive drugs; (g) history of oral contraceptive use and
urgency of therapy will be dependent on the overall risk
hypertension during pregnancy; (h) history of previous
stratification (Table 6).
antihypertensive therapy, including adverse effects experienced,
if any; and (i) psychosocial and environmental factors. MANAGEMENT OF HYPERTENSION
PHYSICAL EXAMINATION Goals of Therapy
In uncomplicated mild to moderate hypertension, physical The primary goal of therapy of hypertension is effective control
examination other than raised BP may be normal. The signs, of BP to prevent, reverse or delay the progression of
when present, are those of target organ damage or those of complications, and thus, reduce the overall risk of an individual
the underlying cause of secondary hypertension. without affecting the quality of life.
688
 Hypertension
Table 5: Factors Influencing Risk
Risk Factors for Cardiovascular Target Organ Associated Clinical
Disease Damage Conditions
Age >55 years Left ventricular hypertrophy detected by Cerebrovascular Disease
Male sex electrocardiogram and/or echocardiography Ischaemic stroke
Post-menopausal women Microalbuminuria/proteinuria and/or elevation Cerebral haemorrhage
Smoking and tobacco use of serum creatinine (1.2 to 2.0 mg/dL) Transient ischaemic attack
Diabetes mellitus Ultrasound or radiological evidence of atherosclerotic Heart Disease
Family history of premature plaques in the carotids Myocardial infarction
CAD (Men <55 years, Women <65 years) Generalised or focal narrowing of retinal arteries Angina
Increased waist-hip ratio Coronary revascularisation
High LDL or total cholesterol, low HDL Congestive heart failure
cholesterol and high triglycerides Renal Disease
Diabetic nephropathy
Renal failure (serum
creatinine 2.0 mg/dL)
Vascular Disease
Symptomatic arterial
disease including non-
specific aortoarteritis
Dissecting aneurysm
Advanced Hypertensive
Retinopathy
Haemorrhages or exudates
Papilloedema

Table 6: Risk Stratification

Blood Pressure (mm Hg)
Other Risk Factors Stage 1 Stage 2 Stage 3
and Disease History SBP 140 to 159 or SBP 160 to 179 or (Severe Hypertension)
DBP 90 to 99 DBP 100 to 109 SBP ≥ 180 or DBP ≥ 110
No other risk factors Low risk Medium risk High risk
1 to 2 risk factors* Medium risk Medium risk Very high risk
3 or more risk factors or High risk High risk Very high risk
Target organ damage*
and/or diabetes
Associated clinical Very high risk Very high risk Very high risk
conditions**
Risk strata (typical 10-year risk of stroke or myocardial infarction): Low risk < 15%, Medium risk 15% to 20%, High risk 20% to 30%, Very high risk > 30%
SBP = Systolic blood pressure; DBP = Diastolic blood pressure.
* See Table 5; ** See Table 7

Antihypertensive therapy should achieve and maintain SBP lower risk of CAD in patients with the lowest target DBP of
below 140 mm Hg and DBP below 90 mm Hg and lower if <80 mm Hg.
tolerated, while controlling other modifiable risk factors.
The United Kingdom Prospective Diabetes Study (UKPDS)
The ultimate public health goal of antihypertensive therapy is showed that a tight control of BP (average achieved
to reduce cardiovascular and renal morbidity or mortality. Since 144/82 mm Hg) in diabetic patients conferred a substantial
most individuals with hypertension, especially those >50 years reduction in the risk of CAD compared to a less tight control of
age, will reach the DBP goal once the SBP goal is achieved, BP (average achieved 154/87 mm Hg).
therefore, the primary focus should be of attaining the SBP goal.
Treating SBP and DBP to targets that are <140/90 mm Hg is In view of the above studies, it would seem desirable to achieve
associated with a decrease in CVD complications. In patients optimal or normal BP in young, middle-aged and (below
with hypertension and diabetes or renal disease, the BP goal is 130/80 mm Hg) in diabetic patients and those with renal
<130/80 mm Hg. Gradual reduction of BP to the optimal level disease, at least high normal BP in elderly patients (below
over a period of 2 to 6 months is prudent therapeutic goal 140/90 mm Hg).
except in stage 3 hypertension.
MANAGEMENT STRATEGY
Threshold of Therapy and Level of Control Having assessed the patient and determined the overall risk
Among diabetic patients participating in the hypertension profile management of hypertension should proceed as
optimal treatment (HOT ) study, there was a significantly follows: In low risk patients, institute lifestyle modifications 689
 Table 7: Lifestyle Interventions for Blood Pressure Reduction
Intervention Recommendation Expected Systolic Blood Pressure Reduction (Range)
Weight reduction Maintain ideal body mass 5 to 20 mm Hg per 10 kg weight loss
index below 23 kg/m2
DASH diet Consume diet rich in fruits, vegetables, low-fat 8 to 14 mm Hg
dairy products with reduced content of
saturated and total fat
Dietary sodium Reduce dietary sodium intake to <100 mmol/day 2 to 8 mm Hg
restriction (<2.4 g sodium or <6 g sodium chloride)
Physical activity Engage in regular aerobic physical activity, for 4 to 9 mm Hg
example, brisk walking for at least 30 minutes
most days
Alcohol Men 60 mL per day, twice a week 2 to 4 mm Hg
moderation Women 30 mL per day, twice a week
Abstinence is preferred
Tobacco Total abstinence Smoking or consumption of tobacco in any form is the
single most powerful modifiable lifestyle factor for the
prevention of major cardiovascular and non-cardiovascular
disease in hypertensives

and observe BP for a period of three months before deciding that the level of SBP control correlates better with reduction of
whether to initiate drug therapy or not (Table 7). mortality than the level of DBP control.
In high risk group, use lifestyle modification therapy with drug RECOMMENDED READINGS
therapy forthwith. 1. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the
Joint National Committee on Prevention, Detection, Evaluation, and Treatment
In medium risk patients, institute lifestyle modifications and of High Blood Pressure: The JNC 7 report. JAMA 2003; 289: 2560-72.
monitor BP on a monthly basis. If after a period of three months,
2. Duprez DA. Role of the rennin-angiotensin-aldosterone system in
BP remains above 140/90 mmHg then initiate drug therapy. vascular remodeling and inflammation: A clinical review. J Hypertens 2006;
In high and very high risk groups, initiate immediate drug 24: 983-91.
treatment for hypertension and other risk factors. The primary 3. Victor RG, Shafiq MM. Sympathetic neural mechanisms in human hyper
concern should be to lower SBP as recent evidence suggests tension. Curr Hypertens Rep 2008; 10: 241-7.

690
 12.21 Management of Hypertension

Sandhya Kamath

INTRODUCTION Table 1: Keith-Wagener-Barker Classification

The management of hypertension is a multifaceted blood I Sclerosis of arterioles—focal, diffuse constriction, copper wire
pressure (BP) exercise. The goal is optimum control so that and silver wire arteriolar reflex
complications can be prevented. II AV crossing changes
APPROACH TO THE PATIENT III Flame shaped haemorrhages, cotton wool spots, retinal
oedema, retinal microaneurysms
The first step is to confirm the diagnosis of hypertension by
IV Grade III changes with papilledoema with or without macular
accurate measurement of BP. A detailed history and physical
star
examination should be done to screen for other cardiovascular
disease risk factors, secondary causes of hypertension, Laboratory Investigations
consequences of hypertension, associated co-morbidities,
Basic laboratory tests for initial evaluation are enumerated in
assess lifestyle and determine what should be the ideal
Table 2.
treatment.
History Table 2: Laboratory Investigations
Most people with primary hypertension do not have any Complete blood count, ESR and haematocrit
obvious symptoms. The more common symptoms can be: Routine urine examination
Chronic headache that lasts for days rather than hours Albuminuria—for renal involvement
frequently present in the occipital area, dizziness or vertigo, Microscopic haematuria—malignant hypertension
blurry vision, double vision, increased sleepiness, nausea, BUN and serum creatinine
shortness of breath, palpitations, fatigue, general tiredness, Serum potassium, sodium for adrenal involvement and as baseline
flushed face, epistaxis, a strong need to urinate often (especially prior to institution of treatment
during the night), tinnitus and many other non-specific Blood sugar, and lipidogram (total cholesterol, triglycerides) for
symptoms. co-morbid conditions
Physical Examination ECG, 2D-echocardiogram for diastolic dysfunction
BP should be measured in both arms in sitting, standing and Abdominal ultrasonography for kidney size, vascular anomalies.
supine position to evaluate for postural hypotension; and at
least once in both lower extremities in young hypertensives MEASUREMENT OF BLOOD PRESSURE
to rule out aortoarteritis. Heart rate and rhythm should be Various devices for the measurement of BP and their relative
recorded. Irregularly, irregular pulse suggests atrial fibrillation merits have already been discussed in the earlier chapter.
which is very common in hypertension. Height, weight, waist-
to-hip ratio should be measured and body mass index (BMI) MANAGEMENT
calculated. Examine the neck for thyromegaly. Palpation of the The management of hypertension, especially the primary
blood vessel wall for stiffness, and bruit in the carotids will hypertension comprises of two major aspects: (i) lifestyle
identify atherosclerotic disease. Cardiovascular system modification; and (ii) pharmacotherapy of hypertension.
examination may reveal the apex beat to be displaced
Lifestyle Modifications
downward and outward depicting left ventricular hyper-
trophy. Loud S2 due to closure of aortic valve and S 4 gallop These are presented in brief in Table 3. In addition the
(attributed to noncompliant left ventricle and diastolic behavioural theory and discussed.
dysfunction) may be heard. Evaluate for signs of congestive Behavioural techniques, meditation and yoga
heart failure. Auscultate for an abdominal bruit that may Transcendental meditation and yoga are also widely believed
be heard in the lower epigastrium on either side of the midline to reduce BP. However, larger and more random controlled trials
as a sign of renovascular hypertension. An enlarged, palpable are needed to confirm benefits of these practices.
kidney is most probably due to polycystic kidney. A thorough
neurologic examination including fundoscopy should be Antihypertensive Agents
performed. Fundus examination has to be done and it may show Principles of treatment
changes which are shown in Table 1. These changes reflect the
The BP remains poorly controlled in many of the patients. The
duration of hypertension roughly. most important reason is lack of awareness about the condition
One should look out for features of secondary hypertension in and its ensuing complications. Asymptomatic nature of the
the history and physical examination. condition results in poor compliance; and last but not the least
691
 side effects of antihypertensive agents like weakness, sleepiness, Significance of Systolic and Diastolic Blood Pressure and
forgetfulness and impotence cause the patients to avoid the Pulse Pressure
drugs. But this can be overcome by prescribing newer agents In the past, recommendations for the treatment were based on
that have fewer side effects. diastolic blood pressure (DBP). Today systolic blood pressure
Before initiating therapy, additional risk factors, extent of (SBP) has assumed prominence. Joint National Committee
target organ damage and other associated conditions should on prevention, detection, evaluation and treatment of high
be assessed (Table 4). The prognosis, choice and urgency of BP (JNC-7) has stated that SBP is a much more important
therapy will depend on the overall risk stratification (Table 5). cardiovascular risk factor than DBP in those older than 50 years.
The algorithm for the management of hypertension in general A wide pulse pressure largely reflects a high SBP, and may be
is depicted in Figure 1. the most accurate predictor of all.

Table 3: Lifestyle Modifications for Blood Pressure Reduction

Intervention Recommendation Expected BP Reduction
Weight reduction Maintain body mass index <23 kg/m2 10 mm Hg/10 kg weight loss
Diet Rich in fruits, vegetables, low-fat dairy products, and 8 to 14 mm Hg
Less of saturated and total fat
Dietary sodium restriction Reduce dietary sodium intake to <2.4 g sodium or < 6 g NaCl 2 to 8 mm Hg
Physical activity Regular aerobic physical activity, e.g. brisk walking for at least 4 to 9 mm Hg
30 min most days
Alcohol moderation Men <60 mL per day. 2 to 4 mm Hg
Women <30 mL per day.
Abstinence is preferred
Tobacco Total abstinence —
Source: Adapted from Indian Hypertension Guidelines – II. As minimum number of times as feasible.

Table 4: Factors Influencing Risk of Cardiovascular Diseases

Risk Factors for Coronary Target Organ Damage Associated Clinical Conditions
Artery Disease
Age >55 years Left ventricular hypertrophy detected Cerebrovascular disease
Male sex by electrocardiogram and/or Ischaemic stroke
Post-menopausal women echocardiography Cerebral haemorrhage
Smoking and tobacco use Microalbuminuria/proteinuria and/or Transient ischaemic attack
Diabetes mellitus elevation of serum creatinine Heart disease
Family history of premature CAD (1.2 to 2.0 mg/dL) Myocardial infarction
(Male <55 years) Urinary albumin creatinine ratio Angina
(Female <65 years) Ultrasound or radiological evidence of Coronary revascularisation
Increased waist-hip ratio, atherosclerotic plaques in the carotids Congestive heart failure
High LDL or total cholesterol, Hypertensive retinopathy Renal disease
low HDL cholesterol and high Diabetic nephropathy
triglycerides Renal failure (serum creatinine >2.0 mg/dL)
High sensitivity C-reactive protein and Vascular disease
homocysteine levels might evolve Peripheral arterial disease including non-specific
as markers for high risk of vascular aorto-arteritis
damage Aortic dissection
Estimated GFR <60 mL/min Advanced hypertensive retinopathy
Haemorrhages or exudates
Papilloedema
CAD=Coronary artery disease; GFR= Glomerular filtration rate; LDL=Low density lipoprotein; HDL=High density lipoprotein.
Source: Adapted from Indian Hypertension Guidelines – II.

Table 5: Risk Stratification of Patients with Hypertension

Blood Pressure (mm Hg)
Stage Other History Stage 1 Stage 2 Stage 3
SBP 140 to 159 or SBP 160 to 179 or SBP >180 or
DBP 90 to 99 DBP 100 to 109 DBP >110
I No other risk factors Low risk Medium risk High risk
II 1-2 risk factors Medium risk Medium risk Very high risk
III >3 or more risk factors/TOD/diabetes High risk High risk Very high risk
IV ACC Very high risk Very high risk Very high risk
SBP=Systolic blood pressure; DBP=Diastolic blood pressure; TOD=Target organ damage; ACC=Associated clinical conditions.
Source: Adapted from Indian Hypertension Guidelines – II.
692
 Management of Hypertension
Figure 1: Algorithm for the management of hypertension.

Blood Pressure Level 130/80 mm Hg, in those with stroke should be below 130/85
mm Hg and at least high normal (below 140/90 mm Hg) in the
It is desirable to achieve optimal or normal BP in young and
elderly.
middle aged patients with uncomplicated hypertension.
Antihypertensive therapy should achieve and maintain Choice of antihypertensive agents and their dosage are given
SBP below 140 mm Hg and DBP below 90 mm Hg or lower if in Tables 6 and 7. It is cautioned that there can be interactions
possible; simultaneously controlling other modifiable risk between antihypertensive agents and other concomitant
factors. The goal BP in diabetic patients should be below medications (Table 8).

Table 6: Guidelines for Selecting the Most Appropriate Antihypertensive Drugs

Class of Definite Possible Definite Relative
Drugs Indications Indications Contraindications Contraindications
Diuretics Heart failure Diabetes Gout Dyslipidaemia
Elderly patients
Systolic hypertension
Beta-blockers Angina Pregnancy Asthma and chronic pulmonary Dyslipidaemia
Post-myocardial infarction Diabetes disease
Tachyarrhythmia Heart block Peripheral vascular disease
Heart failure
Calcium channel Angina Peripheral vascular disease Heart block Congestive heart failure
blockers Elderly Cerebrovascular
Systolic hypertension accident (CVA)
Diabetes
Angiotensin converting Heart failure CVA Pregnancy and lactation Moderate renal failure
enzyme (ACE)-inhibitors Left ventricular dysfunction Bilateral renal artery stenosis (creatinine levels >3 mg/dL)
Post-myocardial infarction Hyperkalaemia
Significant proteinuria
Diabetes
Angiotensin II receptor ACE-inhibitor induced cough Heart failure Pregnancy and lactation Moderate renal failure
blockers (ARBs) or CVA Bilateral renal artery stenosis (creatinine levels >3 mg/dL)
intolerant to ACE-inhibitor Hyperkalaemia
Alpha-blockers Prostatic hypertrophy Glucose intolerance — Orthostatic hypotension
Dyslipidaemia Congestive heart failure

CVA = Cerebrovascular accident.

Source: Adapted from Indian Hypertension Guidelines – II.

693
 The issue of which drug is the best choice for initial therapy Diuretics
and which is the ideal combination are still debated. JNC VII Diuretics are basically divided into four groups: (i) Thiazide
has advocated a low-dose thiazide diuretic for initial therapy. diuretics, (ii) loop diuretics, (iii) aldosterone antagonists and (iv)
European Hypertension Society guidelines has recommended other potassium sparing diuretics.
that whatever class of antihypertensive seems most
appropriate should be used. World Health Organization Diuretics are recommended as first-line agents in the treatment
(WHO) guidelines state that a diuretic is preferred, but any of hypertension. Their advantage is that these are more effective
class of antihypertensives may be used. Thus, two of the three in reducing cardiovascular mortality, coronary heart disease
major guidelines have given preference to low-dose diuretics (CHD), cardiac failure, stroke and overall mortality than other
as initiating agents in uncomplicated patients. However, agents. These are inexpensive and combine well with most
because of their metabolic complications these are not of the other antihypertensive agents like beta-blockers,
very popular. Diuretics combine well with most of the angiotensin converting enzyme (ACE)-inhibitors and, angiotensin
antihypertensives. II receptor blockers (ARBs). However, because of inherent
natriuretic property of dihydropyridine calcium channel
Table 7: Commonly Used Antihypertensive Drugs and Their blockers, this combination is less effective. Low-dose diuretics
Dosage remain the preferred initial treatment in the elderly and obese
Class Drug Dosage hypertensives.
(mg/day) It should be emphasised that diuretics should be prescribed in
Diuretics Hydrochlorothiazide 6.25 to 25 low dosage equivalent to 12.5 mg of hydrochlorothiazide. High
Chlorthalidone 12.5 to 25 doses of diuretics give rise to metabolic side effects like
Indapamide 1.5 to 2.5 dyslipidaemia, hyperglycaemia, hyperuricaemia, hypokalaemia
Amiloride 5 to 10 and hypomagnesaemia. This is the reason why death due to
Triamterene 50 to 100 coronary artery disease (CAD) has not decreased as much as
Spironolactone 25 to 50 expected. Quality of life is disturbed as impotence is a frequent
Beta-blockers Atenolol 25 to 100 side effect. Another disadvantage is that the antihypertensive
Metoprolol 25 to 100 response to diuretics is not immediate, but takes at least two
Bisoprolol 2.5 to 10 weeks to manifest.
Nebivolol 2.5 to 5
Calcium channel Amlodipine 2.5 to 10 Beta-blockers
blockers (CCBs) Diltiazem 90 to 360 The available evidence does not support the use of beta-
Verapamil 80 to 240 blockers as first-line drugs in the treatment of hypertension.
ACE-inhibitors Enalapril 2.5 to 20 This conclusion is based on the relatively weak effect of beta-
Lisinopril 2.5 to 20 blockers to reduce stroke and the absence of an effect on CHD
Ramipril 1.25 to 10 when compared to placebo or no treatment. These have
Perindopril 2 to 8 multiple adverse effects like increased risk of diabetes mellitus
Quinapril 10 to 80 due to loss of insulin sensitivity, rise in plasma triglycerides and
Angiotensin II receptor Losartan 50 to 100 lowering of HDL, increase in body weight, easy fatigability and
blockers (ARBs) Candesartan 8 to 32 reduced exercise tolerance. Indications for the use of beta-
Valsartan 40 to 160 blockers in the treatment of hypertension are enumerated in
Irbesartan 150 to 300 Table 6.
Telmisartan 40 to 160
The ideal beta-blocker for treatment of hypertension would be
Alpha-blockers Prazosin 2.5 to 10
Doxazosin 1 to 4
one that is long-acting, cardioselective, lipid neutral, glucose
neutral and with vasodilating effects. Vasodilator beta-blockers
Centrally acting drugs Clonidine 0.1 to 0.3
labetalol, carvedilol and nebivolol cause less metabolic side
Methyldopa 500 to 1500
effects and should be used instead of metoprolol or atenolol.
Source: Adapted from Indian Hypertension Guidelines – II. However, there are no good outcome data for their use in
hypertension without concomitant indications.
Table 8: Drug Interactions
Calcium channel blockers
NSAIDs including COX-2 inhibitors decrease efficacy of diuretics,
beta-blockers and ACE-inhibitors
Calcium channel blockers (CCBs) are divided into two groups:
dihydropyridine (DHPs—nifedipine, amlodipine, nicardipine,
Concomitant use of beta-blockers and non-dihydropyridine CCBs
lacidipine) and non-dihydropyridine (verapamil, diltiazem).They
can result in heart blocks
reduce the BP primarily by reducing the peripheral vascular
Combined use of ACE-inhibitors and potassium sparing diuretics resistance (PVR) aided by an initial natriuretic effect. Due to the
may result in hyperkalaemia reduction in PVR, CCBs especially the DHPs cause reflex
Cyclosporine levels are increased with diltiazem and verapamil stimulation of the adrenergic system and tachycardia. Hence,
Concomitant use of tricyclic antidepressants with methyldopa is to these should be used with caution in patients with CAD
be avoided especially the short-acting ones. Non-DHPs tend to decrease
catecholamine levels. Several studies have shown that CCBs are
Source: Adapted from Indian Hypertension Guidelines – II.
safe and effective and particularly useful to prevent stroke.
694
 Management of Hypertension
CCBs seem to be particularly suitable for elderly hypertensive blockers have differing potencies in relation to BP control, with
patients since these agents do not cause salt and fluid retention, statistically differing BP effects at the maximal doses.
postural hypotension, sedation, depression, or biochemical
ARBs block the renin-angiotensin system as do ACE-inhibitor,
abnormalities. Moreover, their use is compatible with several
with much the same effects but at greater cost. Thus, it is
common diseases of old age, such as diabetes, obstructive lung
preferable to use ACE-inhibitor and ARB should be substituted
disease, and peripheral vascular disease. CCBs should be used
only if ACE-inhibitor intolerance develops.
as initial monotherapy for hypertension in angina pectoris
(non-DHPs), Raynaud’s phenomenon and supraventricular Alpha-adrenergic blockers
tachycardia (non-DHPs). Because of their favourable metabolic Prazosin, terazosin and doxazosin are the common α-blockers
profile, CCBs are recommended in diabetes mellitus and available. They are free from metabolic or lipid side effects, but
dyslipidaemias. Patients on CCBs do not require regular blood postural hypotension, dizziness, diarrhoea, tachycardia and fluid
chemistry checks. retention can be troublesome.
Potential side effects from taking a CCBs include oedema of Today, α-blockers are used in patients with features of metabolic
lower extremities, headache, light-headedness, dry mouth, skin syndrome or in men with benign prostatic hypertrophy in
rash, fatigue, nausea, constipation, gastro-oesophageal reflux whom they provide symptomatic relief. These combine well
disease (GERD). with other drugs and when used as third-line of therapy provide
ACE-inhibitors the required lowering of BP in patients who had not fully
responded to full doses of initial two drugs.
The commonly used ACE-inhibitor are listed in Table 7 along with
their dosages. The various ACE-inhibitor have few practical Phenoxybenzamine and phentolamine are combined α1 and
differences except for duration of action. ACE-inhibitor block the α2 blockers used in pheochromocytoma. Labetalol and
conversion of angiotensin I to angiotensin II. Therefore, these carvedilol also have limited α-blocking activity.
lower arteriolar resistance and increase venous capacity; increase
Renin inhibitors
cardiac output and cardiac index, stroke work and volume, lower
renovascular resistance, and lead to increased natriuresis. Aliskiren is the agent belonging to this group which is the only
new class introduced in the past decade. It provides dose-
ACE-inhibitor preferentially relax the renal efferent arterioles, dependent and sustained 24-hour efficacy, the magnitude of
thereby reduce intraglomerular pressure, and may cause a rise this effect is similar to other classes of drugs when the maximum
in serum creatinine. The commonest adverse effect of ACE- recommended dose is used (300 mg). Aliskiren adds to the
inhibitor is intractable cough; others being hypotension, antihypertensive effect of an ARB or concomitant diuretic.
hyperkalaemia, headache, dizziness, fatigue, nausea and
Direct vasodilators
angioedema. There is also some evidence to suggest that ACE-
inhibitor might increase inflammation-related pain. Hydralazine is infrequently used today because it has no effect
Contraindications to ACE-inhibition are bilateral renal artery on regression of left ventricular hypertrophy, and patients
stenosis and pregnancy. Caution should be used when using taking hydralazine may develop lupus-like syndrome. The use
ACE-inhibitor in patients with serum creatinine >2 mg% and of minoxidil is limited due to its sodium-retaining properties
they should be avoided when serum creatinine is >3 mg%. and development of hirsutism.

ACE-inhibitor can be used as monotherapy in mild or moderate Centrally acting agents

hypertension. They form effective combinations with diuretics Alpha-methyldopa still remains the drug of choice in hyper-
and CCBs. Moderate salt restriction is essential for optimal tension in pregnancy. Clonidine and guanethidine are not used
effect. They are preferentially used in diabetic hypertensive because of their unfavourable side effect profile.
patients, for cardioprotection post-myocardial infarction and
in hypertension with heart failure. These are also known to METABOLIC ABNORMALITIES IN ASSOCIATION WITH
reduce proteinuria especially in diabetics. Contrary to earlier HYPERTENSION
belief, they are well-accepted in the elderly. These offer vascular The dysmetabolic syndrome of insulin resistance is the
protection in diabetics and in renal disease. common denominator of the complex inter-relation between
hypertension, obesity and maturity-onset diabetes. High-doses
Angiotensin-II receptor blockers (ARBs) of diuretics and beta-blockers worsen insulin resistance with
ARBs are the fastest growing class of antihypertensive drugs. risk of overt diabetes and/or lipid abnormalities. Other classes
These are virtually free from side effects. of antihypertensive agents such as ACE-inhibitor, ARBs or alpha-
Angiotensin II receptor antagonists are primarily used for the blockers improve insulin sensitivity, and CCBs are neutral. Hence,
treatment of hypertension where the patient is intolerant of these classes become the logical first-line antihypertensives for
ACE-inhibitor therapy. These do not inhibit the breakdown of patients with any component of the dysmetabolic syndrome.
bradykinin or other kinins, and are thus, only rarely associated
HYPERTENSION WITH SPECIAL SITUATIONS
with the persistent dry cough and/or angioedema that limit ACE-
inhibitor therapy. More recently, these have been used for the Dyslipidaemias
treatment of heart failure in patients intolerant of ACE-inhibitor A statin should be concomitantly administered in patients with
therapy, particularly candesartan. These show benefit in hypertension and dyslipidaemia because of the significant
hypertensive patients with type II diabetes, and may delay the cardioprotection and stroke prevention that has been shown
progression of diabetic nephropathy.The angiotensin II receptor by the ASCOT-LLA study. Antihypertensive drugs that can be 695
 used are CCBs, ACE-inhibitor, ARBs and α-blockers. Alpha- The drug of choice for hypertension in pregnancy is
blockers are clearly known to improve lipid profile. alpha-methyldopa. CCBs and labetalol can also be used.
ACE-inhibitor, ACE-II receptor blockers are contraindicated.
Obesity
Use of low-dose diuretics is discouraged because pre-
The characteristics of obesity-related hypertension are eclampsia is a volume-depleted state. Intravenous labetalol
increased plasma volume, high cardiac output, and low and hydralazine are effective agents in emergency situations.
peripheral vascular resistance. The basic mechanisms include Intravenous magnesium sulphate is the drug of choice for
salt and water reabsorption, insulin resistance and increased prevention and treatment of seizures, and can lower the BP
sympathetic outflow. Weight loss should be advocated very to some extent. In some instances, antihypertensive drugs
strictly. Low-dose diuretic, ACE-inhibitor and/or ARB is advocated. fail to lower the BP and the only means of controlling BP is
Beta-blockers should be avoided. to induce delivery.
Angina
HYPERTENSION IN SOME SPECIAL SITUATIONS
CCBs (verapamil) and α-blockers are effective anti-anginal
and antihypertensives as well. ACE-Is, ARBs and diuretics help Cerebrovascular Accidents
indirectly by regression of LVH and/or reduction in BP. In ischaemic stroke, the BP should not be reduced to less than
160/100 mm Hg. This should be done gradually and carefully
POST-INFARCT HYPERTENSIVE PATIENTS monitored over 24 to 48 hours. In acute intracerebral
Beta-blockers, ACE-inhibitor or ARBs are in any case indicated in haemorrhage, the BP should be maintained below 180 mm Hg
the post-infarct state and should handle the hypertension as well. and 105 mm Hg respectively.
Lowering of BP too rapidly may cause sympathetic activation and Renal Disease
reflex tachycardia and should be avoided. Hypertension in
The BP goal should be less than 120/80 mm Hg. All patients
patients with acute coronary syndrome should be treated
with microalbuminuria, irrespective of the presence of
aggressively. The target BP should be 130-140/90-95 mm Hg.
hypertension need to be treated with antihypertensives in
HYPERTENSION IN THE ELDERLY order to retard the progression of renal disease. Low-dose
Treatment of hypertension in the elderly definitely protects diuretics, CCBs, beta-blockers and alpha-methyldopa can be
against the development of stroke. Systolic rather than diastolic used in patients with renal disease. ACE-inhibitor and ARBs have
hypertension is seen in this age group. SBP should be brought shown favourable effects on progression of renal disease,
down to at least 140 mm Hg. DBP may also come down. But especially in diabetics. However, these should not be used in
caution should be exerted to see that it is not lowered below patients with serum creatinine of ≥ 3 mg/dL. Salt restriction
80 mm Hg in order to avoid coronary hypoperfusion. Also, and protein restriction form an integral part of dietary
postural hypotension should be watched for and taken care of recommendations.
immediately. Lifestyle modifications are important for the Chronic Obstructive Airway Disease
management of hypertension in the elderly. Long-acting CCBs are safe and effective drugs. Low-dose
Low-dose diuretics are the preferred agents. Dihydropyridine diuretics may be used. ACE-I, ARBs, beta-blockers, alpha-beta
calcium channel blockers are able to reduce morbidity and blockers are not recommended.
mortality in the elderly. ACE-inhibitor and ARBs are also used.
Beta-blockers are to be avoided. Combination therapy is RESISTANT HYPERTENSION
required in nearly two-thirds of patients. Resistant hypertension is defined as blood pressure that
remains elevated above treatment goals despite administration
DIABETIC HYPERTENSIVES of an optimal three-drug regimen that includes a diuretic. High
Hypertension is present in nearly 50% of type I diabetics BP that is under control, but requires four or more medications
secondary to renal damage and 80% of type II diabetics as a to treat it, is also considered resistant to treatment.
component of metabolic syndrome. The BP goals are stricter
It is emphasised that measurement of BP should be accurate
than non-diabetics. JNC VII has recommended a goal BP of 130/
before labelling a patient as having resistant hypertension.
80 mm Hg. The choice is ACE-inhibitor or ARB. A low-dose
Proper BP measurement technique must be used, the size of
diuretic may be used. CCBs can be the third drug. Alpha-blockers
the BP cuff should be accurate and the BP readings must be
are metabolically neutral are also appropriate.
recorded on two separate occasions.
Lifestyle modifications have to be aggressive. Tight control of
Causes of resistant hypertension are enumerated in Table 9.
diabetes, effective BP control and low protein diet improve
overall outcome. Table 9: Causes of Resistant Hypertension
HYPERTENSION IN PREGNANCY Noncompliance with treatment
Hypertension in pregnancy is diagnosed when the DBP is more than Lifestyle factors: obesity, excess salt intake, heavy alcohol
85 mm Hg. The diagnosis requires two consecutive measurements consumption
of BP. DBP more than 110 mm Hg requires urgent attention. Secondary hypertension
Fluid retention: usually expansion from kidney failure
Hypertension in pregnancy can be divided as: (i) pre-eclampsia,
Medications: corticosteroids, nonsteroidal anti-inflammatory drugs
(ii) chronic hypertension in pregnancy, (iii) pre-eclampsia
(NSAIDs) like aspirin, sympathomimetic agents present in nasal
superimposed on chronic hypertension in pregnancy, and (iv)
drops
696 gestational hypertension.
 Management of Hypertension
Management observation in the emergency room, can be discharged, with
Resistant hypertension requires special consideration in terms follow-up scheduled within 3 to 7 days.
of evaluation and treatment. Confirming resistance is the first Drugs used in hypertensive emergencies are enlisted in
step in evaluating difficult-to-treat high BP. Successful treatment Tables 10 and 11.
of resistant hypertension requires consideration of lifestyle
factors that contribute to treatment resistance, diagnosing and Table 10: Preferred Drugs for Select Hypertensive Emergencies
treating secondary causes of high BP and using multiple-drug Emergency Drugs of Choice Target Blood Pressure
treatments effectively. Uncontrolled hypertension is not the
Aortic dissection Nitroprusside + esmolol 110 to 120 mm Hg SBP as
same as resistant hypertension. Uncontrolled BP can be
soon as possible
caused by poor medication adherence and/or an inadequate AMI, ischaemia Nitroglycerin, nitroprusside, Secondary to ischaemia
treatment regimen. Additionally, it is important to make sure nicardipine relief
that what appears to be resistant hypertension is actually not Pulmonary oedema Nitroprusside, nitroglycerin, Improve symptoms
‘pseudohypertension’ or ‘white coat hypertension’. labetalol 10% to 15% in 1 to 2 hrs
Renal emergencies Fenoldopam, nitroprusside, Target BP 20% to
Combine agents with different mechanisms of action. A triple labetalol 25% in 2 to 3 hrs
drug regimen of an ACE-inhibitor or ARB, CCBs and a thiazide Catecholamine excess Phentolamine, labetalol Control paroxysms
diuretic is effective and generally well-tolerated. Some patients 10% to 15% in 1 to 2 hrs
may benefit from adding mineralocorticoid receptor antagonist Hypertensive Nitroprusside 20% to 25% in 2 to 3 hrs
encephalopathy
(MRA) to their treatment regimens. Combinations of three or
Subarachnoid Nitroprusside, nimodipine, 20% to 25% in 2 to 3 hrs
more drugs must be tailored to the individual. haemorrhage nicardipine
Dose Timing Ischaemic stroke Nitroprusside (controv- 0% to 20% in 6 to 12 hrs
ersial), nicardipine
Taking at least one antihypertensive medicine at bedtime had
better BP control, in particular, lowering night-time BP. Table 11: Oral Agents for the Treatment of Hypertensive Urgencies
Adherence Agent Dosage Onset/Duration Precautions
Steps should be taken to help patients take medications of Action
regularly and properly. Prescriptions should be simplified as Captopril 25 mg PO; repeat 15 to 30 min/ Hypotension, renal
much as possible by using long-acting combination drugs and as needed; SL, 6 to 8 hrs failure, bilateral renal
25 mg SL 10 to 20 min/ artery stenosis
once-daily dosing. More frequent clinic visits and home BP
2 to 6 hrs
monitoring will generally help patients adhere to their treatment
Clonidine 0.1 to 0.2 mg PO, 30 to 60 min/ Hypotension,
routine. Though an expensive and labour-intense option, a repeat hourly as 8 to 16 hrs drowsiness, dry mouth
team approach to treatment including nurse case managers, required to total
pharmacists and nutritionists can improve treatment results. dosage of 0.6 mg
Labetalol 200 to 400 mg 1 to 2 hrs/ Bronchoconstriction,
HYPERTENSIVE EMERGENCIES PO; repeat every 2 to 12 hrs heart block,
2 to 3 hrs orthostatic hypotension
It is the clinical state of the patient, the degree of and/or
Amlodipine 2.5 to 5 mg 1 to 2 hrs/ Tachycardia,
progression of target organ damage that defines a hypertensive 12 to 18 hrs hypotension
emergency and not the absolute level of BP.
PO = Per orally; SL= Sublingual.
Hypertensive emergencies are severe elevations in BP, often
higher than 220/140 mm Hg, complicated by clinical evidence of CONCLUSIONS
progressive target organ dysfunction. These patients require
Management of hypertension includes not just the control of
immediate admission and BP reduction (not necessarily to normal
BP, but also other risk factors and associated conditions with
ranges) to prevent or limit further target organ damage, e.g.
special attention on prevention of target organ damage. A wide
hypertensive encephalopathy, intracranial haemorrhage, acute
variety of agents are available. Diuretics are preferred agents.
myocardial infarction, acute left ventricular failure with pulmonary
But there are compelling indications in special disease
oedema, dissecting aneurysm of aorta, acute renal failure,
situations. It is essential to achieve ‘goal’ BP, in order to retard
eclampsia of pregnancy.Immediate admission to a monitored unit
and parenteral antihypertensive therapy are indicated. the development of TOD.

Severe hypertension (urgencies) are marked elevations of BP, RECOMMENDED READINGS

usually higher than 180/110 mm Hg. Evidence of target organ 1. Indian Hypertension Guidelines – II.
damage may be often present, but non-progressive. Manifesting 2. Kaplan NM. Systemic hypertension therapy. In: Braunwald E, Zipes DP, Libby
symptoms may include headache, shortness of breath, and P, editors. Braunwald’s Heart Disease; 8th Ed. Philadelphia: Elsevier; pp.
pedal oedema. Management in the emergency department 1049-68.
with oral agents is sufficient. Follow-up within 24 to 72 hours is 3. Kaplan NM, Opie LH. Antihypertensive drugs. In: Opic LH, Gersh BJ, editors.
Drugs for the Heart; 7th Ed. Philadelphia: Elsevier; pp.198-234.
recommended. In many cases patients present with BP higher
than 180/110 mm Hg, without clinical symptoms and have no 4. Kaplan NM, Management of hypertension. In: Kaplan NM, editor. Kaplan’s
Clinical Hypertension; 9th Ed. Lippincot: Williams and Wilkins; 2005.
clinical evidence of target organ damage. They may be initiated
5. Kotchen TA. Hypertensive vascular disease, In: Dennis L, Kasper, Braunvald
on a two-drug regimen if previously untreated, or an existing E, Fauci AS, et al, editors. Harrison’s Principle of Internal Medicine; 17th Ed.
treatment regimen may be modified. Emotional distress or non- New York: McGraw Hill; 2008: pp.1549-62.
adherence to prior treatment may be the cause. These patients 6. The Seventh Report of the Joint National Committee on Prevention,
do not require BP reduction to normal and, after brief Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). 697
 12.22 Secondary Hypertension

BB Thakur, Arohi Kumar

INTRODUCTION examination and common laboratory tests are to be carried out.

India has a very high prevalence of hypertension which is more The history and the investigations may raise the suspicion of
in the urban population (20%) than in the rural population secondary hypertension. Some of the important clinical features
(10%). It is estimated that there are 89 million hypertensive include hypertension starting at extreme of ages, in younger
people in India and about 180 million can be put under the age or elderly people above the age of 50 years. The other
category of pre-hypertension as per the prevailing criteria of indicators are refractory hypertension which is difficult to
Joint National Committee (JNC) VII definition. manage and in endocrinal causes of hypertension the bio-
chemical abnormalities may be seen. Coarctation of aorta
In this large pool of hypertensive population, 93% to 95% should be suspected in cases with radio-femoral delay. Renal
comprise of primary hypertension where no definitive cause is bruits may be heard in renal artery stenosis while episodic
discernible. However, 5% to 7% of individuals suffer from accelerated hypertension with neurofibromatosis may point to
secondary hypertension and these patients are amenable to phaeochromocytoma.The other specific investigations in various
therapy (medical or surgical) depending on the aetiological categories of secondary hypertension are listed in Table 2.
factors. In the early stages of secondary hypertension if
corrective treatment is effectively done, then hypertension can IMPORTANT CAUSES OF SECONDARY HYPERTENSION
be practically cured or alleviated very significantly.
Renal Hypertension
DEFINITION Reno-parenchymal causes
Secondary hypertension is usually caused by treatable This is one of the most common causes of secondary
underlying pathology and it constitutes approximately around hypertension accounting for 2% to 5% of the hypertensive
5% to 7% of the total hypertensive population. Amongst the population. Diabetes, interstitial tubular disease, glomerular
various causative factors, renal hypertension is responsible for disease, polycystic kidney disease (PKD), analgesic and gouty
the largest proportion followed by the endocrinal hypertension nephropathy are some of the important causes.
and hypertension due to use of oral contraceptives. A very
The other causes which are renal-mediated are post-renal
small proportion is caused by vascular, immunological and
transplant patients as well as drug-induced due to cyclosporine,
neurological abnormalities (Table 1).
steroids, and sustained use of erythropoietin. In most of these
Table 1: Important Causes of Secondary Hypertension patients, the pathophysiological features are expansion of the
body fluid, sodium retention and inappropriate activation of
Primary/Essential Hypertension 93% to 95% the renin angiotensin aldosterone system (RAAS). The salient
Secondary Hypertension 5% to 7% features of parenchymal hypertension are given below.
Renal causes 3% to 5%
Hypertension occurs early in parenchymal and PKD while
Parenchymal 2% to 3%
interstitial renal disorders cause hypertension in terminal stages.
Renovascular 1% to 2% Hypertension further aggravates the deterioration of renal
Endocrine causes 0.3% to 1.0% function and nephropathy. Treatment of early hypertension is
Phaeochromocytoma <0.1% essential for prevention of cardiovascular disease as well as
Primary aldosteronism 0.3% kidney dysfunction. The rise in glomerular capillary pressure in
Cushing’s syndrome <0.1% glomerulonephritis and diabetic nephropathy leads to
Other endocrinopathies excessive protein loss and therefore aggressive management
Thyroid disorders 0.5% of hypertension is mandatory.
Parathyroid disorders The protein excretion in interstitial kidney disease,
Pituitary disorders pyelonephritis, PKD and hypertensive nephrosclerosis is
Oral contraceptives/drugs 0.5% minimal. However, if protein loss becomes excessive, aggressive
Miscellaneous 0.5% management of hypertension is required. The commonly used
drugs are calcium channel blocking agents and other
DIAGNOSIS conventional drugs. Angiotensin converting enzyme (ACE)-
inhibitors should preferably be avoided in patients with high
The importance of early diagnosis has already been creatinine values.
emphasised. This will help in effective early intervention so that
the disease may be cured even before target organ damage Renovascular hypertension
takes place and may provide a long lasting relief to the patient. The pathophysiology of renovascular disease resulting in
To diagnose secondary hypertension, basic principles are the hypertension is depicted in Figure 1 and the various causes of
698 same as in any other patient of hypertension. A detailed history, renal artery stenosis are tabulated in Table 3.
 Secondary Hypertension
Table 2: Clinical Features and Laboratory Investigations in Secondary Hypertension
Clinical and Laboratory Parameters Suspected Disorder Further Diagnostic Studies
Systolic/diastolic bruit heard in renal area Renovascular disease Ultrasound Doppler imaging, MR angiography,
captopril radioisotopic renography, renal
arteriography
Mass in renal region, loin pain, colic, stones, Nephrolithiasis, UTI, polycystic Ultrasound - KUB, intravenous urography, contrast
haematuria kidney disease CT urography
Renal insufficiency, atherosclerotic cardiovascular Renal parenchymal disease Creatinine clearance, renal ultrasonography
disease, oedema, elevated blood urea nitrogen
and creatinine levels, proteinuria
Paroxysmal or persistent hypertension, headache, Pheochromocytoma Increased urinary catecholamine metabolites
diaphoresis, tachycardia, palpitations, (vinyl mandelic acid, metanephrines, normeta-
neurofibromatosis, café-au-lait spot (skin) nephrines), plasma free metanephrines
Hypernatraemia, hypokalaemia muscles weakness Hyperaldosteronism Ratio of plasma aldosterone to plasma renin
activity, CT of adrenal glands
Weight gain, fatigue, weakness, hirsutism, Cushing’s syndrome Dexamethasone suppression test
amenorrhoea, moon facies, buffalo hump,
purple striae, truncal obesity, hypokalaemia
Headache, fatigue, visual problems, enlargement Acromegaly Growth hormone levels, CECT brain
of hands, feet, tongue, coarse features
Heat intolerance, weight loss, tachycardia, Hyperthyroidism Thyroid profile
palpitations, systolic hypertension, exoph-
thalmos tremor, sweating, etc.
Fatigue, weight loss, hair loss, swelling, Hypothyroidism Thyroid profile
diastolic hypertension, muscle weakness
Kidney stones, osteoporosis, depression, Hyperparathyroidism Serum calcium, parathyroid hormone levels
lethargy, muscle weakness
Snoring, day-time somnolence, obesity Obstructive sleep apnoea Sleep study
Weak pulses, decreased or delayed femoral pulse Coarctation of aorta, Doppler or CT imaging of aorta-angiography
of low amplitude, pulsations in neck, bruit over aorto-arteritis
inter-scapular region, abnormal chest radiograph
High salt intake, excessive alcohol intake, obesity Dietary effects Detailed history, alcoholic intake and calculate salt
intake
Polycythaemia in COPD, erythropoietin use in Side effects of erythropoietin Trial of drug if possible
renal disease
MR = Magnetic resonance; KUB = Kidney, ureter, and bladder; CT = Computed tomography; CECT = Contrast enhanced computed tomography;
COPD = Chronic obstructive pulmonary disease.

A number of lesions develop in renal arteries which cause

hypertension, the most frequent being atherosclerosis.
Others include fibromuscular dysplasia which has distinct
arteriographic features. The choice of treatment depends on
the type and severity of lesion.
Diagnosis
Most patients present in a way similar to essential hyper-
tension. Certain clinical features may point to renovascular
hypertension. These include abdominal bruit, drug-resistant
hypertension, sudden onset pulmonary oedema, worsening
renal function with use of ACE-inhibitors and sudden
development of hypertension in the elderly.

Figure 1: Renovascular hypertension and role of renin angiotensin aldosterone

Duplex ultrasound screening with colour Doppler flow studies
system. of renal arteries has great potential for diagnosis of occlusive
renal arterial disease with high sensitivity and specificity for
Table 3: Causative Factors for Renal Artery Stenosis detecting stenosis in more than 90% cases. Digital subtraction
Atherosclerosis Vasculitis renal arteriography allows direct visualisation of the site and
Fibromuscular dysplasia Renal artery embolism extent of renal artery stenosis. Though this is an invasive
Aorto-arteritis Radiation arteritis procedure and requires the use of contrast agent, it provides
highly accurate information. Magnetic resonance angiography
699
 is now often used as a non-invasive alternative. It is one of the only in about 70% of cases. Spironolactone is the drug of choice
definitive diagnostic procedures. for primary hyperaldosteronism in small dose, e.g. 12.5 mg to
25 mg per day to start with. However, a higher dose of 200 mg
Management
to 400 mg per day may be required. Spironolactone can cause
Renal angioplasty and stenting are now the treatment of choice impotence, decreased libido, menstrual irregularities and
for renal artery stenosis. Anatomic quantification and functional gynaecomastia. Amiloride (10 to 40 mg per day) is the drug of
significance of the lesion must be established first. Balloon choice for sexually active men. Amiloride blocks sodium
dilatation alone is not sufficient as the lesion particularly in channels at the distal renal tubules thus increasing sodium
atherosclerosis is mostly ostial and re-stenosis is common. and chloride excretion and decreasing potassium excretion.
Therefore, stenting is advocated in most cases. It relieves Side effects include headache, fatigue, impotence, increased
ischaemia to the kidney and even if it does not normalise the uric acid levels, and gastrointestinal complaints. If a second
blood pressure (BP), it will allow an easier control of BP. It will antihypertensive agent is needed, calcium channel blockers and
also contribute to long-term preservation of renal function. ACE-inhibitors can be added.
Renal stenting is particularly useful when the lesion is severe
but renal function is still relatively well-preserved. When the Cushing’s Syndrome
kidney function has severely deteriorated, renal angioplasty It occurs due to glucocorticoid excess and the patients have
often does not help. The drug therapy is an important factor in moon facies, truncal obesity, abdominal striae, hirsutism,
the treatment. Any drug other than the ACE-inhibitor can be hyperglycaemia, weak bones, cataracts, muscle weakness and
initiated for control of hypertension. More than one drug may hypertension. Hypertension is present in 80% of patients with
also be used, if necessary. Cushing’s syndrome which is due to the sodium retaining effects
of glucocorticoids and increased production of mineral-
ENDOCRINAL CAUSES OF SECONDARY HYPERTENSION ocorticoids. Other contributory factors are increased production
Hyperaldosteronism of renin substrate or steroid-induced change in vascular
This endocrinal disorder causes hypertension due to excessive reactivity. Hypertension is common and severe with adrenal
sodium retention, volume expansion and increased peripheral malignancy as compared to Cushing’s disease. Bilateral
resistance. It can be either primary or secondary. The most adrenalectomy virtually cures all patients with Cushing’s disease
common cause of secondary hyperaldosteronism is hyper- but it will also require permanent steroid replacement therapy
reninism secondary to renal artery stenosis. The prevalence of for life. For pituitary adenomas, selective excision of the
primary hyperaldosteronism varies from 0.05% to 2% of the adenoma is warranted. Post-surgery radiotherapy may be
hypertensive population. Aldosterone producing adenoma is needed to reduce the incidence of relapse.
usually unilateral and is the most common cause of primary Phaeochromocytoma
hyperaldosteronism in adults. It is found most commonly in
These are catecholamine secreting tumours, most commonly
patients of 20 to 50 years of age. Primary hyper aldosteronism
seen in the age group of 30 to 50 years. Up to 80% to 90% of
presents with hypertension and hypokalaemia. In primary
pheochromocytoma are found in one or both adrenal glands.
hyperaldosteronism, about 5% to 15% of patients may have
Most patients with pheochromocytoma have headache,
normal serum potassium levels.
sweating or palpitations. Hypertension may be sustained or
Idiopathic hyperaldosteronism (IHA) is the second most paroxysmal. A clinical syndrome of baroreflex failure may be
common cause of primary aldosteronism in adults but it is the confused with pheochromocytoma which occurs from
most common cause in children. The bilateral adrenal denervation of carotid baroreceptor following carotid body
hyperplasia associated with idiopathic hyperaldosteronism is tumour resection, carotid artery surgery, neck irradiation or
thought to be due to an extra-adrenal stimulus. trauma. In this condition, the patient has labile hypertension
Diagnosis with phases of acute severe rise of BP. Pheochromocytomas
can be surgically excised. However, it is appropriate that pre-
The diagnosis of hyperaldosteronism is made by the operatively a stable alpha-adrenergic blockage is achieved
measurement of plasma aldosterone and plasma renin activity and once this is established, beta-blockers can be added to
taking the blood samples in the morning after 15 minutes of the treatment as these can help to prevent catecholamine-
rest. Tests that may help to identify the presence of autonomous
induced arrhythmias. If the tumour is inoperable, radiation
hypersecretion of aldosterone are the fludrocortisone
therapy is the most effective treatment modality with β-
suppression test, saline loading tests and captopril suppression
blockade use. These tumours can be successfully removed
test.
surgically in 90% of cases.
A computed tomography or magnetic resonance image may
identify the presence of an adenoma. An assessment of plasma Hyperthyroidism
aldosterone before (supine) and after 2 to 4 hours of upright It induces systemic vasoconstriction, an increase in blood
posture may also be helpful. volume and increased cardiac activity all of which can lead to
hypertension.
Management
The control of BP with antihypertensive agents, correction of Hypothyroidism
hypokalaemia and surgical removal of adenoma are the Hashimoto’s disease is one of the major causes of
mainstay of treatment. Removal of an adrenal adenoma cures hypothyroidism. However, it is rarely diagnosed due to
hypokalaemia within two weeks in all cases but hypertension hypertension with non-specific symptoms such as malaise,
700
 Secondary Hypertension
goitre and hypercholesterolaemia. Treatment of hyperthyroidism is associated with high BP. The mechanism of hypertension may
(carbimazole, surgical excision or radioablation) is useful. be related to sympathetic activation and hormonal changes
Hypertension can then be easily controlled but use of associated with repeated periods of apnoea-induced hypoxia,
β-blockers may also be useful. It is not very clear why some hypercapnea and stress associated with the loss of sleep.
patients with hypothyroidism develop hypertension. It may be Sleeping with a nasal continuous positive airway pressure
related to decreased tissue metabolism reducing the release (CPAP) device is the treatment of choice. As the sleep apnoea
of vasodilator metabolites, thereby producing vasoconstriction, improves, BP tends to improve as well.
increased systemic vascular resistance and decreased cardiac
Various drugs that can cause hypertension are listed in Table 4.
output.
Other Endocrinal Causes of Hypertension Table 4: Hypertension Caused by Drugs
Acromegaly Drug Class Drug Examples
Acromegaly is caused by growth hormone producing pituitary Immunosuppressive agents Cyclosporine , tacrolimus ,
adenoma and hypertension is noted in about 40% of patients. corticosteroids
Nonsteroidal anti-inflammatory Ibuprofen , naproxen , piroxicam
Primary hyperparathyroidism
drugs
It is caused by parathyroid adenoma or hyperplasia. COX-2 inhibitors Celecoxib , rofecoxib , valdecoxib
Hypertension manifests in about 20% of patients with primary Oestrogens Oestrogen oral contraceptives*
hyperparathroidism. Anti-obesity Sibutramine, phentermine
Stimulants Nicotine, amphetamines
VASCULAR DISORDERS
Mineralocorticoids Fludrocortisone
Coarctation of Aorta Anti-Parkinsonian Bromocriptine
It is an easily diagnosed congenital defect that leads to MAO inhibitors Phenelzine
hypertension. Absent or weak femoral arterial pulse gives clue Anabolic steroids Testosterone
to the diagnosis. It can be confirmed by echocardiography, MR Sympathomimetics Pseudoephedrine
angiography or conventional angiography. Early diagnosis and * Oral contraceptives are one of the common causes of drug-induced
operative treatment before the age of 5 years is essential. Choice hypertension.
of treatment of coarctation is mostly by surgical correction.
Balloon angioplasty and stent implantation is also practiced. Erythropoietin
Aorto-arteritis The underlying mechanisms in drug-induced hypertension
include sympathetically-mediated vasoconstriction, direct
It is a fairly common cause of hypertension in India amongst pressor effect, stimulation of endogenous vasoactive
the younger population. Various regions of the aorta, great substances, e.g. endothelin, increase in blood viscosity, salt and
vessels and renal arteries are involved resulting in hypertension. water retention, stimulation of renin angiotensin-aldosterone
Its pathogenesis is uncertain and most likely immune-mediated. system and interference of central BP regulation.
Diagnosis is clinically suspected due to absent or unequal
peripheral pulsations with thoracic or abdominal bruits. It can DISEASES OF BRAIN AND CENTRAL NERVOUS SYSTEM
be confirmed by MR angiography or digital angiography. Hypertension may be observed in cerebrovascular accidents
Treatment includes immunosuppressive therapy, angioplasty like cerebral haemorrhage, cerebral infarction and chronic
and surgery. subdural haematoma. Hypertension may also been seen due
Arteritis Syndrome to symptomatic activities in patients with head injury, brain
Arteritis syndrome involving the renal arteries can cause tumours and encephalitis. Release of intracranial pressure offers
alternative obstruction and dilatation of renal vessels and this relief in some of these patients.
can start from aorta and its major branches. Hypertension is
CONCLUSIONS
seen in 40% of the patients. The causation of hypertension is
multifactorial. Secondary hypertension has varied and multiple causes
but renal and vascular causes account for a large proportion
Other Forms of Angiitis of patients with secondary hypertension. The success of
These include polyarteritis nodosa and progressive systemic management lies in early diagnosis and effective management.
sclerosis (PSS). All these conditions are autoimmune disorders.
Polyarteritis nodosa is complicated by hypertension in about RECOMMENDED READINGS
30% of patients which can progress to renal failure. While 1. Jamshed J, Dalal. Secondary hypertension. In: Siddharth N Shah, editor.
PSS presents with malignant hypertension and renal crisis, API Textbook of Medicine. 8th Ed. Mumbai: The Association of Physicians
of India; 2009; pp 540-43.
aggressive and rapid control of BP is the key for preventing
2. 2010 CHEP Recommendations for the Management of Hypertension.
kidney damage.
3. Kaplan NM. Renal vascular hypertension. In: Kaplan NM, Lieberman E.
SLEEP APNOEA editors. Clinical Hypertension; 7th Ed. Baltimore: Williams and Wilkins; 1998;
pp. 301-21.
It is a disorder in which breathing halts briefly but repeatedly
4. Wofford MR, King DS, Wyatt SB, et al. Secondary hypertension: detection
during sleep. Most people with sleep apnoea snore and are and management for the primary care provider. J Clin Hypertens 2000; 2:
overweight.Whether overweight or not, even mild sleep apnoea 124-31.
701
 12.23 Bradyarrhythmias

Yash Y Lokhandwala, Gopi Krishna Panicker

DEFINITION Clinical Features

Bradyarrhythmias are a group of rhythm disorders manifested In the early stages, most patients are asymptomatic. The typical
by a ventricular rate in adults less than 60 beats per minute symptoms of sinus node dysfunction due to inadequate cardiac
(bpm) under basal/awake conditions. The prevalence of output are:
bradyarrhythmias is more in elderly patients. It is a frequent Syncope or near-syncope, dizziness, palpitations, and decreased
finding in clinical practice, and its presentation may range exercise capacity or fatigue.
from an incidental finding in asymptomatic patients to life-
threatening atrioventricular (AV) block. The diagnosis of sinus node dysfunction is done by a 12-lead
electrocardiogram (ECG) recordings, routine telemetric
AETIOPATHOGENESIS monitoring in the hospital or 24 hours ambulatory Holter
Automaticity or intrinsic impulse formation is the property of recordings and exercise testing to judge the chronotropic
every cardiac cell. The sino-atrial (SA) node, as the primary response.
cardiac pacemaker with the highest frequency in impulse
Autonomic testing such as carotid sinus massage, head-
formation, maintains the heart rate in response to the
up tilt testing and Valsalva manoeuvres also help in
metabolic requirements and alterations of the autonomic
establishing the diagnosis. Invasive electrophysiology
nervous system. The conduction system of the heart
studies are nearly obsolete for diagnosing sinus node
comprising of the SA node, AV node and the His-Purkinje
dysfunction (SND).
system is responsible for the synchronous conduction of the
impulses from the atria to the ventricles. The various bradyarrhythmias due to SND are:
Bradyarrhythmias occur due to: Sinus Bradycardia
1. abnormalities in impulse generation at sinus node (sinus Sinus bradycardia is conventionally defined as sinus rate less
node dysfunction), than 60 bpm in adults during the wakeful state. However, in
2. abnormalities in conduction of impulse (disturbances in fit populations with a higher vagal tone, the normal waking
atrioventricular conduction system), and sinus rate can go down to even 50 bpm (Figure 1). Sinus
bradycardia is often a benign arrhythmia. Association of
3. a combination of abnormalities in impulse generation and clinical symptoms is, therefore, essential in evaluating sinus
conduction. bradycardia as being physiological or indicative of a
SINUS NODE DYSFUNCTION pathological state.
Sinus node dysfunction is a clinical syndrome, encompassing a
wide range of electrophysiological abnormalities, in combination
with other clinical manifestations. This is also called ‘Sick Sinus
Syndrome’. These are due to abnormalities in the automaticity
of sinus node cells or transmission of the sinus impulse into
atria or increased susceptibility for atrial tachyarrhythmias.
Causes of sinus node dysfunction are given in Table 1.

Table 1: Causes of Sinus Node Dysfunction

Idiopathic
Drug induced
Anti-arrhythmic drugs, especially beta-blockers, sotalol and
amiodarone
Figure 1: Sinus bradycardia.
Antipsychotic agents such as lithium, phenothiazines, amitriptyline
Digitalis
Heart/Systemic disease Sinus Pause and Sinus Arrest
Acute inferior wall MI Sinus pause or sinus arrest is the failure of atrial activation, due
Hypothyroidism, hypothermia, hyperkalaemia and hypoxia to the inability of the sinus node to form impulses. A sinus pause
Infiltrative disorders such as amyloidosis and sarcoidosis
is characterised by the absence of P-waves for a duration of
Autonomically mediated more than 1.5 s. The pause is not an exact multiple of the
Vasovagal syncope
preceding PP intervals (Figure 2). A sinus arrest is a more severe
Carotid sinus hypersensitivity
form where the delay is more than 3 (Figure 3).
702
 Bradyarrhythmias
Figure 2: Sinus pause.

Figure 3: Sinus arrest following termination of atrial fibrillation.

Sino-atrial Exit Block

Sino-atrial exit block is the failure in conduction of sinus impulse
into atria. Sino-atrial exit block can be graded into 3 degrees:
first degree, second degree and third degree.
Figure 4: 2:1 Sino-atrial block.
In a 12-lead surface ECG, SA block is manifest only as a
second-degree or third-degree SA block. Electro-cardio-
graphically, SA block is characterised by the absence of Third-degree or complete SA block
normal P waves and the duration of pause recognisable as
an exact multiple of the preceding PP interval, unlike sinus It is manifest as absence of P-waves, with long pauses resulting
pause/arrest. in ectopic atrial or ventricular rhythms. Complete SA block
cannot be differentiated from sinus arrest on a surface ECG.
First-degree SA block
The time for propagation of the sinus impulse into the atria is DISORDERS OF ATRIOVENTRICULAR CONDUCTION
significantly prolonged. This cannot be identified clinically or Conduction blocks in the AV conduction system can occur in
electrocardiographically. the AV junction or at different levels in the His-Purkinje system.
The blocks in the His-Purkinje system such as bundle branch
Second-degree SA block
blocks or intraventricular conduction defects do not necessarily
Second-degree SA block can be further classified as: show bradycardia.
Mobitz type I SA (Wenckebach) block AV Block
It is characterised electrocardiographically by progressive AV block (erroneously called as heart block) is the failure in
lengthening of SA conduction, until no P-wave appears for one regular conduction of the impulse from atria to the ventricle
beat and the sequence begins again. There is group beating, at the AV junction. The diagnosis of the AV block can be done
with gradually shortening PP intervals, followed by a pause adequately from the ECG from the PR interval, QRS duration
which is less than twice the shortest cycle. and ventricular rates on the surface ECG.
Mobitz type II SA block
AV block can be also graded into 3 degrees: first degree, second
It is characterised electrocardiographically by fixed PP interval, degree and third degree.
before and after the pause with the pause being a multiple of
the PP interval. Type II SA block is named as 2:1, 3:1 block, etc. Causes of AV Block
according to the ratio of the PP interval with the pause (Figure 4). Causes of AV block are given in Table 2. 703
 Table 2: Causes of AV Block Mobitz type II
It is characterised in an electrocardiogram by a PR interval which
Physiologic
Athletes is prolonged but constant, but some P waves are not conducted
Sleep (Figure 7).
Drug-induced
Digitalis, verapamil, beta-blockers, amiodarone, etc.
Vagally mediated
Carotid sinus hypersensitivity
Neurocardiogenic syncope
Heart/Systemic disease
Lenegre’s disease: sclero-degenerative
Lev’s disease: fibrocalcific
Myocardial infarction
Congenital complete AV block
Viral myocarditis
Hyperkalaemia
Traumatic—after surgery or radiofrequency ablation close to the
AV node Figure 7: Second-degree AV block Mobitz 2 – RBBB. The ECG also shows an
evolved anterior wall myocardial infarction with left-axis deviation.
First-degree AV block
The time for conduction of impulse from the atria to the 2:1 AV block
ventricles is significantly prolonged in first-degree AV block. An
ECG with a paper speed of 25 mm/s will show the prolongation In case of only 2:1 AV block, it is not possible to classify it as type
of the PR interval by more than 200 ms (Figure 5). 1 or type 2; hence a separate category of 2:1 AV block in our
classification (Figures 8A and B).

Figure 8A: 2:1 AV block. There is also RBBB and LAFB.

Figure 5: First-degree AV block (PR interval is 260 ms).

Second-degree AV block
Second-degree AV block is further divided into:
Mobitz type I (Wenckebach phenomenon)
It is characterised in an electrocardiogram by a sequence which
begins with a normal or prolonged PR interval, and with each
successful beat the PR interval lengthens until block of the
impulse occurs and a beat is dropped. The R-R interval shortens
typically. This type of block invariably is at the level of the AV
node (Figure 6).

Figure 8B: 2:1 AV block-narrow QRS. The PR interval is also prolonged.

Third-degree or complete AV block

It results in the complete interruption of conduction from
the atria to the ventricle. In an ECG, it is characterised by
the failure of all P waves to conduct to the ventricle. There
is consequently an escape rhythm from a subsidiary
pacemaker in the AV junction at heart rates lower than the
typical sinus rate for the subject. The QRS complexes are
Figure 6: Second-degree AV block Mobitz 1 (AV Wenckebach).
704 normal or near normal in shape if the subsidiary pacemaker
 Bradyarrhythmias
is situated in the lower AV node (Figure 9A) and wide (Figure 9B)
if the ectopic pacemaker is situated peripherally in the
ventricular musculature.

Figure 10: 24-hour Holter showing paroxysmal AV block. Likely to be vagally-

mediated since there is sinus slowing along with asystole.

AV Dissociation
This is a descriptive term for a phenomenon and not a disease
entity by itself. Hence, AV dissociation is not synonymous with
AV block. AV dissociation connotes that the atria and ventricles
Figure 9A: Complete AV block. Narrow QRS escape rhythm.
are activated by separate pacemakers. This is seen in complete
AV block, many cases of ventricular tachycardias, and severe
sinus bradycardia (isorhythmic AV dissociation) (Figure 11).

Figure 11: Isorhythmic AV dissociation. Sinus bradycardia; competing junctional

Figure 9B: Complete AV block. Wide QRS escape rhythm. One premature escape rhythm. The sinus P is occasionally conducted. Arrows denote sinus P
ventricular complex is also seen. waves.

A narrow (normal) QRS escape rhythm is generally more TREATMENT

stable, while a wide QRS escape rhythm carries a grave Bradycardia is a common finding in general practice, and the
prognosis. clinical presentation may range from an incidental finding in
asymptomatic patients to life-threatening heart block.
High-grade AV block
When 2 or more consecutive sinus P waves are blocked, it is For the management of patients with bradycardia, it is
termed as high-grade AV block. crucial that the symptoms be recognised as related to a low
ventricular rate. The suspicion of bradycardia in the differential
Paroxysmal AV block diagnosis of haemodynamically compromised patients must
Sudden episodes of high-grade AV block when there is usually be followed by immediate ECG recording and
otherwise normal conduction is termed as paroxysmal AV block interpretation. A careful clinical evaluation is necessary and
(Figure 10). should include history taking, physical examination and 705
 laboratory studies including tests of thyroid function as well Identification of the cause for AV conductional disturbances is
as continuous 24-hour ECG recording. Identification of important in recognising them as transient or irreversible. Drug-
treatable, reversible causes of the bradycardia is the key for induced AV block can be resolved by withdrawing the causative
successful management. There is no reliable long-term drugs. Permanent pacing must be considered if the drugs are
medication for increasing the sinus rate. essential for treatment of other medical conditions. Temporary
pacing is indicated in AV blocks due to conditions such as
Management of Sinus Node Dysfunction (SND)
digitalis toxicity, hyperkalaemia or acute myocardial infarction
In patients with known causes for sinus node dysfunction (SND), till the resolution of the block. In all other cases, permanent
treatment should be directed towards the underlying aetiology. pacing is indicated. An AV sequential pacemaker is preferable
Theophylline and beta-agonists have been used to treat for AV block (Figure 13).
bradycardia symptomatically, but it does not prevent syncope.
Permanent pacing is considered essential in all symptomatic
cases of sinus node dysfunction. Atrial-based pacing is the ideal
option for patients with significantly symptomatic sinus node
dysfunction (Figure 12).

Figure 13: AV sequential pacing (atrial sensed, ventricle paced).

RECOMMENDED READINGS
1. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines
for device-based therapy of cardiac rhythm abnormalities: a report of the
American College of Cardiology/American Heart Association Task Force
on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE
2002 Guideline Update for Implantation of Cardiac Pacemakers and
Antiarrhythmia Devices): developed in collaboration with the American
Association for Thoracic Surgery and Society of Thoracic Surgeons.
Figure 12: Atrial (AAI) pacing. Circulation 2008; 117: e350-408.
2. Fuster V, O’Rourke RA, Walsh R, et al. Hurst’s The Heart;12th Ed. New York:
McGraw Hill Company; 2008.
Management of Atrioventricular Conduction
3. Gupta AK, Maheshwari A, Lokhandwala Y. Evaluation of syncope: an
Disturbances overview. Indian Pacing Electrophysiol J 2001; 1: 12-22.
The prognosis and management of AV block depends on 4. Panicker GK, Lokhandwala Y, Desai B. Choosing pacemakers appropriately.
the level of AV block and its association with symptoms. Heart Asia 2009; 1:26-30.

706
 12.24 Tachyarrhythmias

Amit Vora

INTRODUCTION area to re-excite it (re-enter) if it has recovered excitability. If

The origin and spread of cardiac electric activity is the function this sequence is repetitive, a tachycardia may then result.
of specialised cells forming the natural pacemaker sites and Re-entry requires the presence of two conducting pathways,
conduction system within the cardiac muscle. Normally, the with slow conduction in one pathway and a unidirectional block
electrical impulse is generated at the sinus node at a rate ranging in the other, as shown in the Figure 2.
from 60 to 100 per minute and propagates to activate both atria
and further reach the ventricles via the atrioventricular (AV) node
and His-Purkinje system. By convention any heart rate beyond
100 per minute would be defined as tachycardia.Tachycardia can
be classified as shown in Figure 1.

Figures 2A to C: (A)The electrical impulse travels through two pathways, i.e. α

and β. These meet at a common exit point. (B) Since the two pathways have
different refractory periods, an extra stimulus is blocked in β pathway but can
conduct slowly over α pathway, and‘ re-enter’ the β pathway retrograde. (C)
This results in sustained circus movement. Tachycardia.

Figure 1: Classification of tachyarrhythmias. SUPRAVENTRICULAR TACHYCARDIA

Sinus Tachycardia
MECHANISMS OF TACHYARRHYTHMIAS The common causes are fever, anxiety, hypovolaemia, hyper-
Disorders of Impulse Formation thyroidism, infection and pulmonary thromboembolism.
Automaticity Upright P waves in the electrocardiography (ECG) leads II, III,
aVF; inverted P in aVF and transition from biphasic to upright
Under certain conditions like ischaemia and electrolyte imbalance,
waveform in the precordial leads help to distinguish from atrial
the resting membrane potential of cardiac muscle cells may
tachycardias. Carotid sinus massage to slow the sinus rate may
become less negative. This can give rise to automaticity, i.e.
help to distinguish the P wave morphology. Sinus tachycardia
spontaneous phase IV depolarisations. This has been implicated
is a marker of underlying pathophysiologic state and by itself
in certain arrhythmias like some types of atrial tachycardia (e.g.
does not warrant any treatment.
digitalis-induced), and accelerated junctional rhythm.
Unusually, there is persistent ‘inappropriate’ sinus tachycardia
Triggered activity
in the absence of any underlying cause. Paroxysmal onset of
Triggered activity is initiated by after-depolarisations, which are rapid sinus rates could be sinus node re-entrant tachycardia.
oscillations in the membrane potential initiated by the Reassurance and beta-blockers are generally effective and only
preceding action potential. These may be early after- rarely does one resort to radiofrequency (RF) ablation with only
depolarisations, i.e. occurring in phase 2 or 3 of the action a modest success.
potential, or delayed after-depolarisations, i.e. occurring after
repolarisation is complete. Early after-depolarisations have been Atrial Tachycardia
implicated in tachycardias in congenital and acquired forms of The ectopic P wave in atrial tachycardia (AT) most often precedes
the long QT syndrome. Delayed after-depolarisations are the QRS complex (Figure 3) and its morphology can suggest
implicated in some digitalis-induced arrhythmias, right the site of origin of the tachycardia. Atrial tachycardia could be
ventricular outflow tract tachycardia related to exercise, etc. paroxysmal, the most common type recognised by its sudden
onset and offset. The rare type is incessant or permanent. The
Disorders of Impulse Conduction
mechanism for paroxysmal atrial tachycardia can be re-entry
Re-entry or triggered activity and in case of more gradual onset and
Under specific circumstances, the cardiac impulse may detour offset, abnormal automaticity. While can arise from any site,
from its destined path and return to a previously depolarised there are certain common sites of origin. These are the right 707
 downwards from the sino-atrial node region along the crista
towards the isthmus. Type 2 or atypical atrial flutter is due to a
reverse circuit, i.e. clockwise with positive flutter waves in inferior
leads. Left atrial flutter, often seen with mitral valve disease is rapid
and atypical in its morphologic characteristics. The ventricular
rate during atrial flutter is usually slower than the atrial rate, due
to physiologic block of some of the atrial impulses in the AV node.
The drug treatment is similar to that of AT. Electrical cardioversion
with 100 to 200 J may be necessary in patients with haemodynamic
compromise or uncontrolled rapid ventricular rates. Both the
typical and atypical right atrial flutter can be cured by RF ablation
along the isthmus. The left atrial flutter or multiple re-entrant
circuits are less amenable to RF ablation.

Figure 3: Atrial tachycardia. The dented T wave suggests ectopic P wave fused Atrial Fibrillation
with it. Multiple, simultaneous re-entrant circuits and rotor waves in
both atria are responsible for initiating and sustaining atrial
atrial appendage, crista terminalis, area around the coronary sinus fibrillation (AF). The common causes are valvular heart disease,
ostium and area around the pulmonary vein orifices. In the corpulmonale, cardiomyopathy, hyperthyroidism and atrial septal
presence of valvular disease and enlarged atria, multiple sites of defect. Occasionally, lone AF is seen without any obvious cause.
origin may be present. The atria are activated 400 to 500 times a minute. The fibrillatory
Incessant atrial tachycardia is a serious arrhythmia as it can result waves may be fine or coarse on the ECG (Figure 5). Like atrial flutter,
in left ventricular dysfunction, described as‘tachycardiomyopathy’. the ventricular rate in AF depends upon the AV nodal conduction.
This ventricular dilatation and dysfunction is entirely reversible The pulse is irregular in rhythm and volume. Currently, AF is
if sinus rhythm is restored. Amiodarone, propafenone, flecainide classified as new onset, paroxysmal (spontaneously terminating),
and quinidine are the drugs that act on the atrium and help persistent (can be terminated pharmacologically or by
terminate as well as prevent atrial tachycardia. For drug-resistant cardioversion) and permanent (cannot be terminated).
atrial tachycardia, ventricular rate can be controlled by drugs
that depress AV nodal conduction, viz. verapamil, diltiazem,
beta-blockers and digoxin. The preferred therapy for sustained
or recurrent atrial tachycardia is RF ablation with a success rate
of 90%. This procedure eliminates the site of origin and achieves
permanent cure.
Atrial Flutter
The underlying mechanism is a macro-re-entrant circuit within
the atrium. There are many varieties of atrial flutter; Type 1 or
common or typical type is identified by inverted flutter waves in
the inferior leads with characteristic ‘saw-tooth’ appearance
(Figure 4). In these patients, there is abnormal slow conduction
of electrical impulse in the isthmus region (area between the
tricuspid annulus, inferior vena cava and coronary sinus). This Figure 5: Atrial fibrillation with rapid ventricular rate.
leads to macro-re-entrant circuit within the right atrium in a
counter-clockwise direction, i.e. superiorly along the septum and
The pharmacologic treatment involves ventricular rate control
or restoring and maintaining sinus rhythm. Rate control
approach is reasonable for first episode of AF, left atrial size
greater than 6 cm, advanced age, pulmonary/thyroid disease
and haemodynamically unrelieved valvular heart disease.
Importantly, the underlying cardiac or pulmonary cause
needs to be tackled. A combination of amiodarone/sotalol
and electrical cardioversion (200 to 360 J) is often effective.
Rarely, drug-resistant AF with rapid ventricular rate resulting
in tachycardiomyopathy can be effectively treated by RF
ablation of the AV node and a permanent pacemaker
implantation to provide a steady, controlled ventricular rate.
Surgical maze procedure especially for patients undergoing
valve surgery can be attempted to restore sinus rhythm. RF
ablation as a cure in patients with paroxysmal AF and no
Figure 4: Typical atrial flutter with 2:1 AV conduction. Note the classic saw-tooth structural heart disease has become a possibility in
pattern of the flutter waves.
708 experienced centres.
 Tachyarrhythmias
Various patients with AF require anticoagulation according to Atrioventricular Re-Entrant Tachycardia
their risk profile (Table 1). AV re-entrant tachycardia (AVRT) is mediated by an accessory
pathway which joins the atrium and ventricle (other than the
Table 1: Guidelines for Anticoagulation in Patients with Atrial
AVN) and is a breach in continuity of the fibrous ring of the AV
Fibrillation
annulus. This has been described as the Kent bundle and
Risk Risk Factors Anticoagulation responsible for the Wolff-Parkinson-White (WPW) syndrome
High risk Prior stroke, TIA, embolism Definitely indicated if and AVRT.
Rheumatic valvular heart any of the risk factors
Accessory pathways are present in 0.2% of people. It is estimated
disease are present
Prosthetic valve that 50% of these people will experience tachycardia at some
Moderate risk Age >75 years Indicated if more than stage in life, generally starting in the second or third decade. This
Hypertension one risk factor are amounts to approximately 2 million patients in India. These
Diabetes mellitus present accessory pathways may manifest in the ECG if they are capable
LVEF ≥ 35% of conducting antegrade. Such overt pathways lead to WPW
Low risk Age 65-75 years Not indicated syndrome. Majority of these pathways are ‘concealed’, since they
Female gender can conduct only retrograde (from ventricle to atrium) and hence
Coronary artery disease cannot be diagnosed from the sinus rhythm ECG. In either case,
Thyrotoxicosis these pathways can give rise to macro-re-entrant tachycardias.
TIA = Transient ischaemic attack; LVEF= Left ventricular ejection fraction. Most of these tachycardias are ‘orthodromic’, the impulse going
down the AV node and up the accessory pathway. The ECG at
Atrioventricular Nodal Re-Entrant Tachycardia such time would show a narrow QRS tachycardia (Figure 7). The
This is the commonest type of paroxysmal supraventricular accessory pathways may conduct antegrade during tachycardia
tachycardia (SVT). The age of onset is usually between 30 and resulting in a wide QRS (pre-excited) tachycardia.This is described
50 years and it is more common in women. The basis for this as anti-dromic tachycardia. AF in these patients can potentially
arrhythmia is dual pathways around the AV node, referred be lethal as the ventricular rate can be faster than 300 per minute
as slow and fast pathways. In these patients, an APB can leading to ventricular fibrillation. Orthodromic tachycardias can
activate the re-entrant circuit producing the typical slow-fast be terminated similar to AVNRT. For pre-excited tachycardias,
AV nodal re-entrant tachycardia (AVNRT) (Figure 6). Due to intravenous flecainide, amiodarone or electrical cardioversion are
simultaneous activation of the atria and ventricles during the alternatives. RF ablation is again the preferred choice as the
AVNRT, the right atrial contraction produces back pressure success rate is as high as 98%. It is almost a mandatory
on the jugular veins, described as the frog sign. Acute recommendation for patients presenting with AF and rapid
termination may be spontaneous or by vagal manoeuvres conduction over the accessory pathway.
like carotid sinus massage, but often intravenous medication
(diltiazem, verapamil or adenosine) is needed. For recurrent
episodes the preferred drugs are verapamil, diltiazem or
beta-blockers. However, the treatment of choice is RF
ablation. The slow pathway is selectively ablated leaving
the normal fast pathway conduction intact. With RF
ablation, 99% of patients with AVNRT can be permanently
and safely cured.

Figure 7: Narrow QRS, regular tachycardia. RP shorter than PR with ST depression

in leads I and aVL and discordant ST deviation in leads aVL and aVR suggestive
of orthodromic AVRT.

Various form of paroxysmal SVTs can be differentiated

depending upon the RP interval and concordance of ST
segment, as summarised in Figure 8.
Usually, SVT presents on ECG as a narrow QRS tachycardia.
Figure 6: A 12-lead ECG of AVNRT. The P wave is buried within the QRS and only Occasionally, there is a wide QRS tachycardia due to bundle
distorting the terminal portion as suggested by a pseudo S wave in inferior branch block during SVT. This can be differentiated from VT as
leads and pseudo R in lead V1.
shown subsequently (Table 2). 709
 complex to complex in a given lead in monomorphic VT.
Constant variation in morphology of QRS is described as
polymorphic. The monomorphic nature must be characterised
on a 12-lead ECG, since on a single monitor lead a polymorphic
VT may falsely appear monomorphic.

Table 5: Ventricular Arrhythmias: Clinical Scenario

Structural heart disease
Ischaemic heart disease
Dilated cardiomyopathy
Figure 8: ECG identification of types of paroxysmal supraventricular tachycardia. Hypertrophic cardiomyopathy
Arrhythmogenic right ventricular cardiomyopathy
Idiopathic VT (in normal heart)
Table 2: VT versus SVT with Aberrancy
Right ventricular outflow tract VT
Ventricular tachycardia SVT with Aberrancy Fascicular VT
Others
VA dissociation and fusion – Typical bundle branch block
present 50% pattern Primarily electrical disease
Long QT and torsades
Prolonged intrinsicoid deflection Concordance of QRS axis and BBB
Brugada syndrome
morphology
Idiopathic VF
Discordance between QRS axis
Specific VT
and BBB morphology (LBBB with RAD) Bundle branch re-entrant VT
Known structural heart disease Bi-directional VT
Simple clinical tools like carotid sinus massage can help in
diagnosis of tachycardia as shown in Table 3.

Table 3: Effect of Carotid Sinus Massage on Tachycardia

Tachycardia Effect
Paroxysmal supraventricular Termination of tachycardia
tachycardia—AVNRT or AVRT
AT/A flutter/A fibrillation AV block; arrhythmia continues,
more P’/F/f waves than QRS
Ventricular tachycardia Tachycardia continues, VA block
Pre-excited tachycardia Termination
Summary of management of paroxysmal supraventricular
tachycardia is given in Table 4.
Figure 9: Rapid, monomorphic ventricular tachycardia.
Table 4: Management of Paroxysmal Supraventricular
tachycardia
Infarct Scar
Acute termination This is the commonest setting of monomorphic VT. Re-entry
Vagal manoeuvres
circuits form in the islands of viable myocardium embedded in
Intravenous Adenosine: 6 to 12 mg or 0.1 to 0.3 mg/kg (rapid bolus)
Intravenous Verapamil/diltiazem: 5 to 15 mg or 0.1 to 0.2 mg/kg fibrous tissue. Commonly, such VT is seen to start a few months
(over 1 to 2 min) to years after a myocardial infarction (MI). The patient may be
Long-term treatment very stable during VT or there may be haemodynamic collapse,
Verapamil depending on the underlying ventricular function. Rarely is
Beta-blockers acute ischaemia a precipitating factor. Emergency management
Flecainide/Propafenone requires intravenous procainamide or amiodarone, since
Permanent cure lignocaine is effective in less than 30% of these patients. If
Radiofrequency ablation haemodynamically unstable, electrical cardioversion with 100-
360 J is advisable. Implantable cardioverter defibrillator (ICD) is
VENTRICULAR TACHYARRHYTHMIAS the treatment of choice in patients with past ischaemic heart
Vast majority (90%) of the wide QRS tachycardia are ventricular disease and VT. ICD is the device like pacemakers implanted
tachycardia (VT). Identifying VT as either being mono-morphic subcutaneously under the clavicle with electrodes in the right
or polymorphic is crucial to determine the prognosis and atrium and ventricle.The device detects VT/VF and delivers either
treatment. From a clinician’s view-point, the next important step overdrive pacing or shock and restores sinus rhythm (Figure 10).
in VT management is to identify the underlying structural/ Beta-blockers often in combination with amiodarone are used
electrical heart disease as shown in Table 5. when ICD is not feasible. Alternatively, sotalol can be tried.
Monomorphic VT Cardiomyopathy
This is usually regular with the rate varying from 150 min to Both dilated cardiomyopathy as well as hypertrophic
710 300/min (Figure 9). The QRS morphology is similar from cardiomyopathy may cause monomorphic VT. Re-entry or
 Tachyarrhythmias
verapamil.With life-threatening VT, an implantable defibrillator
is advisable.
Idiopathic Ventricular Tachycardia
Often VT is seen in healthy young adults who have no structural
heart disease. Two patterns are common, one arising from the
right ventricular outflow tract and the other from the left
ventricular posterior fascicle. The right ventricular outflow tract
VT shows a LBBB-like morphology and a vertical QRS axis and is
either repetitive, ill-sustained or could be sustained (Figure 12).
It is exercise-induced and responds well to beta-blockers. The
idiopathic left VT shows a RBBB-like morphology with left or
north-west QRS axis deviation (Figure 13). It is relatively narrow
as it arises from the left posterior fascicle. Acute termination
with adenosine or verapamil is possible. Hence, idiopathic left
Figure 10: Electrograms from the implantable cardioverter defibrillator. Top VT is often misdiagnosed as SVT. Both the idiopathic VTs have a
panel shows detection of VF and successful treatment with shock. Bottom panel
shows successful overdrive pacing to terminate VT.
natural history very similar to SVTs (benign outcome) and can
be permanently cured by RF ablation. There are many other
locations of idiopathic VT now described, especially the left
automaticity around areas of fibrosis is the usual cause. The
ventricular outflow tract VT.
management is essentially similar to that for infarct scar VT.
Treatment Plan for Sustained Monomorphic Ventricular
Tachyarrhythmias
Anti-arrhythmic drugs:-
Intravenous procainamide 10 to 14 mg/kg bolus (< 50 mg/min)
and 1 to 4 mg/min as maintenance;
Intravenous amiodarone 150 mg over 10 minutes, 1 mg/min
for 6 hours and then 0.5 mg/min over 18 hours
Figure 12: Right ventricular outflow tract (RVOT) VT. Holter strip show repetitive
Over-drive pacing form and the bottom 12-lead ECG show sustained VT.
Electric cardioversion
Arrhythmogenic Right Ventricular Cardiomyopathy
Young adults presenting with VT showing a left bundle branch
block like morphology. It is often misdiagnosed as idiopathic
VT. In 30% of cases, it is familial.The ECG in sinus rhythm is usually
abnormal, showing T inversions and sometimes the classical
epsilon wave in lead V1 (Figure 11). The right ventricular disease
may be subtle and hence missed at echocardiography. A signal
averaged ECG helps in identifying abnormal late potentials and
magnetic resonance imaging is often diagnostic with right
ventricular wall thinning and fatty replacement of myocardium.
Treatment options are sotalol, amiodarone, beta-blockers and

Figure 13: Twelve-lead ECG of idiopathic left ventricular tachycardia (ILVT). Note
the relatively narrow QRS with RBBB-like morphology and left-axis deviation.

Polymorphic VT
This is a life-threatening arrhythmia since it can degenerate
into ventricular fibrillation (VF). The underlying abnormalities
include long QT syndrome and acute ischaemia.
Long QT Syndrome
This could be either congenital or acquired. The congenital long
QT syndrome is a genetic defect, whereas, the acquired form is
due to hypokalaemia or potassium channel blocking cardiac
Figure 11: Twelve-lead ECG of a patient with ARVC, showing classic epsilon or non-cardiac drugs. The characteristic arrhythmia, torsades de
waves in lead V1 and T wave inversion in precordial leads.
pointes (Figure 14) is triggered by a VPB which occurs while 711
 Table 6: Principles of Managing Electrical Storm
Anti-ischaemic measures
NTG, heparin, thrombolysis, revascularisation
Anti-adrenergic drugs
Heavy sedation
Beta-blockers
Anti-arrhythmic drugs
Lignocaine—no role as primary prophylaxis
Beta-blockers
Adjuvants
Intravenous magnesium
Electrical cardioversion

Primary ventricular fibrillation

It occurs within the first 24 hours of MI. Severe electrical
Figure 14: Torsades de pointes. Polymorphic VT in a patient with acquired instability triggered by ischaemia is the mechanism. If
long QT. terminated by prompt defibrillation, the long-term prognosis
is similar to that of uncomplicated infarction. Unless further
the ventricles are still depolarising. The torsades is often arrhythmias occur, anti-arrhythmic drugs (except beta-blockers)
self-terminating, but is fatal in the event it is sustained. The are not necessary.
commonest presentation is unexplained syncope and the ECG Secondary ventricular fibrillation
must be carefully assessed for QT prolongation. Beta-blockers
This is seen after established infarction, usually after 24 hours.
with pacemaker are the treatment of choice for the congenital
Patients who develop secondary VF usually have large infarction
long QT syndrome. Left cervical stellate ganglionectomy and
with severe left ventricular dysfunction.Therefore, the prognosis
ICD implantation are other options for the resistant variety.
is grim. If defibrillation is successful, lignocaine or amiodarone
Removal of the offending agent and correcting electrolyte
are advisable. Urgent efforts to stabilise and improve the
imbalance is the mainstay for the acquired long QT variety.
ventricular function are warranted.
Intravenous lignocaine, phenytoin and isoprenaline are known
to shorten the QT and may be useful. The last decade has seen the potential of the life-saving ICD
Acute ischaemia therapy. It is now established to be beneficial in all patients
with VT and abnormal hearts. Its role has been suggested for
Unstable angina or MI can be complicated by polymorphic VT.
primary prophylaxis in high-risk individuals, i.e. post-MI,
Acute termination can be achieved with defibrillation (300-360
ejection fraction less than 0.30, wide QRS (> 120 ms), NYHA II,
J) or intravenous lignocaine 2 mg/kg. Further management non-sustained VT, T wave alternant or abnormal heart rate
entails aggressive efforts to alleviate ischaemia. Acute coronary variability and electrophysiology study inducing sustained VT.
syndrome can often precipitate an electrical storm defined as Radiofrequency ablation is used only as a salvage procedure
two or more sustained VT requiring electric cardioversion within when there are recurrent VTs requiring multiple ICD shocks.
24 hours. The principles of managing electrical storm are
outlined in Table 6. RECOMMENDED READINGS
1. Wellens HJJ, Conover M. The ECG in emergency decision making. 2nd Ed.
VENTRICULAR FIBRILLATION Saunders Elsevier, 2006.
The commonest setting for ventricular fibrillation (VF) is MI and 2. Wellens HJJ, Bar FW, Brugada P, et al. The differentiation between ventricular
tachycardia and supraventricular tachycardia with aberrant conduction:
structural heart disease with left ventricular systolic dysfunction.
The value of the 12-lead electrocardiograms. In:Wellens HJJ, and Kulbertus
In acute MI the VF occurrence is classified as primary and HE. What’s New in Electrocardiography? The Hague, Martinus Nijhoff; 1981;
secondary. pp.184-99.

712
 12.25 Sudden Cardiac Death

Ashish K Thakur

DEFINITION
Sudden cardiac death (SCD) and sudden cardiac arrest (SCA)
refer to a catastrophic symptom complex due to sudden
cessation of cardiac output and haemodynamic collapse
leading to death or non-fatal outcomes. Over the years, SCD
has been traditionally used as the term encompassing all forms
Figure 2: ECG strip showing ventricular tachycardia.
of this syndrome but successful resuscitation or spontaneous
reversion to a cardiac rhythm compatible with circulation and
life would now be classified as SCD survivor or SCA rather than clinical scenario, death might follow if resuscitation is not
SCD. The 2006 American College of Cardiology/American successful or is not attempted or unavailable. As mentioned, CAD
Heart Association/Heart Rhythm Society (ACC/AHA/HRS) causes up to two-thirds of SCD which occurs most commonly in
defines SCA as ‘sudden cessation of cardiac activity so that the the setting of ACS than stable angina patients.Various causes of
victim becomes unresponsive, with no normal breathing and SCD are listed in Table 1. A minority (about 10%) of SCD is caused
no signs of circulation’. If corrective measures are not taken by dilated cardiomyopathy and heart failure (ventricular
rapidly, this condition progresses to sudden death. Cardiac dysfunction), hypertrophic cardiomyopathy and other structural
arrest should be used to signify an event as described above, heart abnormalities. Arrhythmogenic right ventricular dysplasia
that is reversed, usually by CPR and/or defibrillation or (ARVD) is a condition associated with fibrosis of the right ventricle
cardioversion, or cardiac pacing. Sudden cardiac death should best diagnosed by cardiac MRI and is now an established cause
not be used to describe events that are not fatal. of SCD.
Table 1: Causes of Sudden Cardiac Death (SCD)/Sudden Cardiac
EPIDEMIOLOGY
Arrest (SCA)
Over million people die every year of SCD across the world.
SCD with coronary disease
Accurate data for SCD as a cause of death are difficult to obtain,
Acute coronary syndromes
and are certainly unavailable from Indian subcontinent. Stable angina
However, data from United States suggests up to 15 % of total Coronary embolism
deaths annually could actually be due to SCD. SCD is twice Non-atherogenic CAD (arteritis, dissection, congenital coronary
as more common in men than women and its incidence of anomalies and coronary spasm)
SCD rises with age, coronary artery disease (CAD), ventricular SCD with structurally abnormal heart
dysfunction and structural heart disease. Majority (up to two- Dilated cardiomyopathy
thirds) of SCD/SCA occurs in the setting of CAD where it may Hypertrophic cardiomyopathy
be the initial mode of presentation in about 20% patients. About Valvular heart disease (mitral valve prolapse)
half of all mortality in acute myocardial infarction could be due Congenital heart disease
to SCD, occurring before hospital admission. Various forms of Arrhythmogenic right ventricular dysplasia (ARVD)
structural heart diseases are known to increase SCD risk and Myocarditis
Cardiac tamponade
some continue to be identified.
Cardiac rupture
AETIOPATHOGENESIS Aortic dissection
SCD with no structural heart disease
The most common mechanism of SCD is haemodynamic collapse
Prolonged QT syndrome
due to ventricular fibrillation (VF) (Figure 1) or sustained Brugada syndrome
ventricular tachycardia (VT) (Figure 2). The initial symptoms WPW (pre-excitation) syndrome
leading up to the event are generally very infrequent or Catecholaminergic VT/VF
inconspicuous, unless in the setting of acute coronary syndrome Familial SCD
(ACS) with typical cardiac sounding chest pain.The cardiac arrest Chest wall trauma (commotio cordis)
leads to quick unconsciousness and collapse due to cerebral Non-cardiac causes of SCD
hypoperfusion, respiratory arrest and depending on the specific Pulmonary embolism
Central airway obstruction
Haemorrhagic stroke
Drowning

SCD can also occur in a structurally normal heart in about 10%

cases, especially in young individuals, mainly due to genetic or
acquired predisposition to electrophysiological abnormalities
Figure 1: ECG strip showing ventricular fibrillation.
causing life-threatening ventricular arrhythmias. Prolonged QT 713
 syndrome is well known to predispose to life-threatening Commonly performed cardiac tests in SCD survivors include
ventricular arrhythmias (torsades de pointes). A minority of echocardiogram and coronary angiogram. Cardiac MRI and
ventricular pre-excitation (WPW syndrome) patients could have electrophysiological testing are further and highly valuable
VF due to antegrade conduction via the accessory pathway if tools to rule out any structural heart disease and abnormal
they went into atrial fibrillation. electrical pathways, respectively.
Brugada syndrome is known to significantly increase the risk SECONDARY PREVENTION
of SCD. This condition is diagnosed by typical ECG findings (right
Device therapy with implantable cardioverter defibrillator (ICD)
bundle branch block and ST elevation in right precordial leads)
is the treatment of choice for majority of SCD survivors after
and electrophysiological testing. Some rather fascinating and
careful consideration. Various criteria and guidance have been
recently identified conditions with high SCD risk include
proposed, and the 2006 UK National Institute of Clinical
catecholaminergic VT/VF (heightened sympathetic surge
leading to arrhythmias). Evidence also suggests that the whole Excellence (NICE) for the use of ICD for secondary prevention is
symptom complex of SCD is actually a very complex process, summarised in Table 2. It is very important to remember that
often triggered by various factors like stress, plaque rupture the ICD itself just treats the dysrhythmia rather than preventing
causing ACS, electrolyte abnormalities (low potassium/ it. Further, some of these difficult clinical scenarios may need
magnesium) and some pro-arrhythmic drugs. Identifying electrophysiological testing with a view towards ablative
otherwise healthy individuals at high-risk for SCD may be very therapy. Patients with propensity for recurrent arrhythmias also
difficult. In general, traditional cardiovascular risk factors also require ‘top up’ medical therapy with beta-blockers or class III
tend to enhance the SCD risk. In addition, family history of SCD anti-arrhythmic agents (e.g. amiodarone). The drugs are much
is a very important risk marker, increasing it by twice at most. less efficacious and should be considered only for their
Non-cardiac conditions presenting as SCD include pulmonary adjunctive role or where ICD implantation is deemed
embolism, aspiration, drowning and other major respiratory inappropriate (much reduced life expectancy otherwise,
emergencies. terminal cancer, significant co-morbidities).

PROGNOSIS PRIMARY PREVENTION

It is important to discuss this at this stage before dealing This is a very interesting area due to various subsets of patients/
with the management aspects of this SCD/SCA. Being a life- people who may be classified as being at high-risk of having
threatening emergency, it occurs mostly out-of-hospital and is SCD Primary prevention is aimed at preventing the occurrence
not witnessed. The risk of recurrence may be as high as 50% in 12 of first SCD event in high-risk patients. This includes careful
months time. The response time to effective resuscitation largely and thorough assessment, which comprises of detailed
determines the clinical outcomes. Understandably the prognosis cardiac evaluation to exclude any structural heart disease,
is much better for in-hospital SCD. It may sometimes be quite patient and family screening where necessary and tests like
difficult to establish whether it is true SCD or ‘non-cardiac SCD’. echocardiogram, coronary angiogram, cardiac MRI and
electrophysiological testing. Genetic tests may also be
Current evidence in the published literature indicates that about necessary to identify patients carrying the high-risk genes and
25% to 40% of witnessed VF is likely to survive until hospital they could be offered prophylactic treatment. The three most
discharge. This is better if the underlying cardiac rhythm is VT, important groups for primary prevention include at-risk post-
where survival may be up to 65% to 70%. However, only about myocardial infarction patients, high-risk cardiomyopathy
30% of the out-of-hospital SCD have successful resuscitation (including hypertrophic cardiomyopathy), and patients with
and eventually just about 10% survive to discharge. Many of Brugada syndrome, Long QT syndrome, Pre-excitation (WPW
these patients have significant neurological problems due to syndrome) and familial SCD. These patients, after careful
anoxic brain injury. The poor outcomes for out-of-hospital SCD assessment, should receive an ICD. The 2006 UK-NICE guidance
can be predicted from factors like advanced age, prolonged for ICD for primary prevention of SCD is listed in Table 3.
resuscitation, haemodynamic support, heart failure, renal Adjunctive medical therapy may be necessary, as explained
impairment, and persistent neurological dysfunction. before.
Interestingly, majority of in-hospital deaths for SCD survivors
are due to non-cardiac causes like pneumonia, sepsis, multi- Table 2: 2006 UK National Institute of Clinical Excellence
organ failure and neurological problems. Guidance for Implantable Cardioverter Defibrillators (ICDs) for
Secondary Prevention (Defined as the Prevention of an
MANAGEMENT Additional Life-Threatening Event in Survivors of Sudden
Cardiac Events or in Patients with Recurrent Unstable Rhythms)
As mentioned before, the outcome following SCD depends
upon numerous factors including the underlying rhythm and Patients who present, in the absence of a treatable cause, with one
the rapidity of resuscitation. Management of a SCD scenario of the following:
initially comprises of aggressive resuscitation as per protocols a. Having survived a cardiac arrest due to either VT or VF.
and, if successful, to find and treat any reversible factors, like b. Spontaneous sustained VT causing syncope or significant
coronary disease amenable to revascularisation by angioplasty haemodynamic compromise.
or bypass surgery. This should be followed by strategies for c. Sustained VT without syncope or cardiac arrest, and who have
secondary prevention (re-occurrence of SCD event). On the an associated reduction in ejection fraction (LVEF of less than
35%) (no worse than class III of the New York Heart Association
contrary, primary prevention strategy is to be adopted for
functional classification of heart failure).
people with high risk of SCD.
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 Sudden Cardiac Death
Table 3: 2006 UK National Institute of Clinical Excellence the iceberg’, with only a handful being diagnosed and treated
Guidance for Implantable Cardioverter Defibrillators (ICDs) for successfully.With its proven benefits, many countries are putting
Primary Prevention (Defined as Prevention of a First Life- in a lot of efforts into primary prevention of SCD and the need
Threatening Arrhythmic Event) to identify the high-risk patient is vital to this. The various ways
Patients who have: to do this in the community include assessment of family history,
1. A history of previous (more than 4 weeks) myocardial infarction
vague symptoms (many have dizzy spells, unexplained
(MI) and: collapses), ECG screening, etc. The role of general practitioners
either is invaluable to suspect and refer these cases to tertiary centres.
left ventricular dysfunction with an LVEF of less than 35% Many cases require genetic screening and there are now
(no worse than class III of the New York Heart Association established clinical genetics services in many countries.
functional classification of heart failure) Information about familial conditions predisposing to SCD is
and widely available on the internet, including support groups for
non-sustained VT on Holter (24-hour ECG) monitoring patients and families, who need on-going counselling and
and specialist input.
inducible VT on electrophysiological (EP) testing
or CONCLUSIONS
left ventricular dysfunction with an LVEF of less than 30% SCD is often a fatal clinical condition with a dramatic
(no worse than class III of the New York Heart Association
presentation, often associated with CRD. Many conditions with
functional classification of heart failure)
and
structural heart disease predispose to SCD. There are now many
QRS duration of equal to or more than 120 milliseconds known conditions with normal structural heart and high-risk
2. A familial cardiac condition with a high-risk of sudden death,
for SCD/SCA due to electrical abnormalities. Over the years, the
including long QT syndrome, hypertrophic cardiomyopathy, prognosis for in-hospital SCD has improved but it still remains
Brugada syndrome or arrhythmogenic right ventricular- very poor for out of hospital events. Advances in diagnostic
dysplasia (ARVD), or have undergone surgical repair of technologies like electrophysiology, cardiac MRI and genetic
congenital heart disease. testing have helped to find out the susceptible patients.
Treatment of SCD is mainly based on device therapy with ICD
In patients with previous MI, the highest risk patients are the
for secondary/primary prevention along with adjunctive drug
ones with significantly impaired ventricular systolic function
and/or electrophysiological options where necessary.
with or without ventricular ectopy. The heart failure patients
may or may not have ischaemic heart disease, and a subset of RECOMMENDED READINGS
them benefit from prophylactic ICD implantation. A lot of
1. Committee ECC: Subcommittees and Task Forces of the American Heart
these patients now receive combined device therapy Association: 2005 AHA Guidelines for cardiopulmonary resuscitation and
comprising of cardiac re-synchronisation (for heart failure) and emergency cardiovascular care. Circulation 2005; 112 (Suppl): IV1-IV5.
ICD (for SCD prevention), which is called CRT-D. In addition to 2. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines
device therapy, conventional secondary prevention treatment for device-based therapy of cardiac rhythm abnormalities: Executive
with beta-blockers and ACE-inhibitors or angiotensin receptor Summary: A Report of the ACC/AHA Task Force on Practice Guidelines. J
Am Coll Cardiol 2008; 51: 2085-2105.
blockers also reduce the SCD incidence, especially in post-MI
patients. 3. Myerburg RJ, Interian Jr A, Mitrani RM, et al. Frequency of sudden cardiac
death and profiles of risk. Am J Cardiol 1997; 80: 10F-19F.
COMMUNITY 4. Myerburg RJ, Wellens HJJ. Epidemiology of cardiac arrest and
sudden cardiac death. In: Priori S, Zipes D. Sudden Cardiac Death: A
There may be many patients at high-risk of SCD but how to Handbook for Clinical Practice. Oxford, UK: Blackwell Publishing; 2006:
identify them? This issue is difficult and currently just a ‘tip of pp. 3-19.

715
 12.26 Congenital Heart Disease

Sunita Maheshwari

The estimated incidence of congenital heart disease (CHD) is No known cause can be identified for most congenital heart
1%, i.e. 1 out of 100 children have some form of CHD, either defects. Drugs such as retinoic acid for acne, alcohol, and
major or minor. In India, it is possible that the incidence may be infections (such as rubella) during pregnancy can contribute
higher due to deficiency of folic acid, consanguinity, etc. Pre- to some congenital heart problems.
conceptual folic acid (i.e. taken 3 months before pregnancy) has
The clinical diagnosis of cardiac lesions in children requires not
been documented to reduce the incidence of heart disease, so
just clinical skills but a high index of suspicion and a systematic
all women planning a pregnancy should be advised to start folic
diagnostic approach.
acid.
The majority of congenital heart diseases (CHDs) occur as As several lesions are now detected early, the main questions
isolated defects and are not associated with other diseases. are whether to intervene or not and if yes, then when? This
However, these can also be a part of various genetic and chapter will focus on some key issues, e.g. operability and clinical
chromosomal syndromes such as Down’s syndrome (AV canal), diagnosis with emphasis on some of the major lesions.
Turner’s syndrome (coarctation), Marfan’s syndrome (aortic
root dilation, mitral valve prolapse), Noonan’s syndrome THE FOETAL CIRCULATION
(pulmonary stenosis), and DiGeorge’s syndrome (tetralogy of Understanding the foetal circulation helps clarify how some
Fallot and other conotruncal anomalies). forms of CHD occur ( Figures 1A and B). The foetus has only a

Figures 1A and B: Changes in the circulation at birth. (A) In the foetus, oxygenated blood comes through the umbilical vein where it enters the inferior vena cava
(IVC) via the ductus venosus (red). The oxygenated blood streams from the right atrium (RA) through the open foramen ovale to the left atrium (LA) and via the left
ventricle (LV) into the aorta. Venous blood from the superior vena cava (SVC) (blue) crosses under the main blood stream into the RA and then, partly mixed with
oxygenated blood (purple), into the right ventricle (RV) and pulmonary artery (PA). The pulmonary vasculature (PV) has a high resistance and so little blood passes
to the lungs; most blood passes through the ductus arteriosus to the descending aorta. The aortic isthmus is a constriction in the aorta that lies in the aortic arch
before the junction with the ductus arteriosus and limits the flow of oxygen-rich blood to the descending aorta. This configuration means that less oxygen-rich
blood is supplied to organ systems that take up their function mainly after birth, e.g. the kidneys and intestinal tract. (B) At birth, the lungs expand with air and PV
resistance falls, so that blood now flows to the lungs and back to the LA. The left atrial pressure rises above right atrial pressure and the flap valve of the foramen
ovale closes. The umbilical arteries and the ductus venosus close. In the next few days, the ductus arteriosus closes under the influence of hormonal changes
(particularly prostaglandins) and the aortic isthmus expands.
716
 Congenital Heart Disease
small flow of blood through the lungs, as it does not breathe
in utero. The foetal circulation allows oxygenated blood from
the placenta to pass directly to the left-side of the heart
through the foramen ovale without having to flow through
the lungs.
Congenital defects may arise if the changes from foetal
circulation to the extra uterine circulation are not properly
completed. Atrial septal defects (ASDs) occur at the site of the
foramen ovale. A patent ductus arteriosus may remain if it fails
to close after birth. Failure of the aorta to develop at the point
of the aortic isthmus and where the ductus arteriosus attaches
can lead to narrowing or coarctation of the aorta (COA).
In foetal development, the heart develops as a single tube
which folds back on itself and then divides into two separate
circulations. Failure of septation can lead to some forms
of ASDs and ventricular septal defects (VSDs). Failure of Figure 2B: Morphology of atrial septal defect (ASD).
alignment of the great vessels with the ventricles contributes ASD = Atrial septal defect; S = Coronory sinus; IVC = Inferior vena cava;
SVC = Superior vena cava; RA = Rightatrium; LA = Left atrium.
to transposition of the great arteries, tetralogy of Fallot and
truncus arteriosus.
Clinical evaluation
ACYANOTIC HEART DISEASES A wide split second heart sound is present. The ECG invariably
Atrial Septal Defect shows some variant of the rsR’ pattern in lead V1, consistent
Atrial septal defect (ASD) is one of the most common congenital with right ventricular volume overload. In sinus venosus defects,
heart defect and occurs twice as frequently in females. a superior P wave axis occurs. Echocardiography-transthoracic
Frequently missed in childhood, this lesion causes problems of or in doubtful cases, transoesophageal echo, can confirm
pulmonary hypertension (PH) after adulthood is reached. the diagnosis (Figure 3). It demonstrates the location of the
ASD, typically, is symptomatic in childhood poor weight gain, ASD-primum, secundum or sinus venosus as well as right heart
frequent respiratory infections and rarely congestive heart volume overload and a non-invasive assessment of pulmonary
failure (CHF) have been ascribed to it. In general, however if a artery pressure (PAP).
child is in cardiac failure and the diagnosis is an ASD, a detailed
evaluation for some other anomaly (e.g. partial or total
anomalous pulmonary venous return), mitral involvement valve
should be performed.
Types of atrial septal defect
Four types of ASDs or interatrial communications exist:
ostium primum, ostium secundum, sinus venosus and
coronary sinus defects (Figures 2A and B). Most are ostium
secundum defects involving the fossa ovalis that in utero
was the foramen ovale. Ostium primum defects result from a
defect in atrioventricular septum and are associated with cleft
mitral valve.

Figure 3: A three-dimensional echocardiographic en face view of atrial septal defect.

Management
As a result of increased flow into the pulmonary circulation,
there is right ventricular volume load and a gradual increase in
pulmonary vascular damage and resistance, which typically
occurs in the 2nd and 3rd decade of life. Although the right
ventricular volume overload is well-tolerated for many years
there is eventual RV failure. Additionally, PH has been noted in
13% of Indian patients less than 10 years of age. Based on this
data, and to avoid the deleterious effect of longer periods of
RV volume overload, the optimal age for closure of ASD is
Figure 2A: Various types of atrial septal defects.
around 4 to 5 years of age.
717
 ASD can either be closed surgically by an open-heart procedure
or non-surgically in the cardiac catheterisation laboratory using
devices. An ostium secundum ASD with septal rim on either
side is amenable to device closure (Figure 4). However, at
present, sinus venosus and ostium primum defects need

Figure 4: The left image is a transoesophageal echocardiogram of ostium Figure 5B: Montage of the different types of ventricular septal defects. The
secundum ASD with colour flow before device closure, whereas the right-side central diagram outlines the location of the various types of defects as seen
shows post-release of an Amplatzer device. from the right ventricle.The two left images show a perimembranous ventricular
septal defect. The bottom middle echocardiogram is a muscular apical defect.
The upper right image is a right anterior oblique view in a doubly committed
surgery. Now-a-days, minimal access surgery to avoid a long
ventricular septal defect. The lower right is a short-axis view showing an outlet
thoracotomy scar can also be performed via a short sternal ventricular septal defect with prolapse of the right coronary cusp.
incision or a lateral thoracotomy. AO=Aorta; LV=Left ventricle; PA=Pulmonary artery; RA=Right atrium; RV=Right
Ventricular Septal Defects ventricle.

VSDs are among the commonest cardiac lesions in children.

Congenital VSD occurs as a result of incomplete separation of
In the classification by Soto et al, the ventricular septum is
ventricles. Embryologically, the interventricular septum has a
considered to have four components: an inlet septum
membranous and a muscular portion, and the latter is further
separating the tricuspid and mitral valves; a trabecular septum,
divided into inflow, trabecular and outflow portions. Most
which extends from the attachments of the tricuspid leaflets
congenital defects are perimembranous, i.e. at junction of
outward to the apex; the smooth-walled outlet or infundibular
membranous and muscular portion.
septum; and the membranous septum (Figures 5A and B).
Physiologically, these are classified as large (PAP equals left Large VSD, severe pulmonary hypertension and low PVR
ventricular pressure), moderate (PAP < LV pressure) and small These VSDs, initially present with tachypnoea, sweating due to
(normal pulmonary artery pressures). Symptoms and natural increased sympathetic activity, poor feeding, and failure to
history, to a large extent, depend on the pulmonary vascular thrive in an infant. On examination, there is evidence of over
resistance (PVR). circulation and pulmonary hypertension: respiratory distress,
an active praecordium, a short systolic ejection murmur, a loud
second heart sound, a mid diastolic rumble from increased flow
across the mitral valve, hepatomegaly and radiographic
evidence of cardiomegaly and plethora. A moderate VSD
(Figure 6) showing turbulence while a large VSD (Figure 7)
showing no turbulence.

Figure 5A: Four components of the ventricular septum. Figure 6: Parasternal long axis view demonstrating turbulence through
Ao = Aorta; PT=Pulmonary trunk. perimembranous VSD.
718
 Congenital Heart Disease
More than 10 years of age:The issue of surgically closing small holes
at this age is controversial. Advocates of closure quote the risk of
endocarditis. Conservatives use the argument that it still may
close, the only ill effect is endocarditis, which is treatable, and
why take the small but present risk of surgery. Most cardiologists
would agree that the risk of open-heart surgery is greater than
the risk of endocarditis, so leave well enough alone.
The only exception to this is in the presence of aortic
regurgitation (AR). In about 5% of VSD, and especially in the
supracristal variety, the aortic valve cusp prolapses into the VSD
as a result of a Venturi effect resulting in AR. Once this occurs, it
is progressive over the following 5 to 10 years. Therefore, the
development of AR detected either by echo or by finding a new
diastolic murmur on examination is an indication for closure of
a small VSD. The indication and timing of VSD closure are
Figure 7: Four-chamber view demonstrating large inlet VSD. summarised in Table 1.

Large VSD, severe pulmonary hypertension and high PVR Table 1: Timing of Closure of Ventricular Septal Defects
Once the pulmonary resistance increases, the pulmonary blood The timing of closure of VSDs is dependent on the size and the
flow reduces and the symptoms regress. At this point, as there symptoms of the defect
is no evidence of CHF, caretakers feel reassured. This is the Large VSD
danger period as intervention gets delayed. Once the pulmonary Persistent CHF, failure to thrive – close by 3 to 4 months of age
resistance becomes higher than the systemic resistance, the flow No CHF but pulmonary artery hypertension (PAH): surgery by
across the VSD changes from right to left leading to cyanosis. On 5 to 6 months
examination, the praecordium is typically quiet with no significant Moderate VSD
murmurs (as the LV and RV pressures are equal in large VSDs, there Wait until age 2 to 4 years, earlier, if failure to thrive
are typically no murmurs across a large VSD; as the pulmonary Small VSD
flow decreases, the pulmonary ejection murmur also disappears), If aortic regurgitation develops or previous episode of
a banging S2 and radiographic evidence of a normal sized heart endocarditis, early surgery is warranted
with distal pruning. Once Eisenmenger syndrome develops, it is
Patent Ductus Arteriosus
too late for intervention.
Clinical evaluation
When an infant is seen with a large VSD, there is a chance that it
The clinical presentation of a patent ductus arteriosus (PDA), like
will get smaller with time, but studies differ in respect to
other left to right shunts, depends on its size and the pulmonary
probability. A patient with a large VSD seen at 1 month has an
vascular resistance (PVR). In large PDA, the presentation is similar
80% chance of closing; whereas a 6-month-old with a large
to a large VSD with signs of over-circulation, absence of a significant
defect has less than a 50% chance of spontaneous closure.
murmur, a loud S2 and radiographic evidence of cardiomegaly
Management and plethora. Bounding pulses are a clue to a large PDA or aorto-
Infants with large VSD typically develop signs of CHF at 6 to 8 pulmonary window (APW) being the cause of the heart failure.
weeks of life when the pulmonary vascular resistance is low and The ECG demonstrating a large continuous flow into the pulmonary
the physiological anaemia is at its nadir. Therapy includes artery from the aorta clinches the diagnosis (Figure 8). Patients
digoxin, diuretics, and after-load reducing agents. Additionally,
treating anaemia is helpful as anaemia can aggravate the failure.
If there is heart failure in spite of medications and/or failure to
thrive, early surgical closure at 3 to 4 months of life is warranted.
If a baby is doing well but has a large VSD, this defect should
still be closed early, i.e. by 5 to 6 months, as an occasional patient
will develop irreversible PH by 6 to 12 months of age.
Moderate VSD
This is a pressure restrictive defect and the PAPs are protected.
Therefore, there is no risk of developing Eisenmenger syndrome.
If there is moderate cardiomegaly and plethora, and the child is
otherwise asymptomatic, one can watch for 2 to 4 years. If the VSD
does not get smaller, surgical closure is advised to prevent the long-
term problems of LV dysfunction secondary to volume over load.
Small VSD
Less than 10 years of age: The consensus is to leave it alone and Figure 8: Ductal view on transthoracic echocardiography demonstrating patent
ductus arteriosus.
follow-up for any development of aortic regurgitation (AR). 719
 with smaller PDA have the classic continuous Gibson’s machinery
murmur heard best at the infraclavicular area or the left upper
sternal border. As the aortic pressure is higher than the PAP in both
systole and diastole this results in a continuous murmur. Patients
with large PDA with substantial PH may develop differential
cyanosis (pink fingers, blue toes). Continuous murmur will be
absent in these cases.
Management
With small PDA, the main risk is endarteritis. However, with larger
ducts, there can be a significant volume load on the left heart.
For both these reasons, PDA need to be closed. Closure of small
PDA is done to prevent subacute bacterial endocarditis (SBE).
If the clinical examination suggests a PDA but there is no
evidence on the echocardiogram, one needs to keep in mind
the diagnosis of APW. This is a connection between the aorta
and the main pulmonary artery and leads to pulmonary over- Figure 9: Echocardiography demonstrating the narrowing of the arch and the
circulation and hypertension and clinical findings similar to a pressure gradient across the CoA.
large VSD or PDA.
the success rate of non-surgical procedures. (Stents are made of
The methods used for closure of a PDA include surgical ligation
stainless steel and can be deployed at the site of coarctation to
or division via a lateral thoracotomy or non-surgical closure via
permanently relieve the obstruction.)
the deployment of coils or devices across the PDA.
Congenital aortic stenosis and pulmonary stenosis have been
Coarctation of the Aorta
discussed in the chapter of Valvular Heart Disease (Chapter 14 of
Coarctation of the Aorta (CoA), a narrowing of the arch, occurs this section).
in 6% to 8% of patients with CHD. Untreated, coarctation has a
poor natural history. In Campbell’s classic study, the mean age CYANOTIC HEART DISEASE
of death was 34 years. The most common causes of death were Tetralogy of Fallot
heart failure (26%), aortic rupture (21%), endocarditis (18%), and
In cyanotic heart disease, by far, tetralogy of Fallot (TOF) remains
intracranial haemorrhage (12%). Early therapy has several
the most common diagnosis. TOF was described over 100 years
advantages, one being the lower incidence of chronic
ago by a French physician, Etienne-Louis Arthur Fallot as a condition
hypertension. The prevalence of hypertension was 6% in
consisting of pulmonary arterial stenosis, an interventricular septal
patients who underwent coarctation repair at less than 5 years
communication, deviation of aorta to the right, and concentric
of age, compared to 30% to 50% in those whose coarctation
hypertrophy of the RV. This lesion still bears his name (Figure 10).
was repaired at an older age. For all these reasons, early
diagnosis and therapy is imperative.
Clinical evaluation
The clinical presentation of CoA is variable. In newborns, the
patent ductus arteriosus supports the distal circulation. The RV
pumps to the descending aorta via the PDA. As a result, neonates
present with signs of right heart failure. Once the PDA closes, the
baby has no flow to the lower body and goes into shock.
In older children, the diagnosis may be more subtle – intermittent
claudication, upper limb hypertension or the finding of diminished
femoral pulses. The best way to never miss a coarctation is to
palpate the femoral or dorsalis pedis pulse at every visit.
The ECG may show left ventricular hypertrophy and the
radiography can demonstrate the classic rib notching (from
development of collaterals) in older children. Echocardiography
is diagnostic and demonstrates the narrowing of the arch and
the pressure gradient across the CoA (Figure 9).

Management
Once diagnosed, CoA is treated either surgically or non-surgically.
In newborns and young infants, surgery is the best option as the Figure 10: Diagrammatic representation of tetralogy of Fallot.
recurrence rate with angioplasty is high. In older infants and 1=Pulmonary stenosis; 2=Ventricular septal defect; 3=Overriding aorta; 4=Right
children, balloon angioplasty can be performed with a high ventricle hypertrophy.
success rate and reasonable degree of safety. In older children Ao = Aorta; LA = Left atrium; LV = Left ventricle; PA = Pulmonary artery; RA = Right
atrium; RV = Right ventricle.
720 with near adult sized aortas, the availability of stents has increased
 Congenital Heart Disease
Clinical Evaluation
The main symptom of cyanosis is related to the degree of
pulmonary stenosis; the more the stenosis the more the right
to left shunt, the less the pulmonary blood flow and the more
the cyanosis. Hypoxic spells occur in infancy, typically in the early
mornings and are characterised by tachypnoea, increasing
cyanosis and at times, syncope.
Physical examination varies from no murmur during a spell to
a systolic ejection murmur to continuous murmurs due to
collaterals. The classical ECG findings are right axis deviation
and RVH with a radiography demonstrating low pulmonary
blood flow and the ‘boot shaped’ heart. Cardiac catheterisation
is no longer routinely indicated. Cardiac computed tomography
(CT) or catheterisation is performed if there is a question
regarding distal pulmonary arteries or coronary arteries.
Management
Medical management is limited to treating spells, preventing
dehydration and fever which can precipitate spells, treating iron
deficiency and advising endocarditis prophylaxis. Beta-blockers
are used as a bridge to delay surgical intervention.
When to surgically intervene in TOF has always been a
contentious issue. In our country, the approach has been to do a
Figure 11: Diagrammatic representation of congenitally corrected transposition
complete correction (i.e. closing the VSD and opening the RVOT of the great arteries.
with or without a transannular patch) by the age of 6 to 18
Ao = Aorta; LA = Left atrium; LV = Left ventricle; PA = Pulmonary artery; RA = Right
months, depending on the centre. Waiting until ’10 kg’ is no
atrium; RV = Right ventricle.
longer required and surgical repair can be done as early as is
indicated, for instance in the United States – total TOF correction The ideal operation is an arterial switch operation where the RV
is done soon after birth. In patients with small pulmonary arteries is connected back to the PA and the LV is connected back to the
or with a coronary artery crossing the right ventricular outflow aorta leading to a ‘normal heart’. Early diagnosis and treatment
tract, a Blalock Taussig (BT shunt) can be performed as a first stage. of d-TGA is essential for the following reason: The LV pumps to
Transposition Complexes the pulmonary artery which is a low pressure artery. Within 4
The key anatomical feature that characterises this group of weeks, the LV undergoes ‘disuse atrophy’ and it regresses. At this
diagnoses is ventriculoarterial discordance. This is most point if an arterial switch is done then the LV is unable to generate
commonly seen in the context of AV concordance, also known enough pressure to pump to the body and it fails. Thus, an arterial
as complete transposition or d-TGA (dextro-TGA). Congenitally switch should ideally be done in the first 4 weeks of life.
corrected TGA or l-TGA (levo-TGA) is combination of ventri- Total Anomalous Pulmonary Venous Connection (TAPVC)
culoarterial discordance with AV discordance (Figure 11). Instead of the pulmonary veins connecting normally to the LA,
Transposition of the Great Arteries (d-TGA) they connect to the RA. An obligatory ASD then allows right to
left shunting to maintain left heart output.
In d-TGA, the right ventricle gives rise to the aorta and the LV to
the pulmonary artery. This leads to deoxygenated blood going to Clinical evaluation
the body and oxygenated blood returning to the lungs. If there is Any obstruction along the pathway leads to significant cyanosis,
inadequate mixing (i.e. via an ASD, VSD, PDA), the baby presents acidosis, low cardiac output, pulmonary venous congestion, a
with increasing cyanosis leading to acidosis and, eventually,death. small heart on radiograph and eventual early death. In non-
Clinical evaluation obstructed TAPVC, the presentation is similar to an ASD with a
systolic ejection murmur and a widely split S2. Clinically, one
Classically it presents in male children with cyanosis, a single can differentiate between the two with an oxygen saturation
second heart sound and no murmur. The radiograph may show probe which will reveal a lower oxygen saturation in TAPVC.
the ‘egg on side’ appearance, and the diagnosis is confirmed on
echocardiography wherein the LV gives rise to the PA and the Management
RV connects to the aorta. Echocardiography is diagnostic and early surgical correction is
indicated; this is one of the true paediatric cardiac surgical
Management
emergencies.
Cardiac catheterisation is no longer indicated unless a balloon
atrial septostomy needs to be performed to increase mixing. A Truncus Arteriosus
non-invasive alternative is prostaglandin (PGE1) which can help In this lesion, the pulmonary arteries arise from the ascending
open the PDA and help with mixing, thus alleviating cyanosis. aorta and typically are at high pressure. This is one of the causes
The dose needs to be titrated and reduced if hypotension or of babies presenting with heart failure and cyanosis, other
apnoea occurs. lesions being single ventricle, TGA-VSD, TAPVC, etc. 721
 Clinical evaluation
These babies are present with CHF and bounding pulses (due
to rapid run off into the pulmonary arteries). On examination,
these may have a high-pitched early diastolic murmur from
truncal regurgitation, in addition to the single S2 and systolic
murmurs.
Management
The only remedy is surgical correction where the pulmonary
arteries (PA) are connected back to the RV with or without a
homograft. Re-operation may be needed in 2 instances: (1) if a
homograft is placed, which the baby outgrows with growth thus
requiring a new, larger homograft, and (2) pulmonary valve
replacement, in some cases. Families need to be counselled that
re-operation may be needed over time.
Tricuspid Atresia and Other Forms of Single Ventricle
Babies with single ventricle can present in two ways: (1) with Figure 12: Chamber view demonstrating apical displacement of septal leaflet
cyanosis if pulmonary stenosis is the main issue and (2) heart of tricuspid valve in Ebstein’s anomaly.
failure and pulmonary overflow if there is no pulmonary
stenosis. In single ventricle situations, the fundamental issue is IMAGING IN CONGENITAL HEART DISEASE
that one chamber is doing the work of two chambers. The goal, When it comes to the preferred choice of imaging for CHD in
therefore, of treatment is to connect the superior vena caval children, echocardiography has no match. Optimum windows,
blood (Glenn shunt) to the pulmonary arteries to reduce the zero radiation and easy availability of the expertise make
load on the single ventricle. In order to do this, the PAP must be echocardiography, ‘the investigation of choice’. However, CT is
low. So, in babies with pulmonary stenosis, a Glenn shunt can an extremely helpful complementary imaging modality in the
be done by 6 to 9 months of age. In babies with high flow evaluation of CHD. Poor acoustic windows and poor depiction
situations, CHF and high PAP, a pulmonary artery banding needs of extracardiac vascular structures are the major limitations of
to be done at 1 month in order to reduce PA pressure to a level echocardiography, both of which can be successfully overcome
where a Glenn shunt can be done later. The Fontan operation, with the use of cross-sectional CT imaging. Short acquisition
wherein the inferior vena cava is connected to the pulmonary times and, thereby, decreased requirement for sedation leads
artery, relieves cyanosis completely but it has its own long-term to CT definitely scoring over magnetic resonance imaging (MRI)
issues. Its routine use, therefore, has been called into question. in children.
In single ventricle situations, prognosis is variable but not as Cardiac CT and MRI are being increasingly utilised to assess
dismal as previously thought. pulmonary artery anatomy (e.g. in TOF), arch anomalies (e.g.
complex coarctations, interrupted aortic arch), pulmonary veins
Ebstein’s Anomaly
(e.g. TAPVC where pulmonary venous drainage is unclear),
Ebstein’s anomaly refers to a downward displacement of vascular rings and slings, etc.
tricuspid valve tissue into the RV. Thus, a portion of the RV acts
like the atrium.This atrialised RV contracts poorly and interferes ASSESSING OPERABILITY IN CHD
with right ventricular filling. The issue of operability arises often for clinicians involved in
Dyspnoea, fatigue and palpitation are the usual symptoms. the care of children with heart disease. In infants less than 6
Cyanosis is present due to right to left shunt at the atrial level. A months of age one can generally make an assumption that
systolic murmur of tricuspid regurgitation is heard at the lower the children are operable as irreversible pulmonary vascular
left sternal border. The first and second heart sounds are widely obstructive disease (PVOD) is unusual at that age. In older
infants, and particularly in older children or adults, the question
split and third and fourth heart sounds may be heard. Thus,
of how much and how reversible the PVOD is often arises.
multiple scratchy quality heart sounds is an important feature
of Ebstein’s anomaly. A key concept is that in all large left to right (L-R) post-tricuspid
shunts (i.e. VSD, PDA, atrioventricular canal (AV canal), APW, etc.)
Box-like globular cardiac configuration is seen on chest the systemic, i.e. aortic pressure is directly transmitted to the
radiography which closely resembles a large pericardial pulmonary artery. Therefore, in large shunts there is severe
effusion. ECG shows tall and peaked P waves. The diagnosis is pulmonary artery hypertension (PAH) right at birth. As time
confirmed by echocardiography (Figure 12). progresses, the high flow and high pressure cause an elevation
Patients who are symptomatic should undergo a tricuspid in pulmonary vascular resistance (PVR). It is this change in PVR
valve repair in which marsupialisation of the atrialised RV that determines symptoms and operability.
is undertaken with realignment of the tricuspid cusps to For a variable period of time after PVR starts to increase, changes
the tricuspid annulus. This procedure is preferred over in lung vasculature may still be reversible following correction
operations in which the tricuspid valve is replaced with a of the defect, i.e. the patient may still be operable. However, once
prosthetic valve. irreversible PVOD is established, closure of the defect may
722
 Congenital Heart Disease
actually worsen the natural history and hasten mortality as a Table 3: Criteria Showing High Pulmonary Vascular Resistance
result of right heart failure. and Inoperable Defects
Fundamental Concept A quiet praecordium
If the PVR is low, the shunt will be L-R and the patient will exhibit Absence of a systolic ejection flow murmur in the presence of a
signs of pulmonary overcirculation. A patient with low PVR is loud banging P2
always operable. Evidence of cyanosis or an oxygen saturation less than 85% to 90%.
(In a PDA the lower limb saturation would be measured)
If the PVR is high, the shunt will become R-L and there will be Right ventricular hypertrophy on ECG
signs of cyanosis without overcirculation. A patient with high Absence of cardiomegaly or plethora on CXR with peripheral
PVR may be inoperable. pruning
Primarily right to left shunting on the echo with right heart dilation
Using this concept one can come to a conclusion of operability
looking for features of pulmonary overcirculation.A child with low
PVR, i.e. who is operable has the following clinical features (Table 2). a cardiac catheterisation may add value in terms of a decision.
Traditionally, a calculated PVR of less than 8 RU with oxygen/
Table 2: Clinical Features Favouring Surgery Based on nitric oxide or other pulmonary vasodilators is considered
Pulmonary Vascular Resistance evidence of operability. Although 100% oxygen has been
Symptoms of heart failure, e.g. failure to thrive, sweating, etc. conventionally used to assess the degree of ‘reversibility’, the
Tachycardia role of oxygen in outcome prediction remains questionable.
Tachypnoea
A recent multicentre haemodynamic study of patients with
An active hyperdynamic praecordium
CHD and PH concluded that the reliability of pre-operative
haemodynamic cath lab evaluation of operability was limited
A loud P2 along with a systolic ejection murmur of high flow (across
the pulmonary valve in a VSD and across the aortic valve in a PDA/ despite the use of vasodilators.
APW)
In a large PDA balloon occlusion of the duct can be performed.
Potentially a mid diastolic rumble related to increased flow across
The demonstration of a substantial fall, especially of the PA
the mitral valve
diastolic pressure, suggests operability. However 100%
Evidence of LV volume load on ECG
correlation between this and operability has not been noted in
Cardiomegaly and pulmonary plethora on CXR
all studies.
An echo showing primarily a left to right shunt and a dilated LA/LV.
In aorto-pulmonary window, reversal of flow in the aortic arch/ In conclusion, CHD is a diverse group of lesions with varying
descending aorta is a powerful predictor of operability as it suggests presentations. Early and accurate diagnosis along with timely
that the PVR is lower than the systemic vascular resistance (SVR)
intervention is the key to long-term good outcomes.
On the other hand, a patient who is inoperable will have no
clinical features of pulmonary over-circulation (Table 3). RECOMMENDED READINGS
1. Joseph Perloff. The clinical recognition of congenital heart disease; 5th Ed.
Borderline Operability Saunders; 2009.
In certain situations the clinical features are borderline. A patient 2. Malcolm S Thaler. The Only Ekg Book You’ll Ever Need; 2nd Ed. Lippincott;
with a quiet praecordium, no flow murmur, an oxygen saturation 1995.
of 90% but mild cardiomegaly on CXR and equal sized ventricles 3. Moss and Adams heart disease in infants, children and adolescents; 5th Ed.
with a bidirectional shunt on echo poses an operability Williams and Wilkins; 1995.
diagnostic dilemma and a therapeutic challenge. In such cases, 4. Nadas’ Pediatric Cardiology; 2nd Ed. Saunders; 2006.

723
 12.27 Heart in Systemic Diseases

Aspi R Billimoria

The heart is involved in many systemic disorders. In most of leakage of fluids into the interstitial spaces, resulting in
these conditions, other manifestations like joint involvement pericardial effusion.
or CNS affection may predominate and the cardiac involvement
Signs and symptoms
is often considered as a ‘complication’. In a few patients, especially
those with thyroid disease, cardiac manifestations may be the There is bradycardia and the pulse is of low volume. The blood
presenting complaints and may even precede other systemic pressure is usually low but in a few cases there may be
manifestations. hypertension. The heart size is enlarged and the heart sounds
may sound distant. A pericardial rub may be heard. Severe
HEART IN ENDOCRINE DISORDERS cardiac failure may be present. A few patients may complain of
Thyroid Disorders angina or suffer myocardial infarction due to secondary
hyperlipidaemia.
Both thyroxine (T4) and triiodothyronine (T3) have a direct
stimulatory effect on the myocardium. Investigations
The electrocardiogram characteristically reveals sinus
Hyperthyroidism
bradycardia, low voltage and flat T-waves. The QT interval may
Excess thyroid hormone has a direct effect on the heart but be prolonged. Changes of pericardial effusion may be seen.
many of the clinical manifestations are due to increased beta- Chest X-ray reveals an enlarged heart and signs of pericardial
adrenergic stimulation. The increased basal metabolism leads effusion. Pericardial effusion can be confirmed by echo-
to increased oxygen demand, resulting in tachycardia and cardiogram.
increased cardiac output. The positive inotropic action of the
hormone increases the force of contraction which, if untreated, Treatment
results in high-output failure. The cardiac manifestations do not respond to conventional
therapy unless hormone replacement therapy is instituted. It is
Signs and symptoms
advisable to start with a low dose of thyroid hormone in elderly
Apart from signs of hyperthyroidism like ocular signs and patients and those with angina, as tachycardia may exacerbate
goitre, the patient may complain of palpitations, dyspnoea or myocardial ischaemia.
angina. The pulse is rapid and of high volume (due to the high-
output state) and may be irregular if atrial fibrillation is present. Adrenal Disorders
Systolic hypertension is invariably present. A loud first heart Hyperaldosteronism
sound and a third heart sound may be present with a systolic Hypersecretion of aldosterone results in hypertension,
murmur in the left parasternal region. The hyperdynamic heart hypokalaemia and metabolic acidosis. The diagnosis is
may cause rubbing of the normal pericardium against the suspected when the patient has diastolic hypertension and low
pleura, resulting in a scratchy sound, the Means-Lerman serum potassium. Treatment is aimed at removal of the
scratch. In advanced untreated cases, there may be signs of mineralocorticoid-producing tumour but in patients who are
cardiac failure. at poor risk for surgery, spironolactone in high doses (up to 200
mg/day) may be given.
Investigations
The commonest electrocardiographic changes are sinus Cushing’s syndrome
tachycardia or atrial fibrillation (which may be at first paroxysmal The cardiac manifestations are usually those of hypertension
and then permanent). The P wave may be notched and the PR and ischaemic heart disease due to hyperlipidaemia. The
interval may be prolonged. About 15% of patients have a right treatment is that of the primary disease.
bundle branch block.
Adrenal insufficiency
Treatment Decreased secretion of glucocorticoids results in marked
Cardiac manifestations generally do not respond to conventional hypotension which worsens on standing.The electrocardiogram
cardiac drugs without specific anti-thyroid treatment. Beta- reveals sinus bradycardia, flat or inverted T-waves and
blockers are useful as they slow the heart rate and suppress beta- generalised low voltage. The treatment is by replacement
adrenergic activity. Digitalis and diuretics are useful in treating therapy with corticosteroids.
cardiac failure.
Phaeochromocytoma
Hypothyroidism This is a catecholamine-producing tumour which causes severe
The heart becomes pale and flabby and dilates. Histopathology adrenergic stimulation, resulting in hypertension and
reveals swelling of the myofibrils, loss of striations and interstitial tachycardia. The catecholamine release and its manifestations
724 fibrosis. There is increased capillary fragility which leads to are usually episodic, though, hypertension may be permanent
 Heart in Systemic Diseases
in a few cases. The heart may develop a cardiomyopathy-like Kwashiorkor may also be seen in adults. The heart becomes
picture in chronic cases. thin-walled and flabby and there is atrophy of the muscle
fibres. Clinically, the patient has hypotension, low pulse
Electrocardiography reveals left ventricular hypertrophy, T-wave
pressure and low cardiac output. Generalised signs of
inversion, sinus tachycardia and occasionally, paroxysmal atrial
malnutrition are seen.
tachycardia.
Beriberi
The adrenergic activity should be blocked initially with alpha-
adrenergic blockers like phenoxybenzamine or prazosin. Later Beriberi is due to thiamine (vitamin B1) deficiency and is either
on, beta-blockers or calcium-channel blockers may be added. of the dry or wet variety. The heart is involved in wet beriberi. It
Treatment is by surgical excision of the tumour. may occur due to deficient intake in patients eating polished
rice, or in alcoholics and in diabetes. It may also form part of
Pituitary Gland Disorders generalised hypovitaminosis.
Acromegaly
Thiamine helps in the oxidation of pyruvic acid to lactic acid
The cardiovascular manifestations include hypertension, and deficiency leads to pyruvate and lactate accumulation. This
ischaemic heart disease and congestive heart failure. The results in peripheral vasodilatation and reflex tachycardia, a
heart size is markedly enlarged, out of proportion to the rest hyperkinetic circulatory state. Renal retention of sodium and
of the splanchnomegaly. The hypertension responds well to water leads to increased blood volume. Chronic beriberi may
conventional therapy. result in congestive cardiac failure.
HEART IN ANAEMIA Signs and symptoms
Chronic severe anaemia (haematocrit < 25%) leads to a high- The patient complains of severe dyspnoea on exertion and
output state. Since the oxygen-carrying capacity of the RBCs is swelling of the legs, along with the classical signs of dermatitis
reduced, accumulation of metabolites occurs in the tissues and and peripheral neuropathy. On examination, there is tachycardia,
causes peripheral vasodilatation leading to reflex tachycardia wide pulse pressure and signs of cardiac failure, with pericardial
and hyperkinetic circulatory state. Chronic anaemia leads to or pleural effusion. Auscultation may reveal a third heart sound
work hypertrophy of the heart and finally to its dilatation and and apical systolic murmur.
cardiac failure.
Investigations
Signs and Symptoms Electrocardiogram shows sinus tachycardia, low-voltage QRS
The commonest symptoms are fatigue, dyspnoea on exertion, complex and T-waves, and prolongation of the QT interval. Chest
anginal pains and swelling of the ankles. X-ray will show an enlarged cardiac shadow and signs of
pericardial or pleural effusion.
Physical examination reveals tachycardia and collapsing pulse,
and pistol-shot sound and Duroziez’s murmur may be audible Diagnosis
over the femoral artery. The heart may be clinically enlarged The diagnosis is made clinically by the presence of hyperkinetic
and the apex beat hyperdynamic. There may be loud heart circulatory state, skin changes and peripheral neuropathy.
sounds and a systolic ‘haemic’ murmur at either the base or the Laboratory analysis will reveal increased blood pyruvate and
apex of the heart. Mid-diastolic murmurs across the mitral and lactate levels.
tricuspid valves may be heard and are due to increased flow. If
Treatment
the ventricles dilate, murmurs of tricuspid and mitral regurgitation
may be heard. Dilatation of the great vessels may cause murmurs Patients do not respond well to conventional cardiac therapy.
of aortic and pulmonary regurgitation. There may be signs of Thiamine given in doses of 100 mg daily, either intravenous or
congestive cardiac failure. intramuscular, brings about dramatic improvement in a few
days. Concurrent treatment with digoxin, diuretics and a low-
Investigations sodium diet is also advisable.
Electrocardiogram reveals tachycardia and flattened or inverted
T waves. X-ray chest may show a normal or dilated heart. The HEART IN COLLAGEN DISEASES
haemogram reveals the underlying anaemia. Systemic Lupus Erythematosus
Treatment The heart is involved in 50% to 60% of cases of SLE. There are
The treatment is that of anaemia and, if possible, it’s underlying three modes of involvement.
cause. Severe anaemia may require blood transfusions.Transfusion Pericarditis is the commonest lesion. Exudative pericardial
of whole blood may overload the circulation; in these cases effusion occasionally may cause cardiac tamponade. Rarely
packed cells may be transfused after intravenous frusemide there may be constrictive pericarditis.
injection. Digoxin is not useful in treating cardiac failure due to
anaemia, though diuretics may help in reducing the oedema. Endocarditis takes the form of Libman-Sacks verrucous
vegetations, which are formed of degenerated valve tissue and
HEART IN MALNUTRITION AND VITAMIN DEFICIENCY may be as large as 3 mm. Usually, they do not cause any valvular
Protein-Calorie Malnutrition malfunction.
This is seen mainly in children either as marasmus or Myocarditis is present on histopathology at autopsy which
kwashiorkor and is due to deficiency of protein intake. reveals fibrinoid necrosis and changes of angiopathy.
725
 Polyarteritis Nodosa Treatment
This disease is characterised by necrotising inflammation of the All patients with cardiovascular syphilis should be given
blood vessels, also involving those of the heart. The coronary antibiotic therapy to check further progress of the disease.
arteries are involved and angina pectoris and myocardial Surgery is indicated for aneurysm and aortic regurgitation.
infarction may result. Hypertension, due to renal artery Coronary ostial narrowing may be treated by endarterectomy
involvement, is very common and may lead to congestive heart or bypass grafting.
failure. Atrial flutter and fibrillation are also observed in some
cases. HYPERKINETIC CIRCULATORY STATES
Hyperkinetic circulatory states comprise conditions where the
Scleroderma resting cardiac output is increased to more than 6 litres/minute.
This disease is characterised by vasculitis, but the process is The principal contributing factor is lowered peripheral vascular
slow and results in scarring and fibrosis, leading to obliteration resistance (afterload) leading to increased venous return. This
of small vessel lumen. Obliteration of pulmonary vessels leads may be the result of peripheral vasodilatation or of peripheral
to the development of pulmonary hypertension. Coronary shunting as in arteriovenous fistulae. The cardiac output rises
artery involvement is common and leads to precipitation of due to an increase in heart rate, stroke volume or both. Usually,
anginal attacks and myocardial infarction. Myocardial the patients cope with the problem well and do not develop
involvement due to fibrosis results in congestive cardiac cardiac failure. However, in patients in whom the problem
failure. Atrio-ventricular conduction defects are also observed, develops acutely, cardiac failure may result. Causes of
as is pericarditis. Cardiac dilatation may produce regurgitation hyperkinetic circulatory states are given in Table 1.
murmurs.
Table 1: Causes of Hyperkinetic Circulatory States
Rheumatoid Arthritis
Physiological
All the cardiac tissues are involved. Valvular involvement is due After a hot bath
to rheumatoid granulomas, and the commonest valves affected Vigorous exercise
are the aortic and the mitral, with regurgitation as the end result. Pregnancy
Myocarditis, due to granulomas, may precipitate left ventricular Pathological
failure. Pericarditis resembling tuberculosis is quite common Chronic high-output states
and may occur in as many as 50% of cases. About 20% of the Thyrotoxicosis
cases may have coronary arteritis. Chronic severe anaemia
Beriberi
Reiter’s Disease High fever
Paget’s disease of bones
The heart is involved usually only in the acute stages of the
Systemic arteriovenous fistulae
disease when pericarditis and atrio-ventricular conduction Hyperkinetic heart syndrome
defects may occur. Auscultation may reveal apical systolic Hepatic diseases
murmur and occasionally aortic and mitral regurgitation. Acute high-output states
Severe anaemia and thyrotoxicosis that worsen suddenly
SYPHILITIC HEART DISEASE Acquired arteriovenous fistulae
Syphilitic Aortitis and Aortic Regurgitation
Syphilis most commonly involves the ascending aorta, probably Paget’s Disease of Bones
because it has a richer lymphatic supply. Fibrous tissue replaces This is characterised by a process of rapid bone formation and
normal aortic wall tissue, leading to weakening of the walls and resorption at various sites, with increased vascularity of the affected
aneurysm formation.The aneurysm is usually fusiform in shape. bones.However, this is not the cause of the high-output state,which
The aorta assumes a ‘tree bark’ appearance due to wrinkling of is believed to be due to increased blood flow in the cutaneous
the intima. If the infection and inflammation extend into the vessels overlying the affected bones, in order to dissipate the
root of the aorta, it may cause dilatation of the aortic annulus heat produced because of increased metabolism of the bones.
and result in aortic regurgitation. The latter is characterised by
There are no specific findings in the cardiovascular system.
a loud second sound (‘bruit de tambour’) and an early diastolic
Metastatic calcification of the valve rings and conduction tissues
regurgitation murmur which is better heard on the right sternal
may occur, resulting in atrioventricular blocks. There is no
border, owing to the dilated aorta. The EDM of rheumatic aortic
specific treatment for the high-output state, except that for
regurgitation is better heard in the left third intercostal space Paget’s disease itself.
(Erb’s area).
Arteriovenous Fistulae
Coronary Ostial Narrowing
They produce high-output states only if they are large in size.
This results in angina pectoris. However, it differs from the Clinical findings reveal a high-volume pulse and mild tachycardia.
angina caused by atherosclerosis in the following manner: Pressure over the fistula may slow the heart rate (Nicaladoni-
attacks come on at rest, anginal pain lasts for a longer period of Branham’s sign). If the fistula is superficial, the skin over it may be
time, and angina is not relieved by sublingual nitrates. warmer and auscultation usually reveals a ‘machinery’ murmur.
Syphilitic Myocarditis Auscultation of the heart may reveal third and fourth heart
sounds. These fistulae may be congenital or acquired.
This is not commonly seen now. Gumma formation was
common in earlier times and resulted in atrio-ventricular Congenital fistulae may be single or multiple and may vary in
726 conduction blocks. size from that of a strawberry birthmark to huge, ugly swellings
 Heart in Systemic Diseases
that disfigure the limbs. They are more common in the lower Hyperkinetic Heart Syndrome
limbs. The affected limb may be swollen and enlarged. This syndrome usually occurs in young men; they have a high-
Hereditary haemorrhagic telangiectasia is a congenital output state without any detectable cause. They complain of
condition in which arteriovenous fistulae may occur.These often palpitations and atypical chest pain. Examination shows a high
involve the liver and lungs. The liver may be enlarged and pulse pressures and third and fourth heart sounds; in some
palpable and a bruit may be heard over it. patients, systolic murmurs are heard. The exact cause of the
Acquired fistulae usually occur after gunshot and stab wounds syndrome is not known.
and are commonly found in the thighs. Due to the increased Treatment with beta-adrenoreceptor blockers yields excellent
blood flow, the affected limb increases in size. Other types of results.
acquired fistulae are shunts that are surgically made for
Hepatic Diseases
haemodialysis, those occurring in Wilms’ tumour and, rarely, by
rupture of an aortic aneurysm into the inferior vena cava. Hepatocellular failure leads to vasodilatation resulting in high-
output states. There may also be arterio-venous fistulae in
Diagnosis the lungs. The exact cause is not known. These may be due to
The skin changes over the fistula, the enlarged limb and the hypoxia or diminished deactivation of vasodilator substances
continuous murmur are pathognomonic. The electrocar- and oestrogens in the liver.
diogram may be either normal or may reveal mild left ventricular
enlargement. Chest roentgenograms reveal either a normal RECOMMENDED READINGS
sized or a slightly enlarged heart. To localise the site of the fistula, 1. Klein I. Endocrine Disorders and Cardiovascular Disease Chapter 81.
Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine; 8th Ed.
angiograms may be necessary. 2007: pp. 2033-46.
Treatment 2. Whitworth JA, Mangos GJ, Kelly JJ. Cushing, cortisol, and cardiovascular
disease. Hypertension 2000; 36:912-6.
Small fistulae may be left alone, especially if they do not cause
3. Moder KG, Miller TD, Tazelaar HD. Cardiac involvement in systemic
cosmetic embarrassment. Surgical excision yields excellent lupuserythematosus. Mayo Clin Proc 1999; 74:275-84.
results; this may, however, not be possible in all patients, 4. Kitas G, Banks MJ, Bacon PB. Cardiac involvement in rheumatoid disease.
especially those having multiple or very large fistulae. Clin Med 2001; 1:18-21.

727
 12.28 Disorders of the Myocardium

KK Talwar, Pawan Poddar

Disorders of the myocardium are an important and of cases of DCM are familial. A large number of genes have been
heterogeneous group of diseases. The term ‘cardiomyopathy’ implicated. Modes of inheritance include autosomal dominant
was first used in 1957 and is defined by World Health (AD) with incomplete penetrance, autosomal recessive (AR) and
Organization as ‘a disease of the myocardium associated with X-linked.
cardiac dysfunction’. Various classifications for cardiomyopathies
Clinical Presentation
have been proposed. American Heart Association has divided
cardiomyopathies into 2 groups: primary cardiomyopathies Clinical picture is dominated by symptoms of left ventricular
(solely or predominantly confined to heart muscle); and failure. Some patients remain asymptomatic for years. Others
secondary cardiomyopathies (pathological myocardial present with symptoms of fatigue and weakness due to
involvement as part of generalised systemic disorders) diminished cardiac output. Elevated left ventricular (LV)
(Figure 1). filling pressures result in symptoms of exertional dyspnoea,
paroxysmal nocturnal dyspnoea and orthopnoea. Clinical
DILATED CARDIOMYOPATHY course is punctuated by thromboembolism and atrial or
ventricular arrhythmias. Chest pain may result from underlying
Dilated cardiomyopathy (DCM), the most common form of
coronary artery disease (CAD) or pulmonary embolism.
cardiomyopathy, is characterised by ventricular dilatation and
Features of right heart failure may develop in late stages of
impaired contraction of left or both ventricles leading to systolic
the disease.
dysfunction. It is more common in males and between the ages
of 20 and 50 years. The 5-year survival after diagnosis is 50%. Physical findings include tachycardia, low arterial pressure and
cool extremities secondary to low cardiac output. Jugular
Aetiology venous pressure (JVP) may be elevated with prominent ‘a’ and
Dilated cardiomyopathy can occur in an idiopathic form or ‘v’ waves. Dependent oedema, ascites and hepatomegaly
secondary to other cardiac or systemic diseases (Table 1). indicate right heart involvement. Cardiovascular examination
Idiopathic form may represent sequelae of remote episodes of reveals marked cardiomegaly with palpable third heart sound.
viral myocarditis. Autoimmunity has also been implicated as the Auscultatory findings include soft S1, prominent S3 and
underlying mechanism in idiopathic DCM. About 25% to 35% pansystolic murmurs of mitral and tricuspid regurgitation.

Figure 1: American Heart Association (AHA) classification of cardiomyopathies.

HCM = Hypertrophic cardiomyopathy; DCM = Dilated cardiomyopathy; ARVD/C = Arrhythmogenic right ventricular dysplasia/cardiomyopathy; LVNC = Left ventricular
noncompaction; LQTS = Long-QT syndrome; SQTS = Short-QT syndrome; CVPT = Catecholaminergic polymorphic ventricular tachycardia; SUNDS = Sudden unexplained
nocturnal death syndrome.

728
 Disorders of the Myocardium
Pulmonary venous congestion produces tachypnoea and rales Pathology
over bilateral basal lung fields. Grossly, there is cardiomegaly with increase in myocardial mass
and marked chamber dilatation (Figure 3). Mural thrombi are
Table 1: Secondary Causes of Dilated Cardiomyopathy
seen frequently at various stages of organisation.
Endocrine disorders
Cushing’s disease
Diabetes mellitus
Growth hormone abnormalities
Hypothyroidism/hyperthyroidism
Phaeochromocytoma
Nutritional deficiencies
Carnitine
Selenium
Thiamine
Metabolic disturbances
Hypocalcaemia
Hypophosphataemia
Uraemia
Toxins
Ethanol
Antiretroviral agents
Chemotherapeutic agents: Anthracyclines
Radiation
Cocaine
Phenothiazines
Heavy metals: cobalt, lead, mercury

Investigations
Electrocardiographic findings are non-specific. They include
isolated T-wave changes, septal Q-waves, prolonged atrio-
ventricular conduction, bundle branch blocks, and atrial or
ventricular arrhythmias. Echocardiography is the main stay of
diagnosis and reveals dilatation of left ventricle and other Figure 3: Gross photograph showing left-side of the heart with dilated cavity,
chambers with globally diminished systolic function (Figure 2). endocardial sclerosis and mural thrombus in DCM.
It may identify mural thrombi, quantify mitral and tricuspid
regurgitation and assess severity of pulmonary hypertension. Microscopic findings are non-specific and consist of myocyte
Echocardiography excludes secondary causes like valvular hypertrophy, myocyte atrophy and interstitial fibrosis.
heart disease. Thallium myocardial perfusion imaging or Characteristic histologic findings in certain secondary forms of
coronary angiography is required to definitely exclude CAD. DCM include lymphocytic infiltration in myocarditis,
Endomyocardial biopsy (EMB) is done in selected cases to granulomas in sarcoidosis and intramyocellular iron deposition
rule out myocarditis, infiltrative disorders like amyloidosis, in haemochromatosis.
sarcoidosis, haemochromatosis and storage disorders.
Treatment
Detection of viral antigen in EMB specimen may help to plan
anti-viral therapy. Treatment is directed to control heart failure symptoms.
Diuretics, β-blockers, angiotensin converting enzyme inhibitors
(ACEIs)/angiotensin receptor blockers (ARBs) and digoxin form
the mainstay of treatment. Diuretics and digoxin provide
symptomatic relief whereas β-blockers, ACEIs/ARBs and
spironolactone improve survival as well. Therapy with
β-blockers and ACEIs/ARBs should be initiated in lowest dose
and then gradually up-titrated to maximum tolerated dose.
Counselling regarding the natural history of the disease and
the need for long-term treatment goes a long way in ensuring
compliance to medications. Salt and fluid intake is restricted.
All patients with prior ventricular fibrillation/sustained
ventricular tachycardia should be offered implantable
cardioverter defibrillator (ICD). Implantation of ICD also
improves survival in patients with left ventricular ejection fraction
less than 30%. In patients with left bundle branch block (LBBB)
with wide QRS (>120 ms) and left ventricular ejection fraction
Figure 2: 2D echocardiographic image (apical 4-chamber view) showing (LVEF) ≤35%, who remain symptomatic despite maximum
dilatation of all four cardiac chambers in a patient with DCM.
medical therapy, cardiac resynchronisation therapy (CRT) using 729
 biventricular pacing improves survival, functional status, Pathology
exercise tolerance and ejection fraction. Patients who have Gross
progressed to end-stage disease are candidates for heart
During the active phase, the gross appearance of the heart is
transplantation. Anticoagulation is indicated in patients with
variable as the myocardial involvement may be focal, patchy or
mural thrombus and prior thromboembolism. Arrhythmias
diffuse. The myocardium is often mottled with pale foci and
should be aggressively treated. In patients with atrial fibrillation,
hyperaemic-haemorrhagic areas. Mural thrombi may be
amiodarone is an effective drug and may restore normal sinus
present, especially in dilated hearts.
rhythm in some.
Histopathology
MYOCARDITIS
There is interstitial mononuclear inflammatory infiltrate
Myocarditis is defined as a disease process characterised predominantly lymphocytic, with damage to adjacent
by non-ischaemic inflammatory cellular infiltration of the myocytes (Figure 4). This may be focal, multifocal or diffuse.
myocardium with or without associated myocyte necrosis The nature of myocarditis can be confirmed by immuno-
(Dallas criteria). histochemical and molecular work-up. The most common viral
Aetiology cause of myocarditis is coxsackie virus B as confirmed by
molecular analysis. Lately, parvovirus is emerging as an
The most common underlying aetiology of myocarditis is
important cause of viral myocarditis.
common viral infections (coxsackie virus A and B, echovirus,
adenovirus, poliovirus, parvovirus B-19, influenza virus, HIV and
others). Less commonly, myocarditis results from other
infections (bacterial, fungal, parasitic or rickettsial), toxic or
hypersensitive drug reactions, collagen vascular disorders,
snake/insect bites, radiation injury or electric shock.
Pathogenesis
Myocyte injury may result from direct cytopathic effect of
inciting agent, cell-mediated cytotoxicity or autoantibody-
mediated damage.
Clinical Presentation
Clinical presentation of myocarditis is variable and includes
asymptomatic presentation with ECG abnormalities, sub-acute
presentation with symptoms and signs of heart failure and
ventricular dilatation (resembling DCM), and fulminant
presentation with severe LV dysfunction without chamber
dilatation. Symptoms may include dyspnoea, orthopnoea, chest
Figure 4: Microphotograph showing myocarditis with lymphocytic infiltrate
pain, cough, fatigue, palpitations and syncope. A viral prodrome and myocyte necrosis (H and E X 280).
with fever, myalgia, and respiratory or gastrointestinal
symptoms may precede the development of cardiac symptoms.
Treatment
Atrial and ventricular arrhythmias are common. Conduction
blocks, including complete heart block, may be seen. Acute Treatment is supportive with diuretics, ACEIs and β-blockers. In
coronary syndrome remains an important differential diagnosis. patients who worsen on medical therapy, mechanical circulatory
assist devices may be used as a bridge for transplantation or recovery.
Investigations About 40% of patients recover uneventfully with supportive
Electrocardiography shows tachycardia with non-specific ST- treatment. Antiviral therapy is being evaluated in patients with
segment and T-wave abnormalities, occasionally mimicking positive viral antigen in EMB specimen and immunosuppressive
acute myocardial infarction. Cardiac biomarkers like troponins therapy in patients with negative viral antigen.
and CK-MB are elevated. Echocardiography reveals globally
decreased ventricular function with chamber dilatation. HYPERTROPHIC CARDIOMYOPATHY
However, in fulminant myocarditis, ventricular cavity may be Hypertrophic cardiomyopathy (HCM) is a primary genetic
small with increased wall thickness. Contrast-enhanced cardiac disorder resulting from mutation in genes encoding
magnetic resonance imaging (MRI) reveals delayed gadolinium sarcomeric proteins. The hallmark of HCM is left (± right)
enhancement of the myocardium in T2-weighted images and ventricular hypertrophy in the absence of chronic pressure or
suggests myocarditis. Coronary angiography is done to rule out volume overload. HCM has intrigued clinicians and researchers
CAD. Endomyocardial biopsy is the gold standard for diagnosis for decades due to its heterogenous expression, unique
of myocarditis but has limited sensitivity and specificity. It is pathophysiology and variable clinical presentation. It is known
indicated in patients with unexplained rapidly progressive heart by various other names like hypertrophic obstructive
failure of less than 2 weeks duration refractory to conventional cardiomyopathy (HOCM), idiopathic hypertrophic subaortic
treatment and in those with unexplained heart failure stenosis (IHSS), and asymmetric septal hypertrophy (ASH).
associated with life-threatening ventricular arrhythmias or Hypertrophic cardiomyopathy is the most common inherited
conduction system disease. Detection of viral antigen in EMB cardiovascular disorder with a prevalence of 0.2% (or 1 in 500)
730 specimen confirms a viral aetiology. in the general population.
 Disorders of the Myocardium
The HCM phenotype usually manifests during adolescence with
marked increase in wall thickness accompanying adolescent
growth spurt. Differentiating HCM from physiological hyper-
trophy in ‘athlete’s heart’ is important for clinical implications
(Table 2). Apical HCM (wall thickening confined to the left
ventricular apex) is a morphological variant characterised by
spade-shaped ventricular cavity (Figure 5) and giant symmetrical
T wave inversions in lateral precordial leads on ECG (Figure 6).
This variant has a benign course and good prognosis.

Table 2: Differentiating Hypertrophic Cardiomyopathy from

Athlete’s Heart
HCM Athlete’s Heart
Family history of HCM + –
Marked LVH or unusual patterns of + –
hypertrophy
LV cavity dilatation – +
LA enlargement + –
Abnormal ECG patterns + –
Figure 5: Left ventriculogram at end diastole showing ‘spade-shaped
Abnormal LV filling pattern on pulse + –
ventricular cavity’ in a patient with apical HCM.
Doppler interrogation of mitral inflow
velocities
hypertrophy, interstitial fibrosis, myocardial ischaemia and
Female gender + –
abnormal calcium influx. Systolic function is normal or increased
Thickness with deconditioning – +
in HCM.
Aetiology: Genetics Left ventricular outflow tract obstruction
Hypertrophic cardiomyopathy is inherited as an autosomal Left ventricular outflow tract obstruction (defined as gradient
dominant trait with positive family history in over 60% of cases. The ≥30 mm) in HCM is dynamic and varies with changes in preload,
remainder of the cases arise from de novo mutations in known or as afterload and contractility (Table 3). It is seen at rest in 25% of
yet unknown genes or may include other causes of LV hypertrophy individuals and that at rest or on provocation in 70%. It is
like Fabry’s disease and glycogen storage disorders. More than 450 produced by systolic anterior motion (SAM) of the mitral valve
mutations in 13 sarcomeric genes have been implicated. and mid-systolic contact with hypertrophied septum and is an
Pathophysiology independent predictor of heart failure and cardiovascular deaths.
Diastolic dysfunction Myocardial ischaemia
Diastolic dysfunction is seen in 80% of patients and manifests Myocardial ischaemia in HCM results from multiple mechanisms
as dyspnoea and exercise intolerance. This is related to LV —reduced arteriolar density, myocardial hypertrophy, micro-

Figure 6: ECG of a patient with apical HCM showing giant T wave inversions (defined as ≥5 mm in limb leads and ≥10 mm in chest leads) with tall R waves.
731
 vascular dysfunction, left ventricular outflow tract obstruction measure left ventricular outflow tract (LVOT) pressure gradient and
(LVOTO) and diastolic dysfunction. quantify mitral regurgitation. Since LVOT gradient is dynamic,
Doppler assessment should be done both at rest and after
Table 3: Effect of Changes in Preload, Afterload and Myocardial provocative manoeuvres like Valsalva and exercise. Magnetic
Contractility on LVOT Gradient and HCM Murmur resonance imaging (MRI) is useful when hypertrophy is confined
Manoeuvres increasing LVOT Manoeuvres Decreasing to unusual areas like apex or anterolateral free wall, which are
Gradient and Intensity of LVOT Gradient and Intensity difficult to image adequately with echocardiography.
Murmur of Murmur
I Decreased preload I Increased preload
Valsalva manoeuvre IV fluids
Standing Supine position
Nitrates II Increased afterload
II Decreased afterload Squatting
ACEIs/ARBs Isometric handgrip
Amyl nitrite/Nitroglycerine
III Increased myocardial contractility
Premature ventricular contractions
Exercise

Natural History
Natural history of HCM is variable. Some patients remain
asymptomatic throughout life, whereas in others, clinical course
is marked by occurrence of symptoms of heart failure, atrial
arrhythmias or sudden cardiac death (SCD). Symptoms may
develop at any age. Hypertrophic cardiomyopathy related Figure 7: 2D echocardiographic image (apical 4-chamber view) showing
mortality in the community is about 1% per year in adults and hypertrophied basal septum (arrows) in a patient with HCM.
2% per year in children. Three per cent of patients develop end-
stage disease characterised by wall-thinning and systolic
dysfunction mimicking dilated cardiomyopathy.
Clinical Presentation
Most common presenting symptoms in affected patients include
dyspnoea on exertion, angina, fatigue, presyncope or syncope
and palpitations. Syncope may result from sudden reduction in
cardiac output secondary to atrial or ventricular arrhythmias or
significant LVOTO. Physical examination in patients without
obstruction may just reveal brisk carotid upstroke and a left-sided
fourth heart sound. In patients with LVOTO physical examination
demonstrates a prominent ‘a’ wave in jugular venous waveform,
bifid carotid pulse with brisk upstroke and a secondary shoulder,
double or triple apical impulse, reversed splitting of second heart
sound and a dynamic ejection systolic murmur at the left lower
sternal border and apex. Ejection systolic murmur varies in
Figure 8: 2D echocardiographic image (parasternal long-axis view) showing
intensity with the magnitude of LVOTO (Table 3). Pansystolic
hypertrophied basal septum (arrows) in a patient with HCM.
murmur (PSM) of mitral regurgitation is heard at the apex in some
patients with obstruction.
Cardiac catheterisation is indicated in patients with chest pain
Investigation and atherosclerotic risk factors to exclude epicardial coronary
Electrocardiographic abnormalities are seen in 90% to 95% of artery disease. It can quantify LVOT gradient at rest or with
patients with HCM which include LV hypertrophy, left atrial provocation in patients with LVOTO (Figure 9).
enlargement, ST segment and T wave abnormality, prominent Pathology
Q-waves and diminished R-waves in lateral precordial leads.
Grossly the heart is overweight and bulky with regional or
Periodic ambulatory Holter monitoring detects atrial or
concentric left ventricular hypertrophy. Myocardial hypertrophy
ventricular arrhythmias and helps risk stratify patients for SCD.
is strikingly variable in extent and distribution. Asymmetric
Failure of blood pressure to increase during cardiopulmonary
patterns of hypertrophy are more common, often confined to
exercise testing identifies a subset with increased risk for SCD.
basal anterior septum, but occasionally to posterior septum,
Echocardiography is the ‘gold standard’ for diagnosis of HCM and anterolateral free wall or apex. In some patients, disease involves
for screening asymptomatic relatives. Classical 2D echocardio- both the ventricles or is confined only to the right ventricle. The
graphy findings include asymmetrical septal hypertrophy (Figures magnitude of hypertrophy may vary from minimal to marked
7 and 8), small LV cavity,LA enlargement and SAM of anterior mitral (wall thickness up to 60 mm), even in patients with similar
leaflet. Doppler echocardiography can assess diastolic dysfunction, genotypes. Mitral valve is elongated and enlarged in two-thirds
732
 Disorders of the Myocardium
Figure 9: Simultaneous LV and aortic (Ao) pressure tracings in a patient with obstructive HCM showing marked increase in LV-aortic pressure gradient and
decrease in pulse pressure following a premature ventricular contraction—the Brockenbrough Braunwald phenomenon.

of patients. This along with basal anterior septal hypertrophy Treatment

narrows the left ventricular outflow tract and contributes to Affected individuals should be counselled to avoid strenuous
left ventricular outflow tract obstruction. The subepicardial exercise and competitive sports. Symptomatic patients with
coronary arteries are usually normal. LVOTO are first managed medically. Medical therapy consists of
Myocyte disarray with myocardial hypertrophy is appreciable β-blockers, calcium channel blockers and disopyramide. β-
at light microscopy. The myocytes display bizarre forms blockers are used as first-line agents. They improve disabling
with herringbone pattern. Myocyte disarray is characteristic symptoms and limit the latent outflow gradient provoked during
and occupies at least 20% of one or more tissue blocks. exercise when sympathetic tone is high by virtue of their negative
The interstitial arteries are thickened with smooth muscle ionotropic and chronotropic effects. β-blockers lessen LV
proliferation. contractility and myocardial oxygen demand and possibly reduce
microvascular myocardial ischaemia. β-blockers are less effective
Risk Stratification and Sudden Cardiac Death in patients with obstruction under basal condition. Disopyramide
Sudden cardiac death in HCM is most common in adolescents is an important agent in such patients. It decreases both resting
and young adults and has a predilection for early morning and provocable gradients but has anticholinergic side effects
hours. Hypertrophic cardiomyopathy is the most common cause which should be watched for. It should be avoided in patients
of SCD in competitive athletes. Major underlying mechanism with benign prostatic hypertrophy and glaucoma. Disopyramide
of SCD in these patients is ventricular tachyarrhythmias. Several can result in fast ventricular response if patient develops atrial
risk factors for SCD have been identified (Table 4).The incidence fibrillation (AF) and should always be used with β-blockers.
of SCD is 1% per year in patients with ≤1 risk factors and 3% per Angiotensin converting enzyme inhibitors increase outflow tract
year in patients with ≥2 risk factors. obstruction and should be avoided. Patients with obstructive
HCM who remain symptomatic despite medical therapy can be
Table 4: Risk Factors for SCD in HCM treated with surgical myomectomy or alcohol septal ablation. In
Proven Risk Factors alcohol septal ablation, selective injection of 1 to 2 mL of absolute
Aborted cardiac arrest alcohol in first septal branch of left anterior descending artery
Spontaneous sustained ventricular tachycardia causes infarction and necrosis of hypertrophied part of the
Family history of premature SCD septum and relieves outflow obstruction. Elderly patients with
Unexplained syncope obstructive HCM or patients with mid-cavitary obstruction may
LV wall thickness ≥30 mm benefit from dual chamber pacing with short AV delay. Patients
with ≥1 major risk factors for SCD should be offered ICD.
Multiple repetitive non-sustained VT on Holter monitoring
Prospective screening of family members of affected individuals
Abnormal BP response to exercise
should be done with yearly 12-lead ECG and echocardiography
733
 beginning at 12 years of age and continued up to 18 to 21 years congestion. Cardiac size is within normal limits. Echo-
of age and thereafter every five years. cardiography reveals normal-sized ventricles with biatrial
enlargement and evidence of atrioventricular valve
RESTRICTIVE CARDIOMYOPATHY regurgitation (Figure 10). Ventricular walls may be thickened
Restrictive cardiomyopathy (RCM), a less common form of in patients with infiltrative disorders and may show
cardiomyopathy, is characterised by increased ventricular characteristic granular and sparkling appearance and thickened
stiffness that results in impaired diastolic filling of the ventricle. interatrial septum in amyloidosis (Figure 10). Doppler
The systolic function remains normal in early stages of the echocardiography reveals characteristic restrictive pattern of
disease process. The ventricular wall thickness is either normal mitral inflow velocity (Figure 11). Cardiac catheterisation shows
or increased depending on the underlying aetiologies. characteristic ‘dip and plateau’ configuration in ventricular
pressure tracing. Endomyocardial biopsy may reveal specific
Aetiology
causes of RCM like amyloidosis, sarcoidosis and storage
Restrictive cardiomyopathy can occur in an idiopathic form or as disorders. CT chest for pericardial thickness and calcification
part of specific disorders (Table 5). Idiopathic RCM is most common should be done in every case to rule out constrictive pericarditis.
(50% of all cases) and can be familial with autosomal dominant
mode of inheritance. Among the specific forms of RCM, amyloidosis
is the most common outside the tropics. Endomyocardial fibrosis
(EMF) is particularly common in the tropics.

Table 5: Secondary Causes of Restrictive Cardiomyopathy

Amyloidosis
Endomyocardial fibrosis
Sarcoidosis
Storage disorders: Haemachromatosis, Fabry’s disease, Glycogen
storage disorder
Drugs: Anthracyclines, Serotonin, Methysergide
Others
Gaucher’s disease
Scleroderma
Hurler’s syndrome
Hunter’s syndrome
Pseudoxanthoma elasticum Figure 10: 2D echocardiographic image (apical 4-chamber view) showing
Hyper-eosinophilic syndrome dilatation of both the atria with normal-sized ventricles and mild tricuspid
Carcinoid heart disease regurgitation in a patient with amyloidosis. Note the granular and sparkling
Metastatic cancer appearance of interventricular septum.
Radiotherapy

Clinical Presentation
Patients with RCM can present with symptoms and signs of right
or left ventricular failure. Right-sided symptoms and signs
predominate in most patients. Left-sided involvement gives rise
to dyspnoea on exertion, paroxysmal nocturnal dyspnoea and
orthopnoea. Thromboembolic complications are common.
Conduction blocks are common in amyloidosis and sarcoidosis
whereas atrial fibrillation (AF) is seen in idiopathic form.
Physical examination reveals tachycardia. JVP is elevated with
rapid ‘x’ and ‘y’ descents. Kussmaul’s sign is present in some
patients. Hepatomegaly, peripheral oedema and ascites are
often present. Cardiovascular findings include third and fourth
heart sounds and pansystolic murmurs of mitral and/or
Figure 11: Pulse wave Doppler interrogation of mitral inflow velocities showing
tricuspid regurgitation. Cardiomegaly is characteristically restrictive LV filling pattern (E > A) in a patient with RCM.
absent. It is important to accurately differentiate RCM from
constrictive pericarditis (Table 6) which can present with similar
Pathology
findings but can be cured surgically.
Based on pathological involvement, RCM can be divided into
Investigations two groups—with predominant endocardial involvement, or
Electrocardiography shows non-specific ST- and T-wave myocardial involvement. Conditions causing predominant
abnormalities. There may be evidence of left ventricular endocardial involvement include EMF, Loeffler’s endocarditis,
hypertrophy, AF or conduction abnormalities. In amyloidosis, carcinoid heart disease, metastatic cancers, radiation and drugs.
ECG may reveal low voltage in limb leads and normal or Conditions with predominant myocardial involvement include
increased voltage in precordial leads. Chest X-ray may show idiopathic RCM, infiltrative disorders (amyloidosis, sarcoidosis)
734 evidence of atrial enlargement with pulmonary venous and storage disorders (haemachromatosis, Fabry’s disease).
 Disorders of the Myocardium
Table 6: Differentiating Restrictive Cardiomyopathy from Constrictive Pericarditis
Restrictive Cardiomyopathy Constrictive Pericarditis
Physical Examination
JVP Kussmaul’s sign may be present Kussmaul’s sign usually present
Pulsus paradoxus Absent Present in one-third of cases
Apical impulse Prominent Usually not palpable
S2 Loud with narrow splitting Wide split
S3 Present Absent
Pericardial knock Absent Present
Murmur of MR/TR Common Uncommon
Electrocardiography Conduction blocks common Conduction blocks uncommon
Chest X-ray No cardiomegaly; no pericardial calcification; Pericardial calcification may be seen
signs of pulmonary venous congestion present
2D-Echocardiography
Posterior wall flattening in mid/late diastole Absent Present
Septal bounce Absent Present
Atrial enlargement Marked Mild
Pericardial thickness Normal (<2 mm) Increased
Doppler Echocardiography
Significant respiratory variation in mitral Absent Present
(>25%) and tricuspid inflow velocities (>40%)
Hepatic-vein diastolic flow reversal More in inspiration More in expiration
MR/TR Common/Moderate-to-severe Uncommon/Mild
Catheterisation
Difference between LVEDP and RVEDP >5 mm Hg ≤5 mm Hg
RV systolic pressure (RVSP) >50 mm Hg <50 mm Hg
RVEDP/RVSP <one-third >one-third
Endomyocardial Biopsy Abnormal; may reveal aetiological diagnosis Usually normal
CT/MRI Pericardium usually normal Pericardium is thickened

Characteristic gross examination findings in EMF and Loeffler’s Microscopically, Loeffler’s endocarditis is characterised by
endocarditis include diffuse mural thrombi in ventricles eosinophilic necrotising myocarditis. Amyloid deposits appear
obliterating the apices. In amyloidosis, the heart appears tan, as hyaline eosinophilic material surrounding myocytes in the
firm and rubbery (Figure 12). interstitium. This material is congophilic and gives apple green
birefringence on polarised light (Figure 13).

Figure 13: Microphotograph showing amyloid material deposited in the

interstitium and myocytes (Congo Red X 140).

Treatment
Diuretics are used to treat pulmonary and systemic venous
congestion. Atrial fibrillation is poorly tolerated due to loss of
atrial contribution to ventricular filling and rapid ventricular
response. Attempt should be made to maintain sinus rhythm
by electrical cardioversion or anti-arrhythmic drugs. Digoxin
Figure 12: Gross photograph showing normal-sized left ventricle with tan, firm should be used with caution in patients with amyloidosis
and rubbery myocardium and dilated left atrium in a patient with amyloidosis.
due to its arrhythmogenic potential. Patients with AF, valvular 735
 regurgitation and low ejection fraction are at increased risk of Alcoholic Cardiomyopathy
thromboembolism. They should be treated with oral Long-term alcohol consumption is an important cause of
anticoagulation. Patients with conduction blocks may require dilated cardiomyopathy accounting for 3.8% of all cases. Alcohol
pacemaker implantation. ICD is indicated in patients with is a myocardial toxin which causes myocyte apoptosis and
sustained ventricular arrhythmias. changes in many aspects of myocyte function ultimately
Therapies for secondary forms of RCM are tailored to the leading to chamber enlargement and systolic dysfunction.
underlying aetiologies—chemotherapy and autologous stem Asymptomatic alcoholic cardiomyopathy is seen in patients
cell transplantation for amyloidosis, enzyme replacement consuming >90 g of alcohol a day for >5 years. Patients who
therapy for Fabry’s disease, iron chelation for haemachromatosis continue to drink develop symptoms of heart failure. Treatment
and immunosuppressive therapy for sarcoidosis. includes standard heart failure therapy and abstinence from
alcohol. Prognosis of alcoholic cardiomyopathy patients with
Prognosis abstinence is similar to idiopathic DCM whereas patients who
Prognosis in RCM is variable depending on the underlying continue to drink fare worse.
aetiology. RCM secondary to amyloidosis has poor prognosis
Arrhythmogenic Right Ventricular Dysplasia
with a median survival of less than two years. Idiopathic RCM
has intermediate prognosis with five years survival of 64%. Arrhythmogenic right ventricular dysplasia or cardiomyopathy
(ARVD/C) is a familial cardiomyopathy, mainly affecting the right
Endomyocardial Fibrosis ventricle (RV). Most common mode of inheritance is autosomal
Endomyocardial fibrosis (EMF) is characterised by fibrotic dominant. It is characterised by fibrofatty replacement of the
thickening of the endocardium and obliteration of right, left or myocardium. The disease typically affects inflow, apical, and
both the ventriclular cavities. The disease has predilection for outflow portions of the RV (‘triangle of dysplasia’). Sudden
involvement of apices and inflow portion of the ventricles cardiac death due to arrhythmias originating from right
resulting in atrioventricular (AV) valve regurgitation. Right ventricle is the most common mode of presentation.
ventricular involvement is most common followed by left Progressive right heart failure develops in late stages of the
ventricular and biventricular involvement. Endomyocardial disease. Echocardiography and MRI form the main stay of
fibrosis is common in Brazil, Uganda, Nigeria, Ivory Coast and diagnosis. Fatty replacement of RV myocardium can be reliably
Kerala in Southern India. Several hypotheses have been detected by MRI. Therapeutic options in patients with ARVD/C
proposed to explain the aetiology of EMF. They include hyper- include β-blockers, anti-arrhythmic drugs, or an ICD. Patients
eosinophilia, excessive consumption of plantains rich in with progressive right or biventricular systolic dysfunction are
serotonin, excessive consumption of cassava tubers which treated with standard therapy for heart failure.
are rich in vitamin D, or a diet rich in thorium and deficient Tako-Tsubo Cardiomyopathy
in magnesium (geochemical hypothesis). Endomyocardial
fibrosis differs from other forms of RCM by the presence of Tako-tsubo cardiomyopathy is characterised by transient apical
marked cardiac enlargement due to AV valve regurgitation. ballooning of left ventricle and masquerades as an acute
Echocardiography reveals aneurysmal atria and small ventricles coronary syndrome. Ninety per cent of cases involve post-
with apical fibrosis and cavitary obliteration. Intra-atrial thrombi menopausal women. In majority of cases, symptoms are
and AV valve regurgitation are common findings. Endo- precipitated by physical or emotional stress. Catecholaminergic
cardiectomy ± AV valve repair or replacement is the surgical surge is incriminated in the pathophysiology of the disease.
treatment of choice in patients with advanced disease. Mild Presentation is with chest pain and dyspnoea, ST-segment
cases are treated conservatively with diuretics and digoxin. elevation on ECG and elevated cardiac enzymes. Echocardio-
graphy shows akinetic/hypokinetic apical portion of LV with
OTHER SPECIFIC FORMS OF CARDIOMYOPATHY hyper contractile basal regions. The shape of LV resembles an
Peripartum Cardiomyopathy octopus pot (‘tako-tsubo’). Coronary angiography reveals
normal coronaries. Treatment is supportive and prognosis is
Peripartum cardiomyopathy is characterised by development
good.
of left ventricular systolic dysfunction and symptoms of heart
failure between the last month of pregnancy and the first five RECOMMENDED READINGS
months postpartum. Incidence rates vary from 1 in 1,485 to 1 1. Luk A, Ahn E, Soor GS, Butany J. Dilated cardiomyopathy: a review. J Clin
in 15,000 live births. Proposed aetiopathogenesis include Pathol 2009; 62: 219-25.
myocarditis, abnormal immune response to pregnancy, 2. Maron BJ, Towbin JA, Thiene G. et al. Contemporary Definitions and
nutritional deficiencies, abnormal prolactin levels and Classification of the Cardiomyopathies: An Interdisciplinary Working
maladaptive response to the haemodynamic stresses of Groups; and Council on Epidemiology and Outcomes Research and
Functional Genomics and Translational Biology Cardiology, Heart Failure
pregnancy. Peripartum cardiomyopathy is more common with and Transplantation Committee; Quality of Care and American Heart
advanced maternal age, multiparous state, multiple gestation, Association Scientific Statement from the Council on Clinical Epidemiology
obesity, black race and pre-eclampsia. Clinical presentation and and Prevention. Circulation 2006; 113: 1807-16.
treatment are similar to that in DCM. Dopamine agonist, 3. Seth S, Thatai D, Sharma S, et al. Clinico-pathological evaluation of restrictive
bromocriptine has shown encouraging results in pilot studies. cardiomyopathy (endomyocardial fibrosis and idiopathic restrictive
cardiomyopathy) in India. Eur J Heart Fail 2004; 6 (6): 723-9.
Mortality is 25% to 50%. Fifty per cent of patients experience
4. Talwar KK, Bhargava B, Upasani PT, et al. Haemodynamic predictors of early
resolution of symptoms with normalisation of chamber intolerance and long-term effects of propranolol in dilated cardiomyopathy.
dimensions and systolic function. Patients with persistent LV J Card Fail 1996; 2 (4): 273-7.
systolic dysfunction are at increased risk of death in subsequent 5. Talwar KK, Mahajan R. Transient left ventricular apical ballooning – a novel
736 pregnancy and should be advised to avoid pregnancy. acute cardiac syndrome. Indian Heart J 2007; 59 (1): 11-2.
 12.29 Diseases of the Pericardium

Sanjay Tyagi, Amit Mittal

INTRODUCTION Clinical Features

The pericardium is a fibrous sac surrounding the heart, the Symptoms
thicker, outer parietal pericardium and an inner, thinner Most patients with acute pericarditis experience sharp
visceral layer. The two layers are separated by small amount retrosternal chest pain, but in some cases it may be asymptomatic.
of pericardial fluid (25 to 50 mL) produced by the visceral Pericardial pain is usually worse with inspiration and when supine,
pericardium. It is an ultrafiltrate of the plasma and is resorbed and is relieved by sitting forward. Typically, the pain is referred to
by the lymphatics. The pericardium prevents friction the scapular ridge, presumably due to irritation of the phrenic
between the heart and surrounding structures, acts as a nerves, which pass adjacent to the pericardium. Dyspnoea can
mechanical and immunological barrier, and limits distention occur with acute pericarditis but is common with large pericardial
of the heart thereby maintaining a relatively fixed maximal effusions. Patient may experience constitutional symptoms like
heart volume. fever, bodyache, malaise, joint pain, and anorexia.
Only the lower two-third of the parietal pericardium is sensitive Signs
to pain, the pain sensation being carried by the phrenic nerves.
Inspection of the praecordium is normal but on palpation
Inflammation of the pericardial layers is usually caused by
pericardial rub may be felt in left parasternal area and apex of
infection (viral, bacterial, etc.), but can also have a non-infectious
the heart. The characteristic sign of acute pericarditis is the
aetiology. Chronic inflammation with fibrosis and calcification
‘pericardial rub’ heard on auscultation. It is a high-pitched, to-
can lead to a rigid, thickened and calcified pericardium, with
and fro-scratchy sound, heard both in systole and diastole. It is
progression to pericardial constriction.The most common forms
best audible in the third, fourth and fifth left intercostal spaces
of pericardial diseases include acute and recurrent pericarditis,
near the sternal edge, though the location may change with
isolated pericardial effusion with or without cardiac tamponade,
the position of the patient. It is better heard when the patient
and constrictive pericarditis.
sits up, leans forward and is heard louder if the diaphragm of
PERICARDITIS stethoscope is pressed harder to the chest wall. Sometimes only
the systolic or the diastolic component may be heard and so
Pericarditis is inflammation of the pericardium with or without
the rub can be mistaken for a murmur.
an associated pericardial effusion.
It can be of three types: Table 1: Aetiology of Pericarditis
1. Acute (dry or effusive) pericarditis Idiopathic or non-specific pericarditis
2. Recurrent pericarditis Infections
Bacterial, tuberculous, viral (coxsackie, influenza, HIV, etc.), fungal,
3. Chronic (effusive, adhesive, or constrictive)—lasting three
rickettsial, mycoplasma, leptospiral, listeria, parasitic and others
months or more.
Vasculitis and connective tissue disease
Aetiology Rheumatoid arthritis,rheumatic fever,systemic lupus erythematosus,
Pericarditis has a vast array of causes that can be separated scleroderma, giant-cell arteritis, polymyositis (dermatomyositis),
Behçet’s syndrome, familial Mediterranean fever and others
into infectious and non-infectious categories. While in west
idiopathic causes account for a greater number of cases, with Diseases in adjacent structures
viral infections being the most frequent cause; in the Myocardial infarction, aortic dissection, pneumonia, pulmonary
embolism, empyema
developing countries, tuberculosis accounts for 60% to 80%
of the acute pericarditis (dry or effusive). Non-infectious Metabolic disorders
pericarditis can be subdivided into immunoreactive, Uraemia, dialysis-related, myxoedema
neoplastic, traumatic and metabolic causes. Some of the Neoplastic disorders
common causes are listed in Table 1. Primary: Mesothelioma, sarcoma, fibroma, lipoma and others
Secondary (metastatic or direct spread): Lung carcinoma,
ACUTE PERICARDITIS lymphoma, carcinoid and others
Acute pericarditis may be either dry or effusive. Bread and Trauma
butter pericarditis is another name given to dry pericarditis Direct: Pericardial perforation (penetrating injury) and cardiac
injury (cardiac surgery, percutaneous procedures)
because of the typical appearance when the two layers
Indirect: Radiation, non-penetrating chest injury
are separated. Effusive pericarditis involves presence of
fluid in excess of 50 mL in the pericardial cavity. Pericardial Association with other syndromes
effusion may be transudate (hydropericardium), exudate, Post-myocardial and pericardial injury syndromes, inflammatory
bowel disease, Loffler syndrome, Stevens-Johnson syndrome, giant-
pyopericardium or haemopericardium, or a combination of
cell arteritis, hypereosinophilic syndromes, acute pancreatitis, others
these. 737
 The pericardial rub arises from the inflamed visceral and all leads except for aVR, but in post-myocardial infarction
parietal layers of the pericardium rubbing together but most pericarditis the changes may be more localised. Classically,
patients with acute pericarditis (including those with audible the ECG changes of acute pericarditis evolve through 4
rubs) have at least a small pericardial effusion. The pericardial progressive stages shown in Table 2.
friction rub can be differentiated from a pleural rub, which is
Echocardiograhy
absent during held respiration, whereas the pericardial rub is
unaffected. Echocardiography usually demonstrates at least a small
pericardial effusion or it may be normal.
Diagnosis
Prognosis
The diagnosis of acute pericarditis is based on three simple
criteria—typical pericardial chest pain, pericardial friction rub Prognosis depends on the aetiology of acute pericarditis.
and typical electrocardiographic changes. The echo- Acute benign or idiopathic forms have an excellent prognosis,
cardiographic finding of pericardial effusion, which is not an while the uraemic pericarditis is usually a harbinger of death.
accepted diagnostic feature, is justified considering that it is a Pericarditis due to rheumatic fever also has a good prognosis.
confirmatory finding when present (Table 2). Treatment
Investigations Treatment for pericarditis should be targeted towards the
Patients with acute pericarditis usually have evidence of specific aetiology but most cases are idiopathic or viral, so an
systemic inflammation, i.e. leucocytosis, elevated erythrocyte empirical therapy is required. Empirical therapy in form of
sedimentation rate, and increased C-reactive protein. NSAIDs or aspirin is the first-line approach and mainstay of
Troponin levels may also be elevated in acute pericarditis treatment. Anti-tubercular and antibiotic treatment should be
due to some involvement of the myocardium by the instituted whenever required along with supportive therapy
inflammatory process. in the form of salicylates and corticosteroids to bring about early
relief and to prevent formation of adhesions. Symptomatic
Electrocardiography treatment for the relief of fever and pain may be provided with
Early in the course of acute pericarditis, the ECG typically analgesics. Rest and avoidance of physical activity are useful
shows diffuse ST elevation in association with PR-segment adjunctive non-pharmacologic measures that should be
depression (Figure 1). The ST elevation is usually present in adopted until active disease is no longer evident, especially in
case of rheumatic pericarditis.

PERICARDIAL EFFUSION
Pericardial effusion occurs when fluid accumulates in the
intrapericardial space. It can occur with or without evidence of
inflammation and pericarditis. Idiopathic aetiology is less
common in patients with isolated pericardial effusion (Table 3).
Pathology
Under normal conditions, the space between the parietal and
visceral pericardium contains only a small amount of fluid,
usually up to 50 mL or less. In pericardial effusion, the quantity
may vary from 200 mL to well over a litre. The fluid may be an
Figure 1: ECG in acute pericarditis. Diffuse ST segment elevation with
PR segment depression.
exudate or a transudate or may contain blood, pus or chyle.
Clinical Features
Table 2: Diagnostic Pathway in Acute Pericarditis Symptoms
Diagnostic Measure Characteristic Findings They are essentially the same as those of acute pericarditis, but
Auscultation Pericardial rub the dyspnoea may be more marked. Dyspnoea is thought to be
due to compression of the lungs and bronchi and also due to
ECG Stage I, diffuse ST segment elevation and
PR segment depression encroachment on the intrathoracic space. Leaning forward may
Stage II, normalisation of the ST and PR relieve this dyspnoea. This is because the fluid then gravitates
segments forwards and downwards, exerting lesser pressure on the lungs
Stage III, widespread T wave inversions and bronchi. If the effusion is large and produces sufficient
Stage IV, normalisation of the T waves pressure on the bronchi and oesophagus, it may result in a
Echocardiography Pericardial effusion dry hacking cough, hoarseness of the voice and difficulty in
Blood Analysis Raised ESR, CRP, LDH, leucocytes
swallowing.
(inflammation markers) Signs
Troponin I, CK-MB (markers of myocardial
involvement)
On inspection, a cyanotic tinge may be observed in large
effusions. Examination of the heart reveals the apex beat to be
Chest X-ray Ranging from normal to ‘water bottle’ shape
either weakly palpable or it may not be palpable at all. Bulging
Performed primarily to reveal pulmonary
or mediastinal pathology
of the praecordium and the xiphisternum may be seen. There
738 are very few or no palpable precordial pulsations.
 Diseases of the Pericardium
Percussion of the heart reveals an increase in the area of the
cardiac dullness especially on the left-side. Percussion of the
back reveals an area of dullness in the left infrascapular region
with bronchial breathing and aegophony (Ewart’s sign). This
is due to a compression of the base of the left lung. On
auscultation, the heart sounds are muffled. A pericardial rub may
be occasionally heard, though it tends to disappear with the
accumulation of fluid (Table 3).

Table 3: Pericardial Effusion: Salient Features

Silent praecordium
Tachycardia
Ewart’s sign
Muffled heart sounds

CARDIAC TAMPONADE
Cardiac tamponade is a medical emergency and its diagnosis
is of major clinical importance. It has been described as
‘an impaired diastolic filling of the ventricles due to raised
intrapericardial pressure as a result of fluid accumulation in the
intrapericardial space’. Figure 2A: Schematic illustration of leftward septal shift with encroachment of
left ventricular volume during inspiration in cardiac tamponade.
Aetiology
Pericardial disease of almost any aetiology can produce
cardiac tamponade by effusion accumulation and increased
intrapericardial pressure. The most common causes are
idiopathic, malignancy, tuberculosis, radiation, myxoedema,
post-cardiotomy and lupus.
Haemodynamics
Cardiac tamponade occurs when fluid accumulation in the
intrapericardial space is sufficient to raise the pressure
surrounding the heart to the point where cardiac filling is
altered. Ultimately, compression of the heart by a pressurised
pericardial effusion results in markedly elevated venous
pressures and impaired cardiac output producing shock.
Because of its lower pressures, the right heart is most vulnerable
to compression by a pericardial effusion, and abnormal right
heart filling is the earliest sign of a haemodynamically
significant pericardial effusion. Figure 2B: Respiration marker and aortic and right ventricular pressure tracings
in cardiac tamponade. A paradoxical pulse and marked, 180-degree, out-of-
The increased pericardial pressure in cardiac tamponade phase respiratory variation exists in right- and left-sided pressures.
accentuates the interdependence of the cardiac chambers as
the total cardiac volume is limited by the pericardial effusion.
The volume in any cardiac chamber can only increase when and presyncope. With progression, patient presents with shock,
there is an equal decrease in the volume in other chambers. altered mental status and pulseless electrical activity.
Because the total intrapericardial volume is fixed by the effusion, Signs
the increased inspiratory right ventricular filling crowds the left
Cyanosis may be present and the patient usually sits up and
ventricle and impairs its filling (Figure 2A). Thus, in tamponade,
leans forward or may assume a knee-chest position. Cardiac
left heart filling occurs preferentially during expiration when
tamponade is suspected in a patient who runs a rapid down-
there is less filling of the right heart.The small normal respiratory
hill course and exhibits the tetrad of rising venous pressure,
variation in left ventricular stroke volume and systolic arterial
fall in arterial pressure, small quiet heart and tachycardia.
pressure is markedly accentuated in cardiac tamponade,
resulting in the clinical finding of ‘paradoxical pulse’. Owing to The increased venous pressure is usually apparent as jugular
decreased cardiac output a compensatory tachycardia ensues. venous distension. The X-descent is typically the dominant
Eventually, the systemic pressure falls (Figure 2B). jugular venous wave with little or no Y-descent. The heart
sounds are classically soft or muffled; especially if there is a large
Clinical Features
pericardial effusion. The hallmark of cardiac tamponade is a
Symptoms paradoxical pulse. A paradoxical arterial pulse with a diminution
Cardiac tamponade is a treatable cause of cardiogenic shock that in the volume during deep inspiration is quite characteristic of
can be rapidly fatal if unrecognised. Patients with impending or large effusions. This may be further corroborated by the use of
early tamponade are usually anxious and may complain of a sphygmomanometre, i.e. reduction of >10 mm Hg in systolic
dyspnoea and chest pain. Other symptoms include cough, fatigue pressure during inspiration. 739
 Investigations for Pericardial Effusion and Cardiac seen posteriorly. Pericardial effusions large enough to produce
Tamponade cardiac tamponade are almost always circumferential (both
General investigations for pericardial effusion and cardiac anteriorly and posteriorly).
tamponade include routine blood counts and ESR. There may Echocardiography reveals the size of effusions:
be leucocytosis and neutrophilia and the sedimentation rate
1. Small (echo-free space in diastole <10 mm)
may be high.
2. Moderate (at least >10 mm posteriorly)
Electrocardiography
3. Large (>20 mm)
ECG can be normal or non-specific ST-T-wave changes are seen,
4. Very large (>20 mm with compression of the heart)
total electrical alternans is seen in large effusions and tamponade
(Figure 3). Bradycardia and electromechanical dissociation are In cases of gross effusion, the heart assumes a ‘swinging’ effect,
diagnostic of end-stage tamponades. wherein the heart seems to oscillate within the pericardial sac.
Echocardiography also provides information on the significance
of the pericardial effusion. In the presence of cardiac
tamponade, there is diastolic collapse of the free walls of the
right atrium and/or right ventricle (Figures 5 and 6). The
collapse is exaggerated during expiration when right heart
filling is reduced. Right atrial collapse is more sensitive for
tamponade, but right ventricular collapse lasting more than
one-third of diastole is a more specific finding for cardiac
tamponade. On echo Doppler study, there can be marked
reciprocal respiratory variation in mitral and tricuspid flow
velocities reflecting the enhanced ventricular interdependence
that is the mechanism of the paradoxical pulse.
Figure 3: Total electrical alternans seen in large pericardial effusion and cardiac
tamponade.

X-ray
In pericardial effusion, the cardiac silhouette will be increased
in size. Enlarged cardiac silhouette with clear lungs on chest
radiograph is very characteristic of large pericardial effusion
(Money Bag appearance) (Figure 4). The individual chamber
and blood vessel contours are lost.
Echocardiography
Echocardiography is an important part of the evaluation in
patients with pericardial effusion and cardiac tamponade. The
most important finding is the separation of the two pericardial
layers by an ‘echo-free’ space. Small pericardial effusions are only

Figure 5: Echocardiography showing circumferential pericardial effusion with

RA collapse (White or red arrow).

Diagnostic and Therapeutic Pericardiocentesis

Aspiration of the pericardial fluid will not only confirm the
diagnosis but also help in detection of the aetiology. The
aspirated fluid should be analysed and sent for bacteriological
culture and sensitivity tests. If there is no haemodynamic
compromise and the diagnosis can be established by other
means, pericardiocentesis may not be necessary but it is
generally advisable in patients with very large pericardial
effusions (>20 mm on echocardiography), even in the absence
of tamponade. It must be recognised that pericardiocentesis
will not yield a diagnosis in most patients and, therefore,
Figure 4: Enlarged cardiac silhouette with clear lung field in large pericardial the reason for draining large effusions is to avoid potential
effusion.
740 progression to tamponade.
 mammary arteries. It is prudent to drain the fluid in stepped

Diseases of the Pericardium

amounts of less than 1 litre at a time to avoid acute right
ventricular dilatation.
The feasibility of pericardiocentesis is high (>93%) in patients
with anterior effusion more than 10 mm, while the rate of
success is only 58% with small, posteriorly located effusions. The
most serious, but rare, complications are lacerations/
perforations of the myocardium and the coronary vessels. In
addition, patients can experience air embolism, pneumothorax,
arrhythmias (usually bradycardia), and puncture of the peritoneal
cavity or abdominal viscera.
If the fluid withdrawn is found to be purulent or there is large
effusion then an indwelling pigtail catheter is left in pericardial
cavity for drainage of residual or reoccurring effusion later on.
Along with this, appropriate antibiotic therapy should be instituted.

SPECIAL FORMS OF PERICARDITIS

1. Idiopathic Pericarditis
As the name suggests, the cause of this type of pericarditis
Figure 6: Echocardiography showing large posterior pericardial effusion (Red is not known, though it is presumed to be viral. It affects all
arrow).
age groups and presents with fever, bodyache and chest
pain. Pericardial effusion develops in about 75% of the cases.
Other Investigative Procedures
Computerised axial tomography and magnetic resonance Treatment consists essentially of rest and analgesics. If pain
imaging also help, especially when echocardiography does not is very severe and the effusion does not subside, then
reveal good images due to pulmonary disease. corticosteroids may be given. Very rarely, constrictive
pericarditis may ensue.
Prognosis
2. Rheumatic Pericarditis
This depends on the aetiological factor. Tuberculous pericardial
effusion very often results in chronic constrictive pericarditis. This is seen in cases of acute rheumatic fever and is chara-
Pericardial effusion in uraemia and neoplasms are harbingers cterised by tachycardia, chest pain and fleeting joint pains.
of death. Purulent pericardial effusion, if not treated vigorously, Usually, it is dry pericarditis (‘bread and butter’ pericarditis)
may prove fatal. but pericardial effusion may occur. There is complete
regression with treatment and no sequelae are seen.
Treatment
3. Uraemic Pericarditis
The treatment of pericardial effusion is two-fold; treatment of
the aetiological factor and treatment of the effusion. Two forms of pericarditis have been described in renal failure:
(a) Uraemic pericarditis
The treatment of cardiac tamponade is drainage of the
pericardial effusion. Medical management is usually ineffective Fibrinous inflammation with adhesions between the
and should be used only while arrangements are being made thickened pericardial membranes (‘bread and butter’
for pericardial drainage. Fluid resuscitation may be of transient appearance) caused by the high degree of azotemia in
benefit if the patient is volume depleted. The use of inotropic advanced renal failure before dialysis is started or shortly,
agents is usually ineffective because there is already intense thereafter. This is seen usually in the terminal stages of
endogenous adrenergic stimulation. uraemia. The pericarditis is of the dry type.
(b) Dialysis-associated pericarditis
PERICARDIOCENTESIS
Patients on maintenance haemodialysis, and occasionally
Pericardiocentesis is the aspiration of the pericardial fluid for
with chronic peritoneal dialysis caused by inadequate
therapeutic as well as for diagnostic purposes. Indications for
dialysis and/or fluid overload.
pericardiocentesis are: cardiac tamponade, diagnosis of the
aetiology of pericardial effusion and introduction of drugs into Most patients with uraemic pericarditis respond within 1
the pericardial cavity (when indicated). to 2 weeks to haemo or peritoneal dialysis, with resolution
of chest pain and reduction of the pericardial effusion.
Procedure
To avoid intrapericardial haemorrhage, heparin-free
Pericardiocentesis can be performed either using fluoroscopic haemodialysis should be used.
(cardiac catheterisation laboratory) or preferably in the
intensive care unit, under echocardiographic guidance. There 4. Post-Infarction Pericarditis
are various sites for aspiration but the two commonest sites Pericarditis may occur ‘early’ or be ‘delayed’ (Dressler’s
used are the subxiphoid and the left fifth intercostal space. The syndrome) after myocardial infarction. Early pericarditis
subxiphoid approach is the much preferred route, as one can occurs in the first few days of a transmural myocardial
aspirate fluid even in the case of small effusions. This route is infarction, although early thrombolytic treatment has
extrapleural and avoids the coronary, pericardial, and internal decreased its incidence. Dressler’s syndrome occurs from 741
 one week to several months after myocardial infarction and Purulent pericarditis is an absolute indication for pericardial
is considered to be an autoimmune phenomenon. drainage and rinsing of the pericardial cavity, combined with
Aspirin, up to 650 mg every four hours for 2 to 5 days, has high doses of systemic antibiotic treatment. A combination
been successfully used to treat post-infarction pericarditis. of antistaphylococcal antibiotic and aminoglycoside,
Other nonsteroidal agents risk thinning the infarction zone. followed by tailored antibiotic treatment according to the
Corticosteroid treatment is used for refractory symptoms results of pericardial fluid and blood cultures, is mandatory.
but can delay infarction healing. 7. Viral Pericarditis
5. Tuberculous Pericarditis This is a common cause of pericarditis and is clinically difficult
This is possibly the commonest cause of pericarditis and to differentiate from idiopathic pericarditis. Viral pericarditis
pericardial effusion in India. It is even more common after can be caused by direct viral attack (enterovirus, adenovirus,
the advent of HIV infection and AIDS. Infection occurs cytomegalovirus (CMV), Ebstein-Barr virus, herpes simplex
through neighbouring structures, e.g. lungs, bronchi, lymph virus, influenza virus, parvo B19, hepatitis C virus, HIV, etc.),
nodes or by blood-borne infection. the immune response or both. Initial presentation is the
syndrome of acute pericarditis, often resolving within two
The patient may have vague complaints of fever, malaise,
weeks but may progress to pericardial effusion which may
evening rise in temperature, loss of weight, etc. There may
be serous, suppurative, or haemorrhagic.
be no cardiac manifestations initially but later on, chest pain,
cough and dyspnoea may appear due to an increase in the The diagnosis depends on the demonstration of rising titers
size of the effusion. of specific antibodies in the serum. A four-fold rise in serum
Aspiration of the fluid reveals either straw-coloured or blood- antiviral antibodies is suggestive but not diagnostic per se.
tinged exudative fluid. A systematic, multiple diagnostic In most patients, pericardial viral infection is self-limiting
approach is essential, e.g. sputum cultures, analyses of and no specific treatment is necessary.
pericardial effusion by acid-fast staining, mycobacterial 8. Neoplastic pericarditis
culture or radiometric growth detection (BACTEC-460),
Neoplastic pericarditis is also an important specific
adenosine deaminase (ADA), pericardial lysozyme, and PCR
diagnosis to rule out in patients with pericarditis. It is
for Mycobacterium tuberculosis. High ADA (>40 U/L) in
responsible for about 5% of unselected cases of acute
pericardial effusion is diagnostic for tuberculous pericarditis
pericarditis and may metastasise to the pericardium, with
(93% sensitivity, 97% specificity). The absolute criteria for
the most common being lung and breast cancer and
diagnosis are the identification of Mycobacterium tuberculosis
lymphomas. Lung cancer is the commonest malignancy
in the pericardial fluid or tissue, and/or the presence of
giving early invasion of lymph nodes and thus being easily
caseous granulomas in the pericardium. However, pericarditis
responsible for pericardial effusion. Primary tumours of the
in proven extracardiac tuberculosis is strongly suggestive of
pericardium are less common.
a tuberculous aetiology. PCR is as sensitive (75% vs. 83%), but
more specific (100% vs. 78%) for tuberculous pericarditis than 9. Haemopericardium
ADA. Very often, even on a very close search, no evidence of Accumulation of blood in the pericardial cavity usually
tuberculosis may be found anywhere in the body. occurs after rupture of a cardiac chamber (after myocardial
Tuberculous pericarditis should be promptly treated with infarction), coronary artery or a dissecting aneurysm. Rarer
a combination of antitubercular drugs according to causes include scurvy, neoplasms and leukaemia. Pericardial
standard protocols. Prednisone should be administered tamponade may occur and need drainage.
along with antituberculous drugs as it reduces the host
10. Pneumopericardium
reaction to mycobacterial infections, minimises exudation,
fibrin deposition, and proliferation of tuberculomas and Air in the pericardial cavity may result from stab wounds,
may decrease symptoms and signs. However, despite perforation of an air-containing organ into the pericardium,
combination therapy, many patients develop constriction by gas-forming organism or by introduction of air into the
and if untreated, it is one of the commonest causes of pericardial cavity. An X-ray of the chest reveals the presence
constrictive pericarditis in India. of gas in the pericardial cavity. This usually does not require
treatment, but the underlying cause requires treatment.
6. Purulent Pericarditis
This is due to infection of the pericardium by organisms CHRONIC CONSTRICTIVE PERICARDITIS
like the Staphylococcus, Streptococcus, Pneumococcus, Chronic constrictive pericarditis (CCP) is defined as a dense
Meningococcus and Haemophilus, etc. The infection may be and rigid thickening of one or both layers of the pericardium
either blood-borne, extension of an intrathoracic infection with adhesions resulting in compression of the heart with
or from outside as in cases of stab wounds. impairment in the diastolic filling.
Patient presents with high-grade fever and appears very Aetiology
toxic. If the effusion accumulates very rapidly it may result The most common causes include:
in cardiac tamponade. Pericardial fluid aspirate should
 Tuberculosis
undergo urgent Gram’s, acid-fast, and fungal staining
followed by cultures for aerobes and anaerobes.  Idiopathic and viral pericarditis
Purulent effusions have significantly lower fluid glucose  Chest irradiation
742 concentrations than non-infectious effusions.  Collagen vascular disease
 Diseases of the Pericardium
 Post-cardiotomy cardium forms an encasement of the heart and is unable to stretch
 Malignancy during diastole. The unyielding pericardium impairs the diastolic
relaxation of the heart and thereby diminishes venous filling of
In developing countries with high prevalence of tuberculosis,
the right ventricle. However, there is no interference with systole.
it is most common cause of CCP. In India, tuberculosis is
The pathophysiological hallmark of pericardial constriction is
responsible for nearly two-third of the cases of CCP. The
equalisation of the end-diastolic pressures in all four cardiac
aetiology of CCP in the western world has undergone a
chambers. This occurs because the filling is determined by the
significant change, with tuberculosis reported in only 0% to 1%
limited pericardial volume, not the compliance of the chambers
of cases. However, with emergence of the AIDS pandemic these
themselves. Initial ventricular filling occurs rapidly in early diastole
numbers are likely to increase again. The leading identifiable
as blood moves from the atria to the ventricles without much
causes of CCP in western world are following cardiac surgery
and radiation therapy, besides viral pericarditis, but such cases change in the total cardiac volume. However, once the pericardial
are possibly missed in India. constraining volume is reached, diastolic filling stops abruptly.
This results in the characteristic dip and plateau of ventricular
Pathophysiology diastolic pressures. The stiff pericardium also isolates the cardiac
The pericardium undergoes thickening and calcification (normal chambers from respiratory changes in intrathoracic pressures,
thickness of the pericardium is 3 to 5 mm). The thickened peri- resulting in Kussmaul’s sign (Figures 7 and Figures 8A and B).

Figure 7: Schematic representation of transvalvular and central venous flow velocities in constrictive pericarditis. During inspiration, the decrease in left ventricular
filling results in a leftward septal shift, allowing augmented flow into the right ventricle. The opposite occurs during expiration.
EA = Mitral inflow; LA = Left atrium; LV = Left ventricle; RA = Right atrium; RV = Right ventricle.

Figures 8A and B: Pressure recordings in a patient with constrictive pericarditis. (A) Simultaneous right ventricular (RV) and left ventricular (LV) pressure tracings
with equalisation of diastolic pressure, as well as ‘dip and plateau’ morphology. (B) Simultaneous right atrial (RA) and LV pressure with equalisation of RA and LV
diastolic pressure. The y-descent is prominent. 743
 Due to the reduction in venous filling, the stroke output falls calcification of the pericardium.This is best seen in the left lateral
and to compensate for decreased cardiac output the heart rate or oblique views and is present in about two-thirds of the cases.
rises. The systemic pressure rises because of the limited cardiac In the lateral view, if the calcification is seen in the entire
filling. The liver and spleen are enlarged and the capsule is pericardium (i.e. anteriorly, inferiorly and posteriorly) the
thickened as a consequence of chronic congestion. appearance is termed as ‘egg-shell pericardial calcification’
(Figure 9). The lung fields remain clear. Severe venous
Haemodynamics in cardiac tamponade and constrictive
engorgement may lead to pleural effusions.
pericarditis are compared in Table 4.
Symptoms and Signs
The commonest complaint is the distension of the abdomen
due to ascites and swelling of the feet. The next common
complaint is dyspnoea and fatigue.
On inspection, the neck veins are engorged, even in the
standing position. A deep ‘y’ descent (Frederick’s sign) is seen.
JVP is raised and increases/fails to decrease during deep
inspiration (Kussmaul’s sign).The arterial pulse is of a low volume
and the rhythm may be irregular indicating the presence of
atrial fibrillation.

Table 4: Haemodynamics in Cardiac Tamponade and

Constrictive Pericarditis
Tamponade Constriction
Paradoxical pulse Usually present Present in ≈ 1/3
Equal left/right filling pressures Present Present
Systemic venous wave Absent y Prominent ‘y’
morphology descent descent
(M or W shape)
Inspiratory change in systemic Decrease Increase or no
venous pressure (normal) change
(Kussmaul’s sign)
‘Square root’ sign in ventricular Absent Present Figure 9: Chest radiograph showing marked pericardial calcifications in a patient
pressure with constrictive pericarditis.

Inspection of the praecordium reveals a ‘quiet’ heart and Echocardiography

prominent veins may be observed all over the chest. A systolic This is perhaps the most useful investigation to diagnose
retraction at the apex may be observed. On palpation, a constrictive pericarditis. The presence of thickened and/or
diastolic ‘tap’ or ‘shock’ may be palpated. It is due to the rapid calcified pericardium clinches the diagnosis. However, increased
filling of the right ventricle. The characteristic finding on pericardial thickness can be missed on a transthoracic
auscultation is the ‘pericardial knock’.This is a sound due to rapid echocardiogram. Transoesophageal echocardiography is more
filling of the ventricle in the early rapid filling phase. It occurs sensitive and accurate in determining pericardial thickness.
about 0.08 to 0.12 second after the second sound in contrast
to the normal third sound, which occurs a little later (0.13 to Doppler echocardiography is important in the evaluation of
0.16 s). The heart sounds are normal and usually no murmur is patients with suspected pericardial constriction. Doppler
heard. echocardiography frequently demonstrates restricted filling of
both ventricles with a rapid deceleration of the early diastolic
Examination of the abdomen reveals an enlarged, smooth and mitral inflow velocity (E wave) and small or absent a wave. In
tender liver. The chief finding in the abdomen, however, is the addition, there is substantial (>25%) respiratory variation of the
presence of ascites which is massive and out of proportion to mitral inflow velocity (Figure 10). There are signs of systemic
the oedema on the legs (which may be minimal). It tends to venous congestion such as dilation of hepatic veins and
refill very rapidly after aspiration. distension of the inferior vena cava with lack of inspiratory
Investigations collapse (Figure 11).
Electrocardiography CT/MRI
The ECG findings are not characteristic but include low voltage CT and MRI allow accurate measurement of pericardial thickness
of the QRS complexes, flattening or inversion of the and some assessment of diastolic filling patterns. Ancillary
T-waves and occasionally atrial fibrillation. diagnostic findings include conical narrowing of the ventricles,
atrial dilation, and enlargement of the inferior vena cava,
X-ray
hepatomegaly, and ascites. Excellent overall sensitivity (88%),
The heart size is usually normal or slightly smaller. The specificity (100%), and accuracy (93%) have been reported for
744 characteristic finding of constrictive pericarditis, however, is the MRI. Increased pericardial thickening may not always imply
 Diseases of the Pericardium
relaxation of the ventricle during diastole and is usually more
than one-third of the systolic pressure. The right atrial tracings
show a ‘M’ or ‘W’ shaped pattern corresponding to the right
ventricular pressures. It has been observed that the pulmonary
wedge pressure, pulmonary artery diastolic pressure, right
ventricular end-diastolic pressure, mean right atrial pressure and
superior vena cava pressures tend to be equal or near-equal in
constrictive pericarditis.
Diagnosis
The combination of pulsus paradoxus, neck vein signs, ascites
and pericardial ‘knock’ should pose no difficulty in the diagnosis.
However, similar clinical pictures may be seen in tricuspid
valvular diseases, restrictive cardiomyopathies and cirrhosis of
the liver. Tricuspid valvular defects have their characteristic
murmurs, which increase in intensity on deep inspiration.
Cardiomyopathies may be diagnosed on echocardiograms.
Prognosis
Without surgery the prognosis is poor. Long-standing cases of
constrictive pericarditis develop hypoproteinaemia due to a
protein-losing enteropathy. They also develop a myocardial
Figure 10: Doppler echocardiography showing respiratory variation of the failure (probably due to fibrosis) which does not respond to
mitral valve inflow velocity in a case of constrictive pericarditis.
digoxin, even after pericardiectomy.
Treatment
Medical management of constrictive pericarditis, especially in
less severe cases, is aimed at relief of fluid overload with careful
administration of diuretics and is at best, palliative. Surgical
pericardiectomy remains the only definitive management
and should be done before calcification and myocardial
involvement progresses. However, if the cause is thought to be
tuberculosis, then a few weeks on antituberculous drugs should
precede the surgery. The results of surgery are very gratifying.
Other aetiological causes should get their respective treatments.

CONCLUSION
Pericarditis remains a common disorder, particularly as a
complication of modern treatments such as cardiac surgery,
percutaneous interventions, and radiation therapy. Pericardial
effusion and constrictive pericarditis are infrequent sequelae that
can be diagnosed accurately in most cases by use of modern
imaging methods. Cardiac tamponade, a medical emergency
should be promptly diagnosed and managed with urgent
Figure 11: M mode showing dilated IVC with minimal respiratory variation in a pericardiocentesis. Management of uncomplicated pericarditis
case of constrictive pericarditis. rests largely on NSAIDs with the addition of colchicine for relapses.
Pericardial effusion can be managed percutaneously in most
constriction, and conversely, constrictive pericarditis can cases, whereas definitive treatment for constriction remains surgery.
present with normal pericardial thickness on non-invasive
RECOMMENDED READINGS
imaging, histology, or a combination of these.
1. Bernhard Maisch, Arsen D. Ristic. Practical aspects of the management of
Cardiac catheterisation pericardial disease. Heart 2003; 89: 1096-1103.

Though a very valuable tool in the diagnosis of constrictive 2. Hoit BD. Management of effusive and constrictive pericardial heart
disease. Circulation 2002; 105 (25): 2939-42.
pericarditis in the past, it is no longer used routinely after the
3. Imazio M, Spodick DH, Brucato A, et al. Controversial issues in the
advent of echocardiography. Catheterisation reveals an management of pericardial diseases . Circulation 2010; 121: 916-28.
elevation of the right ventricular end-diastolic pressure, 4. LeWinter MM, Kabbani S. Pericardial diseases. In: Braunwald E, et al. editors,
characterised by an early diastolic ‘dip’ and a late diastolic Heart Disease: A Textbook of Cardiovascular Medicine, 7th Ed. Philadelphia:
‘plateau’. The end-diastolic pressure is high due to incomplete Saunders; 2004: pp. 1757-79.

745
 12.30 Surgical Management of Heart Disease

Muhammad Abid Geelani, Nikhil Prakash Patil

INTRODUCTION  Decreased pulmonary blood flow

The era of cardiac surgery was ushered more than a century Tetralogy of Fallot
ago when Ludwig Rehn of Frankfurt operated to relieve cardiac Pulmonary atresia
tamponade and sutured a stab wound to the right ventricle in Tricuspid atresia with pulmonary stenosis
September 1896. However, ‘open-heart surgery’ as we know it Total transposition of great arteries with pulmonary
today began a little over fifty years ago with the development stenosis
of an artificial ‘heart-lung machine’ by John H. Gibbon, Jr. On Ebstein malformation
May 6, 1953, the Gibbons-IBM oxygenator was successfully used All blue babies must be closely observed for cyanotic spells.
for total substitution of the heart and lungs for 26 minutes, Severe and frequent spells constitute an indication for urgent
enabling correction of an atrial septal defect, and thereby operation. Early surgery is preferred as there is always a risk of
the world’s first successful open heart surgery. Since then, paradoxical embolism with its complications.
technological advances and myocardial protection techniques
evolving continuously over the last six decades have enabled Surgery may be classified into:
routine conduction of successful and complex cardiac surgery,  Palliative, e.g. Blalock-Taussig shunt (BT shunt), cavo-
totally bypassing the vital function of lungs and heart for hours pulmonary shunt (Bi-directional Glenn shunt), pulmonary
to days. artery banding.
Cardiac surgery broadly encompasses: surgery for congenital  Corrective, e.g. atrial/ventricular septal defect repair, ligation
heart disease; surgery for valvular heart disease; surgery for of patent ductus arteriosus, arterial switch for simple
ischaemic heart disease and cardiac transplantation and related transposition of great arteries.
heart failure surgery.
Conditions such as patent ductus arteriosus, coarctation of the
SURGERY FOR CONGENITAL HEART DISEASE aorta, atrial septal defect, partial atrioventricular canal and
tetralogy of Fallot can now have corrective surgery with hospital
Congenital heart disease (CHD) has an overall incidence of 0.8%.
mortality ranging from 0% to 5% depending upon the age at
The patient population is diverse. Defects, presentation,
surgery and the complexity of the condition. Many complex
diagnosis, treatment and outcome differ widely according to
conditions such as pulmonary atresia, transposition of the great
age of presentation and complexity of lesions. These can be arteries, tricuspid atresia and many other conditions previously
broadly classified into acyanotic and cyanotic heart defects. considered inoperable are now being successfully treated with
A. Acyanotic acceptable mortality and satisfactory long-term results.
 Increased pulmonary blood flow (Left to Right shunt)
SURGERY FOR VALVULAR HEART DISEASE
Atrial septal defect
Ventricular septal defect Acquired disease of heart valves can be treated by repair
Patent ductus arteriosus procedures or by replacement with an artificial prosthesis
Partial anomalous pulmonary venous connection (Figures 1 to 3). The valves commonly affected are the aortic,
mitral and tricuspid valves; the commonest pathologies are
All these patients must be operated upon before school-
rheumatic and degenerative disease. Rheumatic heart disease,
going age, unless progressive pulmonary arterial
which has been practically eradicated from Western countries,
hypertension supervenes, in which case, early surgery is
continues to be a problem in South Asian countries. Rheumatic
indicated to prevent the development of Eisenmenger
mitral stenosis (MS) without mitral regurgitation (MR) may
complex.
initially be treated by balloon mitral valvuloplasty (BMV) or
 Normal pulmonary blood flow rarely with closed mitral valvotomy when BMV is not possible
Aortic stenosis/bicuspid aortic valve because of difficulty in percutaneous access to mitral valve, e.g.
Mitral regurgitation in inferior vena cava obstruction or inability to puncture the
Coarctation of aorta interatrial septum. But when echocardiography suggests
Mitral stenosis unfavourable anatomy (Wilkins score > 8)* or when a left atrial
B. Cyanotic (Right to Left shunt) clot is present, it is best to do as an open-heart procedure and
 Increased pulmonary blood flow
Truncus arteriosus * A scoring system exists to grade the morphological changes in the mitral valve
Single ventricle during assessment with echocardiography. This takes into account 4
characteristics; leaflet mobility, leaflet thickening, valve calcification and
Transposition of great arteries
involvement of the subvalvular apparatus. The involvement is graded from 0-4.
Total anomalous pulmonary venous connection A total score of more than 8 is predictive of a low success post percutaneous
746 Hypoplastic left ventricle mitral valvuloplasty.
 Surgical Management of Heart Disease
left atrial clot, must be referred for percutaneous/surgical
intervention.
Mitral regurgitation may be caused by degenerative changes
in the leaflet, prolapse of the leaflets, rupture of chordae
tendineae or due to annular dilatation or tethering of the
subvalvular apparatus secondary to ventricular dilatation. In
such cases, a repair procedure may be considered. This is usually
combined with implantation of a flexible or rigid annuloplasty
ring to support the repair. All patients in NYHA class II and
above, having orthopnoea, severe pulmonary hypertension,
gradually dilating left ventricle and falling ejection fraction
(LVEF), must be referred for early surgical procedure for better
outcome.
If a repair is not possible and mitral valve replacement is
indicated, there is a wide choice of prosthetic and bioprosthetic
valves available. Mechanical heart valves have evolved from a
ball and cage design to the tilting disc valve to the bi-leaflet
Figure 1: Tilting disc mechanical valve (TTK Chitra valve). prosthesis. Currently, the bi-leaflet pyrolytic carbon low profile
mechanical prosthesis is the most commonly used prosthesis
as it has the advantage of central flow and excellent long-term
results. The preservation of posterior leaflet with/without
anterior chordal apparatus provides better long-term result as
it maintains left ventricular geometry. Lifelong anticoagulation
is mandatory for all mechanical heart valves to prevent
thromboembolic complications. In spite of this, the incidence
of thromboembolic complications is 1.5% to 2% per patient year.
The alternative to the use of mechanical prosthesis is the use of
bioprosthetic valves, which have a biological origin. These are
generally stent-mounted porcine valves or pericardium treated
with buffered glutaraldehyde to promote cross linkages
between the collagen bundles. Anticoagulation is not essential
for recipients of bioprosthetic valves after 6 weeks of surgery
unless they are in atrial fibrillation. The main disadvantage of
bioprosthetic valves is their limited durability; many of them
degenerate and even calcify in 10 to 15 years time. The long-
term durability of these prostheses have been improved by the
use of proprietary anti-calcification treatment and by the
Figure 2: Bileaflet mechanical valve. development of valves constructed from glutaraldehyde-
treated bovine pericardium mounted within a specially
designed stent. The hospital mortality for mitral valve
replacement for primary non-ischaemic mitral valve disease is
between 2% and 7%. The survival rate following surgery is 65%
to 80% at 5 years, 50% to 60% at 10 years, and 30% to 40% at 15
years from several reported series.
Most patients who need replacement of the aortic valve are in
the older age group and have calcific aortic stenosis. Aortic
regurgitation is either due to rheumatic heart disease causing
fibrosis and shrinkage of the leaflets or due to annular dilation
as in cystic medial necrosis or in aortic aneurysms and dis-
sections. Aortic valve replacement has better early and late
survivals than mitral valve replacement because of afterload
reduction and low thrombogenicity in a high flow area. Small
Figure 3: Bioprosthetic valve (Pericardial).
aortic root and patient-prosthetic mismatch is still a concern
which leads to higher gradient across aortic valve and poor
repair/replacement of the valve may be indicated. Nowadays, exercise tolerance. It is better to use stentless valves in the aortic
BMV is done even in presence of left atrial appendage clot after position (autografts as in the Ross operation, homografts or
giving anticoagulation therapy for 6 weeks. All patients in New xenografts) or root enlargement techniques in such situations.
York Heart Association (NYHA) functional class II or above, Enlarging left ventricle, syncope or angina in aortic valve disease
having dyspnoea, orthopnoea, severe pulmonary hypertension, warrant early surgery. 747
 The tricuspid valve is generally treated with repair procedures or two-vessel disease not involving the proximal LAD and with
and the implantation of annuloplasty rings rather than valve only a small area of viable myocardium or no objective evidence
replacement as prosthetic valves do not function well in this of ischaemia on non-invasive testing.
relatively low pressure area.
Several studies have shown that emergent surgery for relent-
If the patients are offered surgery during late stages of the less unstable angina or non-Q wave MI in the context of failed
disease, the results of valve replacement are adversely affected or unfeasible percutaneous coronary intervention (PCI) is
because of left ventricular dilatation, pulmonary hypertension associated with an increase in peri-operative mortality
and congestive heart failure with hepatic and renal dysfunction. compared with semi-urgent CABG, although surgical
Surgery for valvular heart disease is now standardised in Indian revascularisation may still be preferable to a conservative
centres but problems of late referrals, cost, maintenance of strategy. Consequently, an attempt should be made at
optimal anticoagulation and proper follow-up are the limiting stabilising these patients with maximal medical therapy (and
factors. in some cases the temporary use of an intra-aortic balloon
pump) to allow surgery to be performed on a non-emergent
SURGERY FOR ISCHAEMIC HEART DISEASE basis with a lower operative risk.
Coronary artery bypass grafting (CABG) is one of the procedures Intravenous thrombolytic therapy and primary PCI have
with the highest impact in the history of medicine. CABG is supplanted CABG as the first line of therapy for patients in the
based on the underlying principle that the symptoms and acute period of ST segment elevation MI. As a result, residual
clinical events of coronary artery disease (CAD) are related to ongoing ischaemia and cardiogenic shock despite maximal
stenotic coronary lesions that can be identified by angiography, non-surgical therapy now constitute the main indication for
and if those lesions are bypassed, then those symptoms and emergent CABG in acute MI patients. Other acute indications
clinical events become less common. Surgical attempts at include failed thrombolysis and demonstration of a large
increasing blood flow to the ischaemic myocardium originated myocardial territory at risk in combination with an unsuitable
a century ago when Alexis Carrel anastomosed a carotid artery anatomy for PCI, a left main coronary stenosis, an LV failure with
segment between the descending aorta and the left coronary severe coronary stenosis outside the initial infarct area,
artery in a dog, for which he was later awarded the Nobel prize. significant valve disease, or a mechanical complication of MI.
Three decades later, Arthur Vineberg started implanting the left
PCI may occasionally result in intractable coronary dissection
internal mammary artery (LIMA) into the anterior myocardial
or plaque haemorrhage, threatened proximal occlusion with a
territory of patients with CAD in order to increase arterial inflow large myocardial area at risk, loss of a foreign body in a crucial
and relieve angina, with some experiencing prolonged anatomical position, or coronary rupture. These complications
symptomatic improvement. Surgery on the coronary arteries are indications for immediate surgical intervention, but in-
was introduced clinically in 1958 by William Longmire, who hospital mortality is high in these patients (10% to 14%) because
reported on the use of endarterectomy in five patients operated of unfavourable selection factors such as haemodynamic
without cardiopulmonary bypass (CPB). The first reported compromise and severe impairment of the coagulation system.
successful CABG operation took place in 1964 in Leningrad, CABG should NOT be attempted on an emergency basis in
where Vasilii Kolesov grafted a LIMA to the left anterior stable patients in whom PCI has failed because of unsuitable
descending (LAD) artery without CPB. The world’s first CABG anatomy or no-reflow state.
program started 3 years later in Cleveland, as Favaloro began
to routinely use reversed saphenous veins for aortocoronary Conduit Selection
grafting. CABG today constitutes the keystone of adult cardiac The choice of conduit is determined by the quality of available
surgery, but novel surgical, percutaneous, and medical conduit, the suitability of the target vessels and the age and
alternatives loom large on the horizon. Yet CABG is constantly co-morbidity of the patient.
evolving and remains the most durable means of revasculari-
Internal mammary artery grafts
sation for patients with CAD. Although CAD is largely diagnosed
by conventional coronary angiography, evolving less invasive The internal mammary artery (IMA) is the best conduit available
techniques like cardiac CT angiography may become the for CABG and provides short- and long-term survival benefits
diagnostic modality of choice in the future. in all patients subgroups, including those 75 years of age or
older. Use of the LIMA to graft the LAD (or a main target vessel
CABG is indicated in patients with chronic stable angina and on the left coronary circulation if the LAD is free of disease)
left main coronary artery stenosis ≥ 50%, left main equivalent should be performed except in exceptional circumstances such
(i.e. proximal stenosis of at least 70% of the proximal LAD and as pre-existing or iatrogenic damage to the LIMA, poor flow from
circumflex), three-vessel disease [especially if left ventricular severe spasm, injury, or dissection, involvement of the LIMA in
ejection fraction (LVEF) is less than 0.50], and one- or two-vessel providing collateral supply to the lower extremity, mediastinal
disease with either a large myocardial area at risk on non- irradiation (if other arterial conduits are available), and
invasive testing or depressed LVEF. emergency CABG with cardiogenic shock.
CABG may also be indicated for symptomatic improvement in The use of bilateral IMAs should be considered over single IMA
low-risk patients with significant CAD who do not fulfil the grafting whenever, possible in young patients, as they may lead
above criteria but experience disabling myocardial ischaemia to lower reoperation rates, decreased late PCI rates, and long-
or unacceptable lifestyle restrictions on maximal medical term survival benefits. Relative contraindications to the use of
therapy. CABG is not preferred over PTCA in patients with one- bilateral IMAs include emergency operation, advanced age,
748
 Surgical Management of Heart Disease
diabetes mellitus, obesity, and severe COPD for which the SURGERY FOR HEART FAILURE
patient requires systemic steroid therapy. Heart Transplantation
Radial artery grafts Dr. Christiaan Barnard performed the world’s first human heart
The radial artery likely constitutes, after the left and right IMA, transplant operation on 3 December 1967. The patient, Louis
the next best conduit for CABG. Radial artery harvest is contrain- Washkansky, was a 54-year-old grocer, suffering from diabetes
dicated in the presence of insufficient collateral supply to the and incurable heart disease. Washkansky survived the operation
hand or Raynaud’s syndrome, in patients with high manual and lived for eighteen days. However, he succumbed to
demands such as professional musicians, in the very elderly pneumonia induced by the immunosuppressive drugs he was
(who have a high prevalence of radial arteriosclerosis), during taking. Barnard later wrote, ‘For a dying man it is not a difficult
emergency operations, and in patients who are likely to require decision because he knows he is at the end. If a lion chases you
postoperative vasopressors such as those with very poor LV to the bank of a river filled with crocodiles, you will leap into
function. the water, convinced you have a chance to swim to the other
side.’ Though the first patient with the heart of another human
Saphenous vein grafts being survived for only a little more than two weeks, Barnard
Saphenous veins are known not to be the conduit of choice for had passed a milestone in a new field of life-extending surgery.
CABG due to proven lower short- and long-term patency than Since then, nearly 60,000 of these operations have been done
IMAs. Nevertheless, the long saphenous veins are still used in worldwide, including over a hundred in Indian centres. The main
the majority of CABG operations by a large number of surgeons limiting factor is the availability of suitable donors and the
for practical reasons. They are also particularly useful for specific logistics of the procedure. The prognosis for heart transplant
situations. They constitute the most readily available CABG patients has greatly increased over the past 20 years. With the
conduit, provide immediate and reliable coronary flow with a current immunosuppressive therapy using anti-thymocyte
low propensity for spasm or flow compromise during low- globulin, corticosteroids and azathioprine or mycophenolate
output states, and provide a time-honoured means of coronary survival is now 80% at 1 year, 70% at 5 years and 50% at 10
revascularisation during emergency procedures or in patients years. After the 20% mortality during the first year, the yearly
with severe co-morbidity and limited life expectancy in whom mortality is approximately 4% per year. These results can be
procedural simplicity, expeditiousness, and reliability are most achieved only if the patients are carefully followed-up and
desirable. monitored with percutaneous myocardial biopsy at appropriate
time depending upon the clinical progress and modification
Other conduits
of the immunosuppressive therapy based on the results of
The gastroepiploic artery, short saphenous vein and inferior myocardial biopsy. Tony Huesman was the world’s longest living
epigastric artery constitute additional available conduits that heart transplant recipient, having survived for 31 years with a
are rarely needed for primary revascularisation, but which transplanted heart (he died on August 10, 2009 of cancer)—
may be useful as a last resort in patients with severe conduit the operation was performed in 1978 at Stanford University by
shortage, e.g. redo surgeries. American heart transplant pioneer Dr. Norman Shumway.
Off-pump: CABG versus CPB In patients with severe pulmonary vascular disease heart-lung
CABG can be carried out with CPB (on-pump) or without (off- transplantation may be indicated but this operation is technically
pump: OPCABG). Many surgeons elect to perform CABG on more difficult to perform and to manage post-operatively, and
pump, until recently, the advantages of a still, clear operating carries significantly lower survival rates.
field, myocardial protection and haemodynamic and respiratory Cardiomyoplasty using latissimus dorsi muscle is not used
control, appeared to outweigh the disadvantages of CPB. anymore but Myosplint and its modification, which prevent
However, recent improvements in methods of stabilising the dilatation of LV, are currently undergoing clinical trials.
heart have led to some institutions adopting OPCABG expecting
to see lower morbidity and mortality. OPCABG appears to offer The artificial heart, which is essentially a ‘bridge to trans-
favourable outcomes, leading to reductions in postoperative plantation’, at present holds a very promising future as externally
atrial fibrillation, transfusion requirements, inotrope requirements, rechargeable energy sources are in the final stages of clinical trials.
ventilation times, length of hospital and intensive care unit stay,
and cost compared to on-pump coronary artery surgery. But, RECOMMENDED READINGS
till date, no randomised trial has been sufficiently powered to 1. David D Yuh, Luca A Vricella, William A Baumgartner. The Johns Hopkins
Manual of Cardiothoracic Surgery; 1st Ed. McGraw-Hill Professional; 2007.
detect the widely expected difference in death or stroke at 30
2. Frank W Sellke, Pedro J del Nido, Scott J Swanson. Sabiston and Spencer’s
days or one year. Nevertheless, OPCABG is a suitable alternative Surgery of the Chest; 7th Ed. Elsevier Saunders; 2004.
to CPB in experienced centres. It should probably be the 3. Nicholas T Kouchoukos, Eugene H Blackstone, Donald B Doty, et al. Kirklin/
technique of choice in patients with porcelain (calcified) aorta, Barratt-Boyes Cardiac Surgery; 3rd Ed. Churchill Livingstone; 2003.
poor LV function, renal dysfunction, pulmonary dysfunction and 4. Stephen Westaby, Cecil Bosher. Landmarks in Cardiac Surgery; 1st Ed. Informa
advanced age or other co-morbidity. Healthcare; 1998.

749
 12.31 Diseases of the Aorta

Manotosh Panja

INTRODUCTION
The aorta is composed of a thin intima, a thick media and a thin
adventitia. The media is composed of laminated but
intertwining sheets of elastic tissue in a spiral manner that gives
it not only tensile strength but also distensibility and elasticity.
The aorta is divided anatomically into thoracic and abdominal
segments. The thoracic aorta is further divided into ascending,
arch and descending segments, while the abdominal aorta
consists of suprarenal and infrarenal segments. Aortic isthmus
is the point where aortic arch joins the descending aorta. This
is especially vulnerable to trauma as it is the junction of the
mobile ascending aorta and arch and relatively fixed
descending aorta.This is also the site for coarctation of the aorta.
Other aortic anomalies could be right-sided aortic arch, double
aortic arches and cystic medial degeneration as in Marfan’s
syndrome and acquired degeneration of the aortic wall
secondary to ageing, arteriosclerosis, hypertension and specific
inflammatory, infectious or autoimmune diseases.

AORTIC ANEURYSMS
Aortic aneurysm is a localised dilatation of the aorta having a
diameter at least 1.5 times that of the expected normal diameter
of that given aortic segment. A true aneurysm involves all the
three layers of the aortic wall. It is produced by the progressive
distension of the aortic wall that is weakened by the
degeneration of the tunica media. Sometimes, there may be a
pseudoaneurysm or false aneurysm, which is actually a well- Figure 1: Post-mortem specimen of abdominal aortic aneurysm. Bilateral renal
defined collection of blood and connective tissue outside the artery stenosis with infrarenal aortic involvement.
vessel wall as a consequence of a contained rupture of the aortic
wall.
infrarenal and fusiform, varying in size from a few millimetre to
Morphologically, an aneurysm is either fusiform or saccular. ten centimetre. Only 2% to 5% are suprarenal. Absence of vasa
Fusiform aneurysm is more common. It is a symmetrical vasorum in the infrarenal aorta coupled with atherosclerotic
dilatation of the full circumference of the aortic wall. Saccular thickening of intima may jeopardise nutrient and oxygen supply
aneurysm on the other hand involves more localised dilation to the media of this segment. This may hasten degeneration of
appearing as an outpouching of only a portion of the aortic tunica media in genetically predisposed subjects due to
wall. increased elastolytic activity and lead to aneurysm formation.
Incidence Surprisingly, diabetes mellitus patients are not prone to
development of abdominal aortic aneurysm.
The post-mortem incidence of aortic aneurysm is 1% to 3%.
There has been a gradual decline in the incidence of syphilitic Clinical Features
aneurysms, but this has been offset by an increase in the Symptoms
atherosclerotic variety.
Backache, abdominal pain, limb oedema and venous
ABDOMINAL AORTIC ANEURYSMS congestion are common. Acute pain and hypotension
secondary to rupture may occur.
Abdominal aortic aneurysms (Figure 1) are far more common
than thoracic aneurysms. They are 8 to 10 times more frequent Signs
in men than in women. Their incidence shows a rapid rise after There is palpable pulsatile mass in the abdomen, presence of
55 years in men and 70 years in women. peripheral vascular disease, signs of distal embolisation, and
Aetiopathogenesis haemodynamic collapse.
These aneurysms are usually atherosclerotic. Very rarely they Majority of the cases are asymptomatic and are detected on
may be traumatic, congenital or myxomatous. Most are incidental examinations like abdominal X-ray or ultrasound.
750
 Diseases of the Aorta
Younger patients (50 years old or less) are more likely to be prosthesis, usually Dacron, is advised for all abdominal aortic
symptomatic. The most frequent complaint is a steady, gnawing aneurysms 6 cm in diameter or wider since three-fourth of them
pain in the hypogastrium or lower back, lasting for several hours will rupture. Operative mortality is 4% to 6% in elective repair.
or days at a time and not affected by movement. A pulsatile The benefit of surgery for asymptomatic aneurysms 4 to 5 cm
mass extending variably from the xiphoid process to the in size is not yet established. Complications of surgery include
umbilicus may be felt. Stagnation of blood in the aneurysmal stenosis or occlusion of the prosthetic graft, false aneurysm
sac forms mural thrombus which may embolise to distal arteries formation, infection and rupture. Endovascular treatment in the
leading to absence of femoral and lower limb pulses and bruits form of percutaneously implanted expanding endovascular
over affected arteries. Rarely, an expending aneurysm can stents are new interventional options for the treatment of
compress inferior vena cava or one of the iliac veins to produce abdominal aortic aneurysms not suitable for surgery (older
lower limb oedema and venous congestion. patients, patients at higher risk for surgery). Endoleaks
(persistent residual flow in aneurysmal sac) are a major
The major risk of abdominal aortic aneurysm is its rupture.
disadvantage with this option.
Expansion or impending rupture are heralded by sudden onset
of new or worsening pain that is characteristically constant, THORACIC AORTIC ANEURYSMS
severe, localised to back or lower abdomen and sometimes Thoracic aortic aneurysms are divided according to anatomical
radiating to the groin, buttocks and legs. The pulsatile location into ascending arch and descending aortic aneurysms,
abdominal mass, if present already, may become tender on each differing in aetiology, natural history and therapy.
palpation. Abrupt onset of back pain and abdominal pain with
tenderness, and hypotension characterises actual rupture, but Ascending aorta aneurysms most often result from cystic medial
this pathognomonic sign is present in only one-third cases. In necrosis. Other causes are Marfan’s syndrome, syphilis, mycotic
80% of the cases rupture occurs in the left retroperitoneum aneurysm secondary to aortic bacterial endarteritis and rarely
and is signalled by haematomas in the flanks and groin. Most atherosclerosis. Aortic arch aneurysms may be due to
of the remainder rupture into the peritoneal cavity, causing atherosclerosis, cystic degeneration, syphilis or other infections
uncontrolled haemorrhage and result in abdominal distension. while descending aortic aneurysms are predominantly
Rupture into the duodenum presents as massive gastro- atherosclerotic. The basic pathogenetic mechanism is
intestinal haemorrhage. Rarely, it may rupture into inferior vena progressive dilatation of the aortic wall weakened by tunica
cava, iliac or renal vein producing haemodynamic collapse and media degeneration.
acute high-output cardiac failure. Rupture is associated with Clinical Manifestations
high mortality; 60% die before any medical intervention and
Forty per cent of the patients are asymptomatic and are
50% of those survive after operative correction.
diagnosed on incidental physical examination or X-ray.
Diagnosis and Size Estimation Symptoms reflect either a vascular consequence of the
Aneurysm may be detected and their size estimated by physical aneurysm or a local mass effect. Vascular consequences are
examination, routine roentgenography, abdominal cross- aortic regurgitation and secondary congestive heart failure due
sectional ultrasonography, digital subtraction angiography, to aortic root dilatation, myocardial ischaemia due to coronary
abdominal aortic angiography, CT scan and MRI. artery compression by enlarged sinuses of Valsalva, rupture of
sinus of Valsalva into the right heart producing continuous
In about 70% of cases, plain X-rays show a curvilinear or linear murmur with congestive heart failure and thromboembolism
rim corresponding to the aneurysm wall. In fact aneurysm causing stroke, lower extremity ischaemia, renal infarction or
usually presents as a paravertebral soft tissue mass.With rupture, mesenteric ischaemia. Local mass-effects depend on anatomical
there is distortion of the psoas muscle shadow and absence of location. Ascending aortic aneurysm may cause superior vena
gas in the bowel over the aneurysm. Abdominal ultrasound is cava syndrome due to compression of the superior vena cava.
the most easily available and inexpensive way of detecting an Arch aneurysms cause superior vena cava syndrome; tracheal
aneurysm and assessing its size, wall thickness and presence of or main stem bronchus obstruction leading to wheeze, cough,
thrombus. Aortography is a risky procedure and is used in dyspnoea (may be positional), haemoptysis and recurrent
selective pre-operative cases to assess suprarenal extent of the pneumonitis. Descending aortic aneurysms may cause trachea
aneurysm, any associated iliofemoral disease and for defining or main stem bronchus compression, oesophageal compression
renal and mesenteric arterial anatomy. It may underestimate producing dysphagia or recurrent laryngeal nerve compression
aneurysmal size in the presence of non-opacified mural producing hoarseness.
thrombus lining its wall. CT scan is an extremely accurate
method for both diagnosing and sizing the abdominal aortic Steady, deep, boring and sometimes excruciating chest or back
aneurysms. MR angiography is also a highly effective method pain develop due to compression of intrathoracic structures or
in delineating aneurysm anatomy pre-operatively and it is safe due to erosion of adjacent bone. Aneurysms eroding through
alternative to aortography. Pre-operative aortography is largely the chest wall are visible as pulsating masses. The most serious
replaced by CT scan and MRI now-a-days considering their non- consequence of thoracic aneurysm is rupture that is heralded
invasive nature and high sensitivity and specificity. by sudden increase in the intensity of pain. Rupture most
commonly occurs into the left intrapleural space or the
Treatment intrapericardial space and presents as hypotension. Next
Medical therapy with beta-blockers slows the expansion of common site is the oesophagus that presents as life-threatening
aneurysm although its efficacy is less in aneurysm of bigger haematemesis. Thoracic aneurysm may also develop aortic
size. Aneurysmectomy and replacement by a synthetic dissection. 751
 Diagnosis
Many thoracic aneurysms, except for smaller ones, are evident
on chest X-ray. Transthoracic Echocardiography (TTE) is useful
in the imaging of aortic valve and proximal aortic root.
Transoesophageal Echocardiography ( TEE) can help in
assessment of aneurysm of ascending and descending aorta
but it cannot visualise aneurysm of the arch. Contrast CT-scan
and MR angiography are very accurate in detecting and sizing
aneurysms. Aortography was a preferred pre-operative
modality to define the anatomy of the aneurysm. However, as
in the case of abdominal aorta, CT and MR angiogram are now
often sufficient in most of the cases to define aortic and branch
vessel anatomy. MR angiography is preferable to CT scanning
when the aortic root is involved.
Treatment
Medical therapy is directed towards risk factor reduction and Figure 2: Schematic diagram of classification of aortic dissection.
control of blood pressure. Aneurysmectomy and replacement
by a prosthetic sleeve or composite graft-valve (in case of Descriptive classification
ascending aorta) is indicated for aneurysms 6 cm or larger; Proximal: DeBakey types I and II or Stanford type A.
however, in case of Marfan’s syndrome, bicuspid aortic valve Distal: DeBakey type III or Stanford type B.
or rapidly growing aneurysms, early surgery is indicated.
Proximal dissections are twice more common and more lethal
Propranolol may be used to delay the surgery in smaller
than distal dissections.
aneurysms. Surgical repair of arch aneurysms is particularly
challenging with high incidence of stroke. Descending Clinical Picture
thoracic aneurysmectomy may produce post-operative A tearing, ripping or severe stabbing pain, from its initiation
paraplegia due to interruption of spinal cord blood supply. and with a tendency to migrate from its point of origin to other
Transluminally placed endovascular stent grafts is an sites following the course of dissection is typically present in
alternative approach for treating descending aneurysms in majority of cases except for those with chronic dissections.
patients with higher risk for surgery. Severe pain from onset differentiates it from myocardial
infarction. Anterior chest pain or neck, throat, jaw or face pain
DISSECTION OF THE AORTA
usually signifies ascending aorta involvement and inter-
Aetiopathogenesis scapular or back, abdomen or lower limb pain that of
Aortic dissection is initiated by entry of blood through an intimal descending thoracic aorta.
tear into a degenerated tunica media of the thoracic aorta. The
Obstruction of the branches by compression of the true lumen
medial degeneration may occur due to classical cystic medial
by the distended false lumen or by obstruction of the vessels
necrosis or connective tissue disorders like Marfan’s or Ehlers-
orifices by a mobile intimal flap may produce pulse deficits,
Danlos syndrome. The blood jet divides the media into two
pseudohypotension, syncope, cerebrovascular accident, cardiac
producing a false lumen.The inner portion of the dissected wall
arrest or sudden cardiac death, ischaemic peripheral
forms an intimal flap. The intimal flap may be pushed into the
neuropathy and paraplegia. Pulse deficits and neurological
true lumen, by the false lumen distended with blood, or it may
manifestations are more common in proximal dissection.
be torn open by the blood jet producing an exit site. Old age
Hypertension is seen in 80% to 90% of distal dissection and
(50 to 70 years), female sex, pregnancy, hypertension, bicuspid
hypotension is more common in proximal dissection.
or unicuspid aortic valve, giant cell arteritis, Noonan and Turner
syndromes and cocaine abuse may predispose to dissection. Aortic regurgitation due to dilatation of aortic root and annulus,
Aortic dissection occurs at a rate of 5 to 10 cases per million detachment of aortic leaflet or prolapse of a mobile intimal flap
population per year. through aortic orifice is the characteristic of proximal dissection
and results in congestive cardiac failure. The murmur has a
Classification (Figure 2) musical quality and radiates along the right sternal border.
DeBakey classification Syncope without a focal neurological sign heralds rupture of a
Type I: Begins in the ascending aorta and extends to the proximal dissection into pericardial sac producing cardiac
descending aorta and arch. tamponade or that of distal dissection into the intrapleural space.
Type II: Confined to the ascending aorta. Investigations
Type III: Originates in the descending aorta and extends distally Anaemia may develop from significant haemorrhage or
or rarely, retrograde into arch and ascending aorta. sequestration of blood in the false channel. A mild-to-
moderate polymorphonuclear leucocytosis (10,000-14,000/
Stanford classification
mm3) is common. Lactate dehydrogenase (LDH) and bilirubin
Type A: All dissections involving the ascending aorta, regardless levels are sometimes elevated. Serum glutamic oxaloacetic
of the site of origin. transaminase (SGOT) and CK-MB are usually normal, unless
752 Type B: All dissections not involving the ascending aorta. associated myocardial infarction develops along with
 Diseases of the Aorta
dissection. ECG abnormalities are particularly common in 24 hours, more than 50% within the first week, 75% within one
Stanford type A aortic dissections. ST depression is most month, and more than 90% within one year.
common abnormality. Sometimes, patients present with inferior
Early emergency treatment
wall MI due to involvement of right coronary sinus. Chest X-ray
may reveal widening of the aortic arch in 40% to 50% of cases, All patients should be admitted immediately to an intensive
change in configuration of the aorta on successive X-ray, care unit. Initial therapeutic goals are the elimination of pain
obliteration of the aortic knob with displacement of the trachea and reduction of systolic blood pressure to 100 to 120 mm Hg
with a potent vasodilator like sodium nitroprusside. Nitroprusside
to the right, localised hump on the aortic arch and an increase
when used alone can cause increase in the dp/dt so it should
in distance from intimal calcification to the outer edge of the
be used with a beta-blocker.
aortic shadow of > 1 cm (calcium sign).
Propranolol is used in incremental doses of 1 mg intravenous
TTE is a useful tool for the diagnosis of ascending aortic
every five minutes until there is an evidence of satisfactory beta-
dissections. However, it is limited by its inability to show the
blockade, usually indicated by a pulse rate of 60 to 80 beats/
distal extent. TEE is highly sensitive and specific for evaluating
min. Labetalol and esmolol can also be used in this setting.
proximal aortic dissection.
Patients who have contraindication for beta-blocker therapy
Development of helical CT with multiplanar and 3D should be put on cardioselective calcium channel blockers. In
reconstruction and CT angiography has made CT scan a highly chronic stable dissection propranolol is given orally in dose of
sensitive (83% to 94%) and specific (87% to 100%) mode for 20 to 40 mg six hourly.
diagnosis of aortic dissection. It is fast replacing the Definitive subsequent therapy
conventional angiography (Figures 3A and B and Figure 4) as
a standard diagnostic test in many centres. Results of surgical therapy is superior to medical therapy in
acute (< 2 weeks) proximal dissection and, conversely medical
MRI although highly sensitive and specific it is used preferably therapy offers a relative advantage over surgery in most cases
for chronic aortic dissection and post surgical follow-up. of uncomplicated acute distal dissection (Table 1).
Treatment Table 1: Indications for Definitive Therapy in Aortic Dissection
Therapy is aimed at halting the progression of the dissecting
Surgical
haematoma. Without treatment 25% of the patients die within
Treatment of choice for acute proximal dissection
Treatment of choice for acute distal dissection complicated by
progression with vital organ compromise
Rupture or impending rupture
Aortic regurgitation (rare)
Retrograde extension to the ascending aorta
Dissection in Marfan’s syndrome
Medical
Treatment of choice for uncomplicated distal dissection
Treatment for stable, isolated arch dissection
Treatment of choice for stable chronic dissection
(uncomplicated dissection presenting two weeks or later
after onset)
Figures 3A and B: Aortogram showing aortic dissection. (A) pre-stenting and
(B) post-stenting. Long-term medical therapy to control hypertension and reduce
dp/dt is indicated for all patients regardless of whether they
have received definitive surgical or medical therapy. Follow-up
of patients should include repeated physical examinations,
periodic chest X-rays, CT scans or digital substraction
angiograms (DSA) for evidence of localised aneurysm formation.
MRI also promises to be a valuable tool for follow-up.

INTRAMURAL HAEMATOMA
It is an acute aortic syndrome which is typically characterised
by haemorrhage within medial layer of aortic wall, but unlike
classic aortic dissection, there is no evident tear in intimal layer.
It is proposed that it results from the rupture of vasa vasorum
within aortic wall although some believe that it results from
intimal tear which is too small to be visualised. The risk factors,
signs and symptoms resemble classic aortic dissection. Among
the various available diagnostic modalities CT scan is the most
preferred diagnostic tool to visualise the intramural haematomas.
The natural history of intramural haematoma is debatable
Figure 4: Aortogram showing dissection of aorta.
but they can proceed in four possible ways absorption of 753
 haematoma, persistence of haematoma, development of aortic
aneurysm, and conversion to classic aortic dissection.
Treatment of this aortic syndrome is similar to classic aortic
dissection in the sense that proximal aortic intramural
haematoma should be operated while distal intramural
haematoma should be managed medically.

AORTO ARTERITIS (TAKAYASU’S ARTERITIS)

Takayasu’s arteritis (TA) is a chronic inflammatory disease of the
aorta and its major branches. Though the disease was named
after him,Takayasu was not the first to describe this disease entity.
‘Pulseless’ disease was reported by Adams way back in 1827. In
1908, Takayasu described a peculiar ‘wreath-like’ appearance of
arteriovenous anastomosis around the optic papilla.
The disease has a worldwide distribution, though the majority
of cases are seen in Japan, India, South Africa, Mexico and parts
of South America. Mongoloid races are affected the most,
followed by the Indo-Aryan. The disease predominantly affects
young females. The female: male ratio being 7:1 in Japan, 5:1 in
Mexico and 3:1 in India.
Aetiopathogenesis
The specific cause of the disease is not known, though the bulk
of evidence favours an autoimmune aetiology. Association with
rheumatic fever, streptococcal infection, rheumatoid arthritis, Figure 5: Aortogram showing involvement of aortic arch with both common
carotid arteries with aorto-arteritis.
other collagen vascular disease and tuberculosis were
described. The disease has two stages. The early active phase,
there is non-specific granulomatous panarteritis involving all
the layers of the wall of the aorta and its branches but unlike
other forms of the aortitis, pulmonary artery may be involved
in this disease. The disease progresses variably to a chronic
sclerotic phase, characterised by intimal hyperplasia leading to
purely stenotic lesion in 85% of the patients, purely dilatative
in 2% and mixed lesion in 13% of the patients.
Classification
Lupi-Herrera et al in 1977, described four varieties of disease
based on predominant site of involvement:Type I (Shimizu-Sano)
aortic arch and its branches (Figure 5); Type II (Kimoto) thoraco-
abdominal aorta and its branches; Type III (Inada) combines-
features of both Type I and Type II; and Type IV (Oata) pulmonary Figure 6: Pulmonary artery involvement in a patient with aorto-arteritis.
artery (Figure 6). Another variety of arteritis is proposed as
Type V aorto-arteritis associated coronary artery (Panja et al)
(Figure 7). Criteria of American College of Rheumatology for the
Classification of Takayasu Arteritis (1990) are given in Table 2.
Clinical Manifestations
The disease affects teenagers in three-fourths of cases, though
no age is immune to this disease. More than half of the patients
present with features of active disease viz. fever, anorexia,
malaise, weight loss, night sweats, arthralgias, pleuritic pain
and fatigue. Localised pain and tenderness may be noted over
the affected arteries. Occasionally, it may present as fever of
unknown origin.
In the sclerotic phase, the manifestations include diminished
or absent pulses in 96%, bruits in 94%, hypertension in 74% and
heart failure in 28% patients. Retinopathy leading to retinal
detachment and loss of vision is seen in 25% of the cases.
Patients with types I and III disease present as ‘reverse
Figure 7: Severe coronary artery involvement in a patient of aorto-arteritis.
754 coarctation’ manifested by absent or diminished pulse and
 Diseases of the Aorta
blood pressure in the upper limbs, bruits over diseased arteries Use of contrast may reveal inflammatory lesion prior to
and syncope. Type II disease is manifested by abdominal angina, development of stenosis. Ishikawa and American College of
claudication of limbs and hypertension due to renal artery Rheumatology have proposed criteria for the diagnosis of
involvement. Takayasu arteritis (Table 2).
Hypertension, a major complication of this disease, arises due Table 2: 1990 Criteria of American College of Rheumatology for
to renal artery stenosis (35.85%) (Figure 8), involvement of the Classification of Takayasu Arteritis
baroreceptors by aortitis, loss of elasticity of aorta and
Criteria Definition
coarctation like lesion. Congestive heart failure occurs due to
hypertension, dilated cardiomyopathy or more rarely aortic Age of onset Development of symptoms or
regurgitation. Coronary artery involvement may cause angina, findings related to Takayasu
myocardial infarction. Pulmonary artery involvement may result arteritis at age <40 years
in a clinical picture similar to primary pulmonary hypertension. Claudication of extremities Development and worsening of
fatigue and discomfort in
Investigations muscles of one or more extremity
while in use, especially the upper
During the systemic phase, elevated ESR, low-grade leucocytosis
extremities
and mild anaemia of chronic disease are frequent. IgG or IgM
Decreased brachial artery pulse Decreased pulsation of one or
values are elevated in more than half of the patients. C-reactive both brachial arteries
protein may be elevated with increased anti-streptolysin titre, BP difference in arms Difference of >10 mm Hg in
rheumatoid factor, anti-endothelial antibodies and elevated systolic pressure between arms
fibrogen levels. Bruit Bruit audible on auscultation
Chest X-ray is usually unrevealing although a rim of calcification over one or both subclavian
arteries or abdominal aorta
is sometimes seen in the walls of the affected arteries.
Arteriogram Arteriographic narrowing or
Arteriography reveals irregular intimal surface with stenosis of
occlusion of the entire aorta, its
the aorta or its branches, post-stenotic dilatation, saccular primary branches, or large arteries
aneurysm and even complete occlusion of vessels. The affected in the proximal upper or lower
thoracic aorta has been described as having a rat-tail appearance. extremities, not due to arterio-
Arterial biopsy may be positive in 20% to 35% of the cases. sclerosis, fibro-muscular dysplasia,
Gallium-67 radionuclide scan may demonstrate uptake in aorta or similar causes: changes usually
and its branches. High resolution ultrasono-graphy is useful in focal or segmental
monitoring disease of common carotid and subclavian arteries.
MRI, MR angiography and CT scan are useful for serial For purposes of classification, a patient shall be said to have
examination and diagnosis in early phase of Takayasu arteritis. Takayasu’s arteritis if at least three of these six criteria are
present. The presence of any three or more criteria yields a
sensitivity of 90.5% and a specificity of 97.8%.
Natural History
The disease is basically progressive, though the rate of
progression varies considerably. The cause of death is usually
heart failure, encephalopathy, renal failure, rupture of aneurysms
and cerebral haemorrhage.
Treatment
Medical treatment is recommended for those suffering from
active and early lesions, those in whom surgery is not possible
or considered too risky because of extensive and multifocal
involvement of the arterial tree and where surgery is contra-
indicated due to uncontrollable congestive cardiac failure or
progressive renal failure. Steroids are often effective in relieving
the constitutional symptoms. Cyclophosphamide, cyclosporine,
mycophenolate mofetil and methotrexate can be tried in cases
which fail to respond to steroids. Etanercept and infliximab may
be used for inducing clinical remission in steroid-dependent
patients. Anticoagulant anti-platelet and drugs like warfarin,
aspirin and dipyridamole are recommended to treat transient
ischaemic symptoms and to prevent progression. Aggressive
treatment of hypertension is important. Surgical treatment for
late complications includes endarterectomy, bypass of
obstructed arteries especially renal arteries, resection of
Figure 8: Bilateral renal artery involvement with left common iliac artery localised coarctation, excision of saccular aneurysms and rarely
involvement in patient with aorto-arteritis.
aortic valve replacement. 755
 Percutaneous transluminal coronary angioplasty (PTCA) with autoimmune or infectious origin has been considered. The
or without stenting has emerged as a useful effective and less typical pathological lesion is granulomatous inflammation of
invasive therapeutic option for Takayasu’s disease. This option the media of small-to-medium calibre arteries about the size of
is especially effective for discrete lesions. the temporal artery, with a special predilection for the vessels
of the head and the neck.
CARDIOVASCULAR SYPHILIS
Clinical Manifestations
It is very rare as a result of aggressive antibiotic treatment of
syphilis in its early stages. Cardiovascular complications occur It typically affects patients over the age of 50 years and occurs
in approximately 10% of cases of untreated syphilis. The latent predominantly in females. The typical presentation consists of
period may extend from 5 to 40 years, with a usual time of 10 to fever, malaise and headache. Other constitutional symptoms
25 years. During the secondary phase of the disease the bacteria include anorexia, weight loss, myalgias, night sweats and
directly invade the aortic media. The direct infection and lassitude. Headaches are often intense and unbearable and
subsequent inflammatory response cause destruction of occur over the involved arteries, usually the temporal arteries,
muscular and elastic media followed by its fibrosis. but occasionally over the occipital region. Blindness may occur
due to involvement of the ophthalmic artery. The syndrome of
Clinical Manifestation polymyalgia rheumatica is seen in nearly 40% of these patients.
In the absence of’ aortic regurgitation an aneurysm may Physical examination reveals the patient to be febrile. The
undergo significant enlargement without producing symptoms. involved vessels are thickened and tender, pulse may be lost
Eventually it may expand to compress and erode contiguous and bruits may be heard over the sites of arterial occlusion.
structure, particularly the sternum and the anterior right Investigations
thoracic cage. This causes pain at the point of involvement.
Ascending aortic aneurysms and those involving the arch may A high erythrocyte sedimentation rate (ESR) is virtually inevitable,
cause a tracheal tug, stridor and dysphagia. There may be normocytic, normochromic anaemia may be present. Antinuclear
hoarseness due to compression of the left recurrent laryngeal antibody and rheumatoid factor are not found. The diagnosis is
nerve and cough from pressure against the left main stem usually confirmed by biopsy of the temporal artery (TA). Colour
duplex ultrasonography of TA is a promising alternative for
bronchus. Patients may have anginal symptoms due to
temporal artery biopsy. Angiography may help to confirm the
associated stenosis of the coronary ostia.
diagnosis in cases of larger vessel and aortic involvement. CT, MRI
Diagnosis are used as second-line diagnostic procedure.
There is a history of syphilis and other manifestations of tertiary Treatment
syphilis in 10% to 30% of cases. About 15% to 30% of patients
Treatment consists of prednisolone 60 to 80 mg per day for 1
have negative routine serological tests for syphilis (Wassermann,
to 2 years. With ESR as guide, steroid may be tapered to a
Kahn and VDRL). Serological tests directed against a specific
maintenance dose of 5 to 15 mg per day for 1 to 2 years.
treponemal antigen are almost invariably positive. The chest X-
Cyclosporine and azathioprine or cyclosporine and metho-
ray may show calcification in the ascending aorta proximal to
trexate are used in steroid-resistant cases. The overall prognosis
the brachiocephalic vessels.
with treatment is good.
Angiography may delineate the aneurysm and help to quantify
OTHER ARTERITIS SYNDROMES
the severity of aortic regurgitation. In patients suspected to have
coronary ostial stenosis and in patients where surgical correction These may be seen in association with ankylosing spondylitis,
is contemplated, the coronary artery anatomy, and particularly psoriatic arthritis, ulcerative colitis, and Reiter’s syndrome.
the ostia, should be visualised by coronary angiography. CT and
AORTIC TRAUMA
MRI are quite helpful in evaluating the aneurysm.
Aortic injuries may occur with severe blunt trauma as in motor
Treatment vehicle accident, blast injuries, crush injuries and severe falls.
All patients who are seen one year or more after the initial The most common site of tear is the aortic isthmus just distal to
contact should be given a course of antibiotic therapy, i.e. the origin of the left subclavian artery. Other sites include the
injection benzathine penicillin 2.4 million units IM weekly for supravalvular portion of the ascending aorta, the aortic arch, the
three weeks. For patients allergic to penicillin, tetracycline 500 innominate artery, abdominal aorta and combinations of these.
mg four times daily for 30 days is recommended.
RECOMMENDED READINGS
GIANT CELL ARTERITIS 1. Jonathen L Halperin, Jeffery W Olin. Diseases of Aorta. In: Valentine F,
Alexander WR, Robert A; editors. Hurst’s The Heart 11th Ed. McGraw Hill
This disease is found predominantly in elderly people and Publication House; 2004; 230:1-22.
characteristically involves medium-sized arteries. The aorta and 2. Isselbacher ME. Diseases of Aorta. In: Zipes DR, Libby P, Bonow 0R, Braunwald
its branches are affected in about 15% cases. The aetiology of E; editors. Braunwald’s Heart Disease. 7th Ed. Elsevier Saunders; 2005:
giant cell arteritis is unknown. However, the possibility of an 1403-36.

756
 12.32 Vascular Disorders of the Extremities

Gurpreet Singh Wander, Bishav Mohan

INTRODUCTION neuropathy and increased risk of infection. Most patients with

Vascular disorders of the extremities can involve the arterial, chronic PAD have bad prognosis due to associated coronary
venous or the lymphatic systems. These are generally more and cerebral atherosclerosis. Diabetic foot is one of the dreaded
common in the lower limbs than in the upper limbs. These complication with high rate of amputation. This can be
disorders can have an acute onset or may develop chronically. managed with combined approach of preventive measures
The diagnosis is made in most cases by a thorough clinical, (education, foot care, special shoes) and treatment strategies
ultrasonographic and Doppler evaluation. These abnormalities (angioplasty ± stents). These have reduced the below knee
can be primary in origin or they may be manifestations of a amputation rate.
systemic disorder. Patients often present with intermittent claudication when the
limb ischaemia is less critical. This is a cramp-like pain felt in the
ARTERIAL DISORDERS
calf muscles, brought on by walking and relieved on standing
Vascular occlusion, acute or chronic, is the major arterial disorder still. The distance walked is called ‘claudication distance’ and is
of the extremities. Table 1 outlines the arterial disorders. relatively constant for a patient.
Table 1: Classification of Arterial Disorders Patients with critical limb ischaemia (CLI) are defined as those
Occlusive with rest pain that is felt in the foot at rest and made worse by
Acute occlusion (embolic, thrombotic, traumatic) lying down or elevation of the foot. Characteristically, the pain
Chronic occlusion (Atherosclerotic, Takayasu’s arteritis) is worse at night and relieved by hanging the foot out of the
Gangrene bed. Other changes include coldness, numbness, paraesthesias
Wet (due to acute occlusion) and colour change (ischaemic limbs become blanched on
Dry (due to chronic occlusion) elevation and develop a purple discolouration on dependence).
Aneurysm Severe arterial insufficiency can result in painful superficial
Arteriovenous fistula erosions between the toes, on the dorsum of feet and around
Thromboangiitis obliterans (Buerger’s disease) the malleoli. Later, this can progress to ulceration and frank
Vasospastic disorders gangrene (Figure 1). A severely ischaemic foot is frequently
Raynaud’s disease paralysed and cold but may feel warmer as it takes on the
Livedo reticularis temperature of its surroundings.
Acrocyanosis In the upper limb, atheromatous occlusive disease can involve
subclavian artery and may cause claudication and rarely frank
Chronic Arterial Occlusion
ischaemia of an arm.The subclavian lesion may also cause distal
It presents less dramatically than acute occlusion and is much embolisation and consequent loss of digits. Subclavian steal
more common. Atherosclerotic peripheral arterial disease (PAD) syndrome may occur if the first part of the subclavian artery is
affects the leg eight times more often than the arm. The obstructed and the vertebral artery provides a collateral
pathophysiology of PAD is similar to coronary artery disease. circulation into the arm by reversing its direction of blood flow.
The most important risk factors are smoking, diabetes, The classic syndrome of syncopal attack and visual disturbance
hyperlipidaemia and hypertension. The clinical manifestations associated with arm exercise and a diminished blood pressure
depend on the anatomical site, the presence or absence of in the affected limb is rare. Asymptomatic reversal of flow in
collateral supply, the rapidity of onset and the occurrence of the vertebral artery recognised by duplex scanning or
external trauma. angiography is much more common.
Takayasu’s arteritis (pulseless disease) is another common cause Relevant investigations include tests for diabetes mellitus, lipid
of chronic PAD involving the aorta and its major arteries. Most abnormalities and anaemia. Doppler ultrasound is a very
commonly upper limb vessels are affected. Its prevalence is high sensitive type of stethoscope that can be used in conjunction
in young women of Indian, Japanese and Mexican descent. with a sphygmomanometer to assess the systolic pressure in
There is a panarteritis in the acute stage, culminating in fibrotic
relatively small vessels. Ankle: brachial pressure index (ABPI) is
occlusion in the chronic stage. No definitive therapy is available
the ratio of systolic pressure in the ankle to that in the arm.
for this disease. However, in acute stage steroids are of some
Values under 0.9 indicate mild ischaemia whereas < 0.5 indicate
use. Vascular interventions (balloon angioplasty and metallic
severe ischaemia. Duplex imaging combines B-mode
stents) are often used with variable results.
ultrasound with Doppler ultrasound to give detailed knowledge
In Indian subcontinent, diabetics form the largest group of about vessel-wall thickness, blood flow and turbulence. The
patients with atherosclerotic PAD. The occlusive disease in ‘gold standard’ for arterial occlusive disease is angiography,
diabetics is more extensive and complicated due to associated which involves the injection of radio-opaque dye in the vessels 757
 performed by inserting a balloon catheter into an artery and
inflating it within a narrowed or blocked area. In certain cases, a
metallic stent may need to be inserted to keep the lumen patent
(Figures 2Ato C, and Figures 3A and B). In feasible cases, a
surgical vascular bypass may be performed around the occluded
part of the vessel to permit distal perfusion.The long-term results
of reconstructive aortoiliac surgery are good and they are usually
only marred by a progressive disease producing femoro-popliteal
occlusions at a later stage. Stem cell therapy (therapeutic
angiogenesis) has generated a lot of interest. However, the results
need to be documented in large randomised control trials.

Figures 2A to C: (A) Bilateral common iliac stenosis, (B) Stents placed in both
common iliac arteries, (C) Post-stenting angiogram showing normal flow.

Figure 1: Patient with chronic arterial occlusion of left lower limb showing
discolouration of left foot, thinning of ankle and foot, and dry gangrene of distal
digits.

and then using a real time or single shot X-ray to detect the
status of the vessels. Digital subtraction angiography (DSA)
Figures 3A and B: (A) Angiogram showing stenosis in the peroneal artery, (B)
helps in better delineation of the vessels by subtracting the Post-angioplasty angiogram showing normal flow.
images of overlying tissues. More recently, ultra fast CT-
angiography done by injection of intravenous contrast helps Acute Arterial Occlusion
in studying the arterial tree without the need for arterial
Sudden occlusion of an artery may be due to emboli from a
injection as in conventional angiography. Renal function test
remote site, thrombus formation on a pre-existing atheroma or
should be done before sending the patient for contrast imaging.
trauma (Figures 4A and B). The emboli can arise from an atrial
Magnetic resonance angiography (MRA) provides multiplanar
source as in atrial fibrillation or left ventricular mural thrombus
imaging without the need of ionising radiation.
following myocardial infarction. These tend to lodge at vessel
Arterial occlusive disorders can be managed conservatively in bifurcation. Acute occlusion is an emergency and threatens limb
most cases. Encouraging exercise within the limits of disability is viability. It needs immediate diagnosis and early management
a good way of increasing exercise capacity. Spontaneous since delay can compromise limb viability.
improvement occurs after a few months due to formation of
collaterals. Drugs that have a role in occlusive arterial disorders
include those for underlying diabetes, hypertension and lipid
abnormalities. Antiplatelet agents like aspirin (75 to150 mg od)
or clopidogrel can be used. Cilostazol, a phosphodiesterase
inhibitor with vasodilator and antiplatelet properties has been
shown to improve claudication distance. Naftidrofuryl oxalate
may alter tissue metabolism, thus increasing claudication
distance. Pentoxifylline improves RBC rheology (flexibility) and
has some blood thinning capacity, thus helping to improve
circulation. Prostacyclins may have some minor role in the Figures 4A and B: This patient presented with a tibial fracture and absent distal
management of the critically ischaemic limb. Lumbar pulses: (A) Angiogram showing sudden cut-off of arterial blood flow at the level
sympathectomy has been used for pain relief. In vessels with of the fracture; (B) After stabilisation of the fracture, injection of local vasodilators
and ballooning of the blocked segment, flow is restored.
758 localised blocks, transluminal angioplasty and stenting may be
 Vascular Disorders of the Extremities
The classical signs in the lower limb are the 6 P’s – pain, pallor,
paresis, pulselessness, paraesthesia and poikilothermia. The limb
is cold and, almost immediately, the toes cannot be moved.
Sensation to touch is soon lost and distal pulses become
impalpable. B-mode ultrasound imaging shows lack of pulsation
in arteries and Doppler confirms the diagnosis by showing lack
of blood flow.
Appropriate treatment is the immediate intravenous
administration of heparin. This can halt the extension of the
thrombus and maintain patency in the surrounding vessels. Pain
relief is essential because pain is severe and constant. Surgical
embolectomy for larger vessels till the popliteal artery is the
treatment of choice when done within 12 hours of ischaemia.
Thrombolysis using streptokinase or urokinase is preferred for
distal vessels. This has to be done within 6 to 12 hours to
preserve limb viability. Patients presenting late often go on to
develop gangrene of the distal toes and the feet.
Gangrene
The combination of rest pain, colour changes and hyper-
aesthesias with or without ischaemic ulceration is frequently
referred to as pre-gangrene. Gangrene implies death of
macroscopic portions of tissue. It is commonly seen affecting
the distal part of the limb. A gangrenous part lacks arterial
pulsation, venous return, capillary response to pressure (colour
return), sensation, warmth and function. The colour changes
from pale through dusky-gray to mottled until finally taking on
Figure 5: Wet gangrene of both lower limbs due to acute arterial occlusion
the characteristic dark brown, green-black or black appearance. with blebs, denuded skin and blackish discolouration of both feet.
Dry gangrene Extrinsically, pressure on veins or nerves may cause distal
This occurs when the tissues are desiccated by gradual occlusion oedema or altered sensation.
of the vessels. It is typically due to atheromatous occlusion of
Arteriovenous Fistula
the arteries. The affected part becomes dry and wrinkled,
discoloured and greasy to touch. This is a communication between an artery and vein. This may
be congenital or acquired due to surgical trauma and catheter
Wet gangrene access. AV fistulas may also be created in the upper limb to
This occurs when the artery is suddenly occluded and there is facilitate haemodialysis. Haemodynamically significant fistulas
venous obstruction as well. Infection and putrefaction are may lead to a wide pulse pressure and a thrill is present. A
present and the affected part becomes swollen and discoloured continuous bruit can be heard over the fistula. Pressure on the
and the epidermis may be raised in blebs. Crepitus may also be artery proximal to the fistula may cause the swelling to diminish,
palpated (Figure 5). the thrill and bruit to cease and the pulse rate to fall (Nicoladoni’s
or Branham’s sign) and the pulse pressure to return to normal.
Treatment includes general measures like hydration, pain
Embolisation by autologous material (fat/muscle) or gelatine
control and control of infection. Once gangrene has set in, the
sponges, silicon spheres can obliterate the fistula. Large, painful
reestablishment of blood flow by percutaneous intervention
or bleeding AV fistula can be managed surgically or with
or surgery does not help. Unviable portions of tissue need
endovascular grafts/stents.
to be amputated to relieve pain and prevent the spread of
infection and gangrene. Thromboangiitis Obliterans
Aneurysm This involves occlusive disease of the small and medium sized
arteries, thrombophlebitis of superficial and deep veins, and
An aneurysm is a localised dilatation of a segment of the arterial
Raynaud’s phenomenon. It is also known as Buerger’s disease.
system. Aneurysms can be true (involving the vascular intima,
It is most common in Asian males under the age of 30, generally
media and adventitia) or false (with a fibrous wall). In
smokers. Treatment is primarily cessation of smoking. This helps
appearance, they may be fusiform, saccular or dissecting.
halt the progression of the disease but does not lead to reversal
Aetiology can be atheromatous, traumatic, syphilitic or due to
of the established occlusion. Sympathectomy for pain relief is
collagen disease.
also done. Stem cell therapy has also been tried.
These can present due to expansion, thrombosis or
Vasospastic Disorders
embolisation. Intrinsically, a pulsatile swelling is present along
the course of an artery, which diminishes on application of Raynaud’s disease
proximal pressure. The sac is usually compressible unless It predominantly affects the upper limbs in young women. The
thrombosed. A thrill may be felt and a systemic bruit auscultated. peripheral pulses are normal. Due to an abnormal response to
759
 cold temperature, the vessels constrict and then dilate. This thrombosis in young patients. Common acquired thrombophilic
produces a classic triphasic colour change; pallor, cyanosis states are previous surgery (especially orthopaedic like joint
followed by redness of the digits. This is often accompanied by replacement), trauma, pregnancy, certain malignancies, stroke,
pain. heart failure, prolonged immobilisation and drugs such as oral
contraceptives and hormone replacement therapy (Table 2).
Raynaud’s syndrome shares the clinical features of Raynaud’s
Long haul air travel has been associated with an increased
disease but is much more severe. It is generally a manifestation
incidence of DVT due to the immobilisation.
of collagen vascular disease. It may also follow the use of
vibrating tools and is then known as ‘vibration white finger’. Table 2: Predisposing Causes for Venous Thrombosis
Treatment is primarily directed at the underlying condition.
Calcium channel blockers may have a role in management. Hypercoagulable states
Mutations of factor V (Leiden), prothrombin gene
Livedo reticularis Deficiency of protein C, protein S, antithrombin III
This involves purplish mottling of the skin due to spasm of Antiphospholipid antibody
dermal arterioles in lower extremities, especially on cold Disseminated intravascular coagulation
exposure. Surgery
Orthopaedic, thoracic, abdominal
Acrocyanosis Neoplasia
It is an uncommon condition seen in females and is Pancreas, lung, ovary, testes, breast
characterised by bluish discolouration in hands and fingers. No Trauma
specific therapy is required. Fractures, spinal injuries
Immobilisation (any cause)
VENOUS DISORDERS Hormonal
Blood returns from the limbs via the deep and superficial veins. Pregnancy, oral contraceptives
In the upper limb, the superficial veins are more important. The
superficial veins in the leg are the long and short saphenous The most significant clinical findings are tenderness in the
veins, and they carry only 10% of the blood from the lower limbs. calf and ankle oedema. Pain in the calf on dorsiflexion of
the ankle (Homan’s sign) is rare and often misleading. Other
There is a foot-pump that ejects blood from the plantar veins signs and symptoms are swelling, pain, redness, dilated
as pressure is placed on the foot during walking. On exercise, superficial veins and low-grade pyrexia (Figure 6). Some
the thigh and calf muscles contract compressing the veins and
ejecting blood towards the heart. Venous valves control the
direction of flow of blood in the veins. During muscle relaxation
phase, the pressure within the calf falls to a low level and blood
from superficial veins flows through the perforating veins into
the deep veins. Venous diseases are of two main types; venous
thrombosis and venous incompetence.
Venous Thrombosis
Venous thrombosis of the deep veins involves the lower limbs
more frequently than the upper limbs. In most cases, deep vein
thrombosis (DVT) is asymptomatic and resolves without
sequelae. However, often patients are left with a post-
thrombotic limb that is persistently swollen, often complicated
by venous ulceration. During the acute phase, DVT needs to be
taken seriously since the thrombi can dislodge and embolise
to the pulmonary circulation. A clot from the lower limb veins
detaches from its site and passes via the inferior vena cava and
right heart to the pulmonary arteries. It may totally occlude the
perfusion to a part or all of one or both lungs. In 10% patients
who die in the hospital, the cause of death is pulmonary
embolism following a DVT.
The main causative factors are part of the Virchow’s triad; stasis
(slowing of the blood flow), hypercoagulability (increased
tendency to clot) and vessel wall damage (which releases
thrombogenic substances). The term ‘thrombophilia’ implies an
increased tendency for clotting, often for prolonged periods of
time. This can be inherited or acquired. The common genetic
causes responsible for venous thromboembolism are mutations
involving factor V Leiden (20% to 40%) and prothrombin (6%) Figure 6: Superficial and deep vein thrombosis of right leg showing oedema
genes. Inherited deficiency of protein C (3%), protein S (3%) and and calf swelling due to DVT. There is an accompanying superficial vein
thrombosis as evidenced by the linear redness and swelling.
760 antithrombin III (1%) have also been shown to lead to venous
 Vascular Disorders of the Extremities
patients with DVT may have no symptoms in the leg but initially Axillary Vein Thrombosis
present with sudden onset dyspnoea due to pulmonary This may occur following excessive exercise or as a complication
embolism. of thoracic outlet syndrome. It is occasionally associated with a
For diagnosis, a quantitative D-dimer analysis is done to cervical rib. The arm becomes swollen and the superficial veins
measure the levels of fibrin degradation products. It is become distended. Early treatment with anticoagulants may
recommended to rule-out DVT in clinically suspicious patients. result in rapid resolution. In severe cases, the use of fibrinolytic
It is, however, not very specific and hence the value of a positive therapy, streptokinase or TPA may be considered. Definite
test is limited. The best method for diagnosis is B-mode and treatment of thoracic outlet syndrome by surgical decompression
Doppler ultrasound in which we look for flow in the veins and of the subclavian may be needed, e.g. by resection of the
augmentation on calf compression. Ascending phlebography first rib.
is rarely done. Venous Incompetence
Immobilisation is usually needed only for first 24 hours. Unidirectional venous flow requires the competence of the
Treatment involves anticoagulation after the diagnosis is made. valves in the superficial and deep veins as well as the venous
Standard treatment involves unfractionated intravenous perforators. Dysfunction of these valves leads to venous
heparin (UFH) with dose adjusted according to activated partial incompetence and varicose veins. The incidence of varicose
thromboplastin time (aPTT). The onset of action is rapid and it veins in developing countries is lower than in the western
is given for about 5 days. The aim is to minimise the risk of nations due to genetic, lifestyle and dietary differences. Varicose
pulmonary embolism and to encourage the resolution of the veins develop more frequently in people who stand during their
thrombus. Subcutaneous injections of low molecular weight work and during pregnancy under the influence of oestrogen
heparin (LMWH) are an alternative method and have been and progesterone.
found to produce reliable anticoagulation.These are given twice
daily and are easier to administer. They also do not require aPTT Symptoms include tiredness, aching, tingling, ankle swelling and
monitoring. Many LMWHs are now commercially available and a cramping sensation in the legs, which progressively worsen
are preferred over UFH nowadays. At the same time, the patient towards the end of the day and are relieved by elevating the
should be started on oral anticoagulants (e.g. warfarin, leg. Patients with more severe venous disease may notice skin
acenocoumarol) to reduce risk of recurrence of DVT. Duration changes. Some patients may be asymptomatic and may present
of treatment is usually for 6 to 12 months. Patients who have for cosmetic reasons.
inherited thrombophilia require lifelong anticoagulation. On examination, there is an increase in size of the calf muscles,
The effect of warfarin is monitored by measuring the ankle oedema, and skin complications like brown pigmentation,
international normalised ratio (INR), which should be eczema and severe ulcerations. Later on, lipodermatosclerosis
prolonged to 2.0 to 3.0 times the control values. Inferior may develop. Contraction of the skin and subcutaneous tissue
vena cava (IVC) filters are implanted in patients with is seen and the ankle becomes narrow. A combination of narrow
contraindication to oral anti-coagulants (GI bleed), recurrent
ankle and prominent calf is often referred to as a champagne
DVT and high risk DVT. Retrievable filters are preferred over
bottle leg. Venous ulceration may also develop in these areas.
permanent ones.
Diagnosis can be made by a thorough clinical examination and
Prevention of DVT can be done by both mechanical and Doppler ultrasound evaluation.
pharmacological methods. Graduated elastic compression
The treatment depends on the size of the varices, their extent
stockings have been shown to reduce the incidence of deep
and the symptoms they produce. Compression stockings are
vein thrombosis. Intermittent pneumatic compression devices
are used only peri-operatively. Pharmacological methods used in early stages of disease. Injection sclerotherapy involves
include UFH and LMWH. LMWHs are generally preferred. the injection of an irritant solution, sodium tetradecyl. Surgical
These are considered in all immobilised patients especially treatment involves the ligation of the source of reflux (usually
those with orthopaedic surgery, congestive cardiac failure and the saphenopopliteal or saphenofemoral junction) and removal
occlusive strokes. Prevention of thrombosis during long of the incompetent saphenous trunks and the associated
distance air travel requires the use of graduated compression varices. Endovenous radio frequency and laser ablation have
stockings, exercise during the flight and avoidance of alcohol been used in patients with persistent symptoms and/or who
and sleeping tablets. develop ulceration.

Superficial Vein Thrombosis LYMPHATICS DISORDERS

This is a frequent complication of varicose veins and may also Lymphatic system is composed of interstitial fluid that bathes
follow cannulation of a vein for intravenous infusion. tissues of the body, lymphatic capillaries that collect interstitial
Spontaneous superficial thrombophlebitis may occur in the fluid, transporting vessels and the lymph nodes. The lymphatic
presence of polycythaemia, polyarteritis and Buerger’s disease capillaries absorb interstitial fluid and empty into transporting
and may also herald the presence of a visceral cancer. This vessels, which traverse the extremities and join with the visceral
condition does not carry the risks of deep vein thrombosis and channels to form the cisterna chyli adjacent to the upper
is normally treated symptomatically with simple analgesics and abdominal aorta.These pass through the diaphragm to become
anti-inflammatory drugs. the thoracic duct. The thoracic duct empties into the left

761
 subclavian vein. A separate smaller right lymphatic duct drains ‘Lymphoedema precox’ presents at about the time of puberty
the right upper extremity and neck, and enters the right and is the most common form of primary lymphoedema
subclavian vein. Normally between 2 litres and 4 litres of accounting for >80% of the cases. ‘Lymphoedema tarda’ refers
interstitial fluid is filtered each day and returned to the vascular to lymphoedema that appears at about the third or fourth
system by the lymphatic system. Diseases of the lymphatics decade of life.
include lymphoedema due to lymphatic obstruction,
Secondary lymphoedema
lymphangiomas and tumours.
It is usually due to acquired lymphatic obstruction. The causes
Lymphoedema of obstructive lymphoedema are infiltration of regional lymph
Lymphoedema is caused by excessive accumulation of nodes by tumour, surgical excision of regional lymph nodes in
interstitial fluid in the extravascular, extracellular fluid the treatment of malignancy, repeated infections, inflammatory
compartment due to defects in the lymphatic transport system. processes causing fibrosis and irradiation.
Inadequate removal of the interstitial fluid by the lymphatic In tropical and subtropical countries infestation by filarial parasites
system may be the result of absent hypoplastic or obstructed is the most frequent cause of secondary lymph-oedema. Eight
lymphatic vessels. In the limb, interstitial fluid accumulates filarial species infect humans out of which only two; Wuchereria
mainly in the cutaneous tissues and presents as a swollen bancrofti and Brugia malayi are found in India and South-East Asia.
extremity. In the early stages, the oedema is pitting but W. bancrofti is the most widely distributed human filarial parasite.
later it typically becomes non-pitting. The skin becomes In India, the disease is rampant in Uttar Pradesh, Bihar, Andhra
thickened, hypertrophic and hyperkeratotic. It should be Pradesh, Orissa,Tamil Nadu, coastal Kerala and Gujarat.Tuberculous
distinguished from other causes of unilateral leg swelling such lymphangitis may also cause lymphoedema. In Western countries
as DVT (Table 3). Lymphoedema may be primary or secondary lymphoedema occurs most commonly in the arm after surgical
(Table 4). excision of lymph nodes for carcinoma of the breast.

Table 3: Differences Between Swelling of the Extremity Due to Lymphatic and Venous Obstruction
Lymphatic Obstruction Venous Obstruction
Swelling typically involves the distal aspect of the extremity and Swelling is present distal to the site of obstruction and uniformly involves
characteristically involves the dorsum of the feet and toes the extremity uniformly
Swelling is usually painless. Pain and redness occur only There is pain, redness and dilated superficial veins in the affected
if there is associated cellulitis extremity
Oedema is pitting in nature and responds to limb elevation, Oedema is pitting in nature in the initial phase and responds to limb
however later on it characteristically becomes non-pitting elevation
and does not respond to limb elevation
Due to lymphoedema, skin becomes thickened, hypertrophic Due to increase in foot vein pressure, skin around the ankle becomes
and then hyper-keratotic pigmented due to leakage of blood and fibrin into the surrounding tissues.
With passage of time, the skin becomes eczematous and ulcerated

Table 4: Types of Lymphoedema Lymphangiography is used to diagnose lymphoedema and

to demonstrate the nature of lymphatic abnormality. However,
Primary
as this procedure is invasive and because of the risk of oil
Lymphoedema congenita
embolism, it is being replaced by isotope lymphangiography.
Lymphoedema precox
MRI imaging has also been employed to investigate the
Lymphoedema tarda
lymphatic system.
Secondary
Filariasis Treatment includes prolonged bed rest, limb elevation, elastic
Tuberculosis stockings, meticulous skin hygiene, avoidance of local injury
Neoplasia and prompt treatment with antibiotics if cellulitis occurs.
Recurrent lymphangitis Surgery is reserved for those with severe disabling lympho-
Surgery edema. It includes the excision of hypertrophic tissue, pedicle
Radiotherapy transfer of normal lymphatic bearing tissue and microvascular
bypass.
Primary lymphoedema Lymphangiomas
This is relatively uncommon and often associated with Lymphangiomas are benign overgrowths of lymphatic vessels.
inherited disorders like Turner’s and Klinefelter’s syndromes. It is not certain whether these are congenital malformations,
‘Lymphoedema congenita’ is a severe form of lymphoedema hamartomas or true neoplasms.
that is usually apparent at birth or during early infancy. Familial
cases are termed as Milroy’s disease. These patients have Capillary lymphangiomas are small, circumscribed, pale-white
associated lymphatic abnormalities such as intestinal and to pink lesions composed of network of endothelium-
pulmonary lymphangiectasia. lined, thin-walled lymphatic spaces separated by lymphoid

762
 Vascular Disorders of the Extremities
aggregates. These mainly involve skin or mucous membranes RECOMMENDED READINGS
of the head and neck. 1. Creager MA, et al (eds): Vascular Medicine. Philadelphia, Saunders Elsevier,
2006.
Cavernous lymphangiomas are more common than the
2. Faxon DP, et al. Atherosclerotic Vascular Disease Conference: Executive
capillary variety. They are slow growing, congenital lesions summary: Atherosclerotic Vascular Disease Conference proceeding for
and are composed of numerous dilated lymphatic channels healthcare professionals from a special writing group of the American
filled with lymph and often surrounded by a fibrous capsule. Heart Association. Circulation 2004; 109:p2595.
3. Hiatt WR. Medical treatment of peripheral arterial disease and claudication.
Lymphangiosarcoma N Eng J Med 2001; 344:p1608.
It is a rare malignant lesion that develops in a lymphoedematous/ 4. Parakh R, Kakkar VV, Kakkar AK. For Venous Thromboembolism (VTE) Core
extremity. Malignant transformation is more frequent in cases Group. Management of Venous Thromboembolism. JAPI 2000; 55: 49-70.
of secondary lymphoedema. It appears as purple-red nodules 5. Rockson SG. Lymphoedema. Current Treat Options Cardiovasc Med 2006;
in the skin. It is an aggressive and rapidly fatal tumour. 8: p129.

763
 12.33 Pregnancy and Heart Disease

Amal Kumar Banerjee

INTRODUCTION Table 1: Physical Findings During Normal Pregnancy

Management of pregnancy in patients with heart disease
Mild jugular venous distension
continues to pose a challenge to the clinicians. Heart disease is
Lower-extremity oedema
the third leading cause of death in 25 to 44-year-old women.
Decreased breath sounds at bases
Because it is relatively common in women of childbearing age,
Upward and leftward deviation of point of maximal impulse
heart disease of varying severity complicates about one per cent
Volume-loaded ventricle (active praecordium)
of pregnancies. Rheumatic heart disease accounts for most of
Increased valve closure sounds
the cases and mitral stenosis being the commonest lesion, in India.
‘Flow’ murmurs (pulmonic and aortic)
NORMAL PHYSIOLOGIC CHANGES IN PREGNANCY Mammary soufflé (left sternal border)
Wide pulse pressure
There is an increase in blood volume, by about 50%, and
relatively haemoglobin concentration falls, causing the Increased heart rate
physiological anaemia of pregnancy. Cardiac output increases
Table 2: Some Clinical Indicators of Heart Disease During
as early as 5 weeks after the last menstrual period and rises to
Pregnancy
45% above baseline at 24 weeks’ gestation. Increased cardiac
output is achieved by an increase in heart rate, which rises Symptoms
progressively until 32 weeks’ gestation, and in stroke volume, Progressive dyspnoea or orthopnoea
which begins to increase by 8 weeks and peaks as early as 20 Nocturnal cough
weeks. Twin pregnancies result in an additional 15% rise in Haemoptysis
cardiac output in mothers. The cardiovascular system is taxed Syncope
further by stage one of labour, which is associated with an Chest pain
additional 12% increase in demand for cardiac output. This Clinical Findings
demand increases to a mean of 34% above the already Cyanosis
increased baseline value as labour progresses to its final stages. Clubbing of fingers
After delivery stroke volume decreases by 2 weeks post-partum, Persistent neck vein distension
but a small further reduction occurs up to 6 months after Systolic murmur grade 3/6 or greater
delivery. The stroke volume remains at pregnancy levels for the Diastolic murmur
first 2 days post-partum and then falls dramatically. Heart rate Cardiomegaly
remains elevated for 2 days post-partum and returns to the Persistent arrhythmia
baseline by 10 days after delivery. Cardiac output similarly Persistent split-second sound
decreases from pregnancy levels to normal levels between 24 Criteria for pulmonary hypertension
hours and 10 days post-partum. Systemic vascular resistance
and diastolic blood pressure decrease as a result of changes in Table 3: Changes in Non-invasive Test Results That Occur During
aortic compliance and arterial venous shunting in the uterus. Pregnancy

DIAGNOSIS OF HEART DISEASE Test Changes

Many of the physiological changes of normal pregnancy tend Electrocardiography Leftward axis deviation
to make the diagnosis of heart disease more difficult due to Increased ventricular voltage
alterations in the physical examination of the pregnant patient Increased rate
(Table 1). Symptoms and clinical findings that may indicate Repolarisation changes
heart disease (Table 2), should be carefully recognised. Chest X-ray film Upward diaphragm displacement
Pregnant women who have none of these findings, rarely have Horizontal heart placement
serious heart disease. Enlarged pulmonary silhouette
Diagnostic Studies Echocardiography Increased left ventricular diastolic
dimension
The physiologic changes associated with pregnancy may also alter Increased left ventricular wall thickness
the results of non-invasive evaluations of the heart (Table 3). Mild increase in contractility
In most cases,conventional testing including electrocardiography,
Doppler echocardiography and chest radiography will provide GENERAL MANAGEMENT
necessary data. If indicated, right-heart catheterisation can be Poor maternal functional class, cyanosis, myocardial dysfunction,
performed with limited X-ray fluoroscopy. All X-ray procedures left-heart obstructive lesions, prior arrhythmia, and prior cardiac
764 should generally be avoided, particularly early in pregnancy. events are prognostic of complications during pregnancy. The
 Pregnancy and Heart Disease
likelihood of cardiac complications during pregnancy is 3%, 30% Congestive Heart Failure
and 66% when none, one or more than one of these are present. Management of congestive heart failure (CHF) during pregnancy,
A three tiered risk classification of maternal mortality (Table 4), is not much different from that at other times. Salt restriction and
has been developed. This will help in counselling the woman limitation of activity to a level below that, which causes symptoms
regarding advisability of conception or continuation of pregnancy. are appropriate. In a woman with significant symptoms or
pulmonary oedema, standard therapy can be used with the
Most current management recommendations have been based exception of ACE-inhibitors. Congestive heart failure is one
on expert opinion and/or retrospective series. To date, there situation, where maintaining a woman in supine position may
has been only one large multicenter study to prospectively be beneficial by causing preload reduction with obstruction of
ascertain maternal and foetal outcomes in women with cardiac return of blood from the inferior vena cava to the heart.
disease. This Canadian study also derived and validated a risk
index for the prediction of maternal cardiac complications Low-Cardiac-Output Syndrome
during pregnancy (Table 5). A low cardiac output is an ominous sign in pregnancy with heart
disease. Although potentially treatable causes such as
Women with heart disease who are at intermediate or high- tamponade or severe valvular stenosis should be considered, it
risk for complications should be managed in a high-risk is most often due to intravascular volume depletion. This should
pregnancy unit by a multidisciplinary team from obstetrics, be prevented when possible and corrected when recognised.
cardiology, anaesthesia, and paediatrics.
Thromboembolic Complications
Table 4: Risks for Maternal Mortality Caused by Various Heart The risk of venous thromboemboli increases five-fold during
Disease
and immediately after pregnancy, and there is an increase in
Cardiac Disorder Mortality (%) arterial emboli as well. Prevention is optimal, and prophylactic
Group 1 – Minimal Risk 0 to 1 full-dose heparin or low-molecular-weight heparin is indicated
Atrial septal defect in those at high-risk of a thromboembolic complication. If a
Ventricular septal defect thrombus or embolus is identified, 5 to 10 days of intravenous
Patent ductus arteriosus heparin therapy followed by full-dose subcutaneous heparin is
Pulmonary or tricuspid disease recommended. If a thromboembolus is life-threatening, like a
Tetralogy of Fallot, corrected massive pulmonary embolus or a thrombosed prosthetic valve,
Bioprosthetic valve thrombolytic therapy can be used.
Mitral stenosis, NYHA classes I and II
Pulmonary Hypertension
Group 2 – Moderate Risk 5 to 15
2A: Pulmonary hypertension, whether primary or secondary, is
Mitral stenosis, NYHA classes III and IV associated with 30% to 70% maternal mortality and even with
Aortic stenosis maternal survival, foetal loss exceeds 40%. The mother is most
Aortic coarctation without valvular involvement vulnerable during labour and in the first post-partum week.
Tetralogy of Fallot, uncorrected If detected early in pregnancy, interruption is advised. When
Previous myocardial infarction detected late in pregnancy, close follow-up is necessary.
Marfan’s syndrome, normal aorta Intravascular volume depletion should be promptly corrected,
2B: since it puts these patients at greatest risk. Systemic vascular
Mitral stenosis with atrial fibrillation resistance and pressure must be maintained in patients with
Artificial valve pulmonary hypertension who have a right-to-left shunt, and
Group 3 – Major Risk 25 to 30 meticulous attention is necessary to avoid air or thrombus emboli
Pulmonary hypertension from intravenous catheters, which may lead to systemic emboli.
Aortic coarctation with valvular involvement At the time of labour and delivery, a central venous line allows
Marfan’s syndrome with aortic involvement adequate fluid administration, and a radial artery catheter makes
NYHA = New York Heart Association. determinations of blood pressure and oxygen saturation easier.
These lines should be continued for 48 to 72 hours post-delivery.
Table 5: Risk Factors for Maternal Cardiac Adverse Events
During Pregnancy
Arrhythmias
The rules for the treatment are the same as in the non-pregnant
Adverse Maternal Risk Factor
patient, with the possible exception that a rhythm causing
Cardiac Event
haemodynamic instability should be treated more promptly
Pulmonary oedema General and aggressively because of the concern about diversion of
Arrhythmia NYHA functional class III or IV or cyanosis blood flow away from the uterus.
Stroke Systemic ventricular EF < 40%
Death Mitral valve area < 2 sq cm, aortic valve area Complete heart block, which in this age group is most likely to
< 1.5 sq cm, peak left ventricular outflow be of congenital origin, is consistent with a successful pregnancy.
gradient > 30 mmHg If required, a permanent pacemaker can be implanted.
Cardiac event ( arrhythmia, stroke,
pulmonary oedema ) prior to pregnancy Endocarditis
The general risk factors can be used to create a maternal risk index for adverse Infective endocarditis is uncommon during pregnancy and
cardiac events related to pregnancy: 0 risk factors < 5% risk, 1 risk factor = 27% the puerperium. The clinical presentation and management
risk, ≥ 2 risk factors = 75% risk. of endocarditis during pregnancy is the same as at other times. 765
 SPECIFIC FORMS OF HEART DISEASE prosthesis should be based on its haemodynamic profile and
Rheumatic Heart Disease durability and the need for anticoagulation.
Rheumatic mitral valve disease continues to be the most Mitral Regurgitation
prevalent heart disease encountered in pregnant women in This condition is well tolerated in pregnancy. In symptomatic
India. Women with rheumatic valvular heart disease (VHD), have patients, diuretics are indicated, and digoxin may be beneficial
high rate of clinical deterioration and a marked increase in in cases with impaired left ventricular systolic function.
morbid events during pregnancy, including CHF, arrhythmias
and need to either initiate or increase cardiovascular drug Aortic Stenosis
therapy or to hospitalise patients during pregnancy. Pregnancy Rheumatic aortic stenosis is unusual finding in pregnancy and
with VHD, may be associated with an increased incidence of may occur in conjunction with mitral valve disease in about 5%
intrauterine growth restriction (IUGR), preterm deliveries, and of pregnant patients with rheumatic valvular disease. Most
lower birth weight, especially in cases with moderate and severe patients with aortic stenosis (Valve area > 1.0 cm2), tolerate
stenosis of the mitral or aortic valve. pregnancy well. But patients with more severe stenosis may
experience clinical deterioration with exertional dyspnoea,
Acute Rheumatic Fever
near-syncope or syncope and pulmonary oedema. Serious
This disease occurs only rarely during pregnancy and symptoms during pregnancy, if resistant to medical treatment,
management is similar to that of non-pregnant patients. may necessitate termination of pregnancy or repair of the valve
Mitral Stenosis either surgically (valve replacement) or by percutaneous
This is the commonest VHD in pregnancy and represents a balloon valvuloplasty. For women with critical aortic stenosis,
common health problem in our country. The increased preload intensive monitoring during labour is necessary and epidural
of normal pregnancy, as well as other factors that require analgesia seems ideal, thus avoiding potentially hazardous
increased cardiac output, may cause ventricular failure with hypotension.
pulmonary oedema in these women with relatively fixed cardiac Aortic Regurgitation
output. About 25% of women with mitral stenosis experience This condition is well tolerated in pregnancy. Symptoms
cardiac failure for the first time during pregnancy. In some
necessitate salt restriction, diuretics and digoxin.
cases, this may be confused with idiopathic peripartum
cardiomyopathy. The most prominent complaint is dyspnoea Prosthetic Valve Disease
due to pulmonary venous hypertension and pulmonary A prosthetic valve is a relative contraindication to pregnancy.
oedema. Other common symptoms are fatigue, palpitations, Maternal mortality is 3% to 4% with mechanical valves and
cough and haemoptysis. foetal, loss is common. The critical issue is anticoagulation in
The therapeutic approach is to reduce the heart rate and cases with mechanical prosthesis. Full anticoagulation
decrease blood volume. Limited physical activity is generally throughout pregnancy is recommended with subcutaneous
recommended. Prophylactically beta-blocking agents can be heparin, maintaining anticoagulation at the high therapeutic
used and digoxin may be considered in patients with AF. For level by following levels of factor Xa. Just before delivery, heparin
chronic AF, anticoagulation with heparin is also indicated. If is stopped. Protamine sulphate may be used to counter
symptoms of pulmonary congestion develop, activity is restricted excessive bleeding. Anticoagulant therapy with warfarin or
even more, dietary sodium is restricted and diuretic therapy is heparin may be restarted 6 hours following vaginal delivery.
started. Labour and delivery are particularly stressful for women But anticoagulation should be withheld for at least 24 hours,
with tight stenosis. Epidural analgesia for labour, with strict following caesarean delivery. Antibiotic prophylaxis is necessary
attention to avoid intravenous fluid overload, is ideal. Vaginal during labour.
delivery is preferable. In symptomatic patients with moderate- Mitral Valve Prolapse
to-severe stenosis (mitral valve area < 1.5 cm2), haemodynamic
monitoring is indicated during labour and delivery with Pregnant women with mitral valve prolapse, rarely have cardiac
haemodynamic optimisation by diuretics, beta-blockers, digoxin complications. For women who are symptomatic, beta-blockers
or nitroglycerin. Intrapartum endocarditis prophylaxis is required. are used. Antibiotic prophylaxis for labour and delivery in
patients with mitral valve prolapse, accompanied by valve
Closed mitral commissurotomy is associated with only minimal thickening and/or regurgitation, seems warranted.
risk to the foetus and therefore, preferable to the open
technique. It should be recommended only in centres where it Congenital Heart Disease
is done routinely. A good maternal outcome can be expected in most cases with
acyanotic congenital heart disease. Maternal functional capacity
The safety and efficacy of percutaneous balloon mitral
and cyanosis determine foetal outcome. Foetal wastage is about
valvuloplasty (PBMV) has been reported by several investigators.
45% in cyanotic mothers compared with 20% in acyanotic
Now, PBMV during pregnancy has been reported without foetal
mothers with congenital heart disease. Prematurity and IUGR
loss and should be the preferred modality of treatment in this
are common in cyanotic mothers. Risk of congenital heart
subset of patients. Mitral valve repair or replacement during
disease is increased for the offspring of mothers with congenital
pregnancy should be considered only in cases with severe
heart disease with a reported incidence of 4% to 8%.
stenosis (mitral valve area < 1.0 cm2), refractory to optimal
medical therapy, PBMV is not feasible or when close follow-up Elective induction of labour, when foetal maturity is confirmed,
during pregnancy, labour and delivery is not possible. When may be used in high-risk patients for better planning of
766 valve replacement is indicated, selection of the type of haemodynamic monitoring. Vaginal delivery is preferred for
 Pregnancy and Heart Disease
most patients, and caesarean section is indicated in stable blood pressure must be adequately lowered. Surgical correction
patients only for obstetric reasons. Oxygen should be given to can be performed successfully in patients with severe,
hypoxaemic mother during labour. Haemodynamic and blood uncontrolled systolic hypertension or heart failure.
gas monitoring is necessary in patients with impaired functional
Pulmonic Stenosis
capacity, cardiac dysfunction, pulmonary hypertension, and
cyanotic malformations. Blood loss should be treated promptly. Isolated pulmonic stenosis is usually well tolerated in pregnancy.
Occasionally, progressive right ventricular failure, symptoms
Antibiotic prophylaxis for vaginal delivery in all patients with related to stenotic valve or intracardiac shunt at either the atrial
congenital heart disease (except secundum type of ASD, 6 or ventricular level with cyanosis may develop. Percutaneous
months or more after repair of septal defects or surgical ligation balloon valvotomy should be considered in such situations.
and division of patent ductus arteriosus), is necessary.
Tetralogy of Fallot
Atrial Septal Defect
Successful pregnancy can be achieved, but maternal mortality
Atrial septal defect is well tolerated in pregnancy. Pulmonary is high and foetal loss can exceed 50%. During labour and
hypertension and atrial arrhythmias occur rarely and antibiotic delivery, right to left shunt may increase. Maternal haematocrit
prophylaxis is not indicated. above 60%, arterial oxygen saturation below 80% and syncopal
Ventricular Septal Defect episodes are poor prognostic signs. In cyanotic women, the rate
Isolated ventricular septal defect is usually well tolerated in of spontaneous abortion, premature deliveries and IUGR is high.
pregnancy. The occasional congestive heart failure or Close monitoring of systemic blood pressure and blood gases
arrhythmias, developing during pregnancy, can be managed during labour is necessary for cyanotic or symptomatic patients.
in the usual manner. The incidence of ventricular septal defect Incidence of cardiac defects reported born to such mothers
in the offspring has been reported to be 4% to 11%. Volume infants ranges between 3 and 17%.
depletion during or after delivery, may lead to shunt reversal, Patients who have significant residual defects after repair, such
in patients with pulmonary hypertension. Prompt volume as residual ventricular septal defect, pulmonic stenosis or
replacement is necessary to prevent further complications. regurgitation, and ventricular dysfunction, are still at higher risk
Patent Ductus Arteriosus during pregnancy. Patients who had undergone shunt
procedures to improve cyanosis, may develop pulmonary
A patent ductus arteriosus is tolerated well during pregnancy.
hypertension, which increases the risk of pregnancy. After
On occasion, congestive heart failure can occur, but standard
surgical repair, maternal and foetal outcomes improve markedly.
treatment is effective. Antibiotic prophylaxis is recommended.
Peripartum decrease in systemic blood pressure should be Eisenmenger’s Syndrome
promptly corrected. This condition leads to poor foetal outcome, with high incidence
Congenital Aortic Valve Disease of foetal loss, prematurity, IUGR and perinatal death.
Most patients with mild aortic stenosis have favourable Since there is a high-risk of maternal mortality, patients with
outcome of pregnancy, provided that they are diagnosed early. Eisenmenger’s syndrome should be advised against pregnancy,
Appropriate care, including haemodynamic monitoring during and early abortion should be recommended for those who are
labour and delivery and appropriate anaesthesia are associated already pregnant. In an overview of 125 pregnancies in patients
with favourable outcomes. Moderate and severe aortic stenosis with Eisenmenger’s syndrome, primary and secondary
may be associated with symptomatic deterioration during pulmonary hypertension, maternal mortality was uniformly
pregnancy and may lead to maternal morbidity and even high at 36%, 30% and 56% respectively. The overall neonatal
mortality. Exertional dyspnoea, chest pain, light headedness, and mortality was 13%.
syncope may develop in the second or third trimester. Increased
Management of a patient who decides to proceed to term, must
incidence of cardiac defects has been reported in live born
include close follow-up for early recognition of clinical
infants of mothers with left ventricular outflow obstruction.
deterioration. Anticoagulation is necessary in the third trimester
Optimal management strategies of a pregnant woman with
and 4 weeks post-partum, to prevent peripartum thrombo-
severe aortic stenosis include early abortion followed by valve
embolism. Since premature delivery is common, patients should
replacement and repeat pregnancy, and continuation of
be hospitalised for any sign of premature uterine activity. Early
pregnancy and plan for percutaneous balloon valvuloplasty or
surgical intervention who show clinical deterioration not hospitalisation ensures restricted activity and close follow-up.
controlled by medical therapy. These procedures have been Spontaneous delivery is preferred to induction, and should
performed successfully in pregnant women but are not free lower the chance of prematurity or the need for caesarean
from complications. So, these interventions should be reserved section. Blood pressure, ECG and blood gas monitoring are
for patients with severe disease, not manageable by medical essential during labour and delivery to ensure early detection
therapy and should be avoided during first trimester. and correction of problems. High concentration of oxygen may
be beneficial. Most patients with stable condition, tolerate
Coarctation of Aorta vaginal delivery, but an attempt is to be made to shorten the
Both maternal and foetal outcome is usually favourable. In case second stage of labour by the use of forceps. A planned caesarean
of severe hypertension, congestive heart failure and aortic section is often preferred, to avoid risk of foetal distress during
dissection may occur. To prevent aortic dissection and rupture vaginal delivery and potential need for emergency caesarean
of cerebral aneurysm, physical activity should be limited and section. Swan-Ganz catheter should be avoided.
767
 Ebstein’s Anomaly dysfunction in subsequent pregnancies. About 50% to 60% of
Pregnancy with acyanotic Ebstein’s anomaly is well tolerated. the patients show complete or near complete recovery of
But in cyanotic cases, pregnancy is associated with increased clinical status and cardiac function, usually within first 6 months
risk of maternal heart failure, prematurity and foetal loss. The post-partum. Rest of the patients demonstrate either further
management during labour and delivery in symptomatic or clinical deterioration, leading to early death or persistent left
cyanotic cases, includes antibiotic prophylaxis, oxygen ventricular dysfunction and chronic heart failure.
inhalation, haemodynamic and blood gas monitoring, and Acute heart failure necessitates prompt treatment with oxygen,
measures to prevent a fall in systemic blood pressure due to diuretics, digoxin and vasodilator agents. Anticoagulant therapy
peripheral vasodilatation or blood loss. is necessary. The temporary use of an intra aortic balloon pump
Complex Cyanotic Congenital Heart Disease or left ventricular assist device may help stabilise the patient’s
conditions pending improvement. Intravenous immune
In India, very few successful pregnancies have been reported
globulin use, has shown a favourable effect on recovery of left
in patients with partially corrected and uncorrected cyanotic
ventricular dysfunction. Subsequent pregnancies should be
heart disease, like pulmonary and tricuspid atresia, transposition
discouraged.
of great vessels, truncus arteriosus, single ventricle, double-
outlet right ventricle and double-inlet left ventricle. A report CONCLUSION
(outside India) has demonstrated complications like, heart
With important exceptions, most women with cardiac disease
failure, thromboembolic events, supraventricular tachycardia,
can be expected to do well during pregnancy with appro-
peri-partum infective endocarditis, high incidence of foetal
priate management based on systematic risk stratification.
wastage, premature deliveries, IUGR and both cardiac and non-
Pregnancies deemed to be at intermediate or high-risk should
cardiac congenital malformations, in such situations.
be managed and delivered in a tertiary care setting. More
Marfan’s Syndrome thorough pre-pregnancy cardiovascular evaluations, is likely to
In this condition, pregnancy may be associated with better identify patients who are capable of proceeding safely
cardiovascular complications and a high-risk of having a child with pregnancy and delivery. Best outcome is based on the
who will inherit the condition. Cardiovascular complications strong relationships between physicians in cardiology and in
include dilatation of ascending aorta, leading to aortic high-risk obstetrics.
regurgitation and congestive heart failure, and proximal and
RECOMMENDED READINGS
distal dissections of aorta with occasional involvement of the iliac
1. Bozkurt B, Villaneuva FS, Halubkov R, et al. Intravenous immune globulin
and coronary arteries. Patients with aortic diameter less than 40 in the therapy of peripartum cardiomyopathy. J Am Coll Cardiol 1999; 34:
mm, usually tolerate pregnancy well. Marfan’s syndrome may be 177-80.
associated with cervical incompetence, abnormal placental site 2. Caulin-Glaser T, Setaro JF. Pregnancy and cardiovascular disease. In: Burrow
and post-partum haemorrhagic complications. Women with GN, Duffy TP editors: Medical Complications During Pregnancy, 5th Ed.
Marfan’s syndrome should be advised to avoid pregnancy and if Philadelphia: Saunders; 1999:p111.
already pregnant, interruption is recommended. Preconception 3. Gupta A, Lokhandwala YY, Satoskar PR, et al. J Am Coll Surg 1998; 187: 409-15.
echocardiographic assessment of the aorta and periodic follow- 4. Jose AM, de Souza MD, Eulogio E, Martinez, Jr MD, et al. Percutaneous Balloon
up during pregnancy are necessary and transoesophageal Mitral Valvuloplasty in Comparison with Open Mitral Valve Commissurotomy
for Mitral Stenosis During Pregnancy. J Am Coll Cardial 2001; 37: 900-3.
echocardiography is preferred. During pregnancy, physical
5. Lock JE, Khalilullah M, Shrivastava S, et al. Percutaneous catheter
activity should be restricted and beta-blockers should be commissurotomy in rheumatic mitral stenosis. N Engl J Med 1985; 313:
administered. Substantial dilatation of aorta, necessitates 1515-8.
therapeutic abortion or surgical intervention. Caesarean section 6. Mangione JA, Zuliani MF, Del Castilho JM, et al. Percutaneous double balloon
should be preferred to minimise, haemodynamic stresses of mitral valvuloplasty in pregnant women. Am J Cardiol 1989; 64: 99-102.
vaginal delivery. 7. Mishra S, Narang R, Sharma M, et al. Percutaneous Transseptal Mitral
Commissurotomy in Pregnant Women with Critical Mitral Stenosis. Indian
Hypertrophic Cardiomyopathy Heart J 2001; 53: 192-6.
In this condition, pregnancy is associated with a favourable 8. Presbitero P, Somerville J, Stone S, et al. Pregnancy in cyanotic congenital
outcome in most cases but there may be increased morbidity heart disease: Outcome of mother and foetus. Circulation 1994; 89: 2673-6.
and even mortality. If congestive heart failure or abnormal 9. Rossiter JP, Repke JT, Marales AJ, et al. A prospective longitudinal evaluation
of pregnancy in the Marfan’s syndrome. Am J Obstet Gynecol 1995; 173:
rhythms occur, standard therapy is appropriate. Hypovolaemia 1599-606.
should be avoided. Beta-blockers or calcium channel blockers 10. Siu SC, Sermer M, Colman JM,et al.Prospective multicenter study of pregnancy
may be used if necessary. Vaginal delivery is safe and second outcomes in women with heart disease. Circulation 2001; 104: 515-21.
stage of labour may be shortened by the use of forceps. 11. Siu SC, Colman JM, Sorensen S, et al. Adverse neonatal and cardiac
Antibiotic prophylaxis is necessary during labour and delivery. outcomes are more common in pregnant women with cardiac disease.
Circulation 2002; 105: 2179-84.
Peripartum Cardiomyopathy 12. Weiss BM, Hess OM. Pulmonary vascular disease and pregnancy: Current
Symptoms usually occur during last trimester and is detected controversies, management strategies, and perspectives. Eur Heart J 2000;
in the early peripartum period. The clinical presentation and 21: 104-15.
haemodynamic changes are same as in other forms of dilated 13. Warnes CA, Elkayam U. Congenital heart disease and pregnancy. In Elkayam
U, Gleicher N, editors. Cardiac Problems in Pregnancy. 3rd Ed. New York:
cardiomyopathy. The incidence is greater in elderly multiparous Wiley-Liss; 1998: pp 39-53.
women with pre-eclampsia and twin pregnancies. There is 14. Whittemore R, Wells JA, Castellsague X. A second-generation study of 427
relatively rapid recovery of cardiac size and function in probands with congenital heart defects and their 837 children. J Am Coll
768 large number of patients with recurrence of left ventricular Cardiol 1994; 23: 1459-67.
Section 13
Gastroenterology
Section Editor: Rakesh Tandon
13.1 Clinical Approach—Gastrointestinal Disorders 770
A.C. Anand
13.2 Investigations—Gastrointestinal Disorders 774
Ashok Chacko
13.3 Endoscopy—Diagnostic and Therapeutic Utility 777
Gourdas Choudhuri
13.4 Diarrhoea and Malabsorption 782
B.S. Ramakrishna
13.5 Constipation—Diagnosis and Management 787
Uday Chand Ghoshal
13.6 Gastrointestinal Bleeding 791
Rakesh Kochhar, Mohd. Talha Noor
13.7 Oesophageal Disorders 799
Shobna J. Bhatia, Praveen Mathew
13.8 Diseases of the Stomach and Duodenum 806
Pankaj Dhawan
13.9 Diseases of the Pancreas 813
V. Balakrishnan, G. Rajesh
13.10 Functional Gastrointestinal Disorders 819
Philip Abraham
13.11 Abdominal Tuberculosis 823
Govind K. Makharia
13.12 Inflammatory Bowel Disease 829
Ajit Sood, Vandana Midha
13.13 Ischaemic Bowel Disorders 834
Deepak Kumar Bhasin
13.14 Gastrointestinal Symptoms in Systemic Diseases 837
Rakesh Tandon, Sudeep Khanna

769
 13.1 Clinical Approach—Gastrointestinal Disorders

AC Anand

Patients with gastrointestinal diseases can have varied oropharyngeal dysphagia) and low oesophageal dysphagia.
presentations. Symptoms like dysphagia, heartburn, abdominal Oropharyngeal (transfer) dysphagia is due to diseases of
pain, nausea, vomiting and haematemesis point to diseases of the neuromuscular mechanism of the pharynx and crico-
the upper gastrointestinal tract, while constipation, diarrhoea pharyngeus. The patient is unable to initiate and execute the
and haematochezia are commonly due to disease of the lower swallow mechanism. There may be coughing or regurgitation
gastrointestinal tract. Diagnosis from individual gastrointestinal of fluids from the nose while swallowing besides associated
symptom may however be difficult at times as symptoms may features of cranial nerve palsies in the form of dysarthria and
overlap in a variety of diseases. For example, even the classic hoarseness of voice. Low oesophageal dysphagia is due to
symptoms of peptic ulcer such as relief of pain by antacids or diseases involving the body of the oesophagus and gastro-
food and nocturnal pain are commonly seen in functional oesophageal junction.
dyspepsia.
The common causes of dysphagia are given in Table 1 and the
DYSPHAGIA, ODYNOPHAGIA AND HEARTBURN approach to a patient with dysphagia is summarised in Figure 1.
The diagnosis can be confirmed by barium swallow, upper GI
Dysphagia, odynophagia and heartburn point towards
endoscopy and oesophageal motility study as indicated.
oesophageal diseases as a cause of the symptoms. Dysphagia
is difficulty in passage of solids or liquids from the mouth to NAUSEA, RETCHING AND VOMITING
the stomach. It should be distinguished from odynophagia,
Nausea is an unpleasant feeling of wanting to vomit; this may
which is pain on swallowing. Heartburn is a burning sensation
be associated with autonomic features like increased salivation
behind the sternum.
and sweating. Retching is a strong involuntary effort at vomiting.
It is important to differentiate dysphagia into causes that Vomiting is associated with bringing out of gastric contents
mostly affect the pharynx or proximal oesophagus (high/ through the mouth.

Figure 1: Approach to a case with dysphagia.

* May be intermittent dysphagia in an oesophageal ring.
770
 Clinical Approach—Gastrointestinal Disorders
Gastrointestinal disorders causing vomiting include infections, both sides of the spinal cord. Pain location corresponds to those
bowel obstruction, cholecystitis, pancreatitis, infectious dermatomes that match the innervation of the diseased organ.
hepatitis, appendicitis and peptic ulcer. Vomiting may also be Generally, visceral pain from abdominal organs proximal to the
due to drugs, motion sickness, raised intracranial tension, ligament of Treitz is felt in the epigastrium; pain from organs
meningitis, azotaemia, pregnancy, systemic illness and between the ligament of Treitz and the hepatic flexure of the
psychogenic causes. colon is felt in the periumbilical region; and that from organs
beyond the hepatic flexure is perceived in the lower abdomen
Associated symptoms like abdominal pain and constipation
midline. Pain arising in hollow organs may wax and wane due
point to a gastrointestinal aetiology. Vomitus may be projectile
to peristaltic waves.
in raised intra-cranial tension. There may be stale food in
vomitus in gastric outlet obstruction. The vomitus is bilious in Parietal Pain
obstruction distal to the duodenum. Vomiting of psychogenic Parietal pain is well localised and sharp and is due to peritoneal
aetiology occurs during or soon after a meal. irritation by the inflamed organ, e.g. appendicitis.
Table 1: Causes of Dysphagia Referred Pain
Oropharyngeal or Neurological Cerebrovascular accident Referred pain may be seen, for example, as shoulder pain due
high dysphagia Motor neurone disease to liver abscess causing diaphragmatic irritation.
Parkinson’s disease
Multiple sclerosis
Assessment of cause of abdominal pain includes a careful
Myasthenia gravis history of onset, duration, progress, location, radiation, character
Anatomical Oropharyngeal malignancy and aggravating and relieving factors.
or muscular (uncommon) Clinical examination starts with inspection, which may show
Zenker’s diverticulum scars, hernias, splinting of abdominal movements, and visible
Retropharyngeal abscess
peristalsis. A patient with peritonitis would lie still and the
Cervical osteophyte
abdomen would be tender and would appear rigid. In
Low oesophageal Motility Achalasia
contrast, a patient with ureteric colic may be rolling in bed due
dysphagia disorder Scleroderma
Chagas disease
to pain. Visible peristalsis may be seen in bowel obstruction.
Diffuse oesophageal spasms Palpation may show a lump or tenderness. Guarding or rebound
Mechanical Webs tenderness may be seen in peritonitis. Percussion may show
obstruction Schatzki ring ascites or obliteration of hepatic dullness in bowel perforation.
Neoplasm Auscultation may reveal hyperactive or absent bowel sounds,
Strictures besides bruits. Rectal examination can reveal a rectal growth or
Dysphagia lusoria (due to a pelvic abscess.
aberrant subclavian artery)
GASTROINTESTINAL BLEEDING
DYSPEPSIA Bleeding from the GI tract can present as melaena, haema-
Dyspepsia comprises of a group of upper abdominal symptoms tochezia or haematemesis; patients with occult bleed may
including bloating, pain, postprandial fullness, heartburn present only with anaemia.
and belching. Dyspepsia is defined as chronic or recurrent Melaena is black, tarry foul-smelling stool and usually signifies
pain or discomfort centred in the upper abdomen. The first step the presence of >50 mL of blood. It usually implies a proximal
in assessment is to select patients who will require early GI source. It takes about 12 hours of transit time for melaena to
endoscopy and/or investigations to rule out serious diseases develop. It can rarely develop as a result of bleeding from right
such as malignancy. The warning signs and symptoms that colonic sources.
should alert the physician to a possibility of malignant disease
are shown in Table 2. Haematochezia (maroon bloody stools) can come from a
proximal GI source if intestinal transit is rapid but usually
Table 2: Alarm Symptoms in a Patient with Dyspepsia that signifies a lower GI source. Fresh red blood is commonly due to
Indicate High Risk for Serious Underlying Disease rectal or left colonic disease.
Anaemia
Haematemesis is blood in vomitus. It may be fresh bright-red or
Weight loss
Gastrointestinal bleed older coffee-ground material and signifies an upper GI bleed.
Recent onset of progressive symptoms The presence of haematemesis or melaena signifies an upper
Age >45 years GI source but patients with rapid upper GI bleed may present
Dysphagia with haematochezia.

ABDOMINAL PAIN Preliminary clues to the site of haemorrhage include the

presence of haematemesis, hyperactive bowel sounds, and
Abdominal pain can have three broad patterns: visceral, parietal,
increased blood urea nitrogen out of proportion to creatinine
and referred.
(upper GI), or fresh rectal bleeding (colonic). Insertion of a
Visceral Pain nasogastric tube and aspiration may help in localisation of
Visceral pain is dull crampy and poorly localised. It is often in bleeding. However, it may be negative in some cases of upper
the midline because abdominal organs transmit afferents to GI bleed. 771
 In upper GI bleeding, from a management point of view, it is Evaluation of a case of chronic diarrhoea requires detailed
important to differentiate between variceal and non-variceal clinical history. Malabsorption will be associated with semisolid
aetiology. The clinical evaluation of upper GI bleed is shown (occasionally watery) stools that are bulky, float on water, and
in Table 3. Gastrointestinal endoscopy is usually required to stick to the pan. The stools may be explosive in character and
make a definitive diagnosis. In obscure GI bleeding, one may be associated with flatulence and borborygmi. It may contain
need an isotope scan, angiography, or capsule or double- undigested food particles, increase with lactose intake, and
balloon enteroscopy to determine the source of bleeding. decrease on fasting. There may be mild periumbilical pain
relieved by passage of flatus or stools. Small volume stools
Table 3: Differentiating Variceal from Non-Variceal Bleed associated with blood, mucous and tenesmus are suggestive
of large bowel diarrhoea. The clinical clues to aetiology of
Variceal source suspected if GI bleeding is associated with
chronic diarrhoea are given in Table 4.
Jaundice
Ascites The approach to chronic diarrhoea (>4 weeks) should follow
Splenomegaly the following steps:
Past history of treatment for liver disease
Clinical stigmata of chronic liver disease (spider naevi, palmar Table 4: Chronic Diarrhoea: Clinical Clues
erythema, testicular atrophy, gynaecomastia, etc.)
Clubbing: Immunoproliferative small intestinal disease, Crohn’s
Non-variceal source is suspected if bleeding is associated with
disease, coeliac disease
Absence of the above
History of epigastric pain Fever: Tuberculosis, lymphoma, Whipple’s disease, Crohn’s
Past history of peptic ulcer disease/ulcerative colitis
Recent NSAID intake Response to antibiotics: Bacterial overgrowth, giardiasis, tropical
Recurrent vomiting/retching (Mallory-Weiss tear) sprue, Whipple’s disease
Response to steroids: Inflammatory bowel disease (IBD),
microscopic colitis, eosinophilic gastroenteritis, Addison’s disease
CONSTIPATION
Arthritis: IBD, coeliac disease, Whipple’s disease, collagen disorder
Patients usually define constipation not only by infrequent
Lymphadenopathy: HIV,Whipple’s disease, tuberculosis, lymphoma
stools (typically fewer than three per week), but also by
associated symptoms which are equally important, and Dermatitis herpetiformis: Coeliac disease
probably more important, such as: hard stools, the need for Pyoderma gangrenosum: IBD
excessive straining, a sense of incomplete bowel evacuation, Abdominal mass: Crohn’s disease, lymphoma, tuberculosis
and excessive time spent on the toilet or in unsuccessful
defaecation. Step 1: Rule-Out Irritable Bowel Syndrome
Red flag symptoms that are against the diagnosis of irritable
Constipation is a common symptom, more so in the elderly. A
bowel syndrome are shown in Table 5.
number of commonly used drugs in the elderly often aggravate
constipation, including calcium supplements, iron supplements, Table 5: Red Flag Symptoms that make the Diagnosis of Irritable
diuretics, calcium-channel blockers, etc. A history of recent onset Bowel Syndrome Unlikely
of constipation and/or blood mixed with stool raises the
Fever
possibility of a malignant colonic lesion.
Weight loss
A thorough physical examination should be performed to Nocturnal diarrhoea
exclude systemic or neurological illnesses that may cause Blood in stools
constipation. Abdominal examination may reveal abdominal ↓ Haemoglobin, ↓ albumin, ↑ ESR
mass or palpable stools. Anorectal examination may reveal Recent symptoms in middle age/elderly
fissures, haemorrhoids, lack of anal sphincter tone or a rectal
stricture. Step 2: Large Bowel versus Small Bowel (Table 6)

Stool for occult blood is a useful screening test, while Table 6: Large Bowel Diarrhoea versus Small Bowel Diarrhoea
colonoscopic examination would be required to rule out local Large bowel diarrhoea Small bowel diarrhoea
diseases.
Presence of blood and Malodorous, floating, greasy,
DIARRHOEA mucous containing undigested food
particles
Diarrhoea is defined as increase of volume, frequency or fluidity Rectal/anal symptoms such Large-volume stools
of stool. It could be acute or chronic. Acute diarrhoea (< 4 weeks) as tenesmus/dyschezia
is usually due to infections and is often self-limited. It may be Small-volume Mid-abdominal cramps with
associated with fever, pain in abdomen or dehydration. jelly-like stools borborygmi
Chronic diarrhoea (>4 weeks) may be associated with mala- Associated hypogastric
bsorption and weight loss. cramps

772
 Clinical Approach—Gastrointestinal Disorders
Step 3: Chronic Pancreatitis versus Mucosal Malabsorption
Features of carbohydrate malabsorption with lactose
intolerance causing explosive stool with flatulence are
suggestive of mucosal malabsorption. This can be confirmed
by an abnormal d-xylose test. In chronic pancreatitis, classical
history of pancreatic pain with radiation to back and imaging
evidence of chronic pancreatitis are often clearly evident. The
d-xylose test would be normal in chronic pancreatitis and faecal
fat excretion is often more than 14 gm/day, much more than
that seen in mucosal malabsorption. A clinical approach to
chronic diarrhoea is shown in Figure 2.

RECOMMENDED READINGS
1. Flasar MH, Goldberg E. Acute abdominal pain. Med Clin N Am 2006; 90: 481-
503.
2. Owen W. ABC of the upper gastrointestinal tract-dysphagia. Br Med J 2001;
323: 850-3.
3. Talley NJ, Vakil NB, Moayyedi P. American Gastroenterological Association
Figure 2: Approach to chronic diarrhoea: Basic clinical segregation of patient into technical review on the evaluation of dyspepsia. Gastroenterology 2005;
small bowel diarrhoea and large bowel diarrhoea is usually adequate in directing 129:1756-80.
evaluation. A small subgroup of patients with watery diarrhoea, in whom 4. Thomas PD, Forbes A, Green J, et al. Guidelines for the investigation of chronic
evaluation for the above have been negative, require advanced evaluation. diarrhoea; 2nd Ed. Gut 2003; 52 (Suppl V): v1-v15.

773
 13.2 Investigations—Gastrointestinal Disorders

Ashok Chacko

INTRODUCTION protein losing enteropathy. Stool DNA tests (k-ras, APC, p53) are
The gastrointestinal (GI) tract can be evaluated by examination promising screening tests for diagnosis of sporadic colorectal cancer.
of luminal contents, upper and lower GI endoscopy and various Stool osmotic gap (290 - 2 [Na+ + K+]) is useful to distinguish osmotic
laboratory tests which may help in establishing diagnosis. In from secretory diarrhoea. An osmotic gap > 50 mOsm/kg is
this chapter, author discusses about tests for luminal contents characteristic of osmotic diarrhoea whereas secretory diarrhoea
and laboratory tests while the endoscopy of GI tract has been has osmotic gap <50 mOsm/kg.
covered in next chapter (see Chapter 3 Endoscopy—Diagnostic
and Therapeutic Utility). GASTRIC ACID SECRETION
Measurement of gastric acid output to evaluate peptic ulcer disease
STOOL EXAMINATION
is not relevant now. It is occasionally used to distinguish Zollinger-
Stool examination must be performed in all patients with Ellison syndrome (ZES) from achlorhydria in patients with elevated
abdominal symptoms, especially diarrhoea. Stool inspection, serum gastrin.Basal acid output (BAO) > 15 mmol per hour suggest
often neglected, is important as it gives information regarding ZES (normal BAO <5 mmol/h). Low values are seen in achlorhydria.
volume, consistency and presence of blood and mucous.
ABSORPTION
Stool microscopy helps in detection of RBC and pus cells—
suggesting bacillary dysentery and inflammatory bowel disease, Tests of absorption are shown in Table 1. In assessment of
parasitic ova/cysts, and fat in stools (Sudan stain) suggesting suspected malabsorption, blood tests (CBC, folate, vitamin
malabsorption. In immunocompromised patients with B12, albumin, anti TTG/endomysial antibody), barium meal
diarrhoea, stool evaluation for parasites like Cryptosporidium, follow through and endoscopy with distal duodenal biopsy are
Microsporidium, Isospora belli and Cyclospora should be performed in most cases.
performed. Stool culture is not done routinely except in persistent PANCREATIC EXOCRINE FUNCTION
diarrhoea. Stool positive for occult blood suggests GI blood loss
Tests to evaluate pancreatic exocrine function are shown
and warrants further evaluation.
in Table 2. Clinical use of the tests are limited because
Acidic stools (pH <6) suggests carbohydrate malabsorption. stimulation tests need intubation and tubeless tests are not
Increased stool alpha 1-antitrypsin clearance helps in diagnosis of sensitive to diagnose early chronic pancreatitis.
Table 1: Tests of Small Intestinal Absorption
Absorption Test Method Comments
Xylose (measures small Blood/urine xylose Quantification in blood (1h) or urine Rapid small bowel transit, renal failure,
bowel absorptive (5 h collection) after ingestion of 5 g xylose ascites, incomplete urine collection give
surface area) Normal: Blood >0.55 mmol/L false positive results
Urine >20% of ingested xylose
Fat 72 h faecal fat Quantification of stool fat while patient Non-invasive, slow, unpleasant
ingests 50 g fat/d
Normal: <6 g per day
14
C triolein breath Measurement of 14CO2 in breath after Non-invasive, fast, not quantitative
test ingestion of 14C triolein
Vitamin B12 Schilling test Quantification of 57CO and 58CO (used to Gastric disease: Free vitamin B12 absorption
label free vitamin B12 and vitamin B12 - decreased
intrinsic factor complex) in 24-hour urine Ileal disease: Free vitamin B12 and vitamin B12
Normal: >10% with equal ratio of both - IF factor complex absorption decreased
isotopes Bacterial overgrowth: vitamin B12 normal
after antibiotics
Lactose Breath hydrogen Measurement of breath hydrogen every Early rise of breath H2 in small bowel
30 min for 2 hours after 50 g of lactose bacterial overgrowth
Hypolactasia >20 ppm
75
Bile acids SeHCAT test Isotopic quantification of 7 days whole Accurate and specific
body retention of oral dose 75SeHCAT
Normal: >15% Involves radiation
Abnormal: <5% Slow
774
 Investigations—Gastrointestinal Disorders
Table 2: Tests of Exocrine Pancreatic Functions
Test Method Comment
Secretin stimulation test Injection secretin intra-venously followed by duodenal aspiration Invasive, expensive
Aspirate assayed for bicarbonate Chronic pancreatitis: low volume, low
bicarbonate
Pancreolauryl test Pancreatic esterases cleave fluorescein dilaurate after oral ingestion. Avoids duodenal intubation
Fluorescein absorbed and quantified in urine Test takes 2 days
Low sensitivity for early chronic
pancreatitis
NBT-PABA test Pancreatic chymotrypsin releases PABA which is assayed in urine Less reliable as compared to
pancreolauryl test
Faecal chymotrypsin/ Immunoassay of chymotrypsin/elastase in stool Simple, quick, does not detect mild
elastase disease

TESTS FOR MUCOSAL PERMEABILITY vomiting. Endoscopy and barium studies are often normal.
Mucosal permeability of small bowel can be evaluated by Gastric transit can reliably be measured by calculating the
51
Cr-EDTA and sugar tests (lactulose-rhamnose). Urinary amount of radio isotope retained in the stomach after a test
quantification of label after oral ingestion of 51Cr-EDTA is meal of solids and liquids labelled with different isotopes
performed. Increased level of label in urine suggests increased (Technetium/Indium).
intestinal permeability. Small Intestinal Transit
The small intestine absorbs monosaccharides but not Oro-caecal transit can be estimated by lactulose-hydrogen
undigestable disaccharides (lactulose) unless mucosa is leaky. breath test. Lactulose, a non-absorbable disaccharide reaches
Lactulose-rhamnose test detects increased intestinal permeability the colon intact. Bacterial metabolism of lactulose in the colon
and is abnormal in IBD, coeliac disease, tropical sprue, NSAIDS. produces hydrogen. The time interval between ingestion of
The test is rarely used clinically as it is not specific. lactulose and rise in breath hydrogen give a measure of oro-
caecal transit. Radionuclide techniques can also measure small
MUCOSAL BIOPSY bowel transit. Small bowel transit is seldom measured in clinical
If is obtained either by ‘cupped biopsy forceps’ passed practice.
through an accessory channel of an endoscope or by Crosby Colonic and Anorectal Motility
capsule per orally under fluoroscopic guidance. It provides
definite histological diagnosis of the diseases of oesophagus, Total and segmental colon transit can be measured by plastic
stomach, small bowel (duodenum, proximal jejunum), distal radio-opaque marker technique. The test is useful for evaluation
of chronic constipation and helps differentiate slow transit
ileum and colon. Detection of Helicobacter pylori in stomach
constipation from obstructed defaecation. Obstructed
is rapidly performed by placing two gastric biopsy specimens
defaecation and anorectal physiology are assessed by
(antrum, body) into a container using rapid urease kit which
defaecating proctography and anorectal manometry.
changes colour in a few minutes from yellow to red.
BREATH TESTS
TESTS OF GASTROINTESTINAL MOTILITY
Breath tests are enlisted in Table 3.
Radiological, manometric and radioisotope tests are used for
evaluation of gut motility. Table 3: Breath Tests

Oesophageal Motility Test Indication Positive Test

A careful barium swallow (using video fluoroscopy and bread Hydrogen breath test
barium) may give information about oesophageal motility. Glucose Small bowel >12 ppm rise over
bacterial baseline within
Oesophageal manometry which measures peristaltic perfor-
overgrowth 120 min.
mance, contraction wave configuration (amplitude, velocity), Lactulose Small bowel Time to first
basal and post-swallow lower oesophageal sphincter pressure is transit sustained response
the‘gold standard’ test to evaluate motor disorders of oesophagus, within 3-5 hours
like achalasia cardia and diffuse oesophageal spasm. Lactose Hypolactasia 20 ppm rise over
baseline within
Monitoring gastro-oesophageal acid reflux with pH sensitive 3 h.
electrodes over 24 hours distinguishes refractory gastro- 14 14
C-Xylose breath test Bacterial CO2 > 0.3% at 2-3 h
oesophageal reflux from other causes of chest pain and in relating overgrowth
atypical symptoms to episodes of reflux. A small portable 14
C-Glycocholic acid Bacterial 14
CO2 > 0.3%
recording device allows time of symptoms, meals and sleeping breath test overgrowth at 2-3 h
to be recorded which can be correlated with episodes of low pH. 14
C-triolein breath test Fat malabsorption Breath 14CO2
Gastric Emptying < 0.0005%
13
Delayed gastric emptying due to diabetic gastroparesis or C or 14C-Urea breath Confirm H. pylori 13/14
CO2 > 5-fold
test eradication baseline at 20 min.
gastric surgery may cause bloating, early satiety, nausea and 775
 RADIOISOTOPE TESTS TUMOUR MARKERS
Radioisotope tests are shown in Table 4. CA 19:9 Pancreatic and biliary malignancy
Table 4: Radioisotope Tests CEA Colonic malignancy
Test Isotope Indication
Chromogranin Neuroendocrine tumour

Gastric emptying 99m

Tc pertechnetate Gastroparesis Molecular Tests
111
In-DTPA
14
Disorder Gene Affected
Urea breath test C/13C Urea Confirm H. pylori
eradication Familial adenomatous polyposis APC
99m
Meckel’s scan Tc-pertechnetate Meckel’s diverticulum in
Multiple endocrine neoplasia Menin
obscure GI bleed
Labelled red cell 51
Cr labelled Obscure GI bleed Hereditary non-polyposis colon cancer hMSH 2, hMLH1
scan erythrocytes Peutz-Jegher syndrome LKB1
Labelled leucocyte 111In or 99mTc HMPAO Distribution of activity
scan labelled leucocytes (extent) in inflammatory RECOMMENDED READING
bowel disease
Albumin tagged 125
I-Albumin, Protein losing 1. Feldman M, Friedman LS, Sleisenger MH. Sleisenger and Fordtran’s
scan 51
Cr-Albumin enteropathy Gastrointestinal and Liver Disease; 8th Ed. Philadelphia: WB Saunders and
Co; 2009: pp 81-2.

776
 13.3 Endoscopy—Diagnostic and Therapeutic Utility

Gourdas Choudhuri

INTRODUCTION Table 1: Indications for Upper Gastrointestinal Endoscopy

Advancement in endoscopy has revolutionised our approach Diagnostic Upper gastrointestinal bleeding: past or present
to diagnosis and management of various gastrointestinal Patients with splenomegaly or suspected chronic
disorders. The word endoscopy is derived from Greek, ‘end’ liver disease: for presence and grading of
meaning within and ‘skopein’ meaning to view or observe. In oesophago-gastric varices
this chapter upper gastrointestinal endoscopy, colonoscopy Upper abdominal distress that persists despite an
and endoscopic retrograde cholangio-pancreatography (ERCP) appropriate trial of therapy
will be discussed in brief. Upper abdominal distress associated with
symptoms or signs that suggest serious organic
disease.
HISTORY
Dysphagia or odynophagia
The first attempt at looking into the body cavity was made by Oesophageal reflux symptoms that are persistent
Adolf Kussmaul who devised the first gastroscope in 1868, made or recurrent despite appropriate therapy
up of a rigid metal tube. Subsequently Rudolf Schindler (1888- Persistent nausea and vomiting of unknown cause
1968) improved this instrument but it was Basil Hirschowitz who Surveillance for malignancy
pioneered the use of fibre optics (glass fibre that conduct light) Gastric or oesophageal ulcers
that greatly improved the flexibility and manoeuvrability of the Familial adenomatous polyposis
instrument. In 1957 he himself swallowed the first fibre optic Adenomatous gastric polyps
gastroscope. The use of electronic chips (charge couple devices Barrett’s oesophagus
or CCD) to transmit the image from the tip of the endoscope to Occult gastrointestinal bleeding
a video screen resulted in the present generation of video Small bowel biopsy
Cirrhotic patients in whom prophylactic therapy is
endoscopes since the 1980s. considered
UPPER GASTROINTESTINAL ENDOSCOPY (UGIE) After caustic ingestion to assess for acute injury
Therapeutic Treatment of bleeding lesions
Indications
Sclerotherapy or banding of varices
This largely depends on the suspected diagnosis, availability of Removal of foreign bodies
facilities and expertise, and patient’s choice. The common Removal of selected polypoid lesions or
diagnostic and therapeutic indications for UGIE are given in superficial neoplasms
Table 1 and shown in Figures 1 to 6. Placement of feeding or drainage tubes
Dilation of stenotic lesions
Contraindications Palliative treatment of stenosing neoplasms
The absolute contraindications are given in Table 2. Apart from Drainage of pancreatic pseudocysts
these conditions special precautions should be taken in patients
with Zenker’s diverticulum, compromised cardiovascular and Table 2: Contraindications for Upper Gastrointestinal Endoscopy
pulmonary reserve and coagulopathy. Taking biopsy should be The risks to patient health or life are judged to outweigh the most
avoided in patients with coagulopathy. Pregnancy is not a favourable benefit of the procedure.
contraindication for UGIE, but should only be performed for Adequate patient cooperation cannot be obtained.
pressing indications. A perforated viscus is known or suspected.

Figure 1: Upper gastrointestinal endoscopy showing large oesophageal varices Figure 2: Upper gastrointestinal endoscopy showing polypoidal, ulcerated
with red colour signs. growth suggestive of oesophageal cancer.
777
 Figure 3: Upper gastrointestinal endoscopy showing a benign gastric ulcer. Figure 4: Oesophageal variceal sclerotherapy. Note the blue scleropathy needle.

Figure 5: Glue injection being done in a patient with large, bleeding fundal Figure 6: Oesophageal variceal band ligation. Note the blue ‘O’ ring on one of
varices. the varix.

Preparation and the Procedure as the most useful test for evaluation of the colon and terminal
The procedure is performed after anaesthetising the pharynx ileum.
with lignocaine spray or gel. Tense and apprehensive patients Indications
may need intravenous sedation with midazolam or propofol.
The indications can be divided into two categories; diagnostic
The procedure is performed with the patient lying in the left
and therapeutic (Table 3) and shown in Figures 7 to 9.
lateral position. The endoscope is inserted through the mouth,
pharynx, oesophagus, stomach and then further down to the Table 3: Indications for Colonoscopy
second part of the duodenum under vision.
Diagnostic Unexplained rectal bleeding
Complications of UGIE Unexplained lower gastrointestinal symptoms and
Endoscopic examination of the upper gastrointestinal tract is signs, such as recent onset constipation or feeling
of incomplete evacuation, especially in the elderly
a fairly safe procedure with overall complications being less
Non-diagnostic radiographic examination
than 1% and mortality rate <0.01%. Serious complications
Polyp and cancer screening or follow-up
following diagnostic UGIE like perforation (0.01% to 0.11%)
Inflammatory bowel disease
and bleeding (0.03% to 0.1%) are rare. Pulmonary
Stricture or colonic narrowing (with and without
complications like aspiration, decreased oxygen saturation
inflammatory bowel disease)
and pulmonary infection are known to occur. The cardio-
Diverticular disease
pulmonary complications include premature beats, arrhythmias
Infectious colitis
and respiratory depression, which occur mostly due to use of
Radiation colitis
pre-medications at the time of UGIE. There is a small risk of
Ischaemic colitis
transmission of diseases like hepatitis B, hepatitis C, Helicobacter
Endometriosis
pylori, Pseudomonas, Salmonella and mycobacteria. Transient
Pneumatosis cystoides intestinalis
bacteraemia has been reported following oesophageal
dilatation and sclerotherapy in up to 30% of cases; it has Therapeutic Polypectomy
importance for patients with valvular heart disease who need Foreign body removal
prophylaxis with antibiotics for prevention of sub-acute Dilation of strictures in colon or terminal ileum
bacterial endocarditis. Therapeutic: Haemostasis
Tumour resection (palliative)
COLONOSCOPY Colonic decompression (volvulus and pseudo-
Since early 1970s colonoscopy is in common use in gastro- obstruction)
enterology. Although it is a more difficult and time consuming Placement of stents for non-resectable malignant
778 obstruction
procedure compared to UGIE, it has become widely accepted
 Endoscopy—Diagnostic and Therapeutic Utility
Figure 9: Colonoscopy showing multiple large polyps.

Figure 7: Colonoscopy showing a nodular polypoidal growth in the rectum Complications

suggestive of rectal cancer.
Apart from side-effects of sedatives and analgesics used and
complications of peroral bowel preparation, some serious
complications can occur during colonoscopy (Table 5).

Table 5: Complications of Diagnostic and Therapeutic

Colonoscopy
Diagnostic Colonoscopy Therapeutic Colonoscopy
Complications of bowel Perforation
preparation Haemorrhage
Premedication related problems Mucosal burns
Bacteraemia Incomplete polypectomy
Haemorrhage Explosion
Perforation Accidental removal of a urete-
Diastatic serosal tears rosigmoidostomy stoma
Post-colonoscopy distension Accidental removal of an
Figure 8: Colonoscopy showing ulcerations and pseudopolyps in a patient with
Vaso-vagal reflex intussuscepted appendiceal
ulcerative colitis.
Splenic trauma stump
Cardiac and electrocardiographic Electrical ileal perforation
Patient Preparation abnormalities
A clean colon is mandatory for proper evaluation. Various A dynamic ileus
agents are used to prepare the bowel for colonoscopy; Pneumatosis cystoides intestinalis
Incarceration or impaction of an
they include polyethylene glycol (PEG) with electrolytes
instrument in a hernia
or sodium picosulphate. Before giving peroral bowel
Aortic aneurysm dissection
preparation in any patient, overt or impending bowel Cardiopulmonary problems
obstruction should be ruled out, to avoid precipitating acute
intestinal obstruction. The incidence of perforation and haemorrhage increase from
Sedation and analgesics are more frequently used during <0.07% during diagnostic colonoscopy to 2.2% following
colonoscopy than during UGIE. Most centres use midazolam therapeutic procedures like polypectomy. Deaths have rarely
alone or in combination with pentazocine. been reported following colonoscopy (<0.01%). Bacteraemia
following colonoscopy has been reported in up to 27% of cases.
Contraindications Rarely transmural burns and explosion can occur after using
Contraindications are listed in Table 4. electro-surgical instruments.

Table 4: Contraindications to Colonoscopy ENDOSCOPIC RETROGRADE CHOLANGIO-

Acute inflammation of the colon (fulminant), including PANCREATOGRAPHY (ERCP) (FIGURES 10 and 11)
ulcerative colitis, Crohn’s colitis, ischaemic colitis, diverticulitis, and Endoscopic retrograde cholangio-pancreatography is a
radiation colitis procedure by which the biliary and pancreatic ductal systems
Peritonitis are visualised by injecting radio-opaque contrast solutions after
Suspected or impending intestinal perforation endoscopic cannulation of the duodenal papilla.This is a difficult
Pregnancy (second and third trimester) and potentially risky procedure which should be undertaken
An uncooperative patient only by a properly trained and experienced endoscopist. In
Bleeding disorder expert hands the procedure is successful more than 95% of
Acute cardiorespiratory disease or recent myocardial infarction times.
Shock
Indications
Large aortic or iliac artery aneurysm
Recent pelvic or colonic surgery List of indications for diagnostic and therapeutic ERCP is given
in Table 6. 779
 Contraindications
The contraindications are same as those for upper gastro-
intestinal endoscopy. With advancement in non-invasive
imaging such as MRCP or endoscopic ultrasound, ERCP is rarely
required at present for diagnostic purposes. It should be
undertaken in patients with suspected biliary obstruction only
with sufficient preparations to drain the biliary system as well.
The procedure also requires fluoroscopic guidance and hence
contraindicated during early pregnancy.
Complications of ERCP
ERCP is a potentially risky procedure especially when
therapeutic biliary and pancreatic procedures are performed.
The complication rates are high if ERCP is done as an emergency
procedure and by an inexperienced endoscopist. The
complication rate is 5% to 10% and mortality is 0.5% to 1%.
Major complications include post-ERCP pancreatitis in about
5%, haemorrhage (following sphincterotomy) in 2% to 3%,
cholangitis 1% to 3% and retro-duodenal perforation in 1%. The
list of complications of ERCP is given in Table 7.
Figure 10: Impacted stone at the ampulla of vater being extracted during ERCP.

Table 7: Complications of ERCP

Exposure to radiation Perforation of duodenum
Pancreatitis Haemorrhage
Allergy to contrast Biliary/pancreatic sepsis
Trapped dormia basket Splenic trauma
Subcapsular biloma of liver Emphysematous cholecystitis

In addition to the three common standard procedures mentioned

above, several new ones are now gaining importance.
1. Endoscopic ultrasound (EUS) is an instrument with a high
frequency ultrasound probe mounted on the distal tip of a
Figure 11: Biliary stent inserted during ERCP. video-endoscope, and has emerged as the most accurate
method for loco-regional staging of upper GI and
pancreatobiliary tumours and for imaging the wall of the
Table 6: Indications for ERCP
upper GI tract. It provides high resolution cross sectional
Diagnostic Cholestatic jaundice imaging and is especially useful for imaging sub-mucosal
Acute cholangitis or intramural lesions.
Choledocholithiasis
2. Enteroscopes are long video-endoscopes specially
Sphincter of Oddi manometry designed to inspect the small intestine. There are 2 types
Suspected sclerosing cholangitis depending on whether it has a double or single balloon.
Choledoschoscopy These ballon enteroscopes can be used to inspect up to
Bile for cytology and other studies the mid ileum from the peroral route or from the anal route.
Evaluation of peri-ampullary neoplasm They also have an operating channel for fulgurating
Biliary pancreatitis, recurrent acute pancreatitis, bleeding lesions, removing polyps or taking biopsy.
chronic pancreatitis
Evaluation of pancreatic pseudocyst 3. Cholangioscope is a thin instrument that can be passed
Pancreatic fistula, pancreatic ascites into the bile duct for imaging of stones or tumours. A variety
Pancreatic juice aspiration for study of thin instruments can be passed through the operating
Taking brush cytology or biopsy for confirmation channel of the ERCP scope, and can be useful for managing
of diagnosis tight biliary obstruction due to cholangiocarcinomas or
Therapeutic Biliary drainage for cholangitis, pruritus, post-
large biliary stones.
operative bile leak 4. Contrast endoscopy: There are several new techniques
Extraction of stones, round worms or hydatid that sharpen the distinction between normal and
daughter cysts from bile duct abnormal mucosa, facilitating better recognition and
Bile duct stricture dilatation assessment of extent, as well as more accurate targeting
Pancreatic duct stone extraction, pancreatic duct of biopsy. They include chromoendoscopy or narrow band
stricture dilatation imaging.
Pancreatic duct stenting for pain in chronic
5. Confocal endomicroscopy provides very high magnification
pancreatitis, pancreatic ascites and fistula
780 and enables the cells of the surface layer to be viewed for
 Endoscopy—Diagnostic and Therapeutic Utility
diagnosing dysplastic or anaplastic changes. Using this RECOMMENDED READINGS
instrument one can diagnose a malignancy during the 1. Gary R Zuckerman, editor. Gastrointestinal Clinic of North America –
endoscopic procedure itself, without having to wait for the Complications of Gastrointestinal Endoscopy. Philadelphia: WB Sanders
Company; April 1996.
histopathology report.
2. Gudio NJ Tytgat and Meinhard Classen, editors. Practice of Therapeutic
Endoscopy. Churchill Livingstone: New York; 1994.
FUTURE OF ENDOSCOPY
3. Ira M Jacobson, editors. ERCP and its Applications. Philadelphia: Lippincott
Endoscopes are now being used to enter the peritoneal cavity Raven; 1998.
by producing a controlled gastric perforation. Having reached 4. Maurits J Wirsema, editor. Gastrointestinal Clinic of North America – Emerging
there, a diseased appendix or gallbladder can be removed Technologies in Gastrointestinal Endoscopy. Philadelphia: WB Sanders
Company; April 1997.
through the natural orifice, i.e. mouth without an external
5. Michael V Sivak. Gastroenterologic Endoscopy; 2nd Ed. Philadelphia: WB
scar. Thus, the procedure is called NOTES (Natural Orifice Trans Sanders Company; 2000.
Endoscopic Surgery). It is being actively developed in several 6. Peter B Cotton. Practical Gastrointestinal Endoscopy. In: Christopher B
advanced centres and holds promise in the near future. Williams, editor. London: Blackwell Science Publications; 1990.

781
 13.4 Diarrhoea and Malabsorption

BS Ramakrishna

Diarrhoea and malabsorption are disorders that are common Clinical Features
in India possibly because of the prevailing lower levels of Acute diarrhoea presents with two basic syndromes—watery
hygiene and unsafe water supplies. Diarrhoea is characterised diarrhoea and blood and mucous diarrhoea (also called dysentery).
by increased liquidity of stool or increased frequency of stool When vomiting is very prominent and overshadows diarrhoea,
and is defined in different ways depending on the context in the possibility of viral gastroenteritis or of food poisoning must
which the definition is required. For field studies of the prevalence be considered first. Watery diarrhoea is due to excessive fluid
or incidence of diarrhoea, diarrhoea is defined as three or more secretion from the small and/or large intestine. In its most
stools, taking the form of the container into which they are passed, dramatic form it is seen in cholera, where the patient may
in a 24 h period. For hospital-inpatient studies, diarrhoea is typically lose several litres of fluid in the stool in hours and
defined by a stool weight greater than 400 g/24 h (cf. Western present to the emergency department with peripheral vascular
definition of 200 g/24 h). In the outpatient clinic, diarrhoea is collapse and un-recordable blood pressure. Cholera,
diagnosed when there is an increase in the frequency and enterotoxigenic Escherichia coli infection, and viral gastro-
liquidity of the stool compared to an earlier time period. Diarrhoea enteritis present with acute severe watery diarrhoea. The fluid
is categorised as ‘acute’ or chronic’ depending on whether it has secretion in watery diarrhoea is due to the effect of enterotoxins
lasted less than 2 weeks or more than 4 weeks. In the setting of that increase the mucosal concentrations of cyclic nucleotides—
infectious gastroenteritis, diarrhoea lasting longer than 2 weeks cyclic AMP and cyclic GMP—which inhibit sodium absorption
is labelled as ‘persistent’ diarrhoea. Malabsorption syndromes are while turning on chloride secretion in the intestine. These ion
one of several causes of chronic diarrhoea.This chapter will review movements lead to excessive retention and secretion of fluid
the causes and diagnostic pathways for diarrhoea and into the lumen of the intestine. While cholera toxin and E. coli
malabsorption especially as they pertain to India. heat-labile enterotoxins were the prototypic enterotoxins, it
ACUTE DIARRHOEA is now shown that even viruses (rotavirus) and protozoan
parasites (Cryptosporidium) produce enterotoxins that drive
Acute diarrhoea is usually due to acute infectious gastroenteritis,
fluid secretion. Rotavirus infection is one of the most common
although several other causes are shown in Table 1. Acute
causes of acute diarrhoea in infants and children and is a major
infectious gastroenteritis is a major cause of morbidity and
cause of childhood deaths due to diarrhoea.
childhood mortality. Over 1.5 million children (approximately
500,000 in India) continue to die worldwide each year because Acute blood and mucous diarrhoea (or dysentery) is usually due
of the consequences of acute diarrhoea. This is significantly less to invasive bacteria such as Shigella species, or enteroinvasive
than diarrhoea mortality of five million children per year twenty E. coli, as well as due to the protozoan pathogen, Entamoeba
years ago. Currently, it is estimated that over a half of the histolytica that causes amoebic dysentery. Bacillary dysentery is
diarrhoea deaths in children are associated with malnutrition. characterised by frequent small volume stools which are mostly a

Table 1: Causes of Acute Diarrhoea

Condition Proximate Cause or Agent
Infectious gastroenteritis Bacteria Viruses Parasites
Vibrio cholerae Rotavirus Entamoeba histolytica
Shigella species - S. dysenteriae, S. flexneri, Calicivirus Giardia intestinalis
S. boydii, S. sonnei Enteric adenovirus
Pathogenic Escherichia coli Astrovirus
(enterotoxigenic, enteroinvasive,
enterohaemorrhagic, enteroaggregative)
Salmonellae (non-typhoidal)
Campylobacter jejuni
Clostridium difficile
Aeromonas species
Plesiomonas species
Yersinia enterocolitica
Antibiotic-associated Alteration in commensal flora of gut
diarrhoea Overgrowth of Clostridium difficile
Traveller’s diarrhoea Altered bacterial flora in upper gut
Pathogen (e.g. Giardia, enterotoxigenic Escherichia coli)
Post-operative and Alteration in commensal flora of gut
nosocomial diarrhoea Drugs including antibiotics
Enteral feeding
782
 Diarrhoea and Malabsorption
mixture of blood and pus with little faecal matter. Fever and lower rehydration solution (ORS) cannot be taken orally as in patients
abdominal pain relieved by bowel movement may occur.Amoebic with profuse vomiting, intravenous rehydration is indicated.
dysentery is characterised by fewer stools (frequency of 4 to 6 per Antibiotics are not necessary in most patients with acute watery
day) which are larger in volume and contain mostly dark blood. diarrhoea with the exception of cholera where antibiotic treatment
significantly shortens diarrhoea. In suspected cholera it is usual
Diagnosis
to treat patients with an antibiotic to which the Vibrio in that
In acute watery diarrhoea it is generally not necessary to geographic region is considered to be sensitive, either doxycycline
investigate for the cause. Examination of the stool by dark 300 mg stat or ciprofloxacin 500 mg twice daily for three days or
field microscopy of a hanging drop shows actively motile azithromycin 500 mg stat can be used. Antibiotics prolong faecal
bacteria in cholera infection. Stool culture establishes a bacterial excretion of non-typhoidal Salmonella in immunocompetent
aetiology when present, while rotavirus is diagnosed by enzyme individuals, and are therefore not administered. However,
immunoassay of the stool for rotavirus antigen. In patients antibiotics need to be given to the very young and the elderly
with dysentery, it is very necessary to examine stool or a rectal patient with salmonellosis, as well as to patients who have a
swab smear under the microscope for evidence of pus cells, prosthetic joint or valve.
macrophages that have ingested red blood cells (bacillary
exudate) and presence of E. histolytica trophozoites that have The management of dysenteric illnesses is with an antibiotic to
ingested RBCs. Presence of amoebic cysts alone does not which the organism is sensitive, such as metronidazole 800 mg
establish a diagnosis of amoebic dysentery, since there are non- three times daily for amoebic dysentery or ciprofloxacin 500 mg
pathogenic amoebae in the intestine. Stool culture is necessary twice daily for shigellosis. Patients with amoebic dysentery should
for the diagnosis of invasive bacterial pathogens. Clostridium typically receive diloxanide furoate for two weeks after treatment
difficile infection, that causes antibiotic-associated diarrhoea with metronidazole in order to ensure that the cyst forms of
and colitis, is diagnosed by detecting toxin in the stool using the parasite are eradicated. Antibiotics are used with care in
enzyme immunoassay. enterohaemorrhagic E. coli infection since there is some evidence
that some antibiotics may paradoxically worsen illness.
Complications
Prevention
Haemoconcentration, pre-renal uraemia and renal failure due to
acute tubular necrosis may occur as a consequence of acute Handwashing before and after eating or feeding a child is the
watery diarrhoea. Death in acute gastroenteritis is usually due to most effective preventive intervention. Disinfection of drinking
the excessive loss of fluid with electrolyte imbalance, principally water at home is achieved by a variety of means. Safe drinking
hypokalaemia and acidosis since the intestinal secretion is rich water and implementation of safe food handling practices are
in potassium and bicarbonate. Persistent diarrhoea leading to very important in a general context when eating out. Rotavirus
malnutrition is another cause of death in children presenting with vaccines have been introduced in several parts of the world.
acute infective gastroenteritis. Complications associated with a The first vaccine to be widely used was withdrawn because of
dysenteric illness include sepsis, encephalopathy, haemolytic development of intussusception in some patients. Rotavirus
uraemic syndrome with renal failure, and rarely toxic megacolon, vaccines have now been shown to protect against severe
all of which may be associated with mortality. It is recently diarrhoea in Mexico and Africa but are not yet included in the
recognised that a significant number of individuals are afflicted extended primary immunisation schedule in India. Cholera
with post-infective irritable bowel syndrome following an vaccines using an attenuated strain (Dukoral) are not widely
episode of acute gastroenteritis. available. A new killed whole cell vaccine has been shown to be
effective in a large trial in India and may be widely available soon.
Management
In resource-poor settings, it is generally not necessary to investigate CHRONIC DIARRHOEA
patients with acute watery diarrhoea before initiating therapy. It is Diarrhoea lasting longer than four weeks is termed as chronic
necessary to evaluate the patient for evidence of dehydration. In diarrhoea. Infections, tropical sprue, coeliac disease and
adults, presence of tachycardia and orthostatic or postural bacterial overgrowth in the small intestine are the major causes
hypotension signifies 10% loss of blood volume, while supine of chronic diarrhoea seen in clinical practice. These and rarer
hypotension indicates loss of over 20% of circulating blood volume. causes of chronic diarrhoea are listed in Table 2. This section
In children and adults with severe dehydration, the lost fluid has will briefly describe an approach to the diagnosis of chronic
to be replaced quickly by the intravenous route over a period of diarrhoea but will not elaborate on the individual diseases.
four to six hours. In cholera and severe diarrhoea, the choice of
replacement fluid is Ringer’s lactate solution which is similar in Clinical Features
composition to the fluid lost in the stool and corrects the electrolyte Patients with chronic diarrhoea must be carefully evaluated in
losses. A volume equivalent to 10% of the body weight is infused order to separate functional from organic disease. The duration
over 4 hours in such individuals, the first 30% in one hour and of the history, associated symptoms, co-morbid illnesses, diet
remaining 70% in three hours. In patients with mild dehydration, it history, medication history and family history are all important.
is sufficient to rehydrate the patient through the oral route. Oral A nutritional evaluation is important. The presence of nocturnal
rehydration therapy, which is based on the fact that glucose-linked diarrhoea, presence of blood in the stool, and evidence of
sodium absorption in the small intestine is preserved in most nutritional deficiencies suggests an organic cause such as
patients with acute gastroenteritis even when sodium absorption malabsorption or inflammatory bowel disease. In order to
in the absence of glucose is impaired, efficiently rehydrates facilitate investigation, it is usual for the specialist to categorise
patients with mild dehydration and prevents mortality. When oral chronic diarrhoea as either small bowel or large bowel in origin.
783
 Small bowel diarrhoea may be either secretory (large volume MALABSORPTION
watery stool) or suggestive of steatorrhoea (pale, bulky, frothy, Malabsorption syndromes are encountered not uncommonly
foul smelling) and is often not accompanied by pain. Large in specialist gastroenterology practice in India. Over the last few
bowel diarrhoea is small in volume and is usually associated decades, the profile of such diseases has changed significantly.
with abdominal pain, localised to the iliac fossae and relieved Tropical sprue, once common all over India, has been replaced
by defaecation, and with mucous and/or blood in the stool. as the most common malabsorption syndrome by coeliac disease
particularly in children in the Northern states of India. Table 3
Table 2: Causes of Chronic Diarrhoea and Malabsorption
lists several malabsorption syndromes that occur in India.
Tropical sprue Small intestinal mucosal atrophy
Coeliac disease Table 3: Malabsorption Syndromes and their Diagnosis
Small intestinal Strictures in small intestine,
Syndrome Diagnosis
bacterial overgrowth Motility disorders of gut
Surgical bypass of gut with blind loop Tropical sprue Establish malabsorption
Inflammatory bowel Tuberculosis Exclude other causes
disorders Crohn’s disease Demonstrate villus atrophy in small bowel
Ulcerative colitis biopsy
Collagenous enteritis and colitis Coeliac disease IgA antibody to tissue transglutaminase
Microscopic colitis Small bowel biopsy showing increased
Infections Strongyloidiasis intraepithelial lymphocyte number and villus
Capillariasis atrophy
Isosporiasis Clinical, haematological, biochemical or
Cryptosporidiasis histological response to gluten withdrawal
Microsporidiosis Parasites Examination of wet mounts (stained and
HIV enteropathy unstained) of stool or jejunal fluid for
Chronic pancreatitis Alcoholic, idiopathic and helminths larva or ova and protozoan cysts
tropical pancreatitis Examination of faecal smears with special
Malignancies Lymphoma stains—safranin, methylene blue, modified
Carcinoid syndrome AFB stain
Pancreatic endocrine neoplasm (VIPoma) EIA of faeces for antigens of Giardia,
Infiltrative disorders Whipple’s disease Cryptosporidium, microsporidia
Eosinophilic gastroenteritis Small bowel biopsy
Drug-related Antibiotics, chemotherapeutic agents, Bacterial Low serum vitamin B12 with normal or high
diarrhoea laxatives overgrowth folate
Glucose breath hydrogen test
Laxative abuse
Quantitative culture of jejunal fluid or mucosal
Idiopathic bile acid
biopsy
malabsorption
Pancreatic Increased faecal fat
Factitious diarrhoea
insufficiency Pancreolauryl test
Faecal chymotrypsin and elastase
Diagnosis Pancreatic calcification on radiology
Routine haematology and clinical chemistry are useful to Eosinophilic Peripheral eosinophilia
separate organic from functional disease. Normal haemoglobin gastroenteritis Small bowel biopsy showing increased
and red cell parameters, normal leucocyte counts, sedimentation eosinophilic infiltration
rate, faecal examination for parasites and faecal occult blood, and Immuno- Immunochemical detection of alpha heavy
liver function tests usually indicate absence of significant organic proliferative chain in serum
pathology in an untreated patient with chronic diarrhoea. Faecal small intestinal Barium meal showing picket fence
testing for occult blood and for parasites (routine microscopy disease and appearance of mucosa, and aneurysmal
and special stains for protozoan parasites) is usually done on lymphoma dilatation in frank lymphoma
CT appearances of uniform thickening of
three consecutive samples. Further testing is usually dependent
bowel wall with lymph node involvement
on clinical judgement of the cause of chronic diarrhoea. Where Small bowel biopsy showing characteristic
appropriate, patients may be tested for antibodies to the human effacement of crypts by lymphoplasmacytic
immunodeficiency virus after counselling and for antibodies to infiltrate ranging from benign looking cells to
tissue trans-glutaminase (to exclude coeliac disease). Patients lymphosarcoma
with small bowel type of diarrhoea may undergo testing for Intestinal Duodenoscopy showing milky white spots
malabsorption and imaging studies of the small bowel and lymph lymphangiectasia especially after high fat meal
nodes followed by endoscopy and biopsies of the small intestine. Small bowel biopsy demonstrating dilated
In patients with large bowel type diarrhoea, the directed lymphatics in villi
investigation consists of either sigmoidoscopy and rectal biopsy Whipple’s disease Small bowel biopsy showing infiltration of
or ileocolonoscopy and biopsies. A significant minority of patients lamina propria by PAS positive macrophages
with chronic diarrhoea of organic nature will remain undiagnosed Abetalipo- Acanthocytosis on peripheral blood
after all the above tests. In this group, unusual causes of chronic proteinaemia and smear
hypobeta- Small bowel biopsy demonstrating
diarrhoea such as a pancreatic endocrine tumour or idiopathic
lipoproteinaemia vacuolisation of surface epithelial cells
784 bile acid malabsorption may need to be considered.
 Diarrhoea and Malabsorption
Clinical Features individuals. Protozoan infections that cause malabsorption
Patients with malabsorption usually present with gastro- include Giardia intestinalis, Cryptosporidium parvum, Isospora
intestinal symptoms, particularly chronic diarrhoea and weight belli, Cyclospora cayetanensis, Enterocytozoon bieneusi and
loss. The basis for diarrhoea and other manifestations of Encephalitozoon intestinalis. The last two are now thought
malabsorption is shown in Table 4 which will help the physician to be fungi rather than protozoans. These usually cause
to understand why symptom constellations and specific malabsorption only in immunocompromised individuals
physical signs are associated with particular disease processes. including those with acquired immunodeficiency syndrome
Although diarrhoea is the most common symptom in patients (AIDS) or with congenital immunodeficiencies such as common
with malabsorption, earlier recognition of the malabsorption variable immunodeficiency.
disorders in recent years has led to the emergence of atypical Small intestinal bacterial overgrowth is another cause of
presentations without diarrhoea. malabsorption. Normally, the bacterial population of the small

Table 4: Symptoms and Signs in Malabsorption and their Genesis

Symptom Correlating physical sign Pathophysiology
Diarrhoea Dehydration Water malabsorption due to unabsorbed osmolytes, e.g. sugars
Hypotension Water secretion due to unabsorbed bile acids or fatty acids
Steatorrhoea Reduction of skinfold thickness Fat malabsorption due to mucosal disease
Loss of buccal fat pad Fat maldigestion due to pancreatic insufficiency
Borborygmi, flatulence, Abdominal distension Carbohydrate malabsorption due to mucosal disease or
bloating disaccharidase deficiency
Weight loss Reduction of skinfold thickness Energy, fat and protein malnutrition
Loss of buccal fat pad Inflammation
Tiredness and weakness Muscle wasting Vitamin and mineral deficiency
Night blindness Bitot’s spots, keratomalacia Vitamin A malabsorption due to steatorrhoea or bile salt deficiency
Bone pain Bone tenderness, rickets Vitamin D and calcium malabsorption
Burning in mouth Glossitis, stomatitis Vitamin B deficiencies
Tingling and numbness Loss of ankle jerks Vitamin B deficiencies
in feet and hands Loss of proprioception
Anaemia Flat nails, koilonychias Iron deficiency due to duodenal mucosal disease or blood loss
Hyperpigmentation Vitamin B12 deficiency in bacterial overgrowth, ileal disease
Folate deficiency due to mucosal disease in upper gut
Amenorrhoea Delayed secondary sexual Secondary hypopituitarism
characteristics
Stunting Height for age Z score <-2 Secondary hypopituitarism
Skin lesions Pellagra, nutritional dermatoses Vitamin and essential fatty acid deficiencies
Acrodermatitis Zinc deficiency
Dermatitis herpetiformis Association with coeliac disease

Tropical sprue, also called idiopathic tropical malabsorption, intestine is kept to a minimum by peristalsis. Bacterial
is a disorder characterised by chronic diarrhoea, steatorrhoea, overgrowth occurs primarily in conditions where the clearance
abdominal distension, prominent borborygmi, glossitis and of bacteria from the gut is impaired as in obstructive strictures
multiple nutrient deficiencies. Tropical sprue occurred as due to tuberculosis or Crohn’s disease, in diseases where gut
epidemics in south India in the 1960s and 1970s but then motility is impaired such as diabetic autonomic neuropathy or
disappeared. Sporadic tropical sprue was very common in the progressive systemic sclerosis, and following surgical bypass of
1960s to 1980s but has gradually declined or disappeared in the gut with blind loops.
recent years.
Infiltrative disorders of the intestine cause malabsorption, but
Coeliac disease, caused by allergy to gliadin in wheat gluten, is are rarer. These include eosinophilic gastroenteritis, immuno-
particularly common in Western countries. While it has been proliferative small intestinal disease which includes the stage
reported in Indians since the 1960s, in the last two decades, the of immunoblastic lymphoma, and Whipple’s disease.
incidence of the disease has dramatically increased particularly
A variety of other disorders cause malabsorption in infancy and
in the northern states of Punjab, Uttar Pradesh and Delhi where
childhood including abetalipoproteinaemia, lymphangiectasia,
the largest number of cases have been reported. Atypical
and disaccharidase deficiencies.
presentations with anaemia, bone disease, short stature and
menstrual disorders are described from India as in other Diagnosis
countries.
Initial investigation includes the demonstration of nutrient
Parasitic infestations also rank as a common cause of deficiencies, e.g. anaemia, hypoalbuminaemia, by appropriate
malabsorption in India. Helminth parasites that cause testing, along with faecal examination for parasites and occult
malabsorption include Strongyloides stercoralis and Capillaria blood. Detection of the protozoan parasites that cause
philippinensis and these may affect immunocompetent malabsorption is facilitated by the use of special stains such 785
 as safranin-methylene-blue and modified acid fast stains. with restriction of long chain triglycerides in patients with
Xylose, a pentose sugar that is not metabolised in humans, is symptomatic steatorrhoea, must be maintained. Medium chain
given orally and 5-hour urine excretion (greater than 20% of triglycerides may be used in patients with malabsorption due
dose ingested) is estimated as a direct measure of small to pancreatic insufficiency. Fat-soluble vitamins, A, D and K, need
intestinal sugar absorption. Faecal fat (normal <7 g/day) can to be given orally or parenterally in patients with significant
be measured chemically by collecting stool collectively for long-term steatorrhoea.
three days while ingesting 50 to 100 g/day fat. Breath Specific therapy depends on the nature of the condition causing
hydrogen excretion after oral ingestion of a digestible sugar
malabsorption. Tropical sprue is treated with long-term
such as lactose may be used as a measure of malabsorption
antibiotics, typically tetracycline in a dose of 250 mg four times
but is fraught with inconsistencies. Breath hydrogen
daily for up to 6 months. Coeliac disease is treated with strict
measurement after oral glucose is used to measure bacterial
overgrowth in the upper small intestine. Serum iron, ferritin, gluten restriction, which has to be explained to the patient and
vitamin B12 and folate, calcium and phosphorus are family and monitored. Treatment of parasitic infections causing
commonly measured in these patients. If malabsorption has malabsorption depends on the specific parasite. Strongyloides
been established, the next step is to image the small bowel and Capillaria infestations may be treated with albendazole
by radiology (barium meal follow through or CT enteroclysis) or ivermectin, while protozoan infections are treated with co-
or by endoscopy (enteroscopy) to exclude ulcerative or trimoxazole, ciprofloxacin, or nitazoxanide in appropriate
infiltrative disease. Mucosal biopsies are obtained from the dose. Treatment needs to be for longer periods of time than
third or fourth part of the duodenum or from the jejunum in uncomplicated infection, and in the case of the protozoan
order to elucidate the diagnosis. parasites it may also involve maintenance therapy since these
Tropical sprue is essentially a diagnosis of exclusion, confirmed occur in patients with immunodeficiency. Bacterial overgrowth
by the absence of parasites, tuberculosis or inflammatory bowel is treated with periodic administration of antibiotics such as
disease, and negative coeliac serology, with the presence of metronidazole, ciprofloxacin or with the non-absorbable
villous atrophy, crypt elongation and inflammatory cell antibiotic rifaximin.
infiltration of the lamina propria on small bowel biopsy. Coeliac
RECOMMENDED READINGS
disease diagnosis may be established by the finding of partial
1. Camilleri M. Chronic diarrhea: a review on pathophysiology and
or complete villous atrophy and increased intraepithelial
management for the clinical gastroenterologist. Clin Gastroenterol, Hepatol
lymphocytes on small bowel biopsy, the presence of positive 2004; 2:198-206.
coeliac serology, and clinical and/or histological response to 2. Farthing M, Lindberg G, Dite P, Khalif I, Salazar-Lindo E, Ramakrishna BS,
gluten withdrawal. The serological test used most commonly et al.World Gastroenterology Organization practice guideline: Acute diarrhea.
for the diagnosis of coeliac disease is IgA antibody to human http://www.worldgastroenterology.org/acute-diarrhea-in-adults.html.
tissue transglutaminase (anti-tTG), while anti-endomysial 3. Feldman M, Friedman LS, Brandt LJ, editors. Sleisenger and Fordtran’s
antibody is more specific but also not widely available. Gastrointestinal and Liver Disease, Pathophysiology, Diagnosis, Management;
2010.
Pancreatic insufficiency used to be diagnosed by measuring
4. Manatsathit S, Dupont HL, Farthing M, Kositchaiwat C, Leelakusolvong S,
duodenal trypsin after a fatty meal (Lundh test) but this is given
Ramakrishna BS, et al. Guideline for the management of acute diarrhea in
up for tubeless tests such as the pancreolauryl test where adults. J Gastroenterol Hepatol 2002; 17 (Suppl): S54-S71.
fluorescein dilaurate is cleaved by a pancreatic enzyme 5. Navaneethan U, Giannella RA. Mechanisms of infectious diarrhea. Nat Clin
cholesterol ester hydrolase and fluorescein measured in Pract Gastroenterol Hepatol 2008; 5: 637-47.
the urine. Faecal chymotrypsin and elastase are used also as 6. Ramakrishna BS, Venkataraman S, Mukhopadhya S.Tropical malabsorption.
measures of pancreatic insufficiency. Postgrad Med J 2006; 82: 779-87.
7. Schiller LR. Diarrhea and malabsorption in the elderly. Gastroenterol Clin
Management North Am 2009; 38: 481-502.
Nutrient deficiencies that need to be urgently corrected include 8. Thomas PD, Forbes A, Green J, Howdle P, Long R, Playford R, et al.
deficiencies of potassium and divalent cations (Ca, Mg) in Guidelines for the investigation of chronic diarrhoea, 2nd edition. Gut
2003; 52 (Suppl 5): v1-15.
patients with significant chronic diarrhoea. Megaloblastic
9. World Health Organization. The treatment of diarrhoea: A manual for
anaemia due to vitamin B12 or folate deficiency also needs
physicians and other senior health workers. World Health Organization.
to be urgently treated with the appropriate vitamin given Geneva. 2005. WHO reference number WHO/FCH/CAH/05.1. http://
orally or parenterally. Adequate calorie and protein intake, www.who.int/child_adolescent_health/documents/9241593180/en.

786
 13.5 Constipation—Diagnosis and Management

Uday Chand Ghoshal

DEFINITION AND EPIDEMIOLOGY

The daily stool frequency in healthy population differs from
thrice a week to twice a day in different geographical and ethnic
groups. The Rome II consensus criteria based on western stool
frequency, defines constipation as less than three stools per
week with straining, excessively hard stool, unproductive urges
and feeling of incomplete evacuation. However, many
individuals would report themselves as constipated with stool
frequency of three or more per week. Therefore, in Rome III
criteria, stool frequency has not been given much importance
while defining constipation. The stool frequency in India is
different from that of the West. Therefore, the definition based
on the frequency proposed for Western population does not
hold true for Indian population. Hence, Asian consensus on
irritable bowel syndrome proposed a definition based on the
Bristol stool pattern (Figure 1). Passage of type 1 or 2 stool
should be considered as constipation.
A second point to consider is difficulty in evacuating the bowel.
Patients with this symptom often complain of stool that is hard
to pass or pebble-like. This may suggest an outlet obstruction
such as an intra-rectal intussusception or anismus. A third pattern
is a combination of infrequency and dyschezia. Constipation-
predominant irritable bowel syndrome may not fulfil the
definition of constipation and has other gastrointestinal and
extra-gastrointestinal symptoms in addition.
Constipation is a common symptom at all ages. In a study on
4500 adults from Indian community, 43 (1%) reported passing
less than three stools per week. Although the exact frequency
of constipation using various definitions in the Indian
population is not known, it is likely to be common, but many
individuals manage it on their own and do not consult doctors
for the same. The perceptions of individuals and doctors about
constipation differ, making an exact definition difficult.

AETIOPATHOGENESIS
Of the causes (Table 1) and types of constipation, many occur
in the elderly. The important practical point is to identify the
potentially serious causes. Pathophysiologically, constipation Figure 1: Bristol stool chart.
may result from slow colonic transit, faecal evacuation disorders
(e.g. anismus or puborectal dyssynergia, rectocoele and perineal
descent syndrome) and various combinations of these causes. loss of body weight, rectal bleeding and constipation with
spurious diarrhoea, may point to neoplastic disorder. History
CLINICAL FEATURES also helps in classifying the mechanism of constipation, like
A careful history and physical examination usually give colonic inertia and functional outlet obstruction. Symptoms
adequate pointers to the likely mechanism and type of predict well colonic transit disturbances, but are relatively
constipation. Many patients, due to the chronic nature of the insensitive to suspect pelvic floor problems. Digital evacuation,
disease, tend to take a number of home remedies and seek a passage of ribbon-like stool, feeling of rectal prolapse, and
medical consultation only when a fresh set of symptoms ability to pass stool in postures different from the usual posture,
supervene or the old symptoms get aggravated often due to while pressing in and around the anus and supporting
refractoriness to laxative self-medication. This history is, rectovaginal wall with fingers in the vagina may suggest
therefore, important. Some of these fresh symptoms, particularly functional disorder of faecal evacuation. A feeling that the 787
 rectum is loaded with stool with urge to pass and repeated Table 2: Criteria for Diagnosis of Functional Anorectal Disorders
attempt for evacuation and straining at stool may also suggest Causing Constipation
functional disorder of faecal evacuation. Associated psychosocial
Disorders Diagnostic criteria
disorders are common in these patients.
Anismus Resting anal sphincter pressure >100 mmHg
Table 1: Classification and Mechanisms of Constipation Abnormal balloon expulsion test
Classification Causes Puborectal Failure of anorectal angle to open by >15°
dyssynergia during defaecography between resting and
Primary (idiopathic) defaecatory position
Colonic inertia Limited to colon or part of a No relaxation or increase in pressure on
global disorder attempted defaecation
Functional outlet obstruction Anismus Abnormal balloon expulsion test
Hypertonic internal anal Perineal descent Failure of anorectal angle to open by >15°
sphincter syndrome during defaecography between resting and
Solitary rectal ulcer defaecatory position
Mucosal intussusception Descent of perineum >4 cm during
Rectal prolapse defaecation
Secondary Rectocoele Herniation of rectal wall with either pre-
Endocrine/metabolic diseases Diabetes mellitus ferential filling during defaecography or
Hypothyroidism failure to empty during defaecation
Hypercalcaemia Non-specific Symptoms, abnormal balloon expulsion test,
Porphyria syndrome but other criteria not fulfilled
Neurogenic disorders Spinal lesions: cauda equina
syndrome and tumour
Multiple sclerosis
Autonomic neuropathy
Parkinson’s disease
Hirschsprung’s disease
Rectoanal disease Anal fissure, haemorrhoids,
strictures
Iatrogenic disease Drugs, surgery
Dietary factors Low-residue diet

Physical examination: A good physical examination should

enable the physician to detect primary diseases like
endocrinopathies and neurological disorders leading to
constipation. Anorectal examination helps in diagnosing pelvic
floor muscle weakness, sphincter disturbances, rectal sensitivity,
stool consistency and faecal impaction. Per rectal examination
may reveal low resting sphincter pressure due to weakness of
the external anal sphincter; this may be related to pudendal
neuropathy secondary to stretching of pudendal nerve from
long-standing and prolonged straining during defaecation.
Unusually high squeeze pressure during per rectal examination
and anorectal manometry may suggest anismus, which is best
diagnosed by defaecography.

MODALITIES OF DIAGNOSIS
In most patients with mild constipation, not many investigations
are required. However, in patients with severe and refractory
constipation several tests may be necessary to know the cause.
Table 2 shows the diagnostic tests useful in various forms of
constipation and Figure 2 shows a flow chart to diagnose
various causes of constipation. Since a neoplastic disease always
looms in the diagnosis of constipation in the elderly, the first
investigations should always be proctosigmoidoscopy or if
necessary colonoscopy and barium enema. Assessment of
Figure 2: Flow chart showing a protocol for work-up for patients with refractory
colonic transit by radio-opaque markers (Figures 3A to E) not constipation.
only helps in diagnosis of slow-transit constipation but also gives IBS = Irritable bowel syndrome; PFD = Pelvic floor disorder; STC = Slow-transit
suggestion about faecal evacuation disorder. Balloon expulsion constipation; CTT = Colonic transit time; ARM = Anorectal manometry; BET =
test (Figure 4), in which the patient is asked to expel a latex Balloon expulsion test; BD = Barium defaecography; RAIR = Rectoanal inhibitory
788 balloon tied on a thin catheter that is placed inside rectum and reflex; RP = Resting pressure of anal sphincter; SP = Squeeze pressure.
 Constipation—Diagnosis and Management
Figures 3A to E: (A) Protocol for evaluation of colonic transit using radio-opaque markers (SG-mark), in Indian context. (B) sixty hours abdominal radiograph of a
patient with constipation studied using such protocol, which shows that most of the markers are retained in the recto-sigmoid segment (RS) suggesting faecal
evacuation disorder. Also note that there is retained barium inside rectum from the study done previously, which also suggest evacuation disorder. (C) Anorectal
manometry of the same patient showed very high resting and squeeze sphincter pressure and hence, anismus was diagnosed. The patient improved with repeated
sessions of biofeedback and osmotic laxative. (D) sixty hours abdominal radiograph of another patient with constipation studied using SG-mark, which shows that
most of the markers are retained diffusely suggesting slow transit constipation. (E) Defaecography of a patient with constipation, showing a large rectocoele (marked
with an arrow). (Reproduced from reference 7).

then filled with 60 mL of water while the patient is lying in the TREATMENT
left lateral position, is a good screening test for faecal evacuation Treatment of primary constipation basically aims at symptom
disorders. Faecal evacuation disorders are best diagnosed by relief and improving quality of life. Figure 5 outlines treatment
barium (Figures 3A to E) or magnetic resonance defaecography, protocol for patients with constipation.
which helps in picking up intrarectal intussusception, pelvic floor
descent, puborectal dyssynergia and rectal prolapse. The other Non-Pharmacological Treatment
techniques include anorectal ultrasonography for sphincter Adequate diet replete with nutrition, liquids and fibre and
anatomy, and anorectal manometry. One should also look for physical activity are essential to ensure proper bowel function.
systemic disorders causing constipation, such as hypothyroidism, Fibre intake must be at least 20 gm/day. It may be necessary to
diabetes mellitus, systemic amyloidosis and hypercalcaemia,
when indicated.

Figure 5: Outline of treatment protocol for faecal evacuation disorders.

(Reproduced from reference 7).
Figure 4: Balloon expulsion test. BF = Biofeedback.
789
 supplement with fibre-rich food or fibre medication. Physical particular problem of depleting fat-soluble vitamins, which
activity is important to ensure general interest and zest for life, should then be supplemented.
but attention to abdominal wall and pelvic floor muscles may
Biofeedback Programmes
actively help in initiating defaecation. Existing therapy may
need to be modified; for instance, if the patient is on opioids for Biofeedback has been proved to be useful in faecal evacuation
pain, the drug may have to be discontinued. disorders in about half to two-thirds of patients. Its role in the
treatment of constipation due to other causes remains to be
Pharmacological Treatment (Table 3) proved.
Laxatives are needed in almost all patients with significant
Surgery
constipation. They help in improving the frequency and bulk
of stools and thus ease bowel movements. Patients with colonic Surgical treatment may be rarely necessary to correct
inertia are best treated with bulking agents like isphagula (15 anatomical problems like stenotic diverticulitis or outlet
to 20 gm daily) and methylcellulose (10 gm/day). Bulk laxatives problems. Patients with colonic inertia due to visceral myopathy
may lead to bloating and excessive gas formation and may also require surgical treatment such as colectomy in the
precipitate intestinal obstruction in those with incipient gut long run. Surgical treatment, however, is best avoided as long
obstruction. Patients with outlet obstruction are best treated as possible. Injection of botulinum toxin into the puborectal
with osmotic agents such as magnesium sulphate (15 to 45 mL/ sling has been found to be useful in the treatment of puborectal
day), lactulose (15 to 45 mL/day) or polyethylene glycol (17 to dyssynergia.
34 gm/day) (Table 3). These are poorly absorbed osmotically COMPLICATIONS
active substances that draw water into the lumen. They modify
stool consistency effectively and ease bowel movements. Milk Most causes of constipation usually do not produce major
of magnesia is a cheap and safe medication. Other agents are complications though these impair the quality of life. However,
equally effective and safer but more expensive. Stool softeners prolonged constipation and straining at stool can be complicated
and stimulants are best avoided because of the danger of with haemorrhoids, anal fissure and faecal incontinence due to
cathartic colon or melanosis coli, as with senna. Mineral oil and development of pudendal neuropathy. Also, sometimes patients
enemas should be avoided as regular therapy, but may be may experience symptoms of large bowel obstruction.
necessary in some patients infrequently. Mineral oils have a Megarectum can also develop due to prolonged constipation.
Faecal evacuation disorders may be complicated with solitary
Table 3: Commonly Available Agents for the Management of rectal ulcer syndrome.
Constipation
RECOMMENDED READINGS
Agents Usual adult oral dose
1. Andromanakos N, Skandalakis P, Troupis T, Filippou D. Constipation of
Ispaghula husk 15 to 20 gm/day anorectal outlet obstruction: pathophysiology, evaluation and
Natural (e.g. psyllium husk) 7 gm/day management. J Gastroenterol Hepatol 2006; 21: 638-46.
Synthetic (e.g. methylcellulose, 2. Arce DA, Ermocilla CA, Costa H. Evaluation of constipation. Am Fam Physician
polycarbophil) 4 to 6 gm/day 2002; 65: 2283-90.
Osmotic laxatives 3. Bharucha AE. Update of tests of colon and rectal structure and function. J
Clin Gastroenterol 2006; 40: 96-103.
Polyethylene glycol 8 to 25 gm/day
4. Ghoshal UC, Abraham P, Bhatt C, et al. Epidemiological and clinical
Lactulose 15 to 30 mL/day
profile of irritable bowel syndrome in India: report of the Indian
Lactitol 10 to 20 gm/day Society of Gastroenterology Task Force. Indian J Gastroenterol 2008;
Sorbitol (70%) 15 to 30 mL/day 27: 22-8.
Magnesium hydroxide 2.4 gm (30 mL) 5. Ghoshal UC. Review of pathogenesis and management of constipation.
Magnesium citrate 200 mL/day Trop Gastroenterol 2007; 28: 91-5.
Stimulant laxatives 6. Locke GR, Pemberton JH, Phillips SF. American Gastroenterological
Association Medical Position Statement: Guidelines on Constipation.
Anthraquinones: Senna 8.5 to 17 mg/day
Gastroenterology 2000; 119: 1761-76.
Diphenylmethanes: Bisacodyl 10 to 15 mg or 10 mg
suppository/day 7. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller
RC. Functional bowel disorders. Gastroenterology 2006; 130: 1480-91.

790
 13.6 Gastrointestinal Bleeding

Rakesh Kochhar, Mohd. Talha Noor

Gastrointestinal (GI) bleeding is a common and potentially time, the severity of bleeding must not be underestimated.
life-threatening problem. Mortality rate of upper GI bleeding With administration of intravenous fluids as well as entry of
(6% to 10%) has remained unchanged over the years. Lower extravascular fluid into the vascular space to restore volume,
gastrointestinal bleeding requiring hospitalisation is only one- the haematocrit falls. Serial haematocrit measurements are
fifth as common as upper GI bleeding. helpful in following a patient’s course.

GENERAL FEATURES Table 1: Patient’s Haemodynamic Status with Degree of Blood

Loss
GI bleeding may manifest in several ways. Haematemesis is
defined as vomiting of blood. Gastric acid may alter the colour Patient’s haemodynamic status Blood loss %
of the vomited blood. If vomiting occurs shortly after the onset Resting hypotension >26
of bleeding, the vomitus appears red. Precipitated blood clots Postural hypotension 10-20
and acid-degraded blood produce a characteristic ‘coffee- Normal <10
ground’ appearance of the vomitus. Haematemesis usually
indicates a source of bleed proximal to the ligament of Trietz. Resuscitation
Melaena is black, tarry, foul-smelling stool that results from
Insertion of two large-bore intravenous cannulae is
formation of acid haematin and bacterial degradation of
recommended. Saline or lactated Ringer’s solution should be
haemoglobin in the gastrointestinal tract. Melaena usually
infused to stabilise vital signs. Administration of supplemental
occurs due to bleed proximal to the ligament of Trietz
oxygen may be of benefit in patients with inadequate
but may at times be due to bleed from the small bowel or
oxygenation. Airway protection with endotracheal intubation
ascending colon if gastrointestinal transit time is prolonged.
to prevent aspiration should be strongly considered in patients
Approximately 60 mL of blood is required to produce a single
with ongoing haematemesis if mental or respiratory status
melaenic stool. Melaena can persist for up to one week after an
is altered. Those patients who are in shock have very low
episode of massive upper GI bleed.
haematocrit (less than 20% to 25%), have symptoms related to
Haematochezia, the passage of bright red or maroon blood poor tissue oxygenation (e.g. angina) or those who continue to
per rectum, generally signifies a bleeding source distal to the bleed despite therapy are candidates for transfusion. The target
ligament of Trietz. However, brisk bleeding from a proximal to which the haematocrit value should be raised varies; in elderly
source can also cause haematochezia due to rapid transit. it should be 30%; in younger and otherwise healthy patients it
Occult GI blood loss is evidence of blood as identified should be 20% to 30% and in patients with portal hypertension,
by laboratory testing of stool. Finally, patients with gastro- it should not exceed 27% to 28%, so as not to raise portal
intestinal blood loss may present with symptoms of blood loss, pressure. Transfusion of packed red blood cells is preferred.
such as light-headedness, syncope, dyspnoea, angina, or even Warmed blood should be administered to patients who require
shock. massive transfusion (i.e. >3,000 mL). Fresh frozen plasma (FFP)
or platelets may be required in patients with coagulopathy or
Initial Assessment
severe thrombocytopaenia, and in patients who require ten or
It is necessary to determine whether bleeding is acute or more units of blood.
chronic and whether the patient is haemodynamically stable
or not. The presence of GI bleeding should be confirmed Differentiating Upper from Lower GI Bleeding
by inspection of the stool or nasogastric aspirate. Careful After resuscitation, the source of bleeding must be localised
assessment of the vital signs is the best way to judge a patient’s to direct further management. A nasogastric lavage must be
stability. Blood loss of less than 500 mL is rarely associated performed irrespective of the probable site of the bleed. A
with systemic signs. A postural fall in systolic blood pressure bloody or a coffee ground aspirate confirms an upper GI source
of >10 mmHg usually indicates a 20% or greater reduction in but their absence does not rule it out. A clear aspirate may
blood volume (Table 1). Concomitantly, the patient may have be seen in up to 10% to 20% of patients with bleeding from a
symptoms like light-headedness, syncope, nausea, diaphoresis duodenal source. However, the presence of bile in the clear
and thirst. Shock frequently results when the blood loss is aspirate rules out a duodenal source. Other clues to upper GI
more than 25% of the blood volume. Patients may occasionally bleeding include hyperactive bowel sounds and an elevation
experience a vasovagal reaction with bradycardia during in blood urea nitrogen (BUN); the latter results from volume
bleeding episodes. Haematocrit is used to assess the degree depletion and breakdown of blood proteins in the gut. Patients
of blood loss. However, it does not fall immediately with with lower GI bleed are less likely to present with shock or
haemorrhage because of proportionate reduction of plasma orthostatic symptoms as compared to patients with upper GI
and red cell volumes and it reflects the true magnitude of bleed. They have higher haemoglobin levels at presentation
bleed only after a period of 24 to 48 hours. Hence, during this and also lower transfusion requirements. 791
 DIAGNOSTIC EVALUATION OF PATIENTS WITH GI BLEEDING Other Diagnostic Tests
Acute Upper Gastrointestinal Bleeding Ultrasound of the abdomen can provide evidence of portal
History and physical examination hypertension in the form of coarsened liver echotexture, dilated
splenoportal axis, presence of collaterals and splenomegaly, it
A history of prior episodes of bleeding, illnesses such as ulcers,
should be carried out in all patients.
cirrhosis, cancer or bleeding disorders, prior surgery (such as
for peptic ulcer), consumption of excess of alcohol, and Computed tomography (CT) of the abdomen is useful to look
medications like nonsteroidal anti-inflammatory drugs (NSAIDs) for any evidence of pancreatitis, tumour or haemosuccus
and anti-coagulants should be elicited. Oesophago-gastric pancreaticus, CT angiography is useful in the diagnosis of
variceal bleed is painless and massive. A bleeding episode visceral aneurysms.
preceded by abdominal pain usually indicates underlying
peptic ulcer disease. A history of retching and vomiting prior AETIOLOGY AND MANAGEMENT OF UPPER GI BLEED
to haematemesis may indicate Mallory-Weiss syndrome. The various causes of upper GI bleed and management are
Examination of the skin may reveal cutaneous stigmata of given in Table 2 and Figure 1. In India, most common aetiology
cirrhosis. Rarely, evidence of underlying cancer (e.g. acanthosis is oesophageal variceal bleeding, other common causes are
nigricans), tumours (e.g. neurofibromatosis, blue rubber duodenal ulcer, gastric ulcer and gastritis.
bleb nevus). Henoch-Schönlein purpura or vascular anomalies
Table 2: Causes of Upper Gastrointestinal Bleeding
may be found. Skin and musculoskeletal abnormalities of
pseudoxanthoma elasticum or Ehlers-Danlos syndrome may Common causes
be diagnostic. Further clues on systemic examination include Peptic ulcer disease
lymphadenopathy or abdominal masses, malignancy, Oesophageal and gastric varices
abdominal tenderness (peptic ulcers, pancreatitis) and Oesophagitis
Gastric erosions
splenomegaly with or without prominent abdominal wall veins
Duodenitis
(cirrhosis, portal/splenic vein thrombosis). Mallory-Weiss tear
Gastrointestinal malignancies
INVESTIGATIONS
Uncommon causes
Endoscopy plays a major role in diagnosing the cause of GI Angiodysplasia
blood loss. Other tests that may help include USG abdomen, CT Dieulafoy lesion
scan of the abdomen and angiography. Cameron ulcers
Gastric antral vascular ectasia
Endoscopy Portal hypertensive gastropathy
Endoscopy should be performed only after the patient has been Gastric polyps
haemodynamically stabilised. However, if the patient is bleeding Aortoenteric fistula
massively and responding to resuscitative measures, endoscopy Haemobilia
can be performed at the bedside provided adequate support Haemosuccus pancreaticus
Foreign bodies
personnel and with resuscitative facilities. Repeated gastric
Iatrogenic-nasogastric tube erosions, endoscopic polypectomy,
lavage prior to urgent endoscopy helps in clearing the stomach sphincterotomy
of blood clots, thereby providing a better field of view.
Intravenous erythromycin can help clear the stomach if given Acute Variceal Haemorrhage
half an hour before endoscopy. There is no role of cold saline
In India, non-cirrhotic portal hypertension (NCPF) account for up
lavage in controlling gastrointestinal bleeding. At endoscopy,
to 25% of portal hypertension, and they have a better prognosis
detailed evaluation of the oesophagus, stomach and duodenum
than cirrhosis. Oesophageal varices are the site of bleeding in
is carried out.
most patients. Bleeding from gastric varices can occur in patients
A majority of the bleeds occur from peptic ulcers, varices with active as well as thrombosed oesophageal varices. Some
and erosions (Table 2). If there is no evidence of any of these, patients may bleed from portal hypertensive gastropathy and
other uncommon lesions, especially vascular malformations gastric antral vascular ectasia. Treatment options for bleeding
should be carefully looked for. Endoscopy is superior to barium oesophageal varices include pharmacotherapy, balloon
studies as it detects more lesions, it permits mucosal biopsy of tamponade, endoscopic, transjugular intrahepatic portosystemic
suspicious lesions; it may act as a therapeutic modality; shunt and surgery. In the emergency room, if clinical suspicion
presence of active bleeding or stigmata or recent haemorrhage of bleed being variceal is high, patients can be started on
can provide prognostic information; and results of endoscopy intravenous terlipressin 1 mg every 4 to 6 hourly or octreotide
guides the decision on the level of hospital care, on when to 50 to 100 µg bolus, followed by infusion at 50 µg/hour.
resume feeding and on length of hospitalisation. Endoscopic Continuation of these drugs for 3 to 5 days after endoscopic
Forrest classification of peptic ulcer is useful for stratifying treatment reduces chances of rebleeding. If the patient is
patients into high and low risk of rebleeding. Patient with Forrest bleeding actively and immediate endotherapy is not possible,
1a (active bleeding) and Forrest 1b (oozing vessel) at the time an alternative of endoscopic therapy is balloon tamponade with
of endoscopy have high risk of rebleeding. Patients with Forrest Sengstaken Blakemore tube. It has two balloons, oesophageal
2a (visible vessel), Forrest 2b (adherent clot) and Forrest 2c and gastric, control of haemorrhage requires inflation of gastric
(pigmented base) have moderate risk of rebleeding. Patients balloon with 250 mL of air, oesophageal balloon is usually not
with Forrest 3 (clean base) have low risk of rebleeding. Patients inflated as it is associated with risk of oesophageal rupture. It is
792 in Forrest class 1, 2a and 2b benefit from endotherapy. very effective in immediate controlling of bleeding in over 80%
 Gastrointestinal Bleeding
Figure 1: Algorithm for managing acute upper GI bleeding.
TIPSS = Transjugular intrahepatic porto-systemic shunt; APC = Argon plasma coagulation.

of patients. It is associated with 50% rebleeding after deflation rubber rings and necrotic tissue, leaving shallow mucosal
of balloon. It is also associated with risk of oesophageal rupture, ulcerations that heal in 14 to 21 days. Application of the bands
ulceration and aspiration pneumonia. Though associated with is started at the gastroesophageal junction and progresses
significant complications, balloon tamponade can be instituted cephalad in a helical fashion. EVL sessions are repeated at
even by primary physicians. approximately 2-week intervals until varices are obliterated,
usually requiring 2 to 4 ligation sessions. Complications are less
Endoscopic treatment options for bleeding oesophageal varices
frequent than with endoscopic sclerotherapy.
are endoscopic variceal ligation (EVL) and endoscopic
sclerotherapy (ES). Both have an efficacy of about 90%. Transjugular intrahepatic porto-systemic shunt (TIPSS) is a
Endoscopic sclerotherapy involves visualisation of the varix procedure in which a self-expanding metal stent is placed
during endoscopy, followed by injection of a sclerosing agent radiologically between the portal and hepatic veins. It is highly
into the varix or into the adjacent tissue. Various sclerosing effective in reducing portal pressures and rebleeding and in
agents include sodium tetradecyl sulphate, polidocanol, controlling acute variceal haemorrhage. TIPSS is, however,
sodium morrhuate and ethanol. Variceal obliteration is usually associated with a risk of encephalopathy and shunt stenosis,
achieved after 3 to 6 sclerotherapy sessions at periodic intervals. although the latter risk is reduced with the use of the newer
Complications associated with ES include retrosternal pain, polytetrafluoroethylene covered stents. Recently a removable
oesophageal ulcers and oesophageal stricture. EVL was first self-expanding oesophageal metal stent has also been used
reported in 1989. The technique involves the placement of effectively in patients with variceal bleeding refractory to other
rubber bands around a portion of the varix containing treatment modalities.
oesophageal mucosa. The varix is sucked into a hollow, clear Nowadays surgery is rarely needed for variceal bleeding.
plastic cylinder attached to the tip of the endoscope. Once Surgical options include shunt and non-shunt procedures. The
suctioned into the sheath, a trigger device allows deployment shunts are either total or selective. Total shunts include porta-
of the band around the varix. The blood flow is completely caval, mesocaval and central splenorenal, selective shunt in-
interrupted, producing ischaemic necrosis of the mucosa and clude distal splenorenal shunt. Non-shunt operations are gas-
submucosa. Later granulation takes place with sloughing of the troesophageal devascularisation or disconnection procedures. 793
 For bleeding gastric varices, injection of N-butyl-cyanoacrylate reduce rebleeding rate and the need for surgery. Lansoprazole
can be made into the varices with good results. This modality and esomeprazole are the other PPIs available for intravenous
can be used in actively bleeding gastric varices as well as to use. After the patient’s condition stabilises, intravenous PPI
prevent rebleeding; 1 to 2 mL of cyanoacrylate is injected into therapy may be switched to oral PPI therapy.
the varix using a 21 gauge sclerotherapy needle. In refractory
Endoscopic therapy is accepted as the most effective method
cases TIPSS is an effective treatment modality; it controls acute
for controlling acute ulcer bleeding and for preventing
gastric variceal bleeding in over 90% patients. Balloon-occluded
rebleeding. Depending on the endoscopic appearance of the
retrograde transvenous obliteration (B-RTO) is a new technique;
ulcer, different endoscopic modalities are applied. High risk
it is highly effective in controlling acute gastric variceal bleeding.
ulcers are those that are bleeding actively and those with a
Bleeding from portal hypertensive gastropathy and gastric
non-bleeding visible vessel. These patients are shown to
antral vascular ectasia is not massive but difficult to treat.
benefit the most from endoscopic therapy. Management of
Treatment of portal hypertensive gastropathy is directed
ulcers with adherent clots was controversial earlier, but now
towards underlying portal hypertension. First line therapy
it has been shown that endoscopic therapy is superior to
for gastric antral vascular ectasia (GAVE) is argon plasma
medical therapy for preventing recurrent haemorrhage in
coagulation. Recently, endoscopic variceal ligation has also
patients with bleeding peptic ulcers with adherent clots. Ulcers
been used for its treatment successfully. Apart from the
with flat pigmented spots or those with clean base have no
treatment mentioned above, broad spectrum of antibiotics for
additional benefit from endotherapy. The most popular
a week have been shown to improve survival of these patients.
endoscopic therapy is injection therapy using epinephrine
After control of initial haemorrhage, prevention of variceal (1:10,000). Other injection therapies include use of sclerosants,
rebleeding is an important aspect of the management of portal including sodium tetradecyl sulphate, polidocanol or ethanol.
hypertension. Non-selective beta-blockers reduce cardiac Biologic agents like thrombin, fibrin sealant and cynoacrylate
output and cause splanchnic vasoconstriction, reducing glue can also be utilised. The assistant projects the needle,
portal venous pressure. Several randomised controlled trials originally designed for injection sclerotherapy, about 5 mm
comparing propranolol or nadolol with placebo have shown a beyond the plastic sheath, injects the solution, multiple
reduction in rebleeding and mortality with beta blockers. injections are given around the ulcer to provide tamponade
Addition of isosorbide mono nitrate to beta-blockers enhances effect. Thermal methods for controlling bleeding include laser,
the efficacy of therapy but offers no survival advantage and electrocoagulation and heater probe. These can be combined
reduces tolerance to therapy. with injection therapy. Newer techniques include application
Peptic Ulcer Disease (PUD) of metal clips, band ligation, argon plasma coagulation and
endoloops. In patients with rebleeding, repeat endoscopy
Most ulcer bleeds are from duodenal ulcers, though in patients appears to be useful. Presence of hypotension at admission
on NSAIDs, bleeding from gastric ulcers is more common. An and an ulcer size larger than 2 cm are independent predictors
ulcer bleeds when it erodes into the lateral wall of a blood vessel. of failure of endoscopic therapy.
Ulcers located high on the lesser curve of stomach or on the
posteroinferior wall of the duodenal bulb are most likely to Eradication of H. pylori and stopping NSAIDS are two factors
bleed. Helicobacter pylori infection, NSAID use, and stress due shown to prevent recurrent bleeding. Relook endoscopy with
to critical illness contribute to the development of ulcers. retreatment in peptic ulcer bleeding significantly reduces the
risk of recurrent bleeding, although it does not substantially
Up to 80% of duodenal ulcers are caused by Helicobacter pylori, reduce the need for subsequent surgery or mortality. In
whereas about 50% of gastric ulcers are associated with this summary management of bleeding peptic ulcer include initial
infection. NSAIDs constitute the most important cause of PUD resuscitation, pharmacotherapy with proton pump inhibitors,
after H. pylori infection, all patients who have PUD should be endoscopic therapy and in refractory cases, surgery should
carefully questioned about NSAIDs use. NSAIDs induced ulcers be considered. Indications for surgery include failure of
may be painless because analgesic properties of NSAIDs can mask endoscopic therapy, large ulcer (>2 cm), massive bleeding and
the pain of ulcers. Concurrent aspirin and oral anti-coagulant use development of complications like perforation. Transcatheter
increase the risk of bleeding. Other risk factors are cardiovascular arterial embolisation is reserved for patients who have
or cerebrovascular disease and hospitalisation. exceptionally high risks for surgery (e.g. acute myocardial
Bleeding stops spontaneously in 80% of instances. Patients infarction).
with ongoing bleed, haemodynamic compromise, and high Erosive Gastropathy
transfusion requirements mandate urgent endoscopic therapy,
Erosive gastropathy refers to endoscopically visualised
which can achieve haemostasis in more than 90% of cases.
subepithelial haemorrhages and erosions that may account for
Surgical intervention is indicated in patients whose bleeding is
upper GI bleeding in 15% to 25% of cases. Antacids, H2 receptor
refractory to endoscopic therapy.
blockers, proton pump inhibitors and sucralfate decrease
Proton pump inhibitors (PPI) are the mainstay of pharma- bleeding from gastric erosions. Endoscopic, argon plasma
cological treatment. Proton pump inhibitors elevate the pH, coagulation has been found to be useful in the treatment of
thus, enhancing clot formation and platelet aggregation. PPI severe bleeding.
should preferably be given intravenously, though oral
administration is also shown to be effective. High dose Mallory-Weiss Syndrome
intravenous (IV) omeprazole or pantoprazole (80 mg IV bolus Recurrent vomiting or retching can lead to mucosal tears at the
794 followed by 8 mg per hour for 72 hours) has been shown to gastro-oesophageal junction causing haematemesis. Bleeding
 Gastrointestinal Bleeding
is usually not massive and stops spontaneously. Occasionally AETIOLOGY AND MANAGEMENT OF SPECIFIC CAUSES OF
injection therapy or haemoclips may be required to control the LOWER GI BLEED
bleeding. The various causes and management of lower GI bleed are given
Dieulafoy’s Lesion in Table 3 and Figure 2.
Dieulafoy’s lesions are prominent submucosal vessels, usually Table 3: Causes of Lower Gastrointestinal Bleeding
found in the proximal stomach with no surrounding
ulceration. These lesions are difficult to identify if they are not Common causes Relative frequency
in India
bleeding actively during endoscopy. Standard endoscopic
injection, thermocoagulation, haemoclip, argon plasma Colonic sources 70% to 90%
Haemorrhoids 30% to 40%
coagulation or band ligation can successfully achieve
Inflammatory bowel disease 30% to 40%
haemostasis. Neoplasms 15% to 20%
Gastrointestinal Malignancies Arteriovenous malformation, 2% to 5%
angiodysplasia
Endoscopy is used for diagnosis and for taking biopsies but it is Diverticula 2% to 5%
usually ineffective in controlling the bleed. Small bowel source 10% to 20%
Meckel’s diverticulum or other diverticula
ACUTE LOWER GASTROINTESTINAL BLEEDING
Vasculitis
History and Physical Examination Ulcers, e.g. typhoid
Passage of drops of blood either separately or coating the stool Less common causes 2% to 5%
may indicate bleeding from an anorectal source, especially Solitary rectal ulcer syndrome (SRUS)
Infectious enterocolitis
haemorrhoids. Bloody diarrhoea with or without pain occurs
Ischaemic colitis
in infective colitis or inflammatory bowel disease. Associated
Aortoenteric fistula
weight loss or recent change in bowel habits suggests colorectal Colonic varices in portal hypertension
cancer. A history of radiation therapy suggests radiation Radiation proctitis
proctitis. The abdomen should be carefully examined to detect Lesions associated with use of NSAIDs
tenderness, organomegaly or a mass. A per rectal examination
should always be performed to look for prolapsed haemorrhoids,
mass polyp or ulcer.
Proctoscopy and Sigmoidoscopy
Patients with presumed lower GI bleeding must undergo early
proctoscopy and sigmoidoscopy for the detection of obvious,
low-lying lesions such as bleeding haemorrhoids, anal fissure,
rectal ulcer, proctitis or rectal cancer.
Colonoscopy
If procto-sigmoidoscopy is not informative, colonoscopy is
the next logical investigation. It is superior to barium enema
since it can detect vascular lesions and allows biopsies to be
taken. As 5% to 10% patients with upper GI lesions present with
haematochezia, it is prudent to perform upper GI endo-
scopy before undertaking extensive investigations. Urgent
colonoscopy in lower GI bleeding is safe with high likelihood
of making a specific diagnosis (75% to 100%). Performance of
colonoscopy requires preparation of the patient with
purgatives, polyethylene glycol and sodium phosphate are the
commonly used purgatives.
Angiography
Angiography is helpful in detecting the site of bleed in actively
bleeding patients. Angiodysplasias are the commonest lesions
detected by angiography. It may also show vascular mal-
formations or tumours, even if extravasation of contrast material Figure 2: Algorithm for managing acute lower GI bleeding.
is not noted.
Radionuclide Scanning Anorectal Lesions
It involves intravenous administration of 99mTechnetium tagged Haemorrhoids are the most common cause of lower GI bleed.
sulphur colloid or RBCs followed by imaging with an external Treatment may be in the form of sclerotherapy, banding, and
gamma camera to detect intestinal extravasation of the cryotherapy. Surgery is required for large and prolapsed
substrate. It can detect bleeding even at a slower rate than that haemorrhoids. Solitary rectal ulcer syndrome (SRUS) is a benign
detected by angiography. condition in young individuals, which presents as rectal 795
 bleeding, tenesmus and mucous discharge. Sigmoidoscopy with extrahepatic portal venous obstruction. They can be
biopsy is essential for diagnosis. Treatment consists of avoiding successfully treated by endoscopic variceal ligation.
digital rectal manipulation, laxatives and sucralfate enemas.
Postpolypectomy Bleeding
Inflammatory Bowel Disease (IBD) Postpolypectomy bleeding is the most frequent complication
Patients with IBD have a history of recurrent episodes of bloody of colonoscopy and is seen in 0.2% to 1.8% cases of colonoscopic
diarrhoea. Colonoscopy with biopsy is required to differentiate polypectomy. Delayed bleeding may occur up to 14 days after
IBD from other forms of colitis. Steroids and 5-aminosalicylic polypectomy. Endoscopic clipping is an effective treatment
acid usually control the disease. Colectomy is required for massive modality.
bleeding not responding to medical management.
Polyps SMALL INTESTINAL BLEED
Adenomatous colonic polyps can present with occult or overt Only 3% to 5% of all GI bleeding arises between the second
rectal bleeding (if they are larger than 1 cm). Juvenile polyps portion of the duodenum and the ileocaecal valve. Bleeding
are hamartomas occurring in the first two decades of life. from this site is difficult to diagnose, since the small bowel is
Colonoscopic polypectomy is the treatment of choice. Bleeding relatively inaccessible. Patients present either with chronic
from malignant colonic polyps requires colectomy. occult blood loss or with recurrent episodes of melaena.
Repeated endoscopies and barium studies are often negative.
Infectious Enterocolitis Various causes of small intestinal bleed are given in Table 4.
Various invasive organisms viz. Shigella, Salmonella, Campylobacter, Vascular ectasias are the commonest cause of small intestinal
enteroinvasive E. Coli,Clostridium difficile and Entamoeba histolytica bleed. Benign small bowel tumours (usually leiomyomas) are
present with bloody diarrhoea.Diagnosis is usually made by routine the second most common cause. Meckel’s diverticulum is the
examinations and culture of the stool.Treatment is with antibiotics. cause of bleeding in two-third of males younger than 30 years
presenting with small bowel bleeding. Bleeding is almost always
Colonic Diverticula brisk, resulting from ulceration within the diverticulum or the
Colonic diverticula are less frequent in the Indian population adjoining ileal mucosa.
as compared to the West. However, in elderly patients especially
those with complications, diverticular disease should be Table 4: Differential Diagnosis of Occult-GI Bleeding
considered and looked for. Bleeding is abrupt in onset, usually
Mass lesions in colon or small intestine
painless and often massive, but ceases spontaneously in 80%
Carcinoma
of patients. Colonoscopy is required for diagnosis. Vasopressin
Adenoma
infusion controls bleed temporarily. Segmental surgical
resection is indicated for ongoing bleed. Inflammation
Erosive oesophagitis/gastritis
Angiodysplasia Ulcer (any site)
Angiodysplasia or arteriovenous malformations are also less Coeliac disease
frequent in Indians as compared to Western population. Inflammatory bowel disease
Bleeding from angiodysplasia is painless, trivial to massive Colitis (non-specific)
in amount, recurrent and usually resolves spontaneously. Worm infestation (hookworm, whipworm, strongyloidiasis,
Colonoscopic diagnosis and treatment by endoscopic ascariasis)
electrocoagulation are generally successful in identification and Tuberculous enterocolitis
definitive management of these lesions. Amoebiasis
Other causes
Ischaemic Colitis
Drug intake
Ischaemic colitis usually occurs in the elderly due to occlusion of Haemosuccus pancreatitis
a major vessel or low cardiac output. It usually presents with Haemobilia
sudden, crampy, left lower abdominal pain and passage of bright Vascular disorders (haemangioma, Dieulafoy’s lesion)
red or maroon blood mixed with the stool. Bleeding is usually
moderate. The splenic flexure, descending colon and sigmoid
colon are most commonly affected. Colonoscopy shows GASTROINTESTINAL BLEEDING OF OBSCURE ORIGIN
segmental haemorrhagic mucosa with or without ulcerations. CT
Obscure bleeding is defined as recurrent bouts of acute or
angiography is a non-invasive test which helps in diagnosis.
chronic GI bleeding for which no definite source has been
Colectomy is required only if there are signs of bowel infarction.
discovered by routine endoscopic and barium contrast
Radiation Colitis studies. Obscure gastrointestinal bleeding can be overt or
Symptoms of radiation colitis may occur few months to many occult, depending upon the presence or absence of clinically
years after abdominopelvic radiation usually for cancer of evident bleeding. Causes of gastrointestinal bleeding that
the cervix or prostate. Treatment using laser, argon plasma are commonly missed on upper gastrointestinal endo-
coagulation or sucralfate enema is effective. scopy are Cameron’s erosion, gastric varices, Dieulafoy’s
lesion, angiodysplasia, oesophagitis, portal hypertensive
Rectal Varices gastropathy and gastric antral vascular ectasia. Therefore,
Rectal varices are an uncommon cause of lower gastrointestinal upper gastrointestinal endoscopy should be repeated, if it is
796 bleeding, seen in patients with portal hypertension particularly negative then a cause in the small bowel should be looked
 Gastrointestinal Bleeding
for. The most common cause of obscure GI bleeding is on managing obscure gastrointestinal bleeding. Before the
vascular ectasia of the small bowel. Certain lesions are advent of CE, small bowel was an organ which was very difficult
difficult to diagnose because of their rarity or their subtle to explore with available endoscopic, radiological and nuclear
appearance; and some lesions are detectable only if active medicine techniques. Wireless CE is simple, safe, non-invasive,
bleeding is seen endoscopically (e.g. Dieulafoy’s lesion). reliable procedure, well accepted and tolerated by the patient.
Tubercular enteritis/colitis is another cause of obscure GI This technique evaluates with high resolution images, the whole
bleed in our country. Worm infestation, especially with small bowel, avoiding surgery or radiation exposure. In this
hookworms, is a common cause of anaemia in India. With a technique a small capsule camera is swallowed by the patient
heavy parasite load, some patients may have continuous (capsule enteroscopy). It takes up to 50,000 photographs of the
ooze from the small intestine and may have positive stool entire small intestine and transmits the images to a data recorder
occult blood. Stool examination is diagnostic. An approach externally, enabling visualisation of areas where the endoscope
to management of obscure gastrointestinal bleeding is given cannot reach.
in Figure 3.
Double-balloon enteroscopy is another new technique that
allows access to the whole of the small bowel with the added
advantage of therapeutic option, like haemoclip application
or polypectomy, etc. As inferred from its name, the two
inflatable balloons are the crux of the double balloon system.
An overtube is backloaded onto the endoscope before
intubation. The distal ends of the overtube and of the
endoscope are fitted with inflatable/deflatable air-filled latex
balloons. When inflated to 45 mmHg, the balloons grip the
intestinal lumen, providing traction against the wall without
undue pressure. Exploratory laparotomy with intra-operative
endoscopy is indicated in patients with severe recurrent or
persistent bleeding in whom all other investigative modalities
have proved unsuccessful. Scintigraphy and mesenteric
angiography can also be done to guide the surgeon in patients
prior to exploratory laparotomy.
Faecal Occult Blood
Various causes of occult gastrointestinal bleeding are given
in Table 4. An important cause of chronic occult bleeding is
NSAIDs intake. Other causes are polyps and carcinoma of the
colon. Faecal occult blood loss in normal individuals varies
from 0.5 to 1.5 mL per day. Faecal occult blood tests are to
detect blood not visible overtly. The classic faecal occult blood
tests are of guaiac based type. They are based on haemoglobin
Figure 3: Algorithm for managing obscure gastrointestinal bleeding. pseudoperoxidase activity, guaiac turns blue after oxidation
by oxidants or peroxidases in the presence of an oxygen donor
Angiography is performed only if bleeding is likely to be beyond such as hydrogen peroxide. Various factors influence the result
duodenum and is so massive that endoscopy cannot be safely of guaiac test, presence of animal haemoglobin and dietary
or satisfactorily performed and surgery is contraindicated. Blood peroxidases leads to false positivity while presence of vitamin C
loss must be greater than 0.5 mL/min for angiography to detect results in false negativity. Immunological faecal occult blood
the site of bleed. Selective mesenteric angiography usually tests detect human globin epitopes and are highly sensitive
localises the site of bleeding in about 75% of such patients. for detection of blood. They are more specific than guaiac
Radionuclide imaging studies are not useful in the evaluation based tests; their results are not affected by dietary factors.
of upper GI bleeding. Haem-porphyrin based test relies on spectrofluorometric
method to measure porphyrin derived from haem, they
Radionuclide scanning is a sensitive method for detecting
provide a highly accurate determination of total stool
gastrointestinal bleeding at a rate of 0.1 mL/min. This technique
haemoglobin. Intraluminal degradation of haemoglobin or
is more sensitive, but less specific than angiography. The major
interfering peroxidase producing substances do not effect
disadvantages are that nuclear imaging localises bleeding only
the haem-porphyrin assay, although myoglobin, a haem
to an area of the abdomen and the intraluminal blood is moved
containing protein found in red meats interferes with its
away by intestinal motility leading to false localisation. For
result. The initial investigation for evaluation of occult bleeding
proximal small bowel push enteroscopy permits inspection of
is colonoscopy which should be followed by an upper GI
the entire duodenum and part of the jejunum.
endoscopy to rule out gastroduodenal pathology. If these tests
Capsule endoscopy (CE) was launched at the beginning of this are unrevealing, small intestinal causes of bleed should be
millennium and since then it has had a very important impact considered.

797
 PROGNOSIS OF GASTROINTESTINAL BLEEDING stimulating advancement. Development of endoscopic
Mortality of each episode of variceal bleed in cirrhotics is 30% suturing devices to close gastrointestinal perforations is equally
to 50%. Variceal bleeding in non-cirrhotic causes of portal exciting. These techniques will be increasingly adapted to
hypertension, however, carries a good prognosis. Mortality control gastrointestinal bleeding in future.
for ulcer bleed is much lower (3% to 10%). Lower GI bleed is
RECOMMENDED READINGS
usually less life-threatening than upper GI bleed. Risk factors
1. Anand CS, Tandon BN, Nundy S. The causes, management and outcome of
for increased mortality are presentation with shock, active upper gastrointestinal haemorrhage in an Indian hospital. Br J Surg 1983;
bleeding at presentation, advanced cirrhosis, old age, co-morbid 70: 209-11.
medical illnesses, occurrence of rebleeding and failure of 2. Ferguson CB, Mitchell RM. Non-variceal upper gastrointestinal bleeding:
endoscopic methods to control bleed. standard and new treatment. Gastroenterol Clin N Am 2005; 34: 607-21.
3. Goenka MK, Kochhar R, Mehta SK. Spectrum of lower gastrointestinal
FUTURE PROSPECTS haemorrhage: an endoscopic study of 166 patients. Indian J Gastroenterol
1993;12: 129-31.
Steady progress in engineering including microelectrical
4. Gupta R, Reddy DN. Capsule endoscopy: current status in obscure
systems will affect the performance of capsule endoscopy. With gastrointestinal bleeding. World J Gastroenterol 2007; 13: 4551-3.
the advent of robotic capsule in near future, it will be possible 5. Sass DA, Chopra KB. Portal hypertension and variceal haemorrhage. Med
to perform drug delivery and tissue sampling, robotic capsule Clin North Am 2009; 93: 837-53.
will be equipped with microelectrical system for directed 6. Zaman A, Chalasani N. Bleeding caused by portal hypertension.
therapy. Natural orifice transendoscopic surgery (NOTES) is a Gastroenterol Clin N Am 2005; 34: 623-42.

798
 13.7 Oesophageal Disorders

Shobna J Bhatia, Praveen Mathew

SYMPTOMS Chest pain of oesophageal origin described as squeezing or

Oesophageal disorders are one of the commonest disorder burning sensation, is similar to cardiac angina and may not
of the GI tract. The description is given in next chapters. The be related to swallowing. Almost 90% of times it is associated
passage of food through the body of the oesophagus is not with other oesophageal symptoms. More than 50% of cases of
sensed by an individual in normal circumstances. The major non-cardiac chest pain have GOR disease; other causes are
symptoms of oesophageal diseases are heartburn, chest pain, oesophageal spasm, achalasia cardia, nutcracker oesophagus
regurgitation and dysphagia. and sometimes panic disorders. Water brash is reflex salivary
hypersecretion that occurs in response to GOR. It should not be
Heartburn (pyrosis) is defined as retrosternal burning pain that confused with regurgitation. Globus sensation is a feeling of food
travels cephalad. It is exacerbated by bending or lying down, stuck at the pharyngeal level, but occurs between meal times.
and is worse after meals. It is relieved by upright posture, by
swallowing of saliva or water, or more reliably by antacids or MOTILITY DISORDERS
acid-inhibiting drugs. Heartburn is a characteristic symptom of
Skeletal Muscle Disorders
gastro-oesophageal reflux (GOR), and may be associated with
regurgitation. Pharyngeal paralysis may occur following neuromuscular
diseases; laryngeal and orofacial muscles also may be involved.
Regurgitation is described as effortless appearance of acid or a It is characterised by transfer dysphagia, laryngeal aspiration
bitter taste in the mouth. It occurs in GOR, and may result in and nasal regurgitation. Barium swallow with cineradiography
laryngeal aspiration with spells of coughing and choking which is the investigation of choice, and reveals poor contraction of
awaken the patient from sleep. pharyngeal constrictors, barium in the valleculae and pyriform
It may also result in aspiration pneumonia. Regurgitation of sinuses, and nasal and tracheal aspiration. Oesophageal motility
bland food suggests that an obstruction exists in the lower studies may reveal reduced amplitude of contraction wave in
oesophagus; in GOR, bland regurgitation occurs when acid pharynx and proximal oesophagus, reduction in upper
secretion has been inhibited by drugs. oesophageal sphincter (UOS) resting tone, and incoordination
between the pharynx and oesophagus during a swallow.
Dysphagia, or difficulty in swallowing, is a sensation of
Patients who have pharyngeal paralysis due to myasthenia gravis
obstruction to the passage of food through the mouth,
or polymyositis respond to treatment of the primary disease.
pharynx or oesophagus due to a significant problem in the
In other patients, swallowing exercises usually help. In patients
anatomy or motility of these organs. Dysphagia could be
with a cerebrovascular accident, the extent of impairment of
oropharyngeal (transfer) or oesophageal. Oropharyngeal
swallowing and its subsequent recovery depend on the type and
dysphagia occurs due to neuromuscular or structural
extent of lesion. In severe cases, a permanent feeding gastrostomy
abnormalities of mouth, hypopharynx or upper oesophagus;
may be required. In patients with UOS spasm, botulinum toxin
these patients have difficulty in initiating the swallow.
injection or cricopharyngeal myotomy may be helpful.
Oesophageal dysphagia is classified as mechanical or motor.
Mechanical oesophageal dysphagia is initially to solids only. Cricopharyngeal achalasia is a disorder of unknown cause, and
It could be intermittent (webs or Schatzki ring) or progressive occurs due to failed relaxation of the UOS and can be associated
from solid to blenderised food and finally to liquids (stricture, with Zenker’s diverticulum. Dysphagia and choking are the
malignancy). The severity of dysphagia in mechanical predominant symptoms. On radiography, a prominent bar
obstruction varies with the degree of luminal narrowing, type representing the contracted UOS may be seen. Cricopharyngeal
of food bolus, and presence of associated oesophagitis. On myotomy may be helpful in selected cases, but should not be
the other hand, dysphagia due to motor disorders is equal done in patients with associated GOR, because of increased risk
for solids and liquids, may increase with intake of very cold of pulmonary aspiration post-operatively.
foods and it could be slowly progressive (achalasia cardia)
Smooth Muscle Disorders
or intermittent (less specific motility disorder). Non-
obstructive dysphagia occurs in patients with reflux disease Achalasia cardia
who have oesophageal inflammation associated with a Achalasia cardia is a motor disorder of the oesophageal smooth
motility disorder. muscle in which the oesophageal body is aperistaltic, the lower
oesophageal sphincter (LOS) may be hypertensive and does not
Odynophagia or painful swallowing is due to mucosal non-
relax completely with swallowing. In addition, because of the
infectious inflammation. Causes could be infectious (candidiasis,
non-relaxing LOS, the intra-oesophageal pressure is higher than
herpes, cytomegalovirus, Epstein-Barr virus, etc.) or non-
the gastric pressure.
infectious like corrosive intake, pill oesophagitis, radiation
oesophagitis, severe GOR disease and rarely osesophageal The underlying abnormality is defective innervation of the
carcinoma. smooth muscle portion of the oesophageal body and the LOS. 799
 Classic achalasia shows a marked reduction in myenteric
neurons. Secondary achalasia may be caused by gastric
carcinoma infiltrating the oesophagus, lymphoma, Chagas
disease, neuropathic chronic intestinal pseudo-obstruction
syndrome, irradiation and certain toxins and drugs.
Dysphagia, chest pain and regurgitation are the main symptoms
of achalasia. Dysphagia occurs with both liquids and solids.
Various manoeuvres designed to increase intra-oesophageal
pressure, including the Valsalva, may help passage of the bolus
into the stomach. Regurgitation and pulmonary aspiration
occur because of retention of large volumes of saliva and
ingested food in the oesophagus. The overall course is usually
chronic over months to years.
Chest X-ray may show absence of the gastric air bubble. In
advanced cases, an air-fluid level in the mediastinum in the
upright position represents retained food in the dilated
oesophagus. Barium swallow shows oesophageal dilatation and
a persistent beak-like narrowing, representing the non-relaxing
LOS, in the lower oesophagus (Figure 1).
Oesophageal manometry shows the defining feature of distal
body aperistalsis and incomplete or absent swallow induced
relaxation of LOS. Other features are hypertensive LOS and low
amplitude simultaneous onset oesophageal body contractions.
An increased intra-oesophageal basal pressure that exceeds
intragastric pressure is commonly seen. High resolution
oesophageal manometry with contour plot topographical
analysis has found three variants of achalasia (Figures 2A and B),
type 1—no significant oesophageal pressurisation; type 2—
rapidly progressive compartmentalised pressurisation, either
localised to distal oesophagus or throughout the whole
oesophagus; and type 3—rapidly progressive pressurisation
attributable to spastic contractions. This classification is also
Figures 2A and B: (A) High resolution manometry shows normal peristaltic
helpful in prognosticating outcomes with type 2 responding
wave after a swallow. (B) Manometry shows aperistalsis in oesophageal body
best to therapy; type 3 achalasia does not respond well, and after a swallow with elevated lower oesophageal sphincter pressure suggestive
type 1 has intermediate response to any form of treatment. of achalasia.

Endoscopy is helpful in excluding the causes of secondary

Medical treatment using nitrates is usually unsatisfactory.
achalasia, particularly gastric fundal carcinoma.
Calcium-channel antagonists such as nifedipine have been used
with some success; these need to be administered sublingually
15 to 30 min prior to a meal. The best available non-surgical
therapy involves endoscopy-assisted balloon dilatation of the
LOS; this reduces the basal LOS pressure by tearing muscle fibres.
Endoscopic injection of botulinum toxin into the LOS is effective
in the short term. Heller’s extra-mucosal myotomy of the LOS in
which the circular muscle layer is incised, is equally effective.
Reflux oesophagitis and peptic stricture may develop after
successful treatment of achalasia; this complication is more
frequent after surgery than with balloon dilation. Surgery is
increasingly being performed laparoscopically; additionally,
fundoplication is often done to prevent GOR.
Spastic Disorders of Distal Oesophagus Other than Achalasia
This section includes a spectrum of disorders ranging from
diffuse oesophageal spasm, nutcracker oesophagus, non-
specific spastic disorders and hypertensive LOS. These are
differentiated on the basis of manometry findings (Figure 3).
They all are present with history of chest pain, occasional
dysphagia and rarely regurgitation. Pain is very similar to angina,
Figure 1: Barium swallow showing dilated oesophagus with bird beak may occur at rest or after swallowing, and may radiate to the back
appearance at the lower end and fluid level in the oesophagus, suggestive of or neck. These disorders are associated with other functional
800 achalasia cardia.
bowel disorders and have high association with anxiety
 Oesophageal Disorders
dilatation of LOS has been found to be beneficial in cases
with associated LOS hypertension. In refractory cases, long
oesophagomyotomy has been tried with some success.
Systemic diseases like scleroderma and diabetes mellitus also
cause motor disorders of the oesophagus. Scleroderma
oesophagus is typically one with a low LOS pressure and
aperistalsis. There is atrophy of the smooth muscle. The patient
presents with severe gastro-oesophageal reflux disease with
complications. Diabetes mellitus, when complicated by
autonomic neuropathy, may have associated oesophageal
dysmotility. The patients are rarely symptomatic, but may have
occasional dysphagia and heartburn. Candidal infection should
also be considered; if present, patients may have odynophagia.

GASTRO-OESOPHAGEAL REFLUX DISEASE

Figure 3: High resolution manometry shows simultaneous and prolonged Gastro-oesophageal reflux (GOR) is defined as backward flow
contraction of oesophageal body suggestive of diffuse oesophageal spasm. of gastric contents into the oesophagus. A small amount of GOR
occurs in normal individuals. GORD (gastro-oesophageal reflux
disorders, depression and other psychological abnormalities. disease) is defined as a condition which develops when stomach
The pathogenesis of these disorders is not known, probably contents cause troublesome symptoms or complications, and
functional with no anatomic abnormalities found. adversely affects an individual’s quality of life. The typical reflux
syndrome is defined by presence of troublesome heartburn
Diffuse oesophageal spasm is characterised by non-peristaltic and/or regurgitation. GORD is the most common oesophageal
responses of normal amplitude after 30% or more of swallows disorder, accounting for nearly 75% of all patients with
with a normally relaxing LOS. Barium swallow may reveal oesophageal disorders. In Western studies, 15% to 20% of the
intermittent areas of oesophageal spasm that produce an general population suffers from GORD. The prevalence of GORD
appearance of a corkscrew oesophagus (Figure 4). in Asia is lower (2.3% to 8%), probably due to higher prevalence
Treatment includes ruling out the possibility of ischaemic heart of Helicobacter pylori, lower body mass index, low fat
disease; smooth muscle relaxants like nitrates and calcium consumption in diet and genetic diversity. Adenocarcinoma of
channel blockers are beneficial in a few cases. Anti-depressants the oesophagus is on the rise in the Western world. Barrett’s
like imipramine, trazodone and sertraline have been found to oesophagus, which is a recognised precursor to adenocarcinoma
be useful in a number of patients with chest pain. Pneumatic is strongly associated with GORD.
Pathophysiology
The normal anti-reflux barrier at the gastro-oesophageal
junction is a zone whose functional integrity is maintained by
the LOS pressure, extrinsic compression of the LOS by the crural
diaphragm, the intra-abdominal location of the LOS, integrity
of the phreno-oesophageal ligament, and maintenance of the
acute angle of His.
Transient LOS relaxation is one of the most important causes
for GORD; it is not associated with a swallow. It is more harmful
because it is longer in duration (>10 seconds) compared with
swallow-induced LOS relaxation, accompanied by relaxation of
crural diaphragm and not associated with peristalsis. It is usually
stimulated by gastric distension due to food or gas, or rarely fat
and stress. Small amount of reflux occurs during swallow
induced LOS relaxation. The role of hypotensive LOS seems to
be present only in patients with severe oesophagitis.
Hiatus hernia is seen in 60% to 90% of patients with reflux
oesophagitis, especially in patients with peptic stricture or
Barrett’s oesophagus. Hiatus hernia breaches the anti-reflux
barrier by displacing the LOS from crural diaphragm. Loss of
the intra-abdominal segment of LOS increases transient LOS
relaxation and impairs oesophageal acid clearance.
Impaired oesophageal motor function resulting in inadequate
volume clearance occurs in oesophagitis; peristaltic dysfunction
increases with increasing severity of oesophagitis. The layer
of mucous carpeting the mucosa and mucosal bicarbonate
Figure 4: Barium swallow showing appearance of a corkscrew oesophagus.
also constitute an important line of defence against acid injury. 801
 If acid injury and cell necrosis occur, the rate of regeneration
plays a role in determining the severity of lesions.
There is no increase in gastric secretions in GORD patients, but
there is a pocket of acid in the distal oesophagus which escapes
the buffering action of food; hence the predilection for
oesophagitis at this location. Animal and human studies have
demonstrated that acid and pepsin are responsible for the
mucosal injury. Other factors implicated are duodenogastric
reflux, with conjugated bile acids and trypsin as possible
culprits. Gastroparesis is found in 6% to 38% of patients with
Figure 5: Endoscopy shows evidence of Barrett’s metaplasia in the oesophagus.
GORD. The normal squamous mucosa of the oesophagus is replaced by columnar
gastric mucosa.
Helicobacter pylori infection is currently believed to lower the
frequency of GORD. This is backed by epidemiological data of
metaplasia. There are no symptoms which herald the
low prevalence of GORD in areas with high prevalence of H. pylori
development of Barrett’s oesophagus. Increasing age, male
and vice versa. Prevalence of more virulent strains of H. pylori in
gender, long duration of GORD symptoms, obesity and smoking
developing countries results in corpus or pangastritis, thus are risk factors for Barrett’s oesophagus. Adenocarcinoma may
reducing gastric acid secretion and resulting in decreased develop in patients with Barrett’s oesophagus especially high
symptoms of GORD. grade dysplasia.
Pathology Extra-oesophageal syndromes are classified as those with
Grossly, the spectrum of oesophageal mucosal appearances established associations and those with proposed associations.
varies from normal appearing mucosa (40% to 80%) to mucosal Established associations include reflux cough, reflux laryngitis,
injuries of varying severity-erosions to ulcerations. The earliest reflux asthma and reflux dental erosions. These syndromes
finding, seen on electron microscopy, is dilated intercellular usually occur with the concomitant manifestation of typical
spaces, at least three times greater than controls; this is reversible reflux oesophageal symptoms and rarely in their absence. Reflux
on administering proton pump inhibitors. Light microscopy is rarely the only cause for these extra-oesophageal symptoms.
shows papillary height more than half, and basal zone thickness They have been found to respond to treatment of GORD. Other
more than 1/6th of total mucosal thickness. Acute inflammation symptoms with proposed associations are sinusitis, pulmonary
with neutrophils and eosinophils is seen in up to 40% of cases fibrosis, recurrent otitis media and pharyngitis. The degree of
but is not specific for GORD. evidence for this last group is minimal, epidemiologically or
treatment-response wise.
Development of columnar-lined mucosa, with specialised
intestinal metaplasia is the defining feature of Barrett’s Investigations
oesophagus, visible on endoscopy when normal squamous The diagnosis of GORD is made on the basis of clinical history
mucosa is replaced by salmon pink columnar mucosa. This can and confirmed by response to medications. Diagnostic testing is
progress from low grade to high grade dysplasia, and later to done to avert misdiagnosis, to identify complications of
adenocarcinoma of the oesophagus. GORD and to evaluate the reason for failure of standard therapy.
Clinical Features To avert misdiagnosis and identify reflux complications, the
concept of alarm symptoms has been introduced; these include
Symptom complex of GORD has been divided into oesophageal gastrointestinal blood loss, involuntary weight loss, dysphagia
and extra-oesophageal syndromes. Oesophageal syndromes and anaemia. In these conditions an endoscopy is warranted.
include the typical reflux syndrome and reflux chest pain In case any lesion is seen, biopsies should be taken from it. Less
syndromes. than 50% of patients with GORD have endoscopic features of
Typical reflux symptoms are heartburn, a burning sensation in oesophagitis; visible breaks in mucosa is the most reliable marker
the retrosternum and regurgitation—a perception of flow of of reflux oesophagitis.This does not correlate with the frequency
gastric contents into the mouth or hypopharynx.The prevalence or severity of reflux symptoms. Reflux stricture seen in less than
of these is 75% to 98% and 48% to 91%, respectively. GORD can 5% of GORD patients is defined by a persistent narrowing in the
be diagnosed by these two symptoms without the need for lumen of the oesophagus and manifests as troublesome
endoscopy. Reflux chest pain can be indistinguishable from pain mechanical dysphagia. If endoscopy is normal, the patient should
of ischaemic heart disease, but is usually associated with other be treated empirically as GORD, and further investigated if the
symptoms of GORD. GORD is the most common oesophageal symptoms do not resolve. Manometry is useful in detecting
cause of chest pain. Sleep disturbance is often associated with severe peristaltic dysfunction which is a contraindication for anti-
GORD. In patients with minimal symptoms, exercise has been reflux surgery. Investigations to demonstrate excessive
found to worsen symptoms of GORD. oesophageal acid exposure are conventional catheter based pH-
metry or wireless capsule pH-metry,and impedence-pH monitoring.
Dysphagia in a patient with GORD could be a marker of peptic
stricture or development of malignancy. Dysphagia may also Therapy
occur because of reflux oesophagitis and motor functional Treatment is directed towards decreasing GOR and improving
abnormalities. Barrett’s oesophagus is an endoscopic diagnosis oesophageal clearance. The aim is to alleviate symptoms, heal
802 (Figure 5) confirmed on histology showing specialised intestinal oesophagitis and prevent complications.
 Oesophageal Disorders
Treatment usually begins with dietary and lifestyle modifications. nausea, vomiting and fever may be present. On endoscopy, the
The patient should be asked to avoid food items that increase oesophageal mucosa has 1 to 3 mm vesicles and small, discrete,
reflux (fatty or fried food, caffeinated drinks, chocolate, mint) punched-out lesions, which may proceed to confluent ulcers and
and decrease intake of acidic foods (citrus fruits, spicy food, diffuse erosive oesophagitis.These lesions may get superinfected
carbonated drinks, tomatoes, onions). Lifestyle modifications by bacteria or fungi. Biopsy or cytology may show ballooning
include weight reduction in those who are obese, elevation of degeneration, ground-glass change in nuclei with eosinophilic
the head end of the bed and avoiding eating within 3 hours of inclusions (Cowdry type A) and giant cell formation. Culture may
bedtime in those with night time symptoms. Patients with be positive.Treatment consists of acyclovir 250 mg/m2 intravenous
postprandial symptoms are advised to take small frequent meals. 8 hourly. As the patient improves, oral therapy may be started
with 200 to 400 mg acyclovir 5 times a day. Symptoms resolve
Empirical initial management with acid reduction is the
within a week. Ulcers take a longer time to heal.
accepted approach currently in patients with uncomplicated
heartburn. Evidence suggests that acid reduction helps healing Varicella-zoster virus occasionally produces oesophagitis in
of oesophagitis and relief from symptoms. Meta-analysis of children with chicken pox and adults with herpes zoster. The
randomised control trials show that proton pump inhibitors oesophageal lesions are similar to those of HSV, and necrotising
(PPIs) are more effective than H2 receptor antagonists (H2RAs) oesophagitis may occur in a severely compromised patient.
in treating oesophagitis and ameliorating symptoms. PPIs as a Biopsy from the edge of the ulcer shows findings similar to those
class (omeprazole, lansoprazole, pantoprazole, rabeprazole and of HSV, and differentiation requires culture studies. Acyclovir, in
esomeprazole) are all equally effective in standard doses. There doses higher than for HSV, is required for treatment.
does not appear to be any additional benefit of higher dosage/
twice daily dosing of PPIs or adding a H2RA, except in cases Cytomegalovirus infection occurs only in the immuno-
of severe oesophagitis. Patients whose heartburn has not compromised host. Endoscopy shows serpiginous ulcers which
responded to twice daily PPIs are considered treatment failures. are large and deep with surrounding normal mucosa. In the distal
Preference of a PPI over another is primarily to ameliorate the oesophagus the ulcers may coalesce. Biopsy should be taken
side-effects of the PPI need earlier. Patients with reflux chest from the centre of the ulcer and reveals intranuclear and small
pain can be given a trial of PPI once ischaemic heart disease cytoplasmic inclusions in fibroblasts and endothelial cells of
has been ruled-out. Patients with extra-oesophageal symptoms blood vessels. Early diagnosis may be made by immuno-
require high doses. histochemistry using monoclonal antibodies to CMV. Ganciclovir
is the treatment of choice. Complete healing may take a few
Maintenance therapy is usually necessary as GORD is a chronic weeks to months and treatment should be continued until then.
disease, the lowest possible dose of PPI should be titrated for
symptom control in patients with definite oesophagitis. PPIs HIV causes oesophagitis during seroconversion and during
have been shown to reduce the development of reflux strictures, inversion of T-cell helper: suppressor ratio. The oesophagitis is
but there is no evidence that they reduce the risk of Barrett’s self-limiting. Steroids may help in this condition.
oesophagus or adenocarcinoma. In patients with extra- Bacterial oesophagitis is very rare. However, patients with AIDS
oesophageal symptoms, maintenance therapy is indicated only may develop oesophagitis due to Cryptosporidium or P. carinii.
to control oesophageal symptoms. Long-term PPI therapy is
potentially safe though there is a theoretical risk of hypergastri- Tuberculosis of the oesophagus is rare and is almost always due
naemia, pneumonia, Clostridium difficile colitis and hip fractures. to contiguous spread from the lung or mediastinal lymph nodes.

Anti-reflux surgery and PPIs have equal efficacy for control of Fungal Oesophagitis
oesophageal reflux symptoms. Surgery should be offered when Candidiasis of the oesophagus occurs in immunodeficiency
an individual is intolerant to PPIs, or when a patient with disorders like diabetes mellitus, chronic renal failure, and AIDS.
oesophageal reflux syndrome has troublesome regurgitation. Individuals receiving steroids or immunosuppressive
The potential side-effects of anti-reflux surgery include chemotherapy for malignancy and those with underlying
excessive flatulence, inability to belch, dysphagia and oesophageal diseases that cause stasis of food (achalasia or
recurrence of symptoms post-surgery (30% over 5 years). scleroderma) may also develop candidiasis.
Patients well controlled on PPIs should not be offered surgery.
The surgery recommended is laparoscopic fundoplication. Candida is present in the non-pathogenic form in the oral flora
in normal individuals. Patients who develop oesophagitis may
INFECTIOUS OESOPHAGITIS be asymptomatic, or may have odynophagia and dysphagia.
Infectious oesophagitis can be due to viral, bacterial and Rarely, bleeding may occur, and the deep ulcers may perforate
fungal causes. With an increase in the number of patients with or may form a stricture. Systemic invasion from oesophageal
immunocompromised states, there has been an increased candidiasis is also reported.
frequency of oesophageal infections. Oral candidiasis, if present, suggests the diagnosis by its white
Infections of the oesophagus present with acute dysphagia, flake’s appearance. Endoscopy reveals raised white pseudo-
odynophagia and chest pain. In patients with severe ulceration membranous plaques with mucosal erythema. In severe cases,
of the mucosa, bleeding may occur; this is usually self-limiting confluent linear and nodular plaques with underlying
and small in quantity, but life-threatening haemorrhage may occur. ulcerations may be present. A smear taken from these plaques
may reveal hyphae. Treatment in mild cases is with 10 to 20 mL
Viral Oesophagitis of oral nystatin (100,000 units/mL) 6 hourly, or oral clotrimazole
Herpes simplex virus (HSV) type 1 or 2 may cause oesophagitis in (10 mg 6 hourly), or fluconazole 100 mg per day for 7 days.
If symptoms persist, endoscopic biopsy and culture are 803
immunocompromised individuals. Systemic manifestations like
 recommended. If anti-fungal resistance is demonstrated, guide wire during endoscopy; this serves as a route for
caspofungin may be effective. Narcotics are recommended for maintaining nutrition and also provides a lumen for dilatation
patients with severe odynophagia. in future as these patients are prone to develop strictures.
Measures which have shown to be of no use or are harmful are
Corrosive Injury
administration of activated charcoal, pH neutralisation or
Corrosive is any substance which causes tissue injury upon dilution, by inducing emesis, and intravenous steroids. Antibiotic
contact. Caustic injury of the oesophagus occurs following therapy is required only if secondary infection sets in.
ingestion of strong alkali or acid, most often accidentally or with
suicidal intent. Sodium hydroxide is the most frequent cause Early dilatation of the oesophagus has been associated with a
of alkaline injury. Hydrochloric and sulphuric acids are the high-risk of perforation, and is therefore not recommended.
common acids causing injury. Most corrosives are available as Stricture of the oesophagus is the major long-term
over-the-counter drain cleaners, dish washing detergents, complication. Caustic strictures are often extensive and multiple,
bleaches, battery fluids, button batteries, nail polish removers, etc. involving most of the lower oesophagus. They respond to
repeated dilatation, and the frequency of dilatation may
Alkali ingestion provokes liquefaction or saponification necrosis decrease over time. Recently, self-expandable plastic stents have
of the oesophageal wall and thrombosis of blood vessels. Acids been placed at the site of stricture for 6 to 8 weeks, with good
cause coagulative necrosis. Severity of tissue injury depends upon results. Oesophageal resection with colon or gastric tube
factors like substance pH, physical state (solids adhere to mucosa replacement may be necessary in cases where the lumen is
and cause more damage), quantity, intention (quantity is usually too small for dilatation, or in cases of extensive damage.
larger in suicidal cases), tissue contact time and concentration. Oesophageal squamous cell carcinoma is a potential long-term
There is an acute inflammatory response with mucosal necrosis, complication of corrosive injury.
followed by sloughing of necrotic tissue and ulceration over
4 to 15 days. Risk of perforation is maximum up to 7 days. After Pill-Induced Oesophageal Injury
3 to 4 weeks, cicatrisation begins. Significant oesophageal Pill-induced oesophageal injury results from damage due to
strictures develop when there is circumferential damage. ingestion of certain medications which cause injury by
In the oesophagus, corrosives pool at the post-cricoid area, level either production of caustic solution, hyperosmolar solution or
of aortic arch, tracheal bifurcation, and lower oesophageal direct drug damage. Drugs commonly implicated are
sphincter. These are common locations for strictures. In severe tetracycline, doxycycline, potassium chloride, nonsteroidal anti-
cases, there may be perforation into the mediastinum or pleural inflammatory drugs, alendronate, ferrous sulphate, theophylline,
cavity or development of a tracheo-oesophageal fistula. The quinidine, etc. The injury is more common in individuals with
damage is mainly in the antrum in the fasting stomach, and in anatomic or motility abnormalities of oesophagus. It could be
the gastric corpus if the patient has ingested a meal prior to predisposed by taking inadequate water or assuming
corrosive ingestion. recumbent posture immediately after taking the pill. Symptoms
include severe chest pain, odynophagia and dysphagia.
Symptoms include burning pain in the mouth and throat,
Endoscopy may reveal an ulcer, diffuse oesophagitis or
odynophagia, excessive salivation, stridor, hoarseness, dysphagia
pseudomembrane at the site of damage. Withdrawal of the
and chest pain. Gastric involvement leads to abdominal pain and
offending medication, viscous lignocaine solution, adequate
vomiting, and occasionally symptoms and signs of perforation.
hydration, and use of PPIs to reduce acid exposure results in
There may be oedema and ulceration of the lips, tongue and
healing of the lesion. Rarely there can be perforation,
pharynx. Airway obstruction from severe epiglottic and
oesophago-respiratory fistula or a chronic stricture at the site
laryngeal oedema may occur. As the acute inflammatory
reaction subsides, odynophagia and dysphagia decrease; with of the ulcer. The disorder is preventable in most cases.
the development of oesophageal stricture, dysphagia gradually Eosinophilic Oesophagitis
returns, usually within 1 to 3 months after the accident. Mortality
Eosinophilic oesophagitis (EO) is a disease characterised by
rate is of 1%, usually due to mediastinitis or peritonitis resulting
eosinophilic infiltration of the oesophageal mucosa. Identified
in multi-organ failure.
in 1978, the incidence of EO has been increasing in the Western
The aim of therapy in the acute phase is resuscitation and world. Familial clustering and seasonal variation have been
supportive care. Assessment of the severity of damage is most noted in patients with EO. Almost 80% of children and 40% to
important after resuscitation of the patient. Clinical features 60% of adults have history of allergies. It is postulated to be IgE
do not correlate with severity of damage. X-ray films of chest or non-IgE mediated. Sensitisation could be via food or inhaled
and abdomen are taken to check for perforation, pneumo- allergens. EO appears to be a Th2 mediated immune response;
mediastinum or pneumoperitoneum, which if present can IL-5 and IL-13 appear to play a key role in pathogenesis.
be confirmed by CT scan. If there is evidence of perforation,
The pathognomonic feature of EO is eosinophilic infiltration of
patient should be referred for surgery (oesophagectomy or
≥15 eosinophils/HPF in the oesophageal mucosa; eosinophils
gastrectomy). Flexible endoscopy should be done at the earliest
should be counted in the most densely inflamed part of the
or up to 96 hours of corrosive ingestion, after ruling out a
biopsy (X 400). Other features are eosinophilic micro-abscesses,
perforation and is the best way to assess the severity of mucosal
superficial infiltration of eosinophils in the upper half of mucosa,
damage. Endoscopic grading is helpful in management and
basal zone hyperplasia and papillary lengthening.
prognostication. Patients who have minimal injury can be
started on oral liquids by 48 hours and can be discharged early; Most of the patients are men with a male to female ratio of 3:1,
they also have a low risk of complications. In patients with in the third or fourth decade of life. Presentation varies from
804
advanced damage, a nasojejunal tube can be placed over a dysphagia (60% to 90%), food impaction (50% to 60%), heartburn
 Oesophageal Disorders
and regurgitation (24% to 50%), refractory GORD, chest pain, OESOPHAGEAL WEBS, RINGS AND DIVERTICULA
abdominal pain, diarrhoea and weight loss. Children present Oesophageal webs usually occur in the upper oesophagus, but
with poor feeding, vomiting, regurgitation and failure to thrive. may occur in the mid or lower oesophagus as well. They are
Endoscopic findings include oesophageal rings (felinisation or thin horizontal membranes of stratified squamous epithelium,
trachealisation), raised white specks, longitudinal furrows, whitish usually protrude from the anterior wall, rarely complete and are
exudates and a friable mucosa which may tear by passage of best demonstrated on the lateral view in the barium swallow.
endoscope. Normal mucosa can be seen in up to a third of the They are usually acquired, but webs in the upper third may
patients. Strictures could be seen in any part of the oesophagus. be congenital in origin (Figure 6). A syndrome of cervical
Multiple (>5) biopsies from different levels of the oesophagus oesophageal web, anaemia and platonychia, which occurs
should be taken. Oesophageal pH monitoring should be done in mainly in middle-aged women, is called the Patterson-Kelly or
difficult cases to rule-out GORD, or biopsies should be repeated Plummer-Vinson syndrome.
after 6 weeks of PPI treatment. Barium swallow may reveal
strictures, Schatzki’s ring or a diffuse narrowing of the oesophagus.
Allergic testing by skin prick, skin patch test or food specific
radioallergosorbent testing can be done.
Treatment
Treatment is to control the inflammation using systemic steroids,
prednisolone 1 to 2 mg/kg, tapered over 6 weeks in patients with
severe dysphagia, weight loss and refractory oesophageal
strictures. Steroids should not be used for maintenance therapy.
Other steroids used are swallowed topical fluticasone propionate
(440 to 500 μg/day) twice daily for 6 weeks, swallowed
budesonide mixed with sucralose and beclomethasone have also
been used. Symptoms recur in 50% of patients when treatment
is stopped and can be managed with reintroduction of same
therapy or, use of steroid-sparing drugs like azathioprine.
Leukotriene receptor antagonist montelukast 10 to 40 mg/day
has been used with some success. Endoscopic dilatation of Figure 6: Barium swallow shows a web in upper oesophagus.
strictures should be preferably limited to patients after a trial of
medical therapy, because of the risk of perforation. Dietary Oesophageal rings are found near the lower oesophageal
therapy by eliminating foods like dairy, peanuts, soy, fish, eggs sphincter (LOS). They are of 2 types. Type A is a muscular ring, 4
wheat and other foods identified by allergic testing has been to 5 mm thick and is the hypertrophied upper portion of LOS.
found to be successful in 70% of paediatric cases. Because of poor Type B ring, or Schatzki ring, is a mucosal ring at the squamo-
tolerability, dietary therapy should be used in individuals not columnar junction; its upper surface is squamous epithelium
responding to medical and endoscopic treatment. Studies with and undersurface is columnar. It is usually associated with GORD
targeted therapies to IL-5 are underway. or rarely EO.

Hiatus Hernia Rings and webs present with intermittent dysphagia to solid
food. Rarely, dysphagia progresses to a severe state. Treatment
Herniation through the oesophageal hiatus occurs in two consists of breaking the web or ring by dilatation; webs may
forms: axial or sliding type in which both the distal oesophagus rupture even during a diagnostic endoscopy. The underlying
and a varying portion of the stomach (i.e. the entire oesophago- disorder like anaemia or GOR needs appropriate treatment.
gastric junction) are situated above the diaphragm, and
para-oesophageal or rolling type in which the lower most Diverticula are outpouchings of the oesophageal wall from an
oesophagus and the oesophago-gastric junction retain their area of muscular weakness. Zenker’s diverticulum occurs due
position below the diaphragm, while a portion of the proximal to weakness in the posterior hypopharynx; patients present
stomach protrudes into the thorax alongside the oesophagus. with dysphagia and regurgitation. Treatment consists of
cricopharyngeal myotomy. Epiphrenic diverticula occur in the
The size of the sliding hernia alone does not predict the distal oesophagus and are associated with oesophageal motility
presence or severity of symptoms; larger, long-standing hernias disorders.
are more likely to be associated with symptomatic GOR.
RECOMMENDED READINGS
In the less common para-oesophageal or rolling hernia, the
less-than-atmospheric intrathoracic pressure is transmitted 1. Clouse RE, Diamant NE. Esophageal motor and sensory function and motor
disorders of the esophagus. In: Feldman M, Freidman LS, Brandt LJ, editors.
directly through the pleura to the peritoneal sac. With positive Sleisenger and Fordtran’s Gastrointestinal and Liver Disease; 8th Ed. Saunders
intra-abdominal pressure exerting an upward push, this hernia Elsevier; 2006: pp 855-904.
tends to enlarge progressively. The typical para-oesophageal 2. Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic esophagitis in
hernia is rarely associated with GOR; however, it can get children and adults: a systematic review and consensus recommendations
incarcerated and strangulation or bleeding may occur. for diagnosis and treatment. Gastroenterology 2007; 133: 1342.
3. Kahrilas PJ, Shaheen NJ, Vaezi MF. American Gastroenterological
The management of symptomatic sliding hiatus hernia is similar Association Institute Technical Review on the management of
to that of GORD. Para-oesophageal hernia needs surgical gastroesophageal reflux disease. Gastroenterology 2008;135:1392-
correction to avoid complications. 1413.
805
 13.8 Diseases of the Stomach and Duodenum

Pankaj Dhawan

The stomach is a J-shaped organ continuous with the (M3) type of cholinergic receptor for acetylcholine released from
oesophagus proximally and the duodenum distally. It is post-ganglionic neurons and a cholecystokinin (CCK) receptor
divided from the proximal to distal end into the cardia, fundus, for gastrin released from pyloric and duodenal G cells.
body or corpus, antrum and pylorus (pyloric channel). The
Hydrogen ions are generated in the parietal cell from water.
duodenum is the first part of the small intestine and is in
The corresponding hydroxyl ions combine with cellular carbon
continuity with the pylorus of the stomach proximally and the
dioxide (CO 2) to form HCO 3. This reaction is catalysed by
jejunum distally. It forms a C-shaped loop around the head of
carbonic anhydrase. HCO 3 ions are exchanged at the
the pancreas.
basolateral membrane for Cl – ions, which are ultimately
The arterial blood supply of the stomach is derived from the secreted by the parietal cells. Hydrogen ions are exchanged
coeliac artery and its major branches, the common hepatic, for K+ catalysed by the magnesium dependant H+-K+ ATPase
splenic and left gastric arteries while the duodenum receives pump. The H+-K+ ATPase is inhibited by covalent antagonists
additionally from the superior mesenteric artery. The venous such as the substituted benzimidazoles (e.g. omeprazole). The
drainage is into the portal vein or its tributaries, the superior apical membrane of the parietal cell is impermeable to H+ and
mesenteric and splenic veins. The lymphatic drainage of the Cl– and hence, it does not diffuse back from the lumen into
stomach is to the coeliac lymph nodes. The autonomic the cell.
innervation stems from both the sympathetic (coeliac plexus)
Other Secretions
and the parasympathetic (right and left vagus nerves) nervous
systems. The latter synapses with ganglion cells in the sub- The other important gastric secretion is pepsinogen (PG). This
mucosa (Meissner’s plexus) and myenteric plexuses (Auerbach’s is a proenzyme S which gets activated to pepsin in the gastric
plexus). From these plexuses fibres are distributed to secretory lumen by the gastric acid. Two types of pepsinogen are PG I
components including cells and glands as well as to the gastric and PG II.
smooth muscle. The gastric mucosa also secretes bicarbonates through the
surface cells that are rich in carbonic anhydrase. Under most
MOTOR PHYSIOLOGY
conditions, luminal HCO3 is overwhelmed by luminal H+ and is
The motor function of the gastrointestinal (GI) tract is controlled converted to CO2. Therefore, HCO3 is not ordinarily present in
at 3 levels. The first is the extrinsic neural control from the para- gastric juice. The other secretory products are gastric mucin
sympathetic pathways via the vagus nerve and the sympathetic and intrinsic factor. The role of intrinsic factor in vitamin B12
supply through the coeliac ganglion. The second level is absorption is discussed elsewhere.
provided by the enteric nervous system, which constitutes the
complex network of ganglion cells in the layers of the gut wall. GASTRITIS
The third level of control of GI motility is in the excitable smooth Gastritis is acute or chronic inflammation of the stomach and
muscle cells. Specific receptors in the cell membrane of the is most often diffuse. It is usually diagnosed on upper GI
smooth muscle bind to amines, peptides, and other transmitters endoscopy and can be confirmed and classified histologically
that reach the smooth muscle membrane via neurocrine, by performing a gastric biopsy. A detailed system for
endocrine and paracrine routes. The main transmitters involved classification (Sydney system) has been adopted recently.
in excitation of the gastric muscle are acetylcholine and
Acute Gastritis
tachykinins, such as substance P and substance K. The main
inhibitory transmitters are nitric oxide and vasoactive intestinal This is also called erosive or haemorrhagic gastritis. Of these,
peptide (VIP). the most common cause is use of aspirin and other non-
steroidal anti-inflammatory drugs (NSAIDs). These agents cause
GASTRIC SECRETION gastric mucosal damage by inhibiting prostaglandins, gastric
The human stomach secretes water and electrolytes (H+, Na+, bicarbonate and mucous, disrupting epithelial tight junctions
K+, Cl– and HCO3–), enzymes (pepsins and gastric lipase) and and altering gastric mucosal micro-circulation. The mucosal
glycoproteins (intrinsic factor and mucins). The gastric exocrine damage can result in either slow upper GI bleeding which can
secretions have a variety of functions. be detected as positive faecal occult blood test or can manifest
as massive upper GI bleeding. In some patients, epigastric
Acid Secretion discomfort, anorexia and nausea may be present. Treatment
The most important secretion of the stomach is gastric acid, includes omission of the offending agent, acid-suppressive
secreted from parietal cells in the fundus and body of the agents such as H2 receptor antagonists and proton-pump
stomach. Parietal cells have on their basolateral membrane inhibitors, prostaglandin analogues such as misoprostol (more
receptors for 3 stimulants: histamine (H2) receptor for histamine useful for prevention) and cytoprotective agents, such as
released from ECL cells and possible mast cells, a muscarinic sucralfate.
806
 Diseases of the Stomach and Duodenum
Chronic Gastritis
Chronic gastritis progresses over years in three stages. In
chronic superficial gastritis, there is infiltration of lymphocytes
and plasma cells in the lamina propria; however, the mucosal
thickness is normal. In atrophic gastritis, there is reduction
in the gastric glands (parietal and chief cells) along with
infiltration of plasma cells and lymphocytes. When there is
associated polymorphonuclear cells infiltration, gastritis is
termed active. In gastric atrophy, glands are lost, mucosal
thickness is reduced, infiltration of lymphocytes and plasma
cells is minimal and there may be foci of intestinal metaplasia.
The two main types of chronic gastritis are autoimmune
(formerly type A) and H. pylori-associated (formerly type B).
Autoimmune gastritis involves the gastric body and spares the
antrum. Parietal cell and intrinsic factor antibodies are serum
markers of autoimmune chronic gastritis. Patients present with
pernicious anaemia (megaloblastic anaemia with absolute Figure 2: Duodenal ulcer in first part of duodenum.
achlorhydria) and features of vitamin B 12 deficiency. Also,
autoimmune chronic gastritis is a pre-malignant condition and
can progress to gastric cancer. H. pylori-associated chronic
gastritis usually involves the antrum but over a period of time
may involve the body as well (see Infection Section).
An uncommon cause of chronic gastritis is Menetrier’s disease
(hypertrophic gastritis). The most common presentation is in
middle age with features of protein-losing enteropathy. On
upper GI endoscopy, enlarged rugal folds in the fundus and
body are evident. Histologically, gastric pits and glands are
elongated and tortuous and the parietal and chief cells are
replaced by mucous-secreting glands. Treatment with proton-
pump inhibitors may decrease protein loss. However, in
patients who do not respond, gastric resection may become
necessary.

PEPTIC ULCER DISEASE

Peptic ulcers are defects in the GI mucosa that result when injury
occurs due to the effects of acid and pepsin in the GI lumen.
Although the term ‘peptic ulcer’ is commonly used to describe
ulcers in the stomach (Figure 1) and duodenum (Figure 2),
peptic ulcers can develop in any portion of the GI tract exposed
to acid and pepsin such as the oesophagus, Meckel’s
diverticulum or site of gastrojejunostomy (Figure 3). In the early

Figure 3: Barium meal showing an anastomotic ulcer at the gastro-jejunostomy

site.

part of the 20th Century, stress and diet were thought to be

important pathogenetic factors. During the 1980s, it was
established that most peptic ulcers were related to either
H. pylori infection or due to consumption of NSAIDs. This
revolutionised the management of peptic ulcer disease.
Pathophysiology
Peptic ulcer occurs when the deleterious effects of acid and
pepsin overwhelm the ability of the mucosa to resist these
effects.
Defence Mechanisms
The mechanisms that normally enable the mucosa to resist acid-
peptic attack can be divided into three components: pre-
Figure 1: Benign gastric ulcer at incisura.
epithelial, epithelial and post-epithelial defence mechanisms. 807
 Pre-epithelial defence mechanisms are asymptomatic, but may cause symptoms as well as
A prominent coat of mucous and a layer of unstirred water rich complications such as, bleeding, perforation and obstruction.
in bicarbonate constitutes this component. Within the mucous Asymptomatic ulcers can be endoscopically documented in
layer glycoprotein form a physical barrier to the diffusion of 15% to 45% of patients receiving chronic NSAID therapy.
pepsin. Mucous also contains phospholipids which protect the However, 1% to 4% of patients receiving NSAIDs for 1 year will
mucosa by forming a hydrophobic layer. experience serious GI complications.

Epithelial defence mechanisms The major mechanism of NSAIDs-induced injury appears to be

due to its topical effects leading to ulcers, erosions and
The apical cell membranes and the tight junctional complexes
sometimes acute haemorrhages. Most NSAIDs are weak organic
between the surface cells limit the diffusion of hydrogen. Excess
acids that in acidic gastric juice become unionised, and thus,
hydrogen ions can be removed actively by ion pumps in the
are freely lipid soluble. These diffuse across the gastric
basolateral membrane, such as Na+/H+ exchanger and Cl–/HCO3–
epithelium into the cytoplasm. Uncoupling of oxidative
exchanger. Mucosal cell restitution regulated by growth factors
phosphorylation resulting in decreased mitochondrial energy
(epidermal and fibroblast growth factors) also plays a part.
production, reduction in cellular integrity and increase in
Post-epithelial defence mechanisms cellular permeability. Attenuation of the gastric mucous gel
Mucosal blood flow comprises the post-epithelial defence layer also occurs. Enteric coated NSAIDs produce considerably
mechanism. less acute topical erosive injury than non-enteric coated
formulations over short term (1 to 2 weeks) usage.
Abnormalities in Gastric Acid Secretion, Acid Homeostasis
and Gastroduodenal Motility Injury also occurs through its systemic effects. Peptic ulcers will
develop after intravenous or rectal suppository further
In 1910, Schwarz proposed his famous dictum ‘no acid, no ulcer’.
supporting a systemic effect. Cyclo-oxygenase (COX) is the rate
This followed numerous studies on abnormalities in acid
limiting enzyme for prostaglandin synthesis. Most NSAIDs
homeostasis in peptic ulcer. After the discovery of H. pylori it
(excepting the specific COX-2 inhibitors) reduce mucosal
has been shown that many of these abnormalities may not be
prostaglandin. A small dose of 10 mg of oral aspirin can decrease
the primary defects but reversible consequences of infection
gastric prostaglandin levels by 60% and can cause gastric ulcers.
with H. pylori.
Levels do not recover till 5 to 8 days. Animal experiments
Abnormalities associated with duodenal ulcer indicate that for gastric ulcers to occur both COX-1 and COX-2
Studies have shown these patients to be hypersecretors of must be inhibited. Hence, theoretically, COX-2 specific inhibitors
gastric acid with an increase in the number of parietal cells. This are associated with improved GI toxicity profile.
may be related to H. pylori induced increases in cytokines such Besides COX inhibition NSAIDs increase gastric acid secretion,
as tumour necrosis factor which stimulates gastrin release from decrease gastric mucosal blood flow, decrease mucous
G cells and H. pylori mediated decrease in somatostatin, a production and duodenal bicarbonate. Nitric oxide (NO)
peptide which suppresses gastric release. Also an increased rate protects the GI mucosa from NSAIDs-induced injury. Nitric oxide
of liquid gastric emptying with increased acid burden in donating NSAIDs or COX inhibiting nitric oxide donating drugs
duodenum has also been described. (CINODs) exhibit reduced GI toxicity in animal and human trials.
Abnormalities associated with gastric ulcer Other Ulcerogenic Drugs
Whereas the mucosa of the fundus and body is acid secreting
Besides NSAIDs the other ulcerogenic drugs are 5-fluorouracil,
(oxyntic) mucosa with abundant parietal cells, the gastric
potassium chloride, mycophenolate mofetil, and bisphos-
antrum is normally lined by a columnar epithelium that does
phonates (alendronate and risedronate).
not secrete gastric acid. The majority of gastric ulcers occur
in the non-acid secreting epithelium at or near its junction Hypersecretory Conditions
with oxyntic mucosa. Long standing gastritis as occurs in These should be considered in any patient who has peptic ulcer
H. pylori infection can cause atrophy of oxyntic mucosa with not associated with H. pylori or NSAIDs. Other clues include
development of intestinal metaplasia and extension of the severe complicated disease, ulcers in the post-bulbar
non-acid secreting epithelium into the proximal stomach. duodenum and diarrhoea. Hypersecretory conditions include
Patients who have gastric ulcers in the proximal stomach have gastrinoma, systemic mastocytosis and myeloproliferative
chronic gastritis, substantial gastric atrophy and low gastric disorders with basophilia, and antral G cell hyperfunction.
acid outputs.
Epidemiology
Helicobacter pylori
It has been observed that there is a declining prevalence of
H. pylori is associated with more than 80% of duodenal ulcers peptic ulcer disease, in part related to falling prevalence of H.pylori.
and more than 60% of gastric ulcers patients. Host factors as In contrast ulcer related complications as well as hospitalisation
well as bacterial virulence factors (such as cagA positive H. pylori) is on the rise, particularly in elderly due to increased use of
may determine disease predisposition in those who are H. pylori NSAIDs.
positive.
Cigarette smoking is a risk factor for peptic ulcer disease and
Nonsteroidal Anti-Inflammatory Drugs its complications. It slows healing and predisposes to relapses.
A large number of peptic ulcers not related to H. pylori However, if H. pylori is eradicated, smoking does not influence
are related to NSAIDs use. Typically NSAIDs-induced ulcers relapses.
808
 Diseases of the Stomach and Duodenum
As far as alcohol is concerned, wine and beer are potent containing) or constipation (aluminium containing). Antacids
acid secretagogues but its importance in pathogenesis of must be used cautiously in patients with renal insufficiency.
peptic ulcer is dubious. There is no study which has clearly
demonstrated a link between diet and peptic ulcer disease. Histamine (H2) receptor antagonits
Coffee (both caffeinated and decaffeinated), tea and colas are These include cimetidine, ranitidine, famotidine, roxatidine
potent acid secretagogues. Amongst the diseases associated and nizatidine. These agents competitively inhibit histamine
with peptic ulcer are alcoholic cirrhosis, chronic pulmonary stimulated acid secretion. All of them decrease basal as well
disease and chronic renal failure. Despite popular belief, there as meal stimulated acid output. These agents are well
is no role of emotional stress and peptic ulcers. Some studies absorbed after oral dosing and are not affected by food. All
have suggested that genetics may predispose to peptic ulcer of them are eliminated by a combination of renal excretion
disease. and hepatic metabolism. H 2 receptor antagonists are
remarkably safe and well tolerated. Overall incidence of side-
Clinical Features of Uncomplicated Peptic Ulcer Disease
effects is less than 4% and serious side effects are very
The main symptom of peptic ulcer disease is abdominal pain. uncommon. A variety of central nervous system symptoms
Patients with duodenal ulcer describe burning or gnawing have been rarely reported; these include headache, dizziness,
epigastric pain. Pain occurs 2 to 3 hours after a meal and is depression. Drug interactions (inhibiting elimination of
relieved after food or with antacids. Pain may occur in the night. theophylline, phenytoin, lidocaine, quinidine and warfarin)
Anorexia and weight loss are uncommon. Patients with gastric have been reported due to binding of hepatic cytochrome
ulcers may have pain indistinguishable from duodenal ulcer. P450 (CYP) system. Tolerance appears to develop quickly and
Peptic ulcers may be asymptomatic. Symptoms are neither frequently.
specific nor sensitive for diagnosing peptic ulcers. If peptic ulcer
is suspected, investigations must be carried out. Increase in Proton pump inhibitors
severity of pain, radiation of pain to the back, pallor, vomiting These agents decrease gastric acid by inhibiting the H+/K+
or bleeding should point to the development of complications. ATPase pump of the parietal cell. Currently five PPIs are
It should be remembered that the symptoms of gastric cancer available; omeprazole, lansoprazole, pantoprazole, rabeprazole
may be very similar to those of peptic ulcer. Presence of alarm and esomeprazole. They are all substituted benzimidazoles
signs like increased severity of pain, pallor, weight loss, vomiting, and are weak bases. They are prodrugs and are acid labile. PPIs
high ESR and presence of occult blood in stool should prompt are most effective when administered immediately before
investigations. In uncomplicated peptic ulcer the clinical meals. If the dose is once daily, it is preferable to administer
examination will be unremarkable or the only sign will be immediately before breakfast. Single dose may inhibit gastric
tenderness in the epigastrium or slightly to the right of the acid secretion for more than 24 hours. Newer PPIs inhibit H+/
midline in the upper abdomen. K+ ATPase more rapidly than omeprazole. PPIs are remarkably
Diagnostic Tests safe. Common side-effects are headache and diarrhoea. No
dose adjustment is required in patients with renal or hepatic
Upper GI endoscopy has become the gold standard for impairment. Elevation of gastric pH can interfere with
diagnosis of peptic ulcer. Barium-meal is a far less sensitive absorption of drugs such as ketoconazole (decrease) and
investigation. Also endoscopy allows an opportunity for digoxin (increase). Drug interactions are uncommon. Potential
mucosal biopsy. Studies of acid secretion have little role in the interactions may occur since PPIs are metabolised by CYP
diagnosis of peptic ulcer. However, these are useful in the work system. One such example is reduction in the effect of
up of hypergastrinaemia, and to assess the completeness of clopidogrel. Although PPIs cause hypergastrinaemia, there is
vagotomy in recurrent ulcer. In patients with refractory peptic no human report of development of gastric carcinoid tumours.
ulcer, serum calcium and fasting serum gastrin are indicated. Tolerance to the anti-secretory effects of PPIs is not seen. There
Treatment is no need for routine H. pylori eradication prior to initiating
The treatment of peptic ulcer has dramatically changed over treatment with PPIs.
the years. From bed rest and prescription of ‘bland diets’ came Mucosa protective agents
the era of antacids. The discovery of H2 receptor antagonists
and later of proton pump inhibitors (PPIs) achieved greater ulcer Sucralfate: This is a complex metal salt of sulphated sucrose
healing rates. The real revolution occurred, however, with and aluminium hydroxide. When exposed to gastric acid, the
discovery of the link between H. pylori and peptic ulcer. aluminium hydroxide dissociates, leaving sulphate anions that
can bind electrostatically to positively charged proteins in
Acid lowering drugs damaged tissue. It forms a protective layer over the ulcer
These are not routinely required for patients with uncomplicated craters. Other beneficial effects include increase in mucosal
H. pylori ulcers in whom the bacterium has been successfully prostaglandins, stimulation of mucous and bicarbonate
eradicated. However, anti-ulcer drugs are important for healing secretions, binding of bile salts and promotion of angiogenesis.
of large ulcers, management of complicated ulcer disease such It is effective in promoting healing when given in a dose of 1
as bleeding, reducing the risk of ulcer relapse in patients on g four times a day. Since it is not absorbed, there is no systemic
NSAIDs and treating idiopathic ulcers. toxicity.
Antacids: Besides increasing the gastric pH, antacids have a variety Bismuth: The two commonly used preparations are colloidal
of cytoprotective effects. At present, they are used mainly for bismuth subcitrate and bismuth subsalicylate. The bismuth
relieving symptoms. Side-effects include diarrhoea (magnesium component forms complexes with mucous and coats the ulcer
809
 craters. Also bismuth has anti-microbial action against H. pylori. compliance, failed H. pylori eradication, ongoing NSAIDs,
Bismuth is unabsorbed if given over a short duration and systemic smoking, hyper-secretory condition and other aetiologies
toxicity is rare. (neoplastic, infective).
Prostaglandin E analogues: Prostaglandin E2 regulates mucosal Complications
blood flow, epithelial cell proliferation, epithelial restitution, The complications of peptic ulcer are penetration, perforation,
mucosal immunocyte function, mucous and bicarbonate haemorrhage and obstruction.
secretion, and basal acid secretion. Misoprostol, a prostaglandin
analogue is used for prevention of NSAIDs-induced ulcer Penetration refers to the extension of the ulcer through the
disease. It is well absorbed after oral administration. Dose related bowel wall into the adjacent structures without producing free
diarrhoea is observed in nearly one-third of the patients. It is perforation into the peritoneal cavity. The ulcer can penetrate
contraindicated in pregnant women. into the pancreas, biliary tract, omentum or colon. Perforation
into the colon leads to gastro-colic fistula. Symptoms of
Ulcers associated with H. pylori penetration vary depending on the organ involved. It manifests
Peptic ulcer management was revolutionised after discovery as increase in severity and duration of pain and failure of pain
of H. pylori. It is well established that H. pylori eradication not relief with antacids or food.
only heals ulcers but also prevents relapses. H. pylori is associated
Bleeding from peptic ulcer is a life-threatening complication.The
with 70% to 90% of duodenal ulcers and 40% to 70% of gastric
patient may present with melaena, haematemesis or both.
ulcers. For uncomplicated duodenal ulcers, additional anti-
When the bleeding is massive haematochezia will be present.
secretory treatment is not required. For large gastric ulcers
Old age, shock at the time of admission and massive bleeding
additional anti-secretory treatment may promote ulcer healing.
necessitating transfusion of more than five units of blood indicate
For large gastric ulcers, biopsy must be taken to exclude
poor prognosis, and surgery should be considered in these
malignancy. After successful eradication, maintenance therapy
situations. The first step in the management is resuscitation
with anti-secretory agents is not required.
of the patient by replacing the blood volume and managing
Ulcers associated with NSAIDs haemodynamic instability. Upper GI endoscopy should be done
In this situation NSAIDs should be discontinued, if possible. PPIs as soon as the patient is stable. This will show the site of bleed.
are more effective than H2 receptor antagonists or misoprostol Active bleeding or the presence of high-risk lesions—visible vessel
for healing of NSAIDs-induced ulcers. There is little role of or adherent clot (Figure 4)—call for endoscopic management.
substituting a selective COX 2 inhibitor in place of conventional Injection of saline or dilute adrenaline (Figure 5), application
NSAIDs once an ulcer develops. H. pylori needs to be eradicated of heater probe, endoscopic application of clips (Figure 6) can
if present in these patients. all arrest the bleeding. Anti-secretory treatment (intravenous,
continuous infusion of PPI) should be started.
Prophylaxis of NSAIDs ulcers
H2 receptor antagonists reduce the risk of duodenal ulcers but
not gastric ulcers. Misoprostol reduces the risk of NSAIDs-
induced gastric and duodenal ulcers. Higher dose (800 μg/day)
of misoprostol reduced ulcer complications. PPIs are very
effective in reducing the risk of NSAID-induced gastric and
duodenal ulcers. COX 2 inhibitors induced fewer ulcers than
conventional NSAIDs. New data suggest that a combination
of non-selective NSAIDs with PPI is as effective or better than
using selective COX 2 inhibitors in prevention of NSAIDs-ulcers.
Also studies have shown increased serious cardiovascular
events with the use of COX 2 inhibitors. If H. pylori is present,
it needs to be eradicated. This is also recommended for
patients on long-term, low-dose aspirin. In patients with risk
factors for ulcer complications (Table 1), co-therapy with a PPI
is recommended.

Table 1: Risk Factors for NSAIDs-Induced Ulcer Complications

History of peptic ulcer complication
Increasing age Figure 4: Duodenal ulcer with stigmata of recent bleed (black base).
Use of steroids
Use of anti-coagulants Perforation of peptic ulcer is an emergency. The patient
Use of combination NSAIDs presents with sudden onset of abdominal pain; peritonitis and
Co-morbid diseases free gas in the peritoneum are present. Patients who present
Smoking late and those who develop perforation while in the hospital
have a poor prognosis. Surgical treatment, which involves
Refractory Peptic Ulcers closure of the perforation with an omental patch is the
Most peptic ulcers heal with 8 to 12 weeks of anti-secretory procedure often employed. Effective treatment of H. pylori
810 therapy. If this does not occur, consider the following: lack of infection and strong acid suppressants are available now, and
 Diseases of the Stomach and Duodenum
Figure 5: Injection sclerotherapy being done for bleeding duodenal ulcer with Figure 7: Endoscopic balloon dilatation for pyloroduodenal stenosis.
stigmata of recent bleed (visible vessel).

Ulcers in the lower end of the oesophagus may in the long

run lead to peptic strictures and dysphagia. Endoscopic
balloon dilatation gives symptomatic relief to these patients.
Fibrosis during healing of gastric ulcers may result in rare
deformities of the stomach like ‘tea-pot stomach’ or the ‘hour-
glass stomach’.
Recurrent ulcer is the term used for recurrence of ulcers after
surgical treatment of duodenal ulcer. Incomplete vagotomy and
retained antrum are the most common causes.
Duodenal ulcer does not turn malignant. H. pylori is implicated
as an aetiological agent in carcinoma stomach. In spite of the
high prevalence of H. pylori in persons with peptic ulcer,
duodenal ulcer is not a risk factor for the cancer of the stomach
or of the duodenum. However, persons who had undergone
surgery (partial gastrectomy) for duodenal ulcer are at increased
risk of developing cancer in the post-operative stomach.
Figure 6: Haemoclips applied to base of bleeding ulcer.
GASTRIC VOLVULUS
hence, a definitive surgical treatment may not be necessary in Twisting of the stomach upon itself leads to gastric volvulus which
selected patients; small leaks into peritoneum can be managed can present clinically either acutely or as chronic volvulus. Three
conservatively. types have been described—organoaxial volvulus is the most
Obstruction in peptic ulcer may be due to fibrosis, inflammation common; in this type the stomach twists along its long axis
or spasm. It is the pyloric channel ulcers or ulcers in the first part (cardiopyloric line); mesenteroaxial volvulus is one in which the
of duodenum that develop gastric outlet obstruction. Gastric stomach falls on itself along an imaginary line drawn from the
outlet obstruction (pyloric stenosis) (Figure 7) presents with post- mid-point of the lesser curvature to the mid-point of the greater
prandial bloating, fullness and vomiting. Vomiting brings out curvature and is the least common of the three; mixed gastric
food consumed several (>6) hours ago. Foul smelling eructations volvulus is a combination of organoaxial and mesenteroaxial
may be present. Examination reveals a visibly dilated stomach, types. Anatomical anomalies such as ligamentous laxity,
visible peristalsis or succussion splash. Barium meal shows a paraoesophageal hiatus hernia, eventration of the diaphragm,
dilated stomach with delayed emptying. Endoscopy should be extrinsic compression from adjacent organs or submucosal
performed after thorough cleaning of the stomach. Carcinoma tumours of the stomach can cause gastric volvulus.
of the stomach should be excluded in every patient with gastric Patients with acute gastric volvulus present as an acute
outlet obstruction as malignancy is seen in about half of such abdomen with the classical triad of violent retching and little
cases. Management includes gastric lavage to remove food debris, vomiting, severe epigastric pain and inability to advance a
correction of fluid and electrolyte disturbances and metabolic nasogastric tube into the stomach. In patients with chronic
consequences of prolonged vomiting and loss of gastric acid.
volvulus the major symptoms are epigastric pain, bloating and
Anti-secretory drugs should be administered parenterally since
eructations.
absorption is poor. H. pylori infection and NSAID intake should
be looked for and managed. If the symptoms fail to respond, Barium-meal examination usually demonstrates the twisted
surgery is indicated. Endoscopic balloon dilatation of the stomach. Acute volvulus is an emergency and usually requires
narrowed segment has also been used successfully (Figure 7). an emergent laparotomy although endoscopic derotation of the 811
 volvulus is sometimes successful. Recurrent symptoms in patients
with chronic volvulus need surgical treatment wherein the
stomach is fixed to the anterior abdominal wall by performing a
gastropexy. Recently, percutaneous endoscopic gastrostomy has
been found to be an alternative to surgical gastropexy.

BEZOARS
These have been classified into two main groups: hair or
trichobezoar and plant or phytobezoars. Other materials such as
chemical concretions, food boluses and foreign bodies may also
cause bezoars. For phytobezoars, hypochlorhydria, gastroparesis
and incomplete mastication are important predisposing factors.
In patients with trichobezoar, underlying neuropsychiatric
disturbances may be present. Bezoars present with pain in the
upper abdomen, periodic attacks of nausea and vomiting and a
lump in the abdomen. Complications such as gastric ulcer,
perforation and peritonitis may occur. Plain X-ray abdomen in
the standing position occasionally demonstrates a mass invading
the gastric air bubble. Barium-meal examination demonstrates a
barium shell coating an irregular large filling defect. In most cases
upper GI endoscopy is diagnostic. For treating phytobezoars,
Figure 8: Barium-meal examination showing duodenal diverticulum along
endoscopic internal fragmentation using forceps and medial wall.
polypectomy snares may be tried. Chemical dissolution using
papain, cellulase and acetylcysteine is sometimes successful. If duct. The treatment of a complicated duodenal diverticulum is
these methods fail, surgical removal needs to be done. In most surgical.
cases of trichobezoars, surgery is required.
RECOMMENDED READINGS
DUODENAL DIVERTICULUM 1. Chiba N, Hunt RH. Ulcer disease and Helicobacter pylori infection: aetiology
It is usually single and present along the medial wall of the and treatment. In: McDonald JWD, Burroughs AK, Feagan BG, editors.
duodenum. It is acquired as an outpouching of the duodenal Evidence Based Gastroenterology and Hepatology. Bangalore: Panther
Publishers; 1999: pp 91-117.
mucosa at the point of maximum weakness. Most often this
2. Desai HG. Gastritis: Indian Perspective. Vakils, Feffer and Simons Pvt Ltd 2008.
diverticulum is asymptomatic and incidentally detected during
3. Spechler JS, Cryer B. Peptic ulcer disease. In: Mark Feldman, Lawrence S.
a barium-meal examination or Upper GI endoscopy (Figure 8). Friedman, Lawrence J. Brandt editors. Sleisenger and Fordtran’s
Rarely, duodenal diverticulum may perforate retroperitoneally, Gastrointestinal and Liver Diseases Pathophysiology/Diagnosis/Management.
cause upper GI bleeding or obstruct the bile duct or pancreatic WB Saunders & Co.; 2006: pp 1089-110.

812
 13.9 Diseases of the Pancreas

V Balakrishnan, G Rajesh

ACUTE PANCREATITIS abdominal tenderness. In severe pancreatitis, patients look

Acute pancreatitis (AP) is an acute inflammatory process of the severely ill and often have abdominal distention, especially
pancreas with variable involvement of other regional tissues epigastric, which is due to gastric ileus or dilatation of the
or remote organ systems. transverse colon. Bowel sounds are reduced and may be absent.
Mild acute pancreatitis consists of minimal or no organ Table 2: Aetiology of Acute Pancreatitis
dysfunction and an uneventful recovery. Severe pancreatitis
manifests as organ failure and/or local complications such as Gallstones
necrosis, abscess, or pseudocyst (Table 1). Overall, about 20% Biliary sludge and microlithiasis
Alcohol
of patients with acute pancreatitis have a severe course, and
Mechanical obstruction of ampulla
10% to 30% of those with severe acute pancreatitis die.
Metabolic: Hypertriglyceridaemia and hypercalcaemia
Table 1: Criteria of Severe Acute Pancreatitis Infections: Mumps, HIV, CMV, EBV, Clonorchiasis, and Ascariasis
Toxins: Scorpion venom, organophosphorous insecticides
Organ failure Trauma
Shock: Systolic blood pressure of <90 mm Hg Post ERCP
PaO2 <60 mmHg Pregnancy
S. Creatinine >2 mg/dL Post-operative
Gastrointestinal bleed of >500 mL in 24 hours
Hereditary
And/Or local complications Ischaemia
Necrosis Drugs: Pentamidine, didanosine, salicylates, sulindac, frusemide,
Abscess thiazides
Pseudocyst Sulphasalazine, mesalamine, L-asparaginase, azathioprine, valproic
Unfavourable prognostic signs acid, ACE-inhibitors
>3 Ranson’s signs
>8 APACHE II points Diagnosis
Acute pancreatitis can be diagnosed by the presence of typical
Aetiopathogenesis clinical features along with corroborative laboratory findings
The gallstone disease and alcohol are the two most common of elevated serum enzymes (amylase/lipase) and/or imaging
causes for AP (Table 2). The initial step in the pathogenesis of features. It needs to be differentiated from other abdominal
acute pancreatitis is conversion of trypsinogen to trypsin within causes which may present as an acute abdomen.
acinar cells.Trypsin, in turn, catalyses conversion of pro-enzymes,
Investigations
including trypsinogen and inactive precursors of elastase,
phospholipase A2, and carboxypeptidase, to active enzymes. Blood investigations
Active enzymes autodigest the pancreas and initiate a cycle of The white blood cell count is usually elevated, markedly so in
releasing more active enzymes. Factors that may initiate severe pancreatitis. A raised haematocrit, indicative of haemo-
gallstone pancreatitis include reflux of bile into the pancreatic concentration, may indicate severe disease.
duct or obstruction of the pancreatic duct at the ampulla by a
Serum amylase is the most frequently ordered test. However,
stone(s) or oedema resulting from the passage of a stone. The
hyperamylasemia can also occur in other conditions. In acute
pathophysiology of acute pancreatitis includes microcirculatory
pancreatitis, the serum amylase concentration is usually more
injury, leucocyte chemoattraction and release of cytokines,
than three times the upper limit of normal. Measurement of
oxidative stress, and bacterial translocation.
serum lipase is performed less frequently. Amylase levels
Clinical Features tend to return to normal faster than lipase levels, so that
Abdominal pain is present at the onset, but the timing of measurement of the latter is particularly useful in patients who
abdominal pain is variable. Biliary colic may herald or progress present several days after the onset of pain. An increase in serum
to acute pancreatitis. Alcohol-related acute pancreatitis alanine aminotransferase (ALT) 3 to 4 times the base-line level
frequently occurs 1 to 3 days following drinking. The pain suggests gallstone-induced pancreatitis.
radiates to back and is associated with nausea and vomiting. Its Imaging
onset is rapid and reaches maximal intensity in 10 to 20 minutes.
There can be localised ileus of a segment of small intestine
Occasionally, pain takes several hours to reach maximum
(‘sentinel loop’) or the colon cut-off sign on a plain radiograph
intensity. It is steady and moderate to very severe in intensity.
of the abdomen. Thirty per cent of patients with acute
Physical findings depend on the severity of an attack. Patients pancreatitis have abnormalities in chest radiograph in the form
with mild pancreatitis may not appear acutely ill and have mild of elevation of a hemi-diaphragm, pleural effusion(s), basal or 813
 plate-like atelectasis secondary to limited respiratory excursion, Mild acute pancreatitis
and pulmonary infiltrates. The prognosis of mild pancreatitis is good and can be managed in
Transabdominal ultrasonography is the best initial imaging a regular hospital ward with fluid administration, bowel rest and
modality. It is used during the first 24 hours of hospitalisation analgesics. Fluid resuscitation is important to replace low intra-
to search for gallstones, dilatation of the common bile duct due vascular volume due to vomiting, diaphoresis, and third-space
to choledocholithiasis and ascites. Pancreas is usually diffusely losses. Abdominal pain is treated with parenteral analgesics. Most
enlarged and hypoechoic. patients require no further therapy and recover within a week.

A contrast enhanced computed tomography (CECT) scan of the Severe acute pancreatitis
abdomen is the most important imaging test for the diagnosis Patients with signs of severe acute pancreatitis should be
of acute pancreatitis and its intra-abdominal complications and identified early and admitted promptly to an intensive care
is also used to assess the severity of the disease. unit. The goal is to provide supportive care and treatment of
complications when they develop. Maintaining adequate intra-
Magnetic resonance imaging (MRI) shows the pancreas as well
vascular volume may require 5 to 10 litres of fluid daily for the
CT scan. In addition, it has certain advantages over the latter. It
initial few days. Hypoxaemia (oxygen saturation <90%) requires
does not carry the potential nephrotoxicity of the contrast
oxygen, ideally by nasal prongs or by facemask. If nasal oxygen
required to perform CECT, better than it avoids the radiation
fails to correct hypoxaemia or if there is fatigue and borderline
exposure of CT scan and finally, it shows a greater ability than
respiratory reserve, endotracheal intubation and assisted
CT scan to distinguish necrosis from fluid.
ventilation are required early. Nutritional support via nasojejunal
Endoscopic ultrasound (EUS) helps in timely diagnosis of feedings should be initiated. Hyperglycaemia may present during
common bile duct (CBD) or ampullary stones in the setting of the first several days of severe pancreatitis but usually normalises
acute gallstone pancreatitis; hence it can be used instead of as the inflammatory process subsides. Blood sugar levels can be
diagnostic endoscopic retrograde cholangio-pancreatography variable, and insulin should be administered cautiously.
(ERCP) to identify patients who would likely benefit from
Sterile pancreatic necrosis is managed conservatively. Bacterial
therapeutic ERCP.
infection of pancreatic and peripancreatic tissues develops
Treatment usually after one week in approximately 30% of severe acute
The algorithm for treatment of acute pancreatitis is outlined in pancreatitis. Three approaches to decrease bacterial infections
Figure 1. in acute necrotising pancreatitis are used; they are selective
decontamination of the gut with non-absorbable antibiotics,
prophylactic systemic antibiotics, and enteral feeding to avoid
catheter-related infections associated with a central line, to
maintain gut barrier integrity, and to decrease bacterial
translocation.
Infected pancreatic necrosis should be suspected in patients
with worsening of symptoms after initial improvement; and in
those who develop new fever, marked leucocytosis, positive
blood cultures, or other evidence of sepsis. The important
organisms causing infection in necrotising pancreatitis are
from the gut (Escherichia coli, Pseudomonas, Klebsiella, and
Enterococcus species). Standard regimens include imipenem
500 mg intravenously three times a day; pefloxacin (fluoro-
quinolone) 400 mg intravenously two times a day; or
metronidazole 500 mg three times a day for 10 to 14 days.
Infected pancreatic necrosis usually requires minimally invasive
debridement via endoscopic or surgical approaches.
Urgent therapeutic ERCP should be performed in patients with
suspected or proven biliary pancreatitis, who satisfy the criteria
for predicted or actual severe pancreatitis; or when there is
cholangitis, jaundice, or a dilated common bile duct.
Adequate supply of nutrients plays an important role early in
management. Enteral feeding is safe and as effective. However,
total parenteral nutrition may be necessary for patients who
cannot obtain sufficient calories through enteral nutrition or in
whom enteral access cannot be maintained; but carries an
increased risk of infection.
Prognostic indicators
These include use of single markers like C-reactive protein (CRP),
Figure 1: Algorithm for management of pancreatitis.
814 trypsin activation peptide (TAP), procalcitonin, etc. as well as
 Diseases of the Pancreas
scoring systems like Ranson’s score, Glasgow score, acute deficiencies, especially of micronutrients and antioxidants or/
physiology and chronic health evaluation (APACHE) II, among and dietary toxins such as cyanogenic glycosides (cassava or
others (Tables 3 and 4). A new prognostic scoring system, the tapioca), have been considered as likely aetiological factors.
bedside index for severity in acute pancreatitis—BISAP (blood
Hereditary pancreatitis
urea nitrogen >25 mg/dL, impaired mental status, systemic
inflammatory response syndrome (SIRS), age >60 years, and Hereditary pancreatitis is a rare autosomal dominant disorder
pleural effusions) was comparable to existing scoring systems. with approximately 80% penetrance. It presents typically
in childhood or early adulthood with abdominal pain and
Table 3: Complications of Acute Pancreatitis recurrent acute attacks of pancreatitis.
Local Table 5: Aetiologic Risk Factors Associated with Chronic
Pseudocyst Pancreatitis: TIGAR-O Classification System
Necrosis
Toxic-metabolic
Abscess
Alcohol, tobacco smoking, hypercalcaemia (hyperparathyroidism),
Gastrointestinal bleed due to ulcerations, gastric varices and
chronic renal failure, medications (phenacetin), toxins (organotin
pseudoaneurysm rupture
compounds, e.g. DBTC)
Systemic
Idiopathic
Shock
Early onset, late onset
Coagulopathy
Tropical (tropical calcific pancreatitis,fibrocalculous pancreatic diabetes)
Respiratory failure
Genetic
Renal failure
Autosomal dominant (Cationic trypsinogen codon 29 and 122 mutations)
Metabolic: Hyperglycaemia, hypocalcaemia
Autosomal recessive/modifier genes (CFTR mutations,SPINK1 mutations
Subcutaneous nodules
Cationic trypsinogen codon 16, 22, 23 mutations, α1-antitrypsin
Retinopathy
deficiency)
Psychosis
Autoimmune
Isolated autoimmune chronic pancreatitis
Table 4: Ranson’s Criteria for Assessing Severity of Acute
Pancreatitis Syndromic autoimmune chronic pancreatitis (Sjögren syndrome-
associated chronic pancreatitis, inflammatory bowel disease-associated
Non-gallstone Gallstone chronic pancreatitis
pancreatitis pancreatitis Primary biliary cirrhosis—associated chronic pancreatitis)
On Admission Recurrent and severe acute pancreatitis
Age (years) >55 >70 Post-necrotic (severe acute pancreatitis), recurrent acute pancreatitis,
WBC (/cmm) 16000 18000 vascular diseases/ischaemic, post-irradiation
Glucose (mg/dL) >200 >220 Obstructive
LDH (IU/L) >350 >400
Pancreatic divisum, sphincter of Oddi disorders, duct obstruction
AST (IU/L) >250 >250
(e.g. tumour)
Within 48 hours of admission Pre-ampullary duodenal wall cysts,post-traumatic pancreatic duct scars
Haematocrit fall >10 >10
BUN rise (mg/dL) >5 >2
Obstructive chronic pancreatitis
Calcium (mg/dL) <8 <8
PO2 mmHg <60 — Obstruction of the main pancreatic duct by tumours, scars, cysts,
Base deficit (mEq/L) >4 >5 or stenosis of the papilla of Vater or minor papilla can produce
Fluid deficit >6L >4L chronic pancreatitis in the parenchyma upstream of the
obstruction. Blunt and penetrating trauma to the pancreas can
CHRONIC PANCREATITIS also lead to pancreatic duct strictures.
Chronic pancreatitis (CP) is characterised by pancreatic
Autoimmune pancreatitis
inflammation and fibrosis, the end point of which is destruction
of pancreatic parenchyma with eventual loss of exocrine and This is characterised by presence of autoantibodies, elevated
endocrine function. levels of immunoglobulins especially IgG4, enlargement of the
pancreas (diffuse or focal), pancreatic duct strictures, and
Aetiology pathologic features of a dense lymphocytic infiltrate. A common
The aetiologic risk factors associated with chronic pancreatitis presentation is that of a pancreatic mass mimicking cancer. It is
is given in Table 5. often steroid responsive. Low dose steroids or immuno-
modulators may be needed to maintain remission.
Alcohol
The most common cause of chronic pancreatitis in the Western Idiopathic chronic pancreatitis
world and in Japan is excessive alcohol consumption. In most Idiopathic chronic pancreatitis accounts for 10% to 30% of all
patients, at least five years of alcohol intake exceeding 80 g/ cases of CP in the West and 40% to 60% in India, and appears to
day is required prior to the development of chronic pancreatitis. occur in two forms, early onset and late onset type.
Tropical pancreatitis Pathophysiology
Tropical pancreatitis ( TCP) remains an important form of The pathophysiology of CP remains incompletely understood.
chronic pancreatitis in certain areas of India. The exact Four major theories include toxic-metabolic, oxidative stress, 815
aetiopathogenesis of TCP remains unknown. Nutritional stone and duct obstruction, and necrosis-fibrosis.
 Pathology Imaging
In early CP, areas of interlobular fibrosis are seen, with the fibrosis The demonstration of pancreatic calcification on imaging is
often extending to the ductal structures. Infiltration of the pathognomonic of CP. Diagnosis is difficult in early cases of
fibrotic area and lobules with lymphocytes, plasma cells, and pancreatitis where the patient may have typical symptoms but
macrophages is seen. In affected lobules, acinar cells are lack diagnostic imaging features on ultrasonography (USG)/CT.
replaced by fibrosis. As the disease progresses, fibrosis within In such cases, an endoscopic retrograde pancreatography (ERP)
the lobules and between lobules becomes more widespread. or a EUS may be helpful.
The pancreatic ducts become more abnormal, with progressive
Pancreatic calcifications are most common in alcoholic, late-
fibrosis, stricture formation, and dilation. Protein plugs may
onset idiopathic, hereditary and especially in tropical
calcify and obstruct major pancreatic ducts.
pancreatitis and may be detected on abdominal radiograph.
Clinical Features
Ultrasonography findings indicative of CP include dilation of
The cardinal symptom of CP is abdominal pain. Fat mal- the pancreatic duct, pancreatic ductal stones, gland atrophy or
absorption leading to steatorrhoea and weight loss is common enlargement, irregular gland margins, pseudocysts and changes
in CP. Steatorrhoea does not occur until pancreatic lipase in the parenchymal echotexture.
secretion is reduced to less than 10% of normal. Diabetes in CP is
considered as a secondary form of diabetes mellitus. Weight CECT scan of the abdomen is superior to USG. The sensitivity of
loss is most commonly due to decreased intake in episodes of CT for CP is 75% to 90% and specificity 85% or more.
acute exacerbation. Weight loss may also occur owing to the ERCP is considered the most specific and sensitive test of
development of small bowel bacterial overgrowth, mal- pancreatic structure. The sensitivity of ERCP is between 70%
absorption, uncontrolled diabetes or pancreatic or extra- and 90%, with a specificity of 80% to 100%.
pancreatic malignancy.
Magnetic resonance cholangiopancreatography (MRCP)
Physical examination might show evidence of nutritional agrees with ERCP in 70% to 80% of findings. MRCP is non-
deficiencies. Complications of common bile duct obstruction invasive, avoids ionising radiation and contrast administration,
or a pseudocyst may produce physical findings of jaundice, or and does not routinely require sedation, making it a diagnostic
a palpable swelling in the epigastrium. Ascites may rarely follow procedure of choice in some groups of patients, particularly
a leak from a ruptured pancreatic duct. A palpable spleen may children.
be seen following thrombosis of the splenic vein (Table 6).
EUS is the best among currently available tests for the detection
Diagnosis of early changes of CP. Typical findings in CP include
Serum amylase or lipase may be found to be elevated only parenchyma features like hyperechoic strands, hyperechoic foci,
during acute exacerbations. A full diabetic work-up should be lobularity, cysts; and ductal features like stones, main duct
done for all patients with suspected pancreatitis. A prediabetic irregularity, hyperechoic main duct, visible side branches, main
stage has been well described. duct dilatation.

Table 6: Complications of Chronic Pancreatitis

No. Complication Signs and Symptoms Treatment
1. Pseudocyst Increased abdominal pain, nausea, Endoscopic drainage (transmural or transpapillary)
vomiting, jaundice, palpable mass, Surgical drainage (cyst-gastrostomy or cyst-jejunostomy)
bleeding, increase in amylase and lipase Percutaneous drainage
2. Biliary obstruction Jaundice, biliary pain, cholangitis, Drainage of obstructing pseudocyst
pruritus Endoscopic decompression
Surgical decompression
Surgical biliary bypass, either with a
cholecystojejunostomy or choledochojejunostomy
3. Gastric outlet Abdominal pain, early satiety, Drainage of pseudocyst
obstruction nausea and vomiting Surgical gastrojejunostomy
4. Pancreatic Increased pain, weight loss, Whipple’s or mo