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TRANSPLANTATION
OF THE LIVER
Third Edition

Ronald W. Busuttil, MD, PhD

William P. Longmire, Jr., Chair in Surgery
Distinguished Professor and Executive Chairman
UCLA Department of Surgery
Chief, Division of Liver and Pancreas Transplantation
David Geffen School of Medicine at UCLA
Los Angeles, California

Göran B.G. Klintmalm, MD, PhD

Chief and Chairman
Annette C. and Harold C. Simmons Transplant Institute
W.W. Caruth Chair in Organ Transplant Immunology
Professor of Surgery, Texas A&M College of Medicine
Vice Chair, Department of Surgery
Division Chief, Transplant Surgery
Dallas, Texas
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899

TRANSPLANTATION OF THE LIVER, THIRD EDITION ISBN: 978-1-4557-0268-8

Copyright © 2015, 2005, 1996 by Saunders, an imprint of Elsevier Inc.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopying, recording, or any information storage and retrieval system, without
permission in writing from the Publisher. Details on how to seek permission, further information about the
Publisher’s permissions policies, and our arrangements with organizations such as the Copyright Clearance
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This book and the individual contributions contained in it are protected under copyright by the Publisher
(other than as may be noted herein).

Notices

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broaden our understanding, changes in research methods, professional practices, or medical treatment
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Practitioners and researchers must always rely on their own experience and knowledge in evaluating
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Library of Congress Cataloging-in-Publication Data

Transplantation of the liver (Busuttil)

Transplantation of the liver / [edited by] Ronald W. Busuttil, Göran B.G. Klintmalm. -- Third edition.
   p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-4557-0268-8 (hardback : alk. paper)
I. Busuttil, Ronald W., editor. II. Klintmalm, Göran B., editor. III. Title.
    [DNLM: 1. Liver Transplantation. 2. Liver Diseases--surgery. WI 770]
RD546
617.5’5620592--dc23
2014037966

Executive Content Strategist: Michael Houston

Content Development Manager: Joan Ryan
Publishing Services Manager: Anne Altepeter
Project Manager: Jennifer Nemec Moore
Design Direction: Lou Forgione

Printed in the United States of America

Last digit is the print number: 9 8 7 6 5 4 3 2 1

 Contributors

Kareem Abu-Elmagd, MD, PhD Lars Bäckman, MD, PhD

Professor of Surgery Professor of Surgery
Digestive Disease Institute Director, Transplantation Surgery
Transplantation Center Uppsala University Hospital
Cleveland Clinic Uppsala, Sweden
Cleveland, Ohio Organ Allocation: The European Models
Leukocyte Chimerism—Meaning and Consequences
Talia B. Baker, MD
Chul-Soo Ahn, MD, PhD Associate Professor of Surgery
Professor of Surgery Northwestern University
Hepatobiliary Surgery and Liver Transplantation Director, Living Donor Liver Transplant
Asan Medical Center Comprehensive Transplant Center
Ulsan University College of Medicine Chicago, Illinois
Seoul, South Korea Minimally Invasive Living Donor Hepatectomy
Dual Grafts for Transplantation
William F. Balistreri, MD
Reza Allamezadeh, MD Professor of Pediatrics and Medicine
Clinical Instructor Director, Pediatric Liver Care Center
Department of Medicine Gastroenterology, Hepatology, and Nutrition
Nephrology Division Children’s Hospital Medical Center
Kidney Transplant Program Cincinnati, Ohio
David Geffen School of Medicine at UCLA Transplantation for Cholestatic Liver Disease
Los Angeles, California in Children
Renal Failure in Adults
Rafael Bañares, MD
Estella M. Alonso, MD Professor and Head of Medicine
Professor of Pediatrics Liver Unit
Northwestern University Feinberg School of Medicine Hospital General Universitario Gregorio Marañón
Medical Director Faculty of Medicine
Liver Transplant Program Complutense University of Madrid
Chicago, Illinois Madrid, Spain
General Criteria for Pediatric Transplantation Current Clinical Status of Extracorporeal Devices

Maria H. Alonso, MD Angeles Baquerizo, MD, PhD

Associate Professor Transplant and Hepatobiliary Surgeon
Division of Pediatric General and Thoracic Surgery Scripps Center for Cell and Organ Transplantation
University of Cincinnati La Jolla, California
Surgical Director Current Clinical Status of Extracorporeal Devices
Kidney Transplant Program
Cincinnati Children’s Hospital Medical Center Lokesh Bathla, MD
Cincinnati, Ohio Fellow, Section of Transplant Surgery
Transplantation for Hepatic Malignancy in Children University of Nebraska Medical Center
Omaha, Nebraska
Nancy L. Ascher, PhD Intestinal and Multivisceral Transplantation
Professor and Chair
Department of Surgery William Bennet, MD, PhD
Isis Distinguished Professor in Transplantation Senior Surgeon
Leon Goldman, MD, Distinguished Professor in Director of Liver Transplantation
Surgery Transplant Institute
Division of Transplant Surgery Sahlgrenska University Hospital
University of California, San Francisco Gothenburg, Sweden
San Francisco, California Organ Allocation: The European Models
Rejection After Transplantation
v
vi Contributors

Marina Berenguer, MD Sherilyn Gordon Burroughs, MD

University Valencia Assistant Professor of Surgery
Department of Medicine Weill-Cornell Medical College
Hepatology and Liver Transplantation Unit General Surgery and Organ Transplantation
La Fe Hospital and CIBEREHD Center for Liver Disease and Transplantation
National Network Center for Hepatology and The Methodist Hospital
Gastroenterology Research Houston, Texas
Hospital Universitario La Fe Donor Selection and Management
Valencia, Spain
Transplantation for Hepatitis C Ronald W. Busuttil, MD, PhD
William P. Longmire, Jr., Chair in Surgery
Gabriela A. Berlakovich, MD Distinguished Professor and Executive Chairman
Associate Professor UCLA Department of Surgery
Department of Surgery Chief, Division of Liver and Pancreas Transplantation
Division of Transplantation David Geffen School of Medicine at UCLA
Medical University of Vienna Los Angeles, California
Vienna, Austria Surgical Anatomy of the Liver; Influence of Transplantation
Organ Allocation: The European Models on Liver Surgery; Transplantation for Cholangiocarcinoma;
Transplantation for Biliary Atresia in Children; Management
Jorge A. Bezerra, MD of Portal Hypertensive Hemorrhage; Extended Criteria
Professor of Pediatrics Donors; Recipient Hepatectomy and Grafting; Arterial
Division of Gastroenterology, Hepatology, and Reconstruction; Portal Vein Thrombosis and Other Venous
Nutrition Anomalies; Retransplantation; Situs Inversus and Polysplenia
Cincinnati Children’s Hospital Medical Center Syndrome; Graft Failure; Arterial Complications After
Cincinnati, Ohio Transplantation; Outcome Predictors in Transplantation;
Transplantation for Cholestatic Liver Disease in Children Long-Term Functional Recovery and Quality of Life;
Ischemia-Reperfusion Injury in Liver Transplantation
Jacob L. Bilhartz, MD
Fellow, Division of Gastroenterology Juan Carlos Caicedo, MD
Department of Pediatrics Assistant Professor of Surgery
University of Michigan and C.S. Mott Children’s Northwestern Memorial Hospital
Hospital Northwestern University
Ann Arbor, Michigan Chicago, Illinois
Transition of Pediatric Patients to Adulthood Minimally Invasive Living Donor Hepatectomy

Robert S. Brown, Jr., MD Andrew M. Cameron, MD

Frank Cardile Professor of Medicine and Pediatrics Associate Professor
(in Surgery) Department of Surgery
Columbia University College of Physicians and Johns Hopkins Medical Institutions
Surgeons Baltimore, Maryland
Medical Director, Transplant Initiative Management of Portal Hypertensive Hemorrhage
New York-Presbyterian, Morgan Stanley Children’s
Hospital Jeffrey Campsen, MD
Columbia University Medical Center Assistant Professor of Surgery
Director, Center for Liver Disease and Division of Transplant Surgery
Transplantation University of Utah Health Sciences Center
New York-Presbyterian Hospital/Columbia University Salt Lake City, Utah
Medical Center Transplant-Related Malignancies
New York, New York
Current Indications, Contraindications, Delisting Criteria, Elizabeth J. Carey, MD
and Timing for Transplantation Assistant Professor of Medicine
Gastroenterology and Hepatology
Andrew Burroughs, MD Mayo Clinic Arizona
Professor of Hepatology Scottsdale, Arizona
The University of London Monitoring and Care
Consultant Physician and Hepatologist
Royal Free Hospital Ian C. Carmody, MD
London, United Kingdom Associate Professor of Surgery
Organ Allocation: The European Models Transplant Services
Ochsner Medical Center
New Orleans, Louisiana
Treatment of Acute and Chronic Rejection
 Contributors vii

J. Michael Cecka, MD Ana J. Coito, PhD

Professor Professor of Surgery
Director of Clinical Research Dumont-UCLA Transplantation Research Center
UCLA Immunogenetics Center Department of Surgery
Department of Pathology and Lab Medicine David Geffen School of Medicine at UCLA
University of California, Los Angeles Los Angeles, California
Los Angeles, California Ischemia-Reperfusion Injury in Liver Transplantation
ABO, Tissue Typing, and Crossmatch Incompatibility
Thomas Collins, MD
See-Ching Chan, MBBS, MS, PhD Clinical Associate Professor of Surgery
Professor Transplantation and Hepatobiliary Surgery
Department of Surgery Director of Surgical Skills Lab
University of Hong Kong Transplant Fellowship Program Director
Hong Kong, China Director of Liver Transplant
Outcomes of Living Donor Transplantation: The Eastern University of Iowa
Perspective; Adult Living Donor Right Hepatectomy and Iowa City, Iowa
Recipient Operation Donation After Cardiac or Brain Death: Regulatory and
Ethical Principles
Michael Charlton, MD
Professor of Medicine Jeffrey S. Crippin, MD
Department of Gastroenterology and Hepatology Professor of Medicine
Mayo Clinic and Foundation Marilyn Bornefeld Chair in Gastrointestinal Research
Rochester, Minnesota and Treatment
Transplantation for Nonalcoholic Steatohepatitis Internal Medicine
Washington University School of Medicine
Ali Cheaito, MD St. Louis, Missouri
Assistant Professor of Surgery Transplantation for Sclerosing Cholangitis
David Geffen School of Medicine at UCLA
Los Angeles, California David C. Cronin II, MD, PhD, MHCM
Arterial Complications After Transplantation Professor
Department of Surgery
Pauline W. Chen, MD Medical College of Wisconsin
Clinical Instructor Milwaukee, Wisconsin
Department of Surgery Ethics in Living Donor Transplantation
David Geffen School of Medicine at UCLA
Surgeon Gabriel M. Danovitch, MD
Dumont-UCLA Liver Cancer Center Professor of Medicine
and Transplant Center Department of Medicine
Los Angeles, California Nephrology Division
Treatment of Acute and Chronic Rejection Medical Director
Kidney Transplant Program
Srinath Chinnakotla, MD David Geffen School of Medicine at UCLA
Associate Professor Los Angeles, California
Department of Surgery Renal Failure in Adults
University of Minnesota Medical School
Minneapolis, Minnesota Gary L. Davis, MD
Graft-Versus-Host Disease Professor of Medicine
Director, General and Transplant Hepatology
Ruben Ciria, MD Medicine
Fellow, King’s Healthcare Partners Baylor Healthcare System and Baylor University
Kings College Hospital FT NHS Trust Medical Center
Institute of Liver Studies Dallas, Texas
London, United Kingdom Natural History of Hepatitis C; Recurrent Hepatitis C
Auxiliary Transplantation After Transplantation

Pierre-Alain Clavien, MD, PhD Gloria de la Rosa, MD, PhD

Professor and Chairman Medical Doctor
Department of Surgery Spanish National Transplant Organization
Division of Visceral and Transplant Surgery Madrid, Spain
University Hospital Zurich Organ Allocation: The European Models
Zurich, Switzerland
Principles of Liver Preservation
viii Contributors

Anthony J. Demetris, MD Douglas G. Farmer, MD

Professor Professor of Surgery
Department of Pathology Liver Transplant Surgery
University of Pittsburgh Dumont-UCLA Transplant Center
Pittsburgh, Pennsylvania Los Angeles, California
Histopathology of Liver Transplantation; Leukocyte Situs Inversus and Polysplenia Syndrome
Chimerism—Meaning and Consequences
Constantino Fondevila, MD, PhD
Joseph DiNorcia, MD General Surgery
Assistant Professor of Surgery Hospital Clinic
Division of Hepatobiliary, Pancreas, and Abdominal Barcelona, Spain
Organ Transplantation Extracorporeal Perfusion for Resuscitation of Marginal Grafts
Keck School of Medicine of USC
Los Angeles, California John L.R. Forsythe, MBBS, MD
Extended Criteria Donors Transplant Unit
Consultant Transplant Surgeon
John P. Duffy, MD Royal Infirmary of Edinburgh
Hepatobiliary and Abdominal Transplant Surgeon Edinburgh, United Kingdom
Nazih Zuhdi Transplant Institute Organ Allocation: The European Models
Integris Baptist Medical Center
Oklahoma City, Oklahoma Alyson N. Fox, MD
Arterial Reconstruction; Long-Term Functional Recovery Assistant Professor of Medicine
and Quality of Life Center for Liver Disease and Transplantation
New York Presbyterian Hospital-Weill Cornell Medical
Francisco A. Durazo, MD Center
Associate Clinical Professor of Medicine and Surgery New York, New York
Digestive and Liver Diseases Current Indications, Contraindications, Delisting Criteria,
Dumont-UCLA Transplant Center and Timing for Transplantation
University of California, Los Angeles
Los Angeles, California Ira J. Fox, MD
Unusual Indications for Transplantation Professor of Surgery
University of Pittsburgh School of Medicine
Bijan Eghtesad, MD Director, Center for Innovative Regenerative Therapies
Staff Surgeon Children’s Hospital of Pittsburgh of UPMC and the
Hepato-Pancreato-Biliary/Liver Transplant Surgery McGowan Institute for Regenerative Medicine
Cleveland Clinic Pittsburgh, Pennsylvania
Cleveland, Ohio Liver and Hepatocyte Xenotransplantation
Leukocyte Chimerism—Meaning and Consequences;
Graft-Versus-Host Disease Joel E. Frader, MD, MA
A Todd Davis Professor of Academic General Pediatrics
Jean C. Emond, MD Professor of Medical Humanities and Bioethics
Professor of Surgery Department of Pediatrics
Vice Chair and Chief of Transplantation Feinberg School of Medicine
New York-Presbyterian Hospital Northwestern University
Columbia University Medical Center Chicago, Illinois
New York, New York Ethical Decisions in Transplantation
Postoperative Care of Pediatric Transplant Recipients
Emily M. Fredericks, PhD
Carlos O. Esquivel, MD, PhD Associate Professor of Pediatrics
Professor of Surgery and Chief Division of Child Behavioral Health
Division of Abdominal Transplantation Surgery University of Michigan and C.S. Mott Children’s Hospital
Stanford School of Medicine Ann Arbor, Michigan
Stanford, California Transition of Pediatric Patients to Adulthood
Survival and Quality of Life in Children
James M. Fulmer, MD
Sheung Tat Fan, MS, MD, PhD, DSc Staff Radiologist
Sun C.Y. Chair Professor of Surgery Baylor University Medical Center
Department of Surgery American Radiology Associates, PA
The University of Hong Kong Dallas, Texas
Hong Kong, China Transplantation for Primary Hepatic Malignancy;
Outcomes of Living Donor Transplantation: The Eastern Transplantation for Budd-Chiari Syndrome
Perspective
 Contributors ix

John J. Fung, MD, PhD Michael D. Green, MD, MPH

Chairman of the Digestive Disease Institute Professor
Cleveland Clinic Pediatrics, Surgery, and Clinical and Translational
Cleveland, Ohio Research
Leukocyte Chimerism—Meaning and Consequences University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvania
Juan F. Gallegos-Orozco, MD Pretransplantation Evaluation: Infectious Disease
Assistant Professor of Medicine
Division of Gastroenterology, Hepatology, and Rick Harrison, MD
Nutrition Medical Director
University of Utah Health Sciences Center Mattel Children’s Hospital UCLA
Salt Lake City, Utah Department of Pediatrics
Transplant-Related Malignancies University of California, Los Angeles
Los Angeles, California
Juan Carlos García-Valdecasas, MD Postoperative Intensive Care Management in Children
Professor of Surgery
General Surgery Jeanette M. Hasse, PhD, RD, LD, FADA, CNSC
Hospital Clinic Transplant Nutrition Manager
Barcelona, Spain Baylor Annette C. and Charles C. Simmons Transplant
Extracorporeal Perfusion for Resuscitation of Marginal Institute
Grafts Baylor University Medical Center
Dallas, Texas
Till Gerling, MD, PhD Nutritional Aspects of Transplantation in Adults
Medical Staff
Eurotransplant International Foundation Nigel D. Heaton, MD
Leiden, The Netherlands Professor of Transplant Surgery
Organ Allocation: The European Models King’s Healthcare Partners
Kings College Hospital FT NHS Trust
R. Mark Ghobrial, MD Institute of Liver Studies
Director, Liver Center London, United Kingdom
Chief, Liver Transplantation Surgery Auxiliary Transplantation; Split Liver Transplantation
Director, Immunobiology Research Center for Pediatric and Adult Recipients
The Methodist Hospital System
Houston, Texas Amelia J. Hessheimer, MD, PhD
Donor Selection and Management Resident
General Surgery
Antoinette S. Gomes, MD Hospital Clinic
Professor of Radiological Sciences and Medicine Barcelona, Spain
Radiological Sciences Extracorporeal Perfusion for Resuscitation of Marginal
David Geffen School of Medicine at UCLA Grafts
Los Angeles, California
Radiological Evaluation in Transplantation Jonathan R. Hiatt, MD
Professor of Surgery
Stevan A. Gonzalez, MD Vice Dean for Faculty
Division of Hepatology Vice Chair for Education
Department of Medicine Surgery
Annette C. and Harold C. Simmons Transplant David Geffen School of Medicine at UCLA
Institute Los Angeles, California
Baylor All Saints Medical Center Influence of Transplantation on Liver Surgery
Dallas, Texas
Natural History of Hepatitis C Curtis D. Holt, Pharm D
Clinical Professor
Elisa J. Gordon, PhD, MPH Department of Surgery
Research Associate Professor Division of Liver and Pancreas Transplantation
Comprehensive Transplant Center David Geffen School of Medicine at UCLA
Northwestern University Feinberg School of Los Angeles, California
Medicine Infections After Transplantation
Chicago, Illinois
Ethical Decisions in Transplantation
x Contributors

Johnny C. Hong, MD Fady M. Kaldas, MD

Associate Professor of Surgery Assistant Professor of Surgery
The Mark B. Adams Chair in Surgery, Hepatobiliary Division of Liver and Pancreas Transplantation
Surgery, and Organ Transplantation Department of Surgery
Chief, Division of Transplant Surgery David Geffen School of Medicine at UCLA
Department of Surgery Los Angeles, California
Medical College of Wisconsin Extended Criteria Donors
Director, Solid Organ Transplantation Joint Program at
Medical College of Wisconsin-Froedtert Health- Igal Kam, MD
Children’s Hospital of Wisconsin-BloodCenter of Professor of Surgery
Wisconsin Division of Transplant Surgery
Milwaukee, Wisconsin University of Colorado, Denver
Transplantation for Cholangiocarcinoma; Outcome Aurora, Colorado
Predictors in Transplantation; Ischemia-Reperfusion Injury Living Donor Transplantation: Evaluation and Selection
in Liver Transplantation in Adults

Abhinav Humar, MD Burnett “Beau” S. Kelly, Jr., MD, MBA

Professor of Surgery Assistant Professor
Department of Surgery Surgery
University of Pittsburgh School of Medicine Vanderbilt University
Pittsburgh, Pennsylvania Nashville, Tennessee
Split Liver Transplantation for Two Adult Recipients Donor Selection and Management

Samar H. Ibrahim, MD Vandana Khungar, MD

Gastroenterology, Hepatology, and Nutrition Fellow in Transplant Hepatology
Children’s Hospital Medical Center Division of Digestive and Liver Diseases
Cincinnati, Ohio Columbia University College of Physicians and
Transplantation for Cholestatic Liver Disease in Children Surgeon
Center for Liver Disease and Transplantation
Toru Ikegami, MD New York Presbyterian Hospital-Weill Cornell Medical
Assistant Professor Center
Department of Surgery and Science New York, New York
Graduate School of Medical Sciences Current Indications, Contraindications, Delisting Criteria,
Kyushu University and Timing for Transplantation
Fukuoka, Japan
Small-for-Size Syndrome Khalid Khwaja, MD
Senior Staff Surgeon
Mohamad H. Imam, MD Lahey Clinic Medical Center
Department of Gastroenterology and Hepatology Burlington, Massachusetts
Mayo Clinic Organ Allocation: The U.S. Model
Rochester, Minnesota
Transplantation for Primary Biliary Cirrhosis Kevin King, RN, BSN, CCTC
Adult Post–Liver Transplant Coordinator
Yukihiro Inomata, MD, PhD Division of Liver and Pancreas Transplant
Professor and Chairman Ronald Reagan UCLA Medical Center
Department of Transplantation and Pediatric Surgery Los Angeles, California
Kumamoto University Role of the Posttransplant Clinical Nurse Coordinator
Kumamoto, Japan
Living Donor Transplantation in Children Milan Kinkhabwala, MD
Professor of Surgery
Sally E. Jensen, PhD Chief, Division of Transplantation
Research Assistant Professor Director, Abdominal Transplantation
Medical Social Sciences Montefiore Medical Center
Northwestern University Feinberg School of Medicine Albert Einstein College of Medicine
Chicago, Illinois New York, New York
Ethical Decisions in Transplantation Surgical Anatomy of the Liver

Sheila Jowsey, MD
Assistant Professor of Psychiatry
Psychiatry and Psychology
Mayo Clinic
Rochester, Minnesota
Psychiatric Assessment of Transplant Candidates
 Contributors xi

Allan D. Kirk, MD, PhD Alan Langnas, DO

Chairman of Surgery Chief, Section of Transplantation
Duke University School of Medicine Department of Surgery
Durham, North Carolina University of Nebraska Medical Center
Long-Term Toxicity of Immunosuppressive Therapy; Omaha, Nebraska
Immunosuppressive Biologic Agents Intestinal and Multivisceral Transplantation

Michelle M. Kittleson, MD, PhD Charles R. Lassman, MD

Director, Post-Graduate Education in Heart Failure and Professor of Pathology and Laboratory Medicine
Transplantation Vice Chair of Clinical Education
Cedars Sinai Heart Institute Director of Pathology Residency Training Program,
Los Angeles, California Surgical Pathology Fellowship
Pretransplantation Evaluation: Cardiac Chief of Liver Pathology, Renal Pathology
Department of Pathology and Laboratory Medicine
Göran B.G. Klintmalm, MD, PhD David Geffen School of Medicine at UCLA
Chief and Chairman Los Angeles, California
Annette C. and Harold C. Simmons Transplant Pathology of Nonneoplastic Disease After Transplantation
Institute
W.W. Caruth Chair in Organ Transplant Immunology Sung-Gyu Lee, MD, PhD
Professor of Surgery, Texas A&M College of Medicine Professor of Surgery
Vice Chair, Department of Surgery Hepatobiliary Surgery and Liver Transplantation
Division Chief, Transplant Surgery Asan Medical Center
Dallas, Texas Ulsan University College of Medicine
The History of Liver Transplantation; Transplantation for Seoul, South Korea
Primary Hepatic Malignancy; Transplantation for Dual Grafts for Transplantation
Budd-Chiari Syndrome; Recipient Hepatectomy and
Grafting; Combined Liver-Kidney Transplantation; Henry C. Lin, MD
Clinical Management of Necrotic Liver Before and After Clinical Instructor
Transplantation; Postoperative Intensive Care Department of Pediatrics
Management in Adults; Postoperative Management Beyond Northwestern University Feinberg School of Medicine
the Intensive Care Unit: Adults; Graft-Versus-Host The Siragusa Transplantation Center
Disease; Induction and Maintenance of Immunosuppression; Children’s Memorial Hospital
Novel Immunosuppression in Patients with Hepatic Chicago, Illinois
Malignancies; Outcome Predictors in Transplantation General Criteria for Transplantation in Children

Gregory D. Kunder, RN, BSN, CCTC Chung-Mau Lo, MD

Adult Post–Liver Transplant Supervisor Chair Professor and Head
Surgery, Division of Liver and Pancreas Transplant Department of Surgery
Ronald Reagan UCLA Medical Center University of Hong Kong
Los Angeles, California Hong Kong, China
Role of the Posttransplant Clinical Nurse Coordinator Adult Living Donor Right Hepatectomy and Recipient
Operation
Jerzy W. Kupiec-Weglinski, MD, PhD
Professor of Surgery, Pathology, and Laboratory Steven Lobritto, MD
Medicine Professor of Pediatrics
Joan S. and Ralph N. Goldwyn Chair in Immunobiology NewYork-Presbyterian Hospital
and Transplantation Research Columbia University Medical Center
Director, Dumont-UCLA Transplantation Research New York, New York
Center Postoperative Care of Pediatric Transplant Recipients
Vice-Chairman (Research)
Department of Surgery Jayme E. Locke, MD, MPH
David Geffen School of Medicine at UCLA Assistant Professor of Surgery
Los Angeles, California Abdominal Transplant Surgery
Ischemia-Reperfusion Injury in Liver Transplantation Director, Incompatible Kidney and Kidney Paired
Donation Programs
John R. Lake, MD Director, CTI Outcomes Research Center
Professor of Medicine UAB School of Medicine
University of Minnesota Medical School Birmingham, Alabama
Minneapolis, Minnesota Management of Portal Hypertensive Hemorrhage
Transplantation for Hepatitis C
xii Contributors

Michael R. Lucey, MD James F. Markmann, MD, PhD

Professor of Medicine Chief, Division of Transplant Surgery
Chief, Division of Gastroenterology and Hepatology Claude E. Welch Professor of Surgery
Department of Medicine Harvard Medical School
University of Wisconsin School of Medicine and Public Department of Surgery
Health Massachusetts General Hospital
Madison, Wisconsin Boston, Massachusetts
Transplantation for Alcoholic Liver Disease Retransplantation

Malcolm MacConmara, MB, BCh Mercedes Martinez, MD

Fellow, Abdominal Organ Transplant Surgery Assistant Professor of Pediatrics
Department of Surgery NewYork-Presbyterian Hospital
Emory University School of Medicine Columbia University Medical Center
Atlanta, Georgia New York, New York
Immunosuppressive Biologic Agents Postoperative Care of Pediatric Transplant Recipients

Yoshihiko Maehara, MD, PhD Rafael Matesanz, MD

Professor and Chairman Founder and Director
Department of Surgery and Science Spanish National Transplant Organization
Graduate School of Medical Sciences Madrid, Spain
Kyushu University Organ Allocation: The European Models
Fukuoka, Japan
Small-for-Size Syndrome Tara McCoy, MD
Department of Psychiatry and Psychology
Martin L. Mai, MD Mayo Clinic
Assistant Professor Rochester, Minnesota
Medical Director Psychiatric Assessment of Transplant Candidates
Pretransplant Kidney-Pancreas
Department of Transplantation Suzanne V. McDiarmid, MD
Mayo Clinic College of Medicine Professor of Pediatrics and Surgery
Jacksonville, Florida Chief, Division of Pediatric Gastroenterology,
Pretransplantation Evaluation: Renal Hepatology, and Nutrition
Director, Pediatric Liver Transplantation
Masatoshi Makuuchi, MD, PhD David Geffen School of Medicine at UCLA
President Los Angeles, California
Japanese Red Cross Medical Center Special Considerations for Immunosuppression in Children;
Professor Emeritus Transplantation for Metabolic Disease in Children
University of Tokyo
Tokyo, Japan Greg J. McKenna, MD
Adult Living Donor Left Hepatectomy and Recipient Associate Professor
Operation Department of Surgery
Texas A&M Health Science Center
Kathy Manley, RN, BSN, CCTC College of Medicine
Program Manager Abdominal Transplant Surgeon
Abdominal Transplant Director of Transplant Research
Baylor University Medical Center Baylor University Medical Center
Dallas, Texas Dallas, Texas
Role of the Clinical Nurse Coordinator The History of Liver Transplantation; Postoperative
Intensive Care Management in Adults; Induction and
Victor J. Marder, MD Maintenance of Immunosuppression
Professor of Neurology
Department of Medicine Marian G. Michaels, MD, MPH
Pediatrics Professor of Pediatrics and Surgery
David Geffen School of Medicine at UCLA Division of Pediatric Infectious Diseases
Los Angeles, California Children’s Hospital of Pittsburgh of UPMC
Transplantation for Hematological Disorders Pittsburgh, Pennsylvania
Pretransplantation Evaluation: Infectious Disease
 Contributors xiii

Marta I. Minervini, MD Michael A. Nalesnik, MD

Assistant Professor of Pathology Professor of Pathology
Division of Transplantation Pathology Division of Transplantation Pathology
University of Pittsburgh School of Medicine University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvania Pittsburgh, Pennsylvania
Histopathology of Liver Transplantation Histopathology of Liver Transplantation

Constance Mobley, MD Jaimie D. Nathan, MD

Assistant Professor of Surgery Assistant Professor
Weill-Cornell Medical College Division of Pediatric General and Thoracic Surgery
Surgeon Surgical Director
Houston Methodist Hospital Intestinal Transplant Program
Houston, Texas Cincinnati Children’s Hospital Medical Center
Molecular and Cellular Basis of Liver Failure Cincinnati, Ohio
Transplantation for Hepatic Malignancy in Children
Deok-Bog Moon, MD, PhD
Professor of Surgery Peter Neuhaus, MD, PhD
Hepatobiliary Surgery and Liver Transplantation Chairman and Director
Asan Medical Center Department of General, Visceral, and Transplantation
Ulsan University College of Medicine Surgery
Seoul, South Korea Charité-Universitätsmedizin
Dual Grafts for Transplantation Campus Virchow Klinikum
Berlin, Germany
Elisa A. Moreno, MD Technical Problems: Biliary
Assistant Professor
Department of Psychiatry Jose M. Nieto, DO
David Geffen School of Medicine at UCLA Borland-Groover Clinic
Los Angeles, California Jacksonville, Florida
Psychiatric Assessment of Transplant Candidates; Transplantation for Autoimmune Hepatitis
Neuropsychiatric Complications
Ifeoma Nwadei, MD
Ferdinand Mühlbacher, MD General Surgery Resident
Professor and Head Department of Surgery
Department of Transplantation Emory University School of Medicine
Medical University of Vienna Atlanta, Georgia
Board of Directors of the University Clinic for Surgery Immunosuppressive Biologic Agents
Transplant Center General Hospital
Vienna, Austria John O’Grady, MD
Transplantation for Metastases Honorary Senior Lecturer
Consultant Hepatologist
Paolo Muiesan, MD Institute of Liver Studies
Liver Transplantation and Hepato-Pancreato-Biliary King’s College Hospital
Surgery London, United Kingdom
Queen Elizabeth Hospital Transplantation for Fulminant Hepatic Failure
Birmingham, United Kingdom
Organ Allocation: The European Models Jacqueline G. O’Leary, MD, MPH
Medical Director
Noriko Murase, MD Inpatient Liver and Transplant Unit
Associate Professor of Surgery Annette C. and Harold C. Simmons Transplant Institute
Thomas E. Starzl Transplantation Institute Baylor University Medical Center
Department of Surgery Dallas, Texas
University of Pittsburgh School of Medicine Late Complications and Recurrence of Disease After
Pittsburgh, Pennsylvania Transplantation
Leukocyte Chimerism—Meaning and Consequences
Kim M. Olthoff, MD
Bita V. Naini, MD Donald Guthrie Professor of Surgery
Assistant Professor of Pathology Division of Transplantation
Department of Pathology and Laboratory Medicine Department of Surgery
David Geffen School of Medicine at UCLA University of Pennsylvania
Los Angeles, California Philadelphia, Pennsylvania
Pathology of Nonneoplastic Disease After Transplantation Outcomes of Living Donor Transplantation: The Western
Perspective
xiv Contributors

Nicholas Onaca, MD Phuong-Chi T. Pham, MD

Attending Liver Transplant Surgeon Professor of Medicine
Surgical Director, Kidney Transplantation David Geffen School of Medicine at UCLA
Annette C. and Harold C. Simmons Transplant Institute Los Angeles, California
Baylor University Medical Center Chief of Nephrology
Dallas, Texas Olive View-UCLA Medical Center
Clinical Management of Necrotic Liver Before and After Sylmar, California
Transplantation; Novel Immunosuppression in Patients Renal Failure in Adults
with Hepatic Malignancies; Transplantation for Primary
Hepatic Malignancy Phuong-Thu T. Pham, MD
Professor of Medicine
Justin Parekh, MD, MAS Director of Outpatient Services
Clinical Instructor Department of Medicine
Department of Surgery Nephrology Division
Division of Transplantation Kidney Transplant Program
University of California, San Francisco David Geffen School of Medicine at UCLA
San Francisco, California Los Angeles, California
Rejection After Transplantation Renal Failure in Adults

Chong Parke, MD Jeffrey L. Platt, MD

Clinical Instructor Professor of Surgery
Department of Medicine Professor of Microbiology and Immunology
Nephrology Division Transplantation Biology
Kidney Transplant Program University of Michigan
David Geffen School of Medicine at UCLA Ann Arbor, Michigan
Los Angeles, California Liver and Hepatocyte Xenotransplantation
Renal Failure in Adults
Elizabeth A. Pomfret, MD, PhD
Andreas Pascher, MD Associate Professor of Surgery
Associate Professor of Surgery Tufts University School of Medicine
Deputy Chair, Department of Surgery Chairman, Department of Transplantation
Director, Transplant Program Lahey Hospital and Medical Center
Department of Visceral and Transplantation Surgery Burlington, Massachusetts
Charité-Universitätsmedizin Organ Allocation: The U.S. Model
Campus Virchow Klinikum
Berlin, Germany Paige M. Porrett, MD, PhD
Technical Problems: Biliary Fellow in Abdominal Organ Transplantation
Department of Surgery
Guido G. Persijn, MD, PhD University of Pennsylvania
Medical Director Philadelphia, Pennsylvania
Eurotransplant International Foundation Outcomes of Living Donor Transplantation: The Western
Leiden, The Netherlands Perspective
Organ Allocation: The European Models
Raja Rajalingam, PhD
Henrik Petrowsky, MD Associate Professor
Professor of Surgery UCLA Immunogenetics Center
University of Zurich Pathology and Laboratory Medicine
Vice Chair University of California, Los Angeles
Department of Visceral and Transplant Surgery Los Angeles, California
Head, Section of Hepatobiliary and Pancreatic Surgery ABO, Tissue Typing, and Crossmatch Incompatibility
Program Director
HPB and Liver Transplant Fellowship Jorge Rakela, MD
University Hospital Zurich Professor of Medicine
Zurich, Switzerland Gastroenterology and Hepatology
Principles of Liver Preservation; Graft Failure; Ischemia- Mayo Clinic Arizona
Reperfusion Injury in Liver Transplantation Scottsdale, Arizona
Monitoring and Care
 Contributors xv

Steven S. Raman, MD John F. Renz, MD, PhD

Associate Clinical Professor of Radiology Professor of Surgery
Department of Radiology Director, Liver Transplant Program
David Geffen School of Medicine at UCLA University of Chicago School of Medicine
Los Angeles, California Chicago, Illinois
Imaging Techniques for Partial Grafting The Donor Operation; Surgical Anatomy of the Liver

Michael A.E. Ramsay, MD Lucas Restrepo, MD, PhD

Chairman Clinical Assistant Professor of Neurology
Anesthesiology and Pain Management Comprehensive Stroke and Vascular Neurology
Baylor University Medical Center Program
Dallas, Texas Department of Neurology
Portopulmonary Hypertension and Hepatopulmonary David Geffen School of Medicine at UCLA
Syndrome; Anesthesia for Liver Transplantation Los Angeles, California
Neurological Complications
Parmjeet Randhawa, MD
Professor of Pathology John P. Roberts, MD
Division of Transplantation Pathology Professor and Chief
University of Pittsburgh School of Medicine Department of Surgery
Pittsburgh, Pennsylvania Division of Transplantation
Histopathology of Liver Transplantation University of California, San Francisco
San Francisco, California
Robert R. Redfield III, MD Rejection After Transplantation
Chief Resident in General Surgery
Department of Surgery Bruno Roche, MD
Hospital of the University of Pennsylvania Université Paris-Sud
Philadelphia, Pennsylvania Hospital Staff
Genetic and Genomic Potential in Liver Transplantation Hôpital Paul Brousse, Centre Hépato-Biliaire
Villejuif, France
Alan Reed, MD, MBA Transplantation for Hepatitis A and B
Professor of Surgery
Transplantation and Hepatobiliary Surgery Susanne Rasoul Rockenschaub, MD
Director, UIHC Organ Transplant Center Department of Transplantation
Director, Division of Transplantation and Hepatobiliary Medical University of Vienna
Surgery Vienna, Austria
University of Iowa Carver School of Medicine Liver Transplantation for Metastases
Iowa City, Iowa
Donation After Cardiac or Brain Death: Regulatory and Lainie Friedman Ross, MD, PhD
Ethical Principles Carolyn and Matthew Bucksbaum Professor of Clinical
Ethics
Elaine F. Reed, PhD Departments of Pediatrics, Medicine, and Surgery
Professor of Pathology and Lab Medicine Co-Director
Director, UCLA Immunogenetics Center Institute for Translational Medicine
Department of Pathology and Lab Medicine Associate Director
University of California, Los Angeles MacLean Center for Clinical Medical Ethics
Los Angeles, California University of Chicago
ABO, Tissue Typing, and Crossmatch Incompatibility Chicago, Illinois
Ethics in Living Donor Transplantation
David J. Reich, MD
Professor and Chief Richard Ruiz, MD
Division of Multiorgan Transplantation and Attending Liver Transplant Surgeon,
Hepatobiliary Surgery Surgical Director, Pancreas Transplantation
Vice Chairman Annette C. and Harold C. Simmons Transplant
Department of Surgery Institute
Drexel University School of Medicine Baylor University Medical Center
Hahnemann University Hospital Dallas, Texas
Philadelphia, Pennsylvania Combined Liver-Kidney Transplantation; Postoperative
Donation After Cardiac Death Management Beyond the Intensive Care Unit: Adults;
Long-Term Toxicity of Immunosuppressive Therapy
xvi Contributors

Frederick C. Ryckman, MD Kareem Sassi, MD

Professor of Surgery/Transplantation Department of Medicine
Professor, Division of Pediatric General and Thoracic Ronald Reagan UCLA Medical Center
Surgery Los Angeles, California
Senior Vice President, Medical Operations Transplantation for Autoimmune Hepatitis
Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio Milda R. Saunders, MD
Transplantation for Hepatic Malignancy in Children Assistant Professor
Department of Medicine
Sammy Saab, MD, MPH Faculty, MacLean Center for Clinical Medical Ethics
Professor of Medicine and Surgery Living Donor Advocate Physician
UCLA Digestive Disease Center University of Chicago
David Geffen School of Medicine at UCLA Chicago, Illinois
Los Angeles, California Ethics in Living Donor Transplantation
Transplantation for Autoimmune Hepatitis
Gabriel T. Schnickel, MD
Victor Sai, MD Senior Staff Surgeon
Clinical Instructor Henry Ford Transplant Institute
Department of Radiology Henry Ford Medical Center
David Geffen School of Medicine at UCLA Detroit, Michigan
Los Angeles, California Portal Vein Thrombosis and Other Venous Anomalies
Imaging Techniques for Partial Grafting
Anil Seetharam, MD
Faouzi Saliba, MD Fellow, Internal Medicine
Associate Professor Washington University School of Medicine
Gastroenterology and Hepatology St. Louis, Missouri
University of Paris IX Transplantation for Sclerosing Cholangitis
Villejuif, France
Current Clinical Status of Extracorporeal Devices Kentaro Setoyama, MD
Department of Surgery
Luiz C. Sampaio, MD McGowan Institute for Regenerative Medicine
Assistant Medical Director Children’s Hospital of Pittsburgh of UMPC
Regenerative Medicine Research Pittsburgh, Pennsylvania
Texas Heart Institute Liver and Hepatocyte Xenotransplantation
Houston, Texas
Stem Cells and Liver Regeneration Imtiazuddin Shaik, MD
Assistant Professor of Surgery
Didier Samuel, MD, PhD Department of Transplantation and Hepatobiliary Surgery
Professor of Hepatology New York Medical College
University of Paris-Sud Valhalla, New York
Hospital Staff Treatment of Acute and Chronic Rejection
Paul Brousse Hospital
Hepatobiliary Center Abraham Shaked, MD, PhD
Villejuif, France Eldridge L. Eliason Professor of Surgery
Transplantation for Hepatitis A and B Penn Transplant Institute
University of Pennsylvania
Keiji Sano, MD Philadelphia, Pennsylvania
Professor Genetic and Genomic Potential in Liver Transplantation
Department of Surgery
Teikyo University School of Medicine Ken Shirabe, MD, PhD
Tokyo, Japan Associate Professor
Adult Living Donor Left Hepatectomy and Recipient Department of Surgery and Science
Operation Graduate School of Medical Sciences
Kyushu University
Eizaburo Sasatomi, MD, PhD Fukuoka, Japan
Assistant Professor of Pathology Small-for-Size Syndrome
Division of Transplantation Pathology
University of Pittsburgh School of Medicine Ashwani K. Singal, MD
Pittsburgh, Pennsylvania Department of Gastroenterology and Hepatology
Histopathology of Liver Transplantation Mayo Clinic and Foundation
Rochester, Minnesota
Transplantation for Nonalcoholic Steatohepatitis
 Contributors xvii

Yuji Soejima, MD, PhD Yasuhiko Sugawara, MD

Associate Professor Associate Professor
Department of Surgery and Science Department of Surgery
Graduate School of Medical Sciences University of Tokyo
Kyushu University Tokyo, Japan
Fukuoka, Japan Biliary and Vascular Reconstruction in Living Donor
Small-for-Size Syndrome Transplantation; Adult Living Donor Left Hepatectomy
and Recipient Operation
Thomas E. Starzl, MD
Professor of Surgery Riccardo A. Superina, MD
University of Pittsburgh School of Medicine Department of Surgery
Pittsburgh, Pennsylvania Northwestern University Feinberg School of Medicine
Leukocyte Chimerism—Meaning and Consequences Siragusa Transplantation Center
Children’s Memorial Hospital
Randolph H. Steadman, MD Chicago, Illinois
Professor and Vice Chair General Criteria for Transplantation in Children
Anesthesiology
David Geffen School of Medicine at UCLA Akinobu Taketomi, MD, PhD
Los Angeles, California Professor
Portopulmonary Hypertension and Hepatopulmonary Department of Gastroenterological Surgery I
Syndrome Hokkaido University Graduate School of Medicine
Sapporo, Japan
Zoe Stewart, MD, PhD Small-for-Size Syndrome
Surgical Director
Kidney and Living Donor Transplant Program Jayant A. Talwalkar, MD, MPH
Assistant Professor of Surgery Associate Professor of Medicine
Transplantation and Hepatobiliary Surgery Gastroenterology/Hepatology
University of Iowa Carver School of Medicine Mayo Clinic
Iowa City, Iowa Rochester, Minnesota
Donation After Cardiac or Brain Death: Regulatory and Transplantation for Primary Biliary Cirrhosis
Ethical Principles
Koichi Tanaka, MD
Marvin J. Stone, MD Chairman of the Board of Directors
Director of Oncology Medical Education Kobe International Frontier Medical Center
Associate Medical Director Kobe, Japan
Baylor Charles A. Sammons Cancer Center Living Donor Transplantation in Children
Clerkship Director of Internal Medicine
Baylor University Medical Center William D. Tap, MD
Dallas, Texas Sarcoma Oncology, Melanoma, and Sarcoma Service
Transplantation for Primary Hepatic Malignancy; Memorial Sloan-Kettering Cancer Center
Transplantation for Budd-Chiari Syndrome New York, New York
Transplantation for Hematological Disorders
Thomas B. Strouse, MD
Maddie Katz Professor Doris A. Taylor, MD
Vice Chair for Clinical Affairs Director, Regenerative Medicine Research
Psychiatry and Biobehavioral Sciences Texas Heart Institute
David Geffen School of Medicine at UCLA Houston, Texas
Los Angeles, California Stem Cells and Liver Regeneration
Neuropsychiatric Complications
Greg Tiao, MD
Mark L. Sturdevant, MD Associate Professor
Assistant Professor of Surgery Azizkhan Chair of Pediatric Surgery
Department of Surgery Division of Pediatric General and Thoracic Surgery
University of Pittsburgh School of Medicine Surgical Director
Pittsburgh, Pennsylvania Liver Transplant Program
Split Liver Transplantation for Two Adult Recipients Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio
Transplantation for Hepatic Malignancy in Children
xviii Contributors

Myron J. Tong, MD, PhD Hani M. Wadei, MD

Professor Instructor in Medicine
Digestive Diseases/Gastroenterology Department of Transplantation
Physician, Hepatology Assistant Professor
David Geffen School of Medicine at UCLA Mayo Clinic College of Medicine
Los Angeles, California Jacksonville, Florida
Unusual Indications for Transplantation Pretransplantation Evaluation: Renal

James F. Trotter, MD Kenneth Washburn, MD

Medical Director Professor of Surgery
Transplant Hepatology Transplant Center
Annette C. and Harold C. Simmons Transplant Institute University of Texas Health Science Center
Baylor University Medical Center San Antonio, Texas
Dallas, Texas U.S. Trends in Transplantation
Transplantation for Budd-Chiari Syndrome; Living Donor
Transplantation: Evaluation and Selection in Adults; Peter F. Whitington, MD
Postoperative Management Beyond the Intensive Care The Sally Burnett Searle Professor of Pediatrics and
Unit: Adults; Late Complications and Recurrence of Transplantation
Disease After Transplantation Department of Pediatrics
Northwestern University Feinberg School of Medicine
Hideaki Uchiyama, MD, PhD Siragusa Transplantation Center
Director Children’s Memorial Hospital
Department of Surgery Chicago, Illinois
Fukuoka City Hospital General Criteria for Transplantation in Children
Fukuoka, Japan
Small-for-Size Syndrome Drew J. Winston, MD
Division of Liver and Pancreas Transplantation
Parsia Vagefi, MD David Geffen School of Medicine at UCLA
Assistant Professor of Surgery Los Angeles, California
Transplant Associates Infections After Transplantation
Boston, Massachusetts
Retransplantation David Wojciechowski, DO
Assistant Clinical Professor of Medicine
Hugo E. Vargas, MD Division of Nephrology
Professor of Medicine University of California, San Francisco
Chair San Francisco, California
Division of Hepatology Novel Immunosuppressive Drugs
Mayo Clinic
Phoenix, Arizona Deborah J.L. Wong, MD, PhD
Monitoring and Care Division of Hematology/Medical Oncology
David Geffen School of Medicine at UCLA
Robert S. Venick, MD Los Angeles, California
Assistant Professor Transplantation for Hematological Disorders
Pediatrics and Surgery
David Geffen School of Medicine at UCLA Heidi Yeh, MD
Los Angeles, California Transplant Associates
Transplantation for Biliary Atresia in Children; Boston, Massachusetts
Transplantation for Metabolic Disease in Children Retransplantation

Hector Vilca-Melendez, MD, PhD Hasan Yersiz, MD

Consultant Transplant Surgeon Professor of Surgery
King’s Healthcare Partners Division of Liver and Pancreas Transplantation
Kings College Hospital FT NHS Trust David Geffen School of Medicine at UCLA
Institute of Liver Studies Los Angeles, California
London, United Kingdom The Donor Operation
Split Liver Transplantation for Pediatric and Adult Recipients
Tomoharu Yoshizumi, MD, PhD
Flavio Vincenti, MD Associate Professor
Professor of Clinical Medicine and Surgery Department of Surgery and Science
Kidney Transplant Service Graduate School of Medical Sciences
University of California, San Francisco Kyushu University
San Francisco, California Fukuoka, Japan
Novel Immunosuppressive Drugs Small-for-Size Syndrome
 Contributors xix

Ali Zarrinpar, MD, PhD Qiuheng Zhang, PhD

Assistant Professor Assistant Professor
Division of Liver and Pancreas Transplantation Pathology and Laboratory Medicine
David Geffen School of Medicine at UCLA David Geffen School of Medicine at UCLA
Los Angeles, California Los Angeles, California
Molecular and Cellular Basis of Liver Failure; Influence of ABO, Tissue Typing, and Crossmatch Incompatibility
Transplantation on Liver Surgery
Michael A. Zimmerman, MD
Yuan Zhai, MD Associate Professor
Associate Professor of Surgery Surgical Director
Dumont-UCLA Transplantation Research Center Pancreas Transplant Program
Department of Surgery Division of Transplant Surgery
David Geffen School of Medicine at UCLA University of Colorado
Los Angeles, California Denver, Colorado
Ischemia-Reperfusion Injury in Liver Transplantation Novel Immunosuppression in Patients with Hepatic
Malignancies
 Foreword

Over the past 50 years, liver transplantation has advanced pool. These included the acceptance of cadaveric livers
dramatically and is considered the definitive treatment that were once discarded, the division of one organ for
for most types of liver failure, both acute and chronic, as transplantation into two recipients, and the scrupulously
well as for hepatocellular carcinoma in both children and careful use of live volunteer donors. Another way of
adults. Although most other solid organs were attempted stretching the supply is to reduce the need for retrans-
to be experimentally transplanted close to 100 years ago, plantation. In the past, such hopes depended almost
liver transplantation was not reported until 1952 by Vit- exclusively on the development of more potent immuno-
torio Staudacher from Milan, Italy. With the first human suppressive drugs. Almost all were designed to attack spe-
liver transplant performed in 1963, the stage was set for cific targets in the immunologic cascade of rejection.
advances in organ preservation, immunosuppression, and However, some of the most promising possibilities are
surgical technical refinements that led to the first success- instead based on strategies that exploit leukocyte chime-
ful human liver transplant performed on July 27, 1967. rism-dependent mechanisms of alloengraftment and
With the advent of cyclosporine in 1980 and tacrolimus acquired tolerance.
10 years later, the future was primed for substantial
change. Now in 2015, Drs. Busuttil and Klintmalm have success-
fully created the third edition of Transplantation of the
With this better immunosuppression, a rapid prolifera- Liver. The latest edition adds to the first two by increas-
tion on new centers began in the mid-1980s. Two of the ing the number of chapters from 89 in the second edition
largest and most successful programs were founded by to 107 in the current one. Topics that have been expanded
Dr. Ronald Busuttil in 1983 and Dr. Göran Klintmalm in upon include many of the new problems that face the
1985. In 1995, these surgeons published a state-of-the-art liver transplant community today, such as the use of death
book on liver transplantation. The various chapters were after cardiac donation (DCD) grafts; liver transplantation
contributed by surgeons, internists, and pediatricians for the treatment of cholangiocarcinoma; management of
with extensive experience and expertise in various aspects portopulmonary hypertension; an expanded analysis of
of patient selection, the operation itself, and preoperative the use of extended criteria donors; extracorporeal resus-
and postoperative care. Immunologists and others who citation of grafts; combined liver-kidney and multiorgan
provided essential components of the substructure also transplantation; management of the HCV epidemic; and
were represented. The book was a great success at every discussion of the current treatment of antibody-mediated
level of the healthcare hierarchy, from students to rejection of liver grafts, which was not considered a major
professors. problem before.

By the time of the book’s launch in 1995, the combina- As in the previous edition, each chapter is followed by a
tion of acceptable results and the number of centers with Pearls and Pitfalls section that alerts the reader to specific
well-trained surgeons had made liver replacement the points that might otherwise be missed. Some of these sec-
universally accepted “last court of appeal” for virtually all tions are so helpful that it may be beneficial to peruse the
patients dying of nonneoplastic liver disease and for a Pearls and Pitfalls before tackling the main text.
selected subgroup of those with malignant hepatic tumors
that could not be removed with conventional subtotal In both the inaugural and second editions of Transplanta-
hepatic resection. It was also apparent, even from a casual tion of the Liver, I concluded my Foreword as follows:
reading of the first edition of Transplantation of the Liver,
that organ supply had already become the principal deter- The creation of a genuine classic is a cause for wonder,
rent to further expansion of these services. Liver xeno- which inevitably increases with time. Years from now, Drs.
transplantation was discussed as a potential way to deal Busuttil and Klintmalm are apt to look back at their work
with the impending crisis; however, with the opposition product and ask themselves how they had been able in their
by the public, as well as within the profession, to using earlier life to construct something this good.
closely related species (e.g., the baboon) as donors, this
possibility was and still remains remote. They have, in fact, succeeded in raising the bar yet again
and making their work product even better in the third
In 2005, the second edition of Transplantation of the Liver edition of Transplantation of the Liver.
was published. In that text, Busuttil and Klintmalm and
their contributing authors emphasized practical ways of Thomas E. Starzl, MD, PhD
expanding or more efficiently utilizing the human organ

xxi
 Preface: A New Chapter

The first edition of Transplantation of the Liver was pub- transplant pioneers for the benefit of current clinicians in
lished in 1996. At that time, the practice of liver trans- the field who may not have had the opportunity to inter-
plantation had developed internationally and was act with them personally. We highly recommend this
acknowledged as the definitive treatment for virtually all chapter for every reader.
types of end-stage liver disease. The first edition was
designed to serve as a platform to codify what had evolved Several new chapters reflect recent developments in the
in the development of liver transplantation since 1963, specialty. In “Part I: General Considerations,” we have
when Dr. Thomas E. Starzl performed the first clinical incorporated a chapter that discusses regulatory and ethi-
liver transplant. Additionally, it focused on the many cal issues in organ donation, including donation after car-
advances in the field that had developed since that senti- diac death versus brain death. We have expanded “Part II:
nel event. Patient Evaluation: Adult” with two new chapters. One
chapter focuses on liver transplantation for cholangiocar-
In 2005 the second edition was published, and by that cinoma, and the other examines nonalcoholic steatotic
time a revolutionary change in organ allocation had been hepatitis (NASH), a diagnosis that may very well overtake
enacted by the Organ Procurement and Transplantation hepatitis C as the most common indication for liver trans-
Network (OPTN), which had a significant impact on the plantation in many countries during the next few years. A
practice of liver transplantation. Based on the Model for new chapter on pulmonary hypertension and hepatopul-
End-Stage Liver Disease (MELD) and the Pediatric monary syndrome has also been included in “Part IV:
Model for End-Stage Liver Disease (PELD), the new Special Considerations in Patient Evaluation.”
allocation system completely altered the algorithm for
patient evaluation, maintenance, wait listing, and priority A chapter on extended criteria donors was added to “Part
for transplantation. Since the implementation of these V: Operation,” reflecting the ever-increasing need for
changes, there has been a dramatic shift toward organs donors that necessarily compels us to accept donors
being allocated to the sickest of recipients and to patients whom we rarely used when the first edition of this text-
with hepatocellular carcinoma and other primary hepatic book was published. “Part VI: Split and Living Donor
malignancies who were allowed to be listed because they Transplantation” has been greatly expanded as a direct
fulfilled the approved exception criteria. As a result, this result of the substantial increased experience and knowl-
current edition thoroughly discusses these changes in edge in this field. Chapters on biliary and vascular recon-
indications, the benefits, and the potential risks. structions, small-for-size syndrome, minimally invasive
living donor hepatectomy, and dual grafts for transplan-
As editors, our ambition has always been that this text- tation have been added. “In Part VII: Unusual Operative
book would be considered state of the art while concur- Problems,” a new chapter on the varied techniques of
rently keeping the format for general reference. To that arterial reconstruction is featured.
end, we have completely updated all of the chapters and
added new ones to reflect new knowledge and expertise. Two new chapters can be found in “Part VIII: Postopera-
tive Care.” The first broaches an increasingly common
The third edition of Transplantation of the Liver essen- yet delicate challenge: the transition of pediatric patients
tially follows the same format as its predecessors. The to adulthood. This topic was not adequately addressed in
Pearls and Pitfalls sections have been expanded signifi- prior editions and is a growing issue that puts a very spe-
cantly as these summaries are intended to serve as salient cial and novel demand on the transplant care team. The
words of wisdom from experienced mentors to share with second new chapter concerns recurrent hepatitis C after
their less-experienced counterparts in the field. liver transplantation, which is a significant problem today.
Hopefully, with the new drugs that have recently become
As in the previous editions, when recruiting new authors, available, this will be primarily of historical ­interest by
we turned to individuals recognized for their expertise in the time the fourth edition is contemplated. The complex
a particular specialty. When possible, we strived to have and difficult complication of graft-versus-host disease
different views that might apply to a specific issue or was given a separate chapter in “­ Part X: Immunology of
problem because, in many cases, successful approaches Liver Transplantation.” Along with the maturation of
are often varied. Furthermore, all chapters have been liver transplantation, large numbers of patients are living
updated to be relevant to our current practice. Chapter 1, several decades after transplantation. Thus, we thought it
on the history of liver transplantation, has been entirely prudent to address the effect of long-term toxicity of
reworked to illustrate the tremendous contributions of immunosuppressive therapy with a new chapter in

xxiii
xxiv Preface: A New Chapter

“Part XI: Immunosuppression.” Finally, in “Part XIII: father of liver transplantation, Dr. Starzl, as leaders of our
Future Developments in Liver Transplantation,” there own programs. We appreciate being able to pass this
are two new chapters that look to the future. The first mantle along through our textbook and our respective
chapter discusses stem cell and liver regeneration, and the fellowship programs. We dedicate this work to Dr. Starzl
second focuses on extracorporeal perfusion to resuscitate and his contemporary pioneers Drs. Roy Calne, Rudolph
marginal grafts. Pichlmayr, and Henri Bismuth. May this text serve as an
ode to their vision and the legacy that they have created
It has been extremely gratifying personally and profes- worldwide.
sionally to watch our field develop and flourish before our
eyes. We both feel very fortunate and humbled to have Ronald W. Busuttil, MD, PhD
the opportunity to safeguard the mantle created by the
Göran B.G. Klintmalm, MD, PhD
 Acknowledgments

We wish to express our appreciation to Colleen Devaney the invaluable mentorship of Dr. Thomas E. Starzl, this
and Therese Dangremond for their tireless efforts and work would not have been possible.
dedication to the third edition of Transplantation of the
Liver. Without their commitment to excellence, as well as Ronald W. Busuttil, MD, PhD
Göran B.G. Klintmalm, MD, PhD

xxv
Copyright&d

PART I
GENERAL
CONSIDERATIONS

1
Copyright&d Material
 CHAPTER 1

The History of Liver

Transplantation
Greg J. McKenna • Göran B.G. Klintmalm

CHAPTER OUTLINE

INTRODUCTION: THE GENESIS OF LIVER HUMAN TRIALS: THE HUMAN LIVER TRANSPLANT
TRANSPLANTATION TRIALS RESUME IN 1967
ANIMAL MODELS: PREREQUISITES FOR CANINE HUMAN TRIALS: ADVANCEMENTS TO THE
REPLACEMENT RECIPIENT OPERATION
ANIMAL MODELS: PATHOLOGY OF LIVER ORGAN PRESERVATION: IN SITU PERFUSION
REJECTION
IMMUNOSUPPRESSION: THE NEW AGE OF
IMMUNOSUPPRESSION: HOST IRRADIATION AND CYCLOSPORINE
CYTOABLATION
REGULATORY DEVELOPMENT: NATIONAL
IMMUNOSUPPRESSION: 6-MERCAPTOPURINE INSTITUTES OF HEALTH CONSENSUS COMMITTEE
AND AZATHIOPRINE AND “THE STAMPEDE”
ANIMAL MODELS: TOWARD LIVER ORGAN PRESERVATION: COLD STORAGE
TRANSPLANTATION BY KIDNEY TRANSPLANT
IMMUNOSUPPRESSION: FURTHER
EXPERIENCE
ADVANCEMENTS USING TACROLIMUS
HUMAN TRIALS: THE HUMAN KIDNEY
ORGAN SUPPLY: MARGINAL DONORS
TRANSPLANT TRIALS
ORGAN SUPPLY: SPLIT-LIVER PROCEDURES
HUMAN TRIALS: THE HUMAN LIVER TRANSPLANT
TRIALS OF 1963 ORGAN SUPPLY: LIVING DONOR
TRANSPLANTATION
HUMAN TRIALS: THE LIVER TRANSPLANT
MORATORIUM ORGAN SUPPLY: XENOTRANSPLANTATION
IMMUNOSUPPRESSION: ANTILYMPHOCYTE REGULATORY DEVELOPMENT: NATIONAL ORGAN
GLOBULIN TRANSPLANT ACT OF 1984 AND BEYOND
ORGAN PRESERVATION: EXTRACORPOREAL REGULATORY DEVELOPMENT: EQUITABLE ORGAN
HYPOTHERMIC PERFUSION AND EX VIVO ALLOCATION AND THE MELD SCORE
PERFUSION ORGAN PRESERVATION: EXTRACORPOREAL
ANIMAL MODELS: DEMONSTRATION OF HEPATIC MACHINE PERFUSION SYSTEMS
TOLEROGENICITY SUMMARY

The history of liver transplantation is a complicated story of organ supply that inspired advances and regulatory
to tell—it is a story of great successes and tragic failures. It developments that helped bring the field into maturation.
is a story of both individual heroics and the power of col- The modern framework and procedures for organ
laboration. It is a story that has many overlapping themes transplantation were born from the bold efforts of a
that all evolved simultaneously—there were developments small number of centers in North America and Europe
in immunosuppression, creation of animal models, between 1954 and 1967. It was a time when it would
advances in organ preservation, and the results from have been easy to have been marginalized from the
human trials. Each of these themes unfolded at the same mainstream, when the conventional wisdom was that
time. And at that same time, the story was affected by issues transplanting tissue from one human to another was at

2
 1 The History of Liver Transplantation 3

TABLE 1-1 Milestones of Liver Transplantation

Year Description Reference
1952 First report on liver transplantation (Vittorio Staudacher, University of Milan) 1
1955 First report on auxiliary liver transplantation (C. Stuart Welch, Albany Medical College) 5
1958-1960 Formal research programs of total hepatectomy and liver replacement in dogs 14,128
1960 Azathioprine introduced for organ transplantation 39,40
1963 Azathioprine-prednisone cocktail introduced for organ transplantation 50
1963 In situ preservation-procurement method described 129
1963 First human liver transplantation (Thomas Starzl, University of Colorado) 53
1966 First liver xenotransplantation (chimpanzee donor) 23
1966 Antilymphocyte globulin introduced for organ transplantation 65
1967 First successful liver transplantation (Thomas Starzl, University of Colorado) 16
1967-1968 Acceptance of brain death concept 130
1968 First successful liver transplantation in Europe (Roy Calne, University of Cambridge) 78
1976 Improved slush liver preservation permits long-distance procurement 25,26
1979 Systematic use of arterial and venous grafts for cadaver organ revascularization 24
1979 Cyclosporine introduced for organ transplantation 89
1980 Cyclosporine-prednisone introduced for organ transplantation 90
1981 80% 1-year liver recipient survival reported using cyclosporine-prednisone 91
1983 Introduction of pump-driven venovenous bypass without anticoagulation 57,58
1983-1984 U.S. Consensus Development Conference concludes liver transplantation is a “clinical service” 92
1984 Standardization of in situ preservation-procurement techniques for multiple cadaver organs 54,55
1984 First reduced-size graft liver transplantation (Henri Bismuth, Paul Brousse Hospital, Paris) 84
1984 First ex situ reduced-size graft liver transplantation (Rudolf Pichlmayr, University of Hannover) 103
1984 National Organ Transplant Act introduced in the United States 119,131
1987 UW solution introduced for organ preservation (F. Belzer, J.H. Southard, University of Wisconsin) 28
1987 First report on extensive marginal donor use (Leonard Makowka, University of Pittsburgh) 100
1987 Scientific Registry of Transplant Recipients created in the United States 121
1989 Tacrolimus introduced for organ transplantation 97
1989 First living donor liver transplantation (Russell Strong, Stephen Lynch, University of Queensland) 108
1994-1998 First right lobe living donor liver transplantation (Yoshio Yamaoka, Kyoto University) 109,110
1995 First in situ split-liver transplantation (Xavier Rogiers, University of Hamburg) 106
2000 First successful ex vivo porcine xenoperfusion (Marlon Levy, Baylor University Medical Center) 118
2002 MELD score introduced in the United States for organ allocation 132
2006 Donor Risk Index score to quantify marginal donor risk (Sandy Feng, University of Michigan) 102
2010 First report of liver hypothermic machine perfusion (James Guarrera, Columbia University) 121

MELD, Model for End-Stage Liver Disease; UW, University of Wisconsin.

best, not possible, and at worst, an unethical undertak- preservation, human trials, regulatory developments, and
ing. Although kidney transplantation opened the door organ supply (Table 1-1).
to the possibility of “transplantation,” it was liver
transplantation that truly became the driving force
behind the innovations and discoveries that ultimately INTRODUCTION: THE GENESIS OF LIVER
advanced the entire field of transplantation. Liver TRANSPLANTATION
transplantation drove the progress in developing
immunosuppression, the improvements in organ pres- The transplantation of all of the other major organs
ervation, and the advances in anesthesia and intensive can be traced back to the early 1900s,1,2 but for liver
care unit care. The research and models created for transplantation the first reported liver transplant was
liver transplantation gave insight into the metabolic in 1952 at the fifty-fourth Congress of the Italian Soci-
interrelations of the intra-abdominal organs, provided ety of Surgery. In 1952 Vittorio Staudacher from the
an understanding of liver-based inborn errors of University of Milan (Fig. 1-1) published a series of
metabolism, and fostered an understanding of liver experiments in which the first description of the tech-
growth and regeneration. nique of liver transplantation in four dogs was out-
The story of liver transplantation unfolds through six lined.3,4 This first liver transplant was an orthotopic
related themes that weave back and forth at different liver transplant, where the host liver was removed and
points throughout the timeline. It is helpful to view this fully replaced by the donor allograft, and in his report
complicated history through the lens of the following six Staudacher clearly describes the procedure in five steps
topics: animal models, immunosuppression, organ that resemble the modern transplant operation. In the
4 PART I General Considerations

m
enu
uod
D

er
Dr. Vittorio Staudacher

liv
or
University of Milan

Don
Milan, Italy
Aorta
Hepatic a.
FIGURE 1-1 n The first liver transplantation was performed in IVC Splenic a.
1952 on a dog by Vittorio Staudacher at the University of Milan. Portal v. L. gastric a.
The results were presented to the fifty-fourth Congress of the Celiac axis
Italian Society of Surgery in 1952. This landmark surgery
remained unknown for many decades before it came to the Common
attention of researchers. (From Busuttil RW, De Carlis LG, Mihay- iliac
lov PV, et al. The first report of orthotopic liver transplantation in the a.v.
western world. Am J Transpl. 2012;12:13851387.)

discussion Staudacher commented that no one had

reported a liver transplant previously. Although Stau- FIGURE 1-2 n Auxiliary liver homotransplantation in dogs (the
dacher’s achievements were known by some colleagues Welch procedure). Note that the reconstituted portal venous
in Italy, his work went essentially unnoticed for almost inflow is from the inferior vena caval bed rather than from the
splanchnic organs. Biliary drainage was with cholecystoduode-
6 decades. nostomy. a., Artery; IVC, inferior vena cava; L, left; v., vein. (From
In 1955 C. Stuart Welch of Albany Medical College Starzl TE, Marchioro TL, Rowlands DT Jr, et al. Immunosuppression
reported the first heterotopic liver transplant in a one- after experimental and clinical homotransplantation of the liver. Ann
page article published in Transplantation Bulletin, the Surg. 1964;160:411-439.)
forerunner of the present day journal Transplantation.5
For more than 50 years, Welch’s report was considered
the first reported liver transplant until the recent discov- regeneration were governed by the amount of portal
ery of Staudacher’s published work. In Welch’s “auxil- venous inflow (known as the “flow hypothesis” of hepatic
iary liver transplant,” a hepatic allograft was implanted homeostasis). Because the portal vein of the auxiliary
into the right paravertebral gutter of dogs without dis- liver allograft received ample systemic blood from the
turbing the native liver.5 Welch followed up this publi- host vena cava, it was felt that the atrophy was not
cation with a more complete description published in related to blood flow but was instead ascribed to immu-
Surgery in 1956.6 These auxiliary livers were revascular- nological factors. It would be more than 10 years before
ized by anastomosing the allograft hepatic artery to the the cause of the auxiliary allograft atrophy was fully
recipient aortoiliac system, and by an end-to-end anas- appreciated and the idea of rejection being the culprit
tomosis of the allograft portal vein to the host inferior was refuted. It ultimately became apparent that the atro-
vena cava (Fig. 1-2). By including a short length of phy was due to the absence of hepatotrophic factors
donor retrohepatic vena cava, Welch avoided anasto- such as insulin, which are present in high concentrations
mosing multiple hepatic veins and instead required just in the splanchnic circulation but were missing from the
one anastomosis; the upper end of the caval segment of systemic blood from the vena cava that perfused the aux-
the graft was anastomosed to the recipient vena cava, iliary liver.7-10
and the lower end was ligated. In 1960 Michael Francis Addison Woodruff of the
In contrast to other types of transplanted organs, an University of Otago Dunedin School of Medicine in
auxiliary liver transplant allograft underwent a marked New Zealand published a compendium of work in
shrinkage beginning within 3 to 4 days of the surgery. transplantation11 up to 1959, and at that time the only
Initially the atrophy was attributed to liver rejection. references to liver transplantation were Welch’s two
The central dogma at the time was that liver size and articles on heterotopic liver transplantation5,6 and a
 1 The History of Liver Transplantation 5

Upper vena cava

anastomosis

Homograft
liver

Ligated
common duct
Gastroduodenal
a. (tied) Anastomosis
of hepatic a.
Hepatic a.
(tied)

Cholecysto-
duodenostomy

Lower vena cava

anastomosis
I.
V.
C. Repaired portacaval
Portal anastomosis
shunt

FIGURE 1-3 n Completed liver replacement in the dog. The fact that the recipient was a dog rather than a human is identifiable only
by the multilobar appearance of the liver. a., Artery; I.V.C., inferior vena cava; P.V., portal vein. (From Brettschneider L, Daloze PM,
Huguet C, et al. The use of combined preservation techniques for extended storage of orthotopic liver homografts. Surg Gynecol Obstet.
1968;126:263-274.)

brief report by Jack Cannon of University of Califor- of studying these metabolic relationships.18,19 In these
nia, Los Angeles (UCLA) published in 1956 that investigations the Northwestern University group pio-
described the liver transplant activities in animals per- neered a new method of total hepatectomy in which the
formed at the recently founded UCLA School of Med- host’s retrohepatic inferior vena cava was preserved,20
icine.12 This article by Cannon was considered for (heralding the approach that would come to be known
many years to be the first experimental description of as the piggyback variation of liver transplantation in
an orthotopic liver transplant, until the recently dis- humans21-23). For liver replacement in the dog, it was
covered work of Staudacher.3 simpler to excise the host retrohepatic vena cava along
However, by the time Woodruff’s book was pub- with the native liver and to replace it with the compa-
lished in 1960, there were already two centers—the rable caval segment of the donor. The vena caval anas-
Peter Bent Brigham Hospital in Boston13 and North- tomosis above and below the liver and the hepatic
western University in Chicago14—that both indepen- arterial and biliary tract anastomoses were performed
dently began studying liver transplantation in 1958, with conventional methods13,14 (Fig. 1-3). When differ-
each center looking at the field from different vantage ent means of portal revascularization were systemati-
points. The investigations from the Brigham Hospital cally tested in the laboratory at the Northwestern
were done under the direction of Francis D. Moore,13,15,16 University program (Fig. 1-4), it was discovered that
and because the focus came from a center with an estab- any deviation from the normal portal supply resulted in
lished history with kidney transplantation, this group reduced survival.
approached liver transplantation from an immunologi- The research teams at Northwestern University in
cal perspective with a therapeutic objective. In contrast, Chicago and the Brigham Hospital in Boston were
the work from the Northwestern University group led unaware of each other’s activities until late 1959, and
by Thomas E. Starzl14,17 stemmed from work regarding direct contact between the programs was not estab-
the metabolic interrelationships of the liver with the lished until the 1960 meeting of the American Surgical
pancreas and intestine, which evolved from earlier Association. By then the cumulative total of liver
investigations done at the University of Miami in the replacement procedures in nonimmunosuppressed
field of hepatotrophic physiology. In this circumstance, dogs was 111 (80 at the Northwestern University pro-
liver replacement was being performed for the purpose gram,14 31 at the Brigham Hospital program13). The
6 PART I General Considerations

Diaphragm

Liver
IVC

PV PV PV

IVC IVC

A B C
FIGURE 1-4 n Alternative methods of portal vein revascularization. A, Reverse Eck fistula. B, With small side-to-side portacaval shunt.
C, Anatomically normal. Survival was best with C. IVC, Inferior vena cava; PV, portal vein. (From Starzl TE, Kaupp HA Jr, Brock DR, et al.
Reconstructive problems in canine liver homotransplantation with special reference to the postoperative role of hepatic venous flow. Surg
Gynecol Obstet. 1960;111:733-743.) IVC, Inferior vena cava; PV, portal vein.

outcomes from these canine liver transplants were

published in 1960 in separate papers and in different
journals.

Gallbladder
ANIMAL MODELS: PREREQUISITES L iv
FOR CANINE REPLACEMENT er

Ringer
The two prerequisites for perioperative survival of canine bottle
liver transplant were independently established in each
laboratory, both at the Brigham Hospital in Boston and at Hepatic a.
Northwestern University in Chicago. The first require- Portal v.
ment for a successful canine liver replacement was preven-
tion of ischemic injury to the allograft. At the Brigham
Hospital program this was accomplished by immersing the
liver in iced saline. At the Northwestern University pro-
gram the method of hypothermia was influenced by F.
John Lewis, who along with Norman Shumway pioneered
total body hypothermia for open heart surgery while at the IVC Aorta
University of Minnesota.24 The livers were cooled by the
intravascular infusion of chilled lactated Ringer solution
(Fig. 1-5) and monitoring core temperature with thermal
probes. This now-universal step in preservation of organs
had never been used before, apparently because of the fear
of damaging the microcirculation. In time, better liver
preservation was obtained by altering the osmotic, oncotic,
and electrolyte composition (i.e., Collins,25 Schalm,26 and
University of Wisconsin solutions27-29).
The second prerequisite for successful canine liver Bottle
replacement was avoiding damage to the recipient (blood)
splanchnic and systemic venous beds when venous drain- FIGURE 1-5 n Cooling of the canine hepatic allograft by infusion
age was obstructed during the host hepatectomy and graft of chilled lactated Ringer solution into the donor portal vein. The
implantation. In both laboratories this was accomplished animals were simultaneously exsanguinated. a., Artery; IVC,
inferior vena cava; v., vein. (From Starzl TE, Kaupp HA Jr, Brock
by using external venovenous bypasses to decompress the DR, et al. Reconstructive problems in canine liver homotransplanta-
venous drainage, although the particular details of the tion with special reference to the postoperative role of hepatic
bypasses differed at each center. venous flow. Surg Gynecol Obstet. 1960;111:733-743.)
 1 The History of Liver Transplantation 7

ANIMAL MODELS: PATHOLOGY OF LIVER the first examples of acquired immunological tolerance in
REJECTION humans.
Exploring a substitute for irradiation, Willard Good-
Until 1960 the kidney had been the only organ allograft win, a urologist from UCLA, pretreated recipients with
whose unmodified rejection had been systematically stud- myelotoxic doses of cyclophosphamide and methotrex-
ied. With development of the canine liver replacement ate.34 One recipient had a prolonged survival of 143 days
models at each of the two programs, the pathology of rejec- and had rejection that was successfully reversed several
tion in a transplanted liver could now be studied. These ini- times with prednisone. Despite these initial moderate
tial histopathological assessments were done by David Brock successes with cytoablation, it quickly became apparent
at the Northwestern University program and Gustav Dam- that cytoablation by medication was not going to be a fea-
min at the Brigham Hospital program. Most of the trans- sible means through which liver transplantation might
planted canine livers were destroyed in about 5 to 10 days. occur.
The pathological examination of the transplanted livers
typically showed a heavy concentration of mononuclear
cells, both in the portal triads and in and around the central IMMUNOSUPPRESSION:
veins, all with extensive hepatocyte necrosis.16,17
A curious exception was noticed in the sixty-third liver 6-MERCAPTOPURINE
replacement experiment. The serum bilirubin level reached AND AZATHIOPRINE
a peak at 11 days but then progressively declined.17 The pre-
dominant histopathological findings in the allograft by day The real advances needed for liver transplantation
21 were more those of repair and regeneration rather than required the arrival of the era of drug immunosuppres-
rejection. This was the first recorded exception to the exist- sion, and 6-mercaptopurine (6-MP) is generally consid-
ing dogma that once rejection was initiated, it was an ines- ered the drug that heralded in this era. Much of the initial
capable process. Five years later, similar observations were research that would be crucial for immunosuppression
made by Ken A. Porter of St Mary’s Medical School in Lon- for liver transplantation was studied in kidney transplant
don, assessing the allografts of long-surviving canine liver models. In 1950, working at Wellcome Research Labora-
recipients from experiments done at the University of Colo- tories, Gertrude Elion and George Hitchings35 used
rado program, where rejection had developed and then innovative drug development methods to create 6-MP
spontaneously reversed under stable daily doses of (work for which they received the Nobel Prize in medi-
azathioprine.30 cine in 1988). The researchers Robert Schwartz and Wil-
liam Dameshek at Tufts Medical School in Boston first
established that 6-MP was immunosuppressive36,37 and
IMMUNOSUPPRESSION: HOST not require overt bone marrow depression to be success-
IRRADIATION AND CYTOABLATION ful. Using a skin allograft model in rabbits, William
Meeker Jr. and Robert Good at the University of Min-
Just when the surgical research in nonimmunosuppressed nesota showed 6-MP provided a modest prolongation of
dogs began to lose momentum, it was dramatically revital- skin allograft survival.38 Upon learning of the immuno-
ized. From January 1959 to February 1962, there were suppressive potential of 6-MP, both Roy Calne (then a
seven successful human kidney transplantations performed, surgical trainee) in London39 and Charles Zukoski at the
the first by Joseph Murray31 at the Brigham Hospital in Medical College of Virginia in Richmond40 indepen-
Boston (work for which he received the 1990 Nobel Prize in dently performed experiments using transplant models
medicine) then six more times by the independent teams led with canine kidney allograft, reporting survival of up to
by Jean Hamburger32 and Rene Kuss,33 both of whom were 40 days.
in Paris (Table 1-2). For these seven transplants the immu- After developing 6-MP, Elion and Hitchings used
nosuppression came from preconditioning the patients with their drug development techniques to synthesize an imid-
sublethal doses of 4.5 Gy total body irradiation. The first azole derivative of 6-MP called azathioprine, a prodrug of
two recipients (they received fraternal twin kidneys) had 6-MP that required processing in the liver to become
continuous graft function for more than 2 decades without active and thereby prolonged the effects of the drug. By
any further posttransplant immunosuppression. They were the end of 1960, both Zukoski, working with David

TABLE 1-2 Kidney Transplantation: 6 Months or Greater Survival as of March 1963

Date Program Surgeon Donor Survival (mo) Alive/Dead
1/24/1959 Peter Bent Brigham Hospital, Boston J.E. Murray Fraternal twin >50 Alive
6/29/1959 Necker Hospital—University of Paris J. Hamburger Fraternal twin >45 Alive
6/22/1960 Centre Medico-Chirugical Foch, Seine R. Kuss Unrelated 18 Dead
12/19/1960 Necker Hospital—University of Paris J. Hamburger Mother 12 Dead
3/12/1961 Centre Medico-Chirugical Foch, Seine R. Kuss Unrelated 18 Dead
2/12/1962 Necker Hospital—University of Paris J. Hamburger Cousin >13 Alive
4/5/1962 Peter Bent Brigham Hospital, Boston J.E. Murray Unrelated 11 Alive
8 PART I General Considerations

Hume in Richmond,41 and Calne, who had moved to survival of a human organ allograft without host condi-
Boston for a fellowship with Murray,42,43 were using aza- tioning with total body irradiation. This positive element
thioprine in kidney transplants42 with survival results that in the report was tempered by the fact it was the only
would sometimes reach 100 days. recipient of the first 13 treated solely with drug immuno-
suppression that survived for more than 6 months.44-46
In the spring of 1962 the University of Colorado group
of Waddell and Starzl, working at the Denver Veterans
ANIMAL MODELS: TOWARD LIVER Administration hospital, obtained a supply of azathio-
TRANSPLANTATION BY KIDNEY prine and began developing experience with the drug.
TRANSPLANT EXPERIENCE Initially the plan had been to study azathioprine in a liver
transplant model, but it became clear quickly that the
Calne’s experiments showing transplant rejection could operation of liver replacement in dogs was too difficult
sometimes be substantially delayed with azathioprine and fraught with technical challenges to use it to evaluate
encouraged the Brigham Hospital program in Boston to an immunosuppressive drug. So the group decided to use
pursue human kidney transplant trials. When the trials of the simpler canine kidney model first as a precursor to
kidney transplant with azathioprine began in Boston in liver transplantation. The results from this transplant
1960-61, there were initially high expectations,44 and the model yielded similar results to other laboratories with
idea of actually transplanting livers seemed less remote. survival that sometimes approached 100 days. However,
In 1961 William R. Waddell left Massachusetts General two key observations came from these canine transplant
Hospital to become chair of surgery at the University of models that would affect future immunosuppressive man-
Colorado, where he was joined by Starzl, coming from agement strategies. The first observation was that the
Northwestern University in Chicago. Their goal at that allograft rejection that occurred after azathioprine mono-
point was to pursue development of liver transplantation, therapy could be reversed by delayed addition of large
especially considering the 3 years of experience Starzl had doses of prednisone.47 The second observation was that
gained at Northwestern University working with the pretreatment of the animals with azathioprine for 7 to 30
canine hepatic replacement models (Fig. 1-6). Unfortu- days before transplant doubled their mean survival, which
nately, the plans for liver transplantation were shelved to that point had been 36 days.48
when reports of the Boston clinical trial of kidney trans-
plantation described disappointing results. The report by
Murray et al,44 published in the Annals of Surgery, did HUMAN TRIALS: THE HUMAN KIDNEY
have one positive element, because it described a kidney TRANSPLANT TRIALS
allograft transplanted from an unrelated donor in April
196245 that was still functioning 120 days later using aza- Beginning in late 1962, the long-standing kidney trans-
thioprine immunosuppression. That kidney ultimately plant program at Brigham Hospital in Boston was joined
functioned for another 13 months after this report for a by two other centers in performing human kidney trans-
total of 17 months, and it was the first example of 1-year plantation: the group at the University of Colorado in
Denver comprising Starzl and Waddell and the group at
the Medical College of Virginia in Richmond led by Hume
(Fig. 1-7). The groups at Colorado and Virginia were in
Dr. Thomas E. Starzl close contact with each other, collaborating on ideas,49 and
both realized early that a combination of “azathioprine and
University of Pittsburgh steroids” was key to a successful outcome; however, they
Pittsburgh, PA
1981 – Present approached the strategy from different directions. The
University of Colorado group reserved steroids for when
University of Colorado
rejection occurred, which invariably happened with aza-
Denver, CO thioprine monotherapy. The Medical College of Virginia
1962 – 1980 group used reduced-dose steroids from the time of the
transplant as part of a dual drug combination.
Northwestern University The University of Colorado group began human kid-
Chicago, IL ney transplants in 1962 using a protocol that gave daily
1959 – 1961 doses of azathioprine 1 to 2 weeks before transplant, as
First Kidney Transplant 1962 well as continuing it after, and added high doses of pred-
First Liver Transplant 1963 nisone to treat any rejection. The successful results of the
first 10 kidney cases using this protocol were described in
the report “The Reversal of Rejection in Human Renal
FIGURE 1-6 n Thomas Starzl started his career at Northwestern
University, where he performed canine hepatic replacements for Homografts With Subsequent Development of Homo-
studying metabolic interrelationships of the liver with the pan- graft Tolerance.”50 The term tolerance referred to the
creas and intestine. When he moved to the University of Colo- time-related decline of need for maintenance immuno-
rado in 1962, those canine models laid the groundwork for suppression. Based on their results using this protocol,
developing human liver transplantation. He performed the first
human liver transplant in 1963. In 1981 he moved to the Univer-
Starzl and the University of Colorado group concluded
sity of Pittsburgh, making it the largest liver transplant program that renal transplantation had reached the level of a bona
in the world. fide (albeit still flawed) clinical service.
 1 The History of Liver Transplantation 9

In 1963 a small conference organized by the Before the 1963 National Research Council confer-
National Research Council ultimately became a land- ence there were only the three active kidney transplant
mark event in transplantation. Twenty-five of the lead- centers in the United States (Brigham Hospital, Univer-
ing transplant clinicians and scientists from around the sity of Colorado, and Medical College of Virginia).
world assembled to review the current status of human Within a year of the conference, and as word of the effec-
kidney transplantation.51 The results were very dis- tiveness of this new immunosuppression protocol spread,
couraging because less than 10% of the several hun- 50 new transplant programs began in hospitals through-
dred human allograft recipients had survived more out the United States, with a similar proliferation of
than 3 months.52 Of those treated with total body irra- transplant centers across Europe.49 Some of the benefits
diation for immunosuppression, only 6 patients had of kidney transplantation proved to be truly long lasting
survival close to 1 year. The results of those with drug- in some cases, because eight of the recipients from the
based immunosuppression were equally poor, as Mur- University of Colorado program from 1962 to 1963 still
ray reported that of his first 10 patients treated with had their kidney transplants 40 years later (making them
6-MP or azathioprine, only the one survived a year, the longest-surviving organ allograft recipients in the
whereas the others died within 6 months. Some par- world) and some of them have lasted 50 years.24
ticipants at the conference began to question whether
human transplantation could still be justified. Ulti-
mately the Colorado group described their success
with their immunosuppressive protocol of using aza-
thioprine and adding large doses of prednisone with
any rejection, which allowed a 1-year survival rate that
exceeded 70%.51 Because the Colorado group, which
had been a late invite to the meeting, reported more
surviving recipients than the rest of the world’s other
centers combined, the audience was incredulous, and it
provoked intense discussions. However, the fact that
Starzl brought with him the wall charts (on the advice
of Goodwin, who was aware of the results) that detailed
the daily progress, urine output, and laboratory work
of each patient, quelled the debate (Fig. 1-8). As Clyde
Barker of the University of Pennsylvania described the
events: “The gloom was dispelled by only one presen-
tation given by Tom Starzl, a virtually unknown new-
comer to the field, who was invited to the conference as FIGURE 1-8 n A segment of a typical kidney transplant wall chart
from the University of Colorado program, 1968. The wall chart
an afterthought…. The outlook for renal transplanta- was designed by T.E. Starzl, and the original version was hand
tion was completely changed by Starzl’s report.”51 drawn. Note the antilymphocyte globulin (ALG), Imuran, predni-
sone (Pred.), and x-ray dosing.

Dr. Francis D. Moore Dr. David M. Hume Dr. Joseph E. Murray

Brigham Hospital Medical College of Virginia Brigham Hospital
Boston, MA Richmond, VA Boston, MA

FIGURE 1-7 n Francis D. Moore, Joseph E. Murray, and David Hume were an integral part of the Peter Bent Brigham Hospital kidney
team in Boston that performed the first human kidney transplant in 1954. Hume moved to the Medical College of Virginia in Rich-
mond in 1956 to become the chairman of the Department of Surgery, where he initiated kidney transplant. In late 1962 the Brigham
Hospital, Medical College of Virginia, and the University of Colorado were the three programs performing kidney transplants in the
United States.
10 PART I General Considerations

HUMAN TRIALS: THE HUMAN LIVER and 8 hours, respectively, and neither recipient had any
TRANSPLANT TRIALS OF 1963 significant ischemic damage as evidenced by modest
increases in the liver enzyme levels after transplant.
Although the follow-up evaluations of the kidney For the operative procedure the various anastomoses
transplant trials were still short, the successful human were performed in the same way as in the dog experi-
kidney transplant experience at the Colorado program ments except for the biliary tract reconstruction. (The
encouraged the decision to go forward with the expo- complete operation was drawn in 1963 [Fig. 1-11], and
nentially more difficult initiative of liver transplanta- that picture could still be used today to depict a human
tion (Fig. 1-9). The first attempted human liver liver transplantation.) The immunosuppression proto-
transplant was on March 1, 1963, in a 3-year-old boy col for the recipients in the University of Colorado
with biliary atresia named Bennie Solis. Bennie had group’s liver transplantation trials derived from that
been operated on numerous times previously and had center’s experience in the human kidney transplant tri-
deteriorated to the point of being unconscious and als, with azathioprine administered both before and
ventilated.53 Unfortunately, Bennie bled to death dur- after transplantation, adding a high-dose course of
ing the actual transplant operation, because of the prednisone with the onset of rejection.
many high-pressure venous collaterals that had formed Although both procedures seemed satisfactory,
and an uncontrollable coagulopathy. This result these recipients—the second and third recipients of
occurred despite the fact that the operative team had the trial, died after 22 and 7.5 days, respectively. Both
performed more than 200 similar transplant operations patients died in part because of pulmonary emboli,
in animal models. The complexity and difficulty was so although interestingly, both were also found to have
extreme, it took the team several hours just to make the extrahepatic micrometastasis56 of their cancers at
incision and enter the abdomen, because of the signifi- autopsy, although with no rejection of the allograft.
cant collateralized adhesions. The strategy of controlling the coagulation using
Two more liver transplantations were performed transfusion of blood products and ε-aminocaproic acid
over the next 4 months in two adults, one transplanted for fibrinolysis, which was adopted following the
May 5, 1963, for a hepatoma, and the second trans- uncontrolled coagulopathy of the first transplant, had
planted June 3, 1963, for a cholangiocarcinoma. The unintentionally backfired. During the implantation of
donor procurement for these transplants had success- the livers, passive venovenous bypass with plastic
ful allograft preservation accomplished by transfemo-
ral infusion of a chilled perfusate into the aorta of the
non–heart-beating donors after cross-clamping the
aorta at the diaphragm (Fig. 1-10)—in much the same
way as the first stage of the multiple organ procure-
ment operation still performed today.54,55 The cold
ischemia time for the two procurements was 2.5 hours

Clam
p on th
orac
er i
Aorta Aort c
Liv

IVC a
Hepatic a.

Inferior
Glucose-primed mesenteric a.
pump oxygenator
and
heat exchanger

rta
in
to Ao

nt
I

oI
VC

FIGURE 1-10 n Extracorporeal perfusion of the deceased donors

reported in 1963. “The venous drainage was from the inferior
vena cava and the arterial inflow was through the aorta after
insertion of the catheters through the femoral vessels. Note
clamp on thoracic aorta to perfuse the lower half of the corpse
FIGURE 1-9 n Thomas E. Starzl at the University of Colorado in selectively. A glucose-primed pump oxygenator was used with
1963 performing one of the first liver transplants from the initial a heat exchanger.” a., Artery; IVC, inferior vena cava. (From Starzl
human liver trials at the Denver Veterans Administration TE, Marchioro TL, Von Kaulla KN, et al. Homotransplantation of the
hospital. liver in humans. Surg Gynecol Obstet. 1963;117:659-676.)
 1 The History of Liver Transplantation 11

tubing was used, similar to the technique used in the shown to be expendable in dogs submitted to common
canine model. However, in the humans who had been bile duct ligation several weeks in advance of trans-
given coagulation-promoting therapy, clots formed in plantation—an animal model of cirrhosis and portal
the bypass tubing and passed to the lungs, causing hypertension—and the venous collaterals that devel-
abscesses and lung damage that contributed to their oped enabled transplantation without venovenous
deaths (and to the next two recipients to follow). Ironi- bypass.60
cally, the use of the venovenous bypass to decompress
the venous system—something that was so crucial to
survival in the canine experiments—was not necessary HUMAN TRIALS: THE LIVER
for most human recipients. (A motor-driven venove- TRANSPLANT MORATORIUM
nous bypass system introduced in Pittsburgh in the
1980s57-59 and later use of percutaneous catheters have During the last half of 1963, two more liver transplanta-
made the procedure easier, but in many centers bypass tions were performed by Starzl’s group at the University
is only used selectively, if at all, and never in infants or of Colorado,7 and one each at the Brigham Hospital in
small children). Ultimately, venous decompression was Boston by Moore61 and at the Hospital St Antoine in
Paris by Jean Demirleau62,63 (Table 1-3). The transplant
in Paris was the first liver transplant in Europe, and used
IVC a 71-year-old donor into a 75-year-old recipient, making
gm this also the first transplant using what would be today
ra
ph L + r. hepatic v.
called a “marginal donor.”63 The operation lasted 4
a
Di

hours, but the patient died 3 hours after transplant from

uncontrollable fibrinolysis.
After the deaths of these seven patients in three dif-
ed)

ferent centers, there was great pessimism worldwide

mov

that the operation was too difficult to be practical, that

r (re

the methods of organ preservation were inadequate for

ladde

Aorta an organ so sensitive to ischemic damage, and that the

Celiac axis available immunosuppression options were too primi-
Gall b

Hepatic a. tive to allow success. This sentiment was reinforced by

Gastro- the fact that long-term survival following liver trans-
IVC duodenal a. plantation had not yet even been achieved in the experi-
Portal v. mental animal models. Clinical activity in liver
transplantation ceased for 3.5 years between January
in

ct
be

du 1964 and the summer of 1967. The worldwide morato-

tu

on rium was voluntary, but the decision to stop was rein-

T-

m
o m forced by widespread criticism that transplantation was
C Pancreas
too formidable to be practical. During the moratorium
Duodenum
on liver transplantation, the field did not stay still; prob-
FIGURE 1-11 n The operation carried out in the first two patients lems that contributed to the failures of the transplants of
who survived liver replacement on May 5 and June 3, 1963. The
patients lived for 22 and 7.5 days. a., Artery; IVC, inferior vena
1963 were addressed, and advances were made across
cava; L, left; r., right; v., vein. (From Starzl TE. Experience in the field, in immunosuppression, organ preservation,
hepatic transplantation. Philadelphia, PA: Saunders; 1969:138.) and operative techniques.

TABLE 1-3 The First Seven Human Liver Recipients

Survival
Date Age Program Surgeon Liver Disease (Days) Cause of Death
3/1/1963 3 University of Colorado, Denver T.E. Starzl Biliary atresia 0 Intraoperative
bleeding
5/5/1963 48 University of Colorado, Denver T.E. Starzl HCC 22 Pulmonary emboli,
sepsis
6/3/1963 68 University of Colorado, Denver T.E. Starzl Cholangiocarcinoma 7 Pulmonary emboli
7/10/1963 52 University of Colorado, Denver T.E. Starzl HCC 6 Pulononary emboli,
liver failure
9/16/1963 58 Brigham Hospital, Boston F.D. Moore Colon metastasis 11 Pneumonitis, liver
abscess/failure
10/4/1963 29 University of Colorado, Denver T.E. Starzl HCC 23 Pulmonary emboli,
sepsis
1/?/1964 75 Hospital St Antoine, Paris J. Demirleau Colon metastasis 0 Intraoperative
bleeding

HCC, Hepatocellular carcinoma.

12 PART I General Considerations

organ preservation was used from 1962 to 1969 before

IMMUNOSUPPRESSION: the acceptance of brain death and was the primary mode
ANTILYMPHOCYTE GLOBULIN used in both the initial liver trials of 1963 and the later
trials of 1967.69 Of note, the preliminary stages of this
A constant objective during the liver transplant morato- approach provided the basis for subsequent in situ tech-
rium was to improve immunosuppression regimens. niques that are used today.
With regard to human kidney transplant trials, despite After the failure from the trials of 1963 and during the
achieving consistent success with 1-year survival of moratorium following, the group at University of Colo-
70%, there was disappointment that the 30% mortality rado worked to improve the pitfalls of organ preservation
could not be improved upon,64 in spite of the increased that remained given that it was necessary to obtain livers
experience with kidney transplant techniques as well as from non–heart beating donors. To help surmount this
refinements in the azathioprine-prednisone protocol difficulty, the University of Colorado group developed an
and the application of histocompatibility matching. The ex vivo perfusion system in 1966 and 1967 that permitted
events leading to the typical patient death or graft loss reliable preservation in experiments with canine livers for
were predictable—the continuing function of the trans- as long as a day. This system combined the use of hypo-
plant kidney was dependent on toxic doses of predni- thermia, hyperbaric oxygenation, and low-flow perfusion
sone.65,66 For some patients, if the clinicians reduced the with fresh diluted blood.70
prednisone, the graft failed and had to be removed, but
if the prednisone dose was not removed, the graft could
be saved, but often at the cost of a lethal infection. ANIMAL MODELS: DEMONSTRATION OF
Between 1963 and 1966, antilymphocyte globulin HEPATIC TOLEROGENICITY
(ALG) was prepared from antilymphocyte serum obtained
from horses immunized against dog for preclinical canine Despite the failures of the human liver clinical trials of
studies, or against human lymphoid cells for later human 1963, during the liver moratorium the feasibility and
trials.67 In the preclinical canine studies, the efficacy of potential of liver transplantation was best reflected in the
dog-specific ALG was demonstrated in kidney transplant growing kennel population of long-surviving canine liver
models when it was given either 5 to 30 days before trans- recipients (Fig. 1-12), none of which was treated with
plant, at the time of transplant, or from 20 to 30 days more than a 4-month course of azathioprine71 or a few
after transplant.65 doses of ALG.64 In presenting the results of 143 canine
After extensive and successful preclinical canine stud- liver replacements to the Society of University Surgeons
ies, human-specific ALG was introduced clinically in in February 1965, it was emphasized that “Although the
human kidney recipients in a trial at the University of early recovery after liver homotransplantations has many
Colorado in June 1966.64-68 With a 1- to 4-month course hazards … the frequency and rapidity with which dogs
of ALG added as an adjuvant to the basic azathioprine could be withdrawn from immunosuppression without an
and prednisone protocol to create a “triple-drug cock- ensuing fatal rejection is remarkable… The consistency
tail,” the quantities of both azathioprine and especially of this state of host-graft nonreactivity and the rapidity
the prednisone were reduced and the function of the with which it seemed to develop exceeds that reported
graft was better maintained Ultimately, the mortality in after renal homotransplantations.”71
these kidney recipients was further decreased, approach- A year later the French surgeon Henri Garnier along
ing 10% using the triple-drug cocktail.64 with Gaston Cordier reported that a significant percentage
of untreated outbred pig liver recipients did not reject their
allografts.72 These observations were promptly confirmed
ORGAN PRESERVATION:
EXTRACORPOREAL HYPOTHERMIC
PERFUSION AND EX VIVO PERFUSION
The techniques of graft procurement and preservation
first developed for the liver grafts led to advances that
could be applied to other whole organs. The first
advancement was core cooling by infusion of chilled lac-
tated Ringer solution into the portal vein (this technique
was modified for use in clinical kidney transplants and
other organs). The first technique of in situ cooling was
by extracorporeal hypothermic perfusion. The catheters
were inserted via the femoral vessels into the aorta and
vena cava as soon as possible after death. A heat exchanger
was used to control the temperature.69 The thoracic
aorta was cross-clamped to limit the perfusion to the
FIGURE 1-12 n Canine recipient of an orthotopic liver homograft,
lower part of the body. The organs were then quickly 5 years later. The operation was on March 23, 1964. The dog was
resected in a bloodless field and then the tissue was dis- treated for only 120 days with azathioprine and died of old age
sected in the cold on the back table. This method of 13 years after transplantation.
 1 The History of Liver Transplantation 13

by Calne at the University of Cambridge program,73 John transplant trials, the young girl survived for more than a
Terblanche and J.H. Peacock at the University of Bristol, year before ultimately succumbing to metastatic recur-
England,74 and Starzl at the University of Colorado.75 rence 400 days after her transplant. The child’s vivacious
Calne and his colleagues at the University of Cambridge and charming personality lead Starzl to remark that Julie
further demonstrated that the tolerance self-induced by “became a metaphor for courage and human progress,”53
the liver extended to other tissues and organs from the and her successful transplant soon led to several more
liver donor, but not from third-party pigs.76 transplants that summer. Despite the advances, however,
the 1-year survival rate of these transplants remained
below 50%, and although it was a significant improve-
HUMAN TRIALS: THE HUMAN LIVER ment, the high mortality rate would lead to liver transplan-
TRANSPLANT TRIALS RESUME IN 1967 tation remaining controversial for another decade. Yet, in
spite of the controversy, the University of Colorado pro-
After the significant advances were made with immuno- gram was soon joined by similarly visioned clinicians at
suppression regarding ALG, and with the improvements other programs, aimed at advancing the field of liver
in organ preservation, once again the idea of liver trans- transplantation.
plantation became viable, and the liver program at the In February 1968 the liver transplant program at the
University of Colorado was reopened in July 1967, end- University of Colorado was bolstered by the opening of
ing a 4-year self-imposed moratorium. The program was Calne’s clinical program at the University of Cambridge,
reinforced by the addition of a powerful colleague, Carl England.22 On May 2, 1968, Calne (with Moore, visiting
Gustav Groth, a 2-year National Institutes of Health unexpectedly at Cambridge, acting as first assistant)78
(NIH) fellow and Fulbright Fellow from Stockholm (Fig. attempted the program’s first transplant (Fig. 1-14).
1-13). With a PhD in rheology (the study of the flow of Although the first patient transplanted by the program
matter), Groth’s knowledge of blood flow and the issues exsanguinated in a fashion similar to the experience at the
of blood coagulation proved vital to helping the Univer- University of Colorado, this was followed by several suc-
sity of Colorado group overcome the clotting issues that cessful liver transplants, aided by a fruitful collaboration
had plagued earlier transplants and had led to several with the hepatologist Roger Williams at King’s College
fatalities.77 Groth became a key member of both the Hospital in London, in what became known as the Cam-
donor and recipient teams at the University of bridge-King’s Program.78,79 By 1969 a total of 33 human
Colorado. liver transplants had been performed throughout the world,
With this hurdle overcome, the team was ready to including 25 performed at the University of Colorado by
attempt the operation in the summer of 1967, and Starzl the Starzl group and 4 performed at Cambridge-King’s
performed the first successful liver transplant in 1967 on Program by the Calne group. The importance of having
an 18-month-old child named Julie Rodriguez, who was another contemporary in the field was crucial for its
diagnosed with hepatoblastoma. With the triple-drug
cocktail16 that had been so successful in the kidney

Sir Roy Y. Calne

University of Cambridge
Cambridge, England
1965 – Present

St Mary’s Hospital
Westiminster Hospital
London, England
1962 – 1965

Brigham Hospital
Boston, MA
1960 – 1961

First Liver Transplant 1968

Developed: 6– MP,
azathioprine & cyclosporin

FIGURE 1-14 n Roy Calne began with studying immunosuppres-

sive drugs in canine kidney models. In 1960 he moved to Boston
to work with Joseph Murray and collaborated with George Hitch-
ing and Gertrude Elion to develop 6-mercaptopurine (6-MP) and
later azathioprine for use in transplantation. Returning to England
in 1962, Calne practiced first in London and then moved to the
University of Cambridge in 1965. He began performing liver trans-
FIGURE 1-13 n The first three human recipients to have pro- plantation at Cambridge in 1968, and together with Thomas E.
longed survival after liver replacements in July and August Starzl he helped define the field. In 1979 Calne initiated the cyclo-
1967. The adult, Carl Groth, was then a National Institutes of sporine clinical trials in liver transplantation that would change
Health–supported fellow from Stockholm, Sweden. the face of transplantation. He was knighted in 1981.
14 PART I General Considerations

Dr. Rudolf Pichlmayr Dr. Henri Bismuth Dr. Ruud A. Krom

University of Hannover Hôpital Paul Brousse University of Groningen
Hannover, Germany Villejuif, France Groningen, Netherlands
First Liver Transplant 1972 First Liver Transplant 1974 First Liver Transplant 1979

FIGURE 1-15 n Rudolf Pichlmayr in Hannover, Henri Bismuth in Paris, and later Ruud Krom in Groningen were the three other pro-
grams along with the University of Colorado and the Cambridge-King’s program that were actively performing liver transplants in the
1970s and early 1980s. These three surgeons were instrumental in helping to develop the field through their collaborations with
Thomas E. Starzl and Roy Calne.

advancement, as described by Starzl: “The fate of liver • The incidence of bile duct complications was reduced
transplantation would depend on an unspoken trans-­ to 30 % with the use of a choledochocholedochos-
Atlantic alliance between Cambridge and Denver without tomy with a T-tube stent.81 In time, this would be fur-
which further efforts could not have continued, much less ther refined and T tubes were no longer necessary.
succeeded, on either side of the ocean. These mutually • The systematic use of pump-driven venovenous
supportive moral and scientific bonds pulled liver trans- bypasses greatly diminished intraoperative bleed-
plantation into the mainstream of medical practice.” By ing; however, improvements in anesthesia and
1969 enough successes from the experience of these 33 intraoperative fluid management have made bypass
transplants allowed publication of the first textbook of liver a selective option.57,58
transplantation, Experience in Hepatic Transplantation.23 • The use of arterial grafts allowed arterialization of
By the early 1970s the two active liver transplant pro- the liver in cases of complex vasculature. The use of
grams of the University of Colorado and Cambridge-King’s venous grafts was introduced in the 1970s82 and
were joined by three other programs (Fig. 1-15) that would eliminated extensive thrombosis of the portal vein
also make important contributions to liver transplantation and superior mesenteric vein as a contraindication
over the next decade: the University of Hannover led by to transplant.83
Rudolf Pichlmayr performed their first liver transplant in • The piggyback operation (Fig. 1-16) that keeps
1972; the group from Hôpital Paul Brousse in Villejuif, intact the recipient retrohepatic vena cava was first
France, led by Henri Bismuth performed their first trans- used in 1968 at both the University of Cambridge
plant in 1974; and the group in Groningen led by Ruud program22 and the University of Colorado pro-
Krom, which followed with their first transplant in 1979. gram23 for pediatric recipients. The adult proce-
(Of note, that first patient from Groningen is still alive after dure was popularized by Andreas Tzakis at the
35 years.) Each of these programs reported a similar phe- University of Miami program.21
nomenon—the nearly miraculous benefits of liver trans- • The shortage of appropriate-sized donors for very
plantation when it was successful, but with the caveat that small pediatric recipients was greatly ameliorated
the mortality rate was too high to allow its practical use. by the use of partial liver segments.84,85
Nonetheless, much of the framework of liver transplanta- • Management of coagulopathy was facilitated by the
tion in place today was developed through the transatlantic thromboelastogram to follow minute-by-minute
alliance of these five mutually supportive centers during the clotting changes in the operating room. With bet-
frustrating period between 1969 and 1979.49,80 ter control of bleeding, the scarring from previous
surgery or prior portosystemic shunts were removed
as adverse factors in transplant.86
HUMAN TRIALS: ADVANCEMENTS TO
THE RECIPIENT OPERATION
ORGAN PRESERVATION: IN SITU
Although the overall procedure for a liver transplant today is PERFUSION
remarkably similar to the operation performed in 1967,
almost all of the elements of the initial transplant procedure The in situ perfusion technique was incorporated start-
have undergone refinements over the last 40 years. Some ing in 1970 and gained more exposure following the
examples of these refinements include the following: passage of brain death laws that allowed for controlled
 1 The History of Liver Transplantation 15

In 1976 Borel presented his finding in a lecture at the

spring meeting of the British Society for Immunology in
London,87 which was of major significance to the devel-
opment of cyclosporine because it stimulated the interest
of many clinicians, particularly Calne of the Cambridge-
Infrahepatic King’s program and his junior associate David White, an
Cava immunologist. White and Calne reviewed a sample of
ligated cyclosporine and began their own clinical studies using a
cut rat transplant model and confirmed it to be a powerful
immunosuppressant and one that could be administered
orally. However, the enthusiasm was not shared by all,
Ao
and Sandoz was not convinced of the commercial poten-
IVC
tial of cyclosporine given its small market. The company
proposed discontinuing the project, but Calne and White
Portal v. (g) traveled to Basel to make the case to the company direc-
tors, and the company ultimately relented.88
Portal v. (r)
During the 12 years spanning the period from the
FIGURE 1-16 n Transplantation of a liver piggybacked onto an restart of liver transplantation in 1967 until the discovery
inferior vena cava (IVC), which is preserved through its length. of cyclosporine, the 1-year survival for liver transplanta-
Note that the suprahepatic vena cava of the homograft is anas-
tomosed to the anterior wall of the recipient vena cava. The ret- tion remained stalled at an upper limit of 35%, despite
rohepatic vena cava of the homograft is sutured or ligated, continual attempts to improve it. This frustration ended
leaving a blind sac into which empty numerous hepatic veins. when cyclosporine became available in 1979,89 and it was
Ao, Aorta; g, graft; r, recipient; v., vein. (From Tzakis A, Todo S, first used initially by the Cambridge-King's group as a
Starzl TE. Orthotopic liver transplantation with preservation of the
inferior vena cava. Ann Surg. 1989;210:649-652.)
monotherapy drug. The improvements in transplant out-
comes were sudden, and by 1982 the Cambridge-King's
group passed the 50% 1-year survival mark for liver
organ procurement. The in situ perfusion of organs transplant, leading to several other transplant programs
developed out of the beginning stages of the hypother- opening in England and across Europe. The results of
mic and core cooling methods. Eventually in situ cold cyclosporine were taken up by Starzl at the University of
infusion techniques were perfected that allowed the Colorado, but as with past immunosuppression cocktails,
removal of all thoracic and abdominal organs, including Starzl combined cyclosporine with prednisone or ALG as
the liver, without jeopardizing any of the individual a double-drug combination.90 Of the first 12 liver recipi-
organs.54 With in situ cooling for multiple organ pro- ents treated with cyclosporine and prednisone in the first
curement, limited dissection of the aorta and great 8 months of 1980,91 11 (92%) lived for more than a year
splanchnic veins is performed, cannulating both. After and 7 of them were still alive over 12 years later. At last,
placing an aortic cross-clamp above the celiac axis, cold with the use of cyclosporine, liver transplantation was
infusates are run through these cannulas and they are able to achieve the success rates that could allow main-
used to chill the organs in situ. Modifications of this stream support.
procedure were made for unstable donors and donation
after cardiac death donors. By 1987 the techniques of
multiple organ procurement were interchangeable REGULATORY DEVELOPMENT:
among the various centers worldwide. NATIONAL INSTITUTES OF HEALTH
CONSENSUS COMMITTEE AND “THE
IMMUNOSUPPRESSION: THE NEW AGE STAMPEDE”
OF CYCLOSPORINE
In December 1981 the promising developments regard-
The immunosuppressant cyclosporine would revolution- ing liver transplantation with cyclosporine were reported
ize liver transplantation, and yet it came close to not com- to C. Everett Koop, who was the surgeon-in-chief at
ing into production at all. Cyclosporine was introduced Children’s Hospital of Philadelphia (CHOP). Koop had
by the company Sandoz in Basel, Switzerland, coming helped establish the biliary atresia program at CHOP by
from their routine study of fungi from soil samples bringing the pioneering Japanese surgeon Morio Kasai to
brought in from around the world. Sandoz began screen- CHOP in 1959-1960 as a research fellow—and liver
ing soil samples in 1970 looking for the cytostatic activity transplantation represented a crucial therapeutic option
among the fungi that might indicate an antibacterial or for biliary atresia. But more importantly, less than 2
anticancer property. In late 1971 a fungal extract contain- months after hearing about these results, Koop was
ing cyclosporine was submitted to the Sandoz laboratory appointed U.S. Surgeon General. Koop initiated steps
for testing its cytotoxic activity,87 and it was Jean-Fran- leading to a Consensus Development Conference for
cois Borel who was tasked with characterizing cyclospo- liver transplantation at the NIH in June 1983. In addition
rine’s immunological properties. Borel showed to Starzl’s program, which had moved to the University
cyclosporine caused a marked reduction of antibody for- of Pittsburgh, the conference also included the four vet-
mation in mice. eran European centers (Cambridge-King’s, Paris,
16 PART I General Considerations

University of Hannover, University of Groningen). This

consensus committee concluded that liver transplanta- U.W. Solution Composition
tion had become a “clinical service” as opposed to an
Potassium 125 mmol/L
experimental procedure.92 Sodium 30 mmol/L
After the success brought about by cyclosporine and Magnesium 5 mmol/L
the impact of the NIH Consensus report, there was a Lactobionate 100 mmol/L
worldwide stampede to develop liver transplant centers. Phosphate 25 mmol/L
In 1989, only 6 years after the NIH report, a 17-page Sulphate 5 mmol/L
Raffinose 30 mmol/L
article in the New England Journal of Medicine, spread over Adenosine 5 mmol/L
two issues, began with the following opening statement: Allopurinol 1 mmol/L
“The conceptual appeal of liver transplantation is so great Glutathione 3 mmol/L
that the procedure may come to mind as a last resort for Insulin 100 units/L
Dexamethasone 8 mg/L
virtually every patient with lethal hepatic disease.”49 Hydroxyethyl starch 50 g/L
Bactrim 0.5 mL/L

ORGAN PRESERVATION: COLD STORAGE Dr. Folkert Belzer Osmolality 320 mmol/kg pH 7.4
University of Wisconsin
Madison, WI
Another major advancement for liver transplantation was
the development of cold storage with preservation solu- FIGURE 1-17 n Folkert Belzer along with James H. Southard
tions. Working with kidney grafts, the idea of static cold developed University of Wisconsin (U.W.) preservation solution
storage was first proposed in 1969 by Geoffrey Collins as a way to avoid the cold-induced cellular injury that limited
from UCLA, working in the laboratory of Paul Terasaki. Euro-Collins solutions. After first developing the solution in
1979, they patiently made adjustments to the formula, improv-
He proposed cold storage after flushing out the kidneys ing the solution, so that in 1987 it was suitable for use in liver
with a simple electrolyte solution containing a high con- transplantation. This improved preservation solution allowed
centration of potassium designed to mimic the intracel- donor procurement from longer distances.
lular environment and also a high concentration of
glucose to increase osmolarity and minimize cell swell-
ing.93 After the kidney was flushed, the organ was placed appeared excessively toxic. The discrepancy likely was
in a sterile bag and kept on ice without perfusion. This explained by an inability to test levels and an unclear
fluid was further modified by removing magnesium and understanding of the drug pharmacokinetics.96 The pro-
substituting mannitol for glucose, and this modified Col- gram at the University of Pittsburgh was licensed to study
lins solution became known as Euro-Collins. Because of tacrolimus, initially restricting it to patients with chronic
the simplicity of the method and the success of Euro- rejection or having severe side effects from cyclospo-
Collins solution, cold storage of kidneys was adopted by rine.97 In the first trial, tacrolimus was successful in sal-
many kidney centers worldwide,94 although it was not vaging 7 out of 10 chronically rejecting grafts. In January
suitable for preserving liver grafts for transplant. 1989 a phase I trial of 110 new patients treated with
With the idea of cold static storage now a practice, tacrolimus showed a 1-year survival of 93%.98
Folkert Belzer (Fig. 1-17) now at the University of Wis- A multicenter trial of 20 centers examining tacrolimus
consin, along with James H. Southard worked to improve initially suffered from toxicity from high starting doses,
upon the strategy, turning their attention to ways to pre- but the investigators were able to salvage the trial after
vent the cold-induced cellular injury that limited Euro- adjusting the trial based on the learning curve of the drug
Collins solution. They experimented with different dosing. A randomized trial at the University of Pittsburgh
preservation solutions and perfusion solutions to create was notable in that 47 of 75 patients randomized to the
the initial University of Wisconsin (UW) solution in cyclosporine control arm were switched to the tacrolimus
1979 and then patiently made adjustments on more than study arm to salvage their rejection, at the recommenda-
a dozen different ingredients,27-29 improving the solution tion of the multi-institutional Patient’s Rights Commit-
so that in 1987 it was first employed successfully in liver tee given the evidence of the superiority of tacrolimus.97
transplantation. This advance would change the whole These study results led to the substitution of tacrolimus
strategy underlying liver transplantation. for cyclosporine as the benchmark immunosuppression
(Fig. 1-18). The Food and Drug Administration fol-
lowed, with fast track approval of tacrolimus for use in
IMMUNOSUPPRESSION: FURTHER liver transplantation in November 1993.95,97
ADVANCEMENTS USING TACROLIMUS
Following Sandoz’s commercial success with cyclospo- ORGAN SUPPLY: MARGINAL DONORS
rine, the Fujisawa Pharmaceutical company began testing
microorganisms and fungi from the soil and identified the As early as 1987, Leonard Makowka and his colleagues
macrolide FK506 in 1984 as a potential immunosuppres- at the University of Pittsburgh100 identified the impend-
sant. The first experimental reports appeared in 1987, ing organ shortage and reported the feasibility of sys-
and to investigators at the University of Pittsburgh,95 the tematically using livers from older donors, donors with
drug appeared very effective and free of many side biochemical or histopathological evidence of liver injury,
effects96; however, to investigators in England, the drug and those whose terminal course was characterized by
 1 The History of Liver Transplantation 17

100 involve dividing the liver into two segments, making

more efficient use of deceased donor liver allografts by
sharing one between two recipients. The first ex situ
80
split-liver transplant was reported by Pichlmayr103 from
Patient survival (%)

the University of Hannover in 1988, and similar proce-

60 dures were reported very soon after in Paris by Bis-
AZA (n  168) muth's team84 and at the University of Chicago by
CYA-EC (n  623) Christopher Broelsch.104,105 The first in situ liver trans-
40 CYA-UW (n  1217)
FK (n  1391)
plant was performed by Xavier Rogiers at the University
of Hamburg in 1995.106,107 The in situ technique used
20 the lessons learned from living donor liver transplanta-
tion to create the two separate segments that could be
used as liver allografts.107
0 Initially the results were inferior to those obtained
0 1 2 3 4 5 from whole livers, but after a learning curve and adopt-
Time after transplantation (yr) ing lessons from living donor transplantation, the
FIGURE 1-18 n Stepwise improvements in patient survival after results with livers split between adult and pediatric
liver replacement. These were associated with the advent of recipients have been comparable to standard deceased
increasingly potent immunosuppressive drugs. Most of the differ-
ence between the CYA-EC and CYA-UW lines was because of the
donor transplantation. There are two main types of
availability of FK for the rescue of cyclosporine failures. The data split livers. The first is the classic split into an extended
shown here were presented to the American Surgical Association right graft and a left lateral segment suitable for creat-
in April 1994. AZA, Azathioprine; CYA-EC, cyclosporine before the ing grafts for pediatric patients. The second type
availability of University of Wisconsin solution; CYA-UW, cyclo- results in a right and left segment that can be suitable
sporine after the availability of University of Wisconsin solution;
FK, tacrolimus. for two adults.107
The current role for split livers is controversial.
Although the evidence shows the outcomes are similar to
those of whole livers, the current regulatory environment
management errors, physiological abnormalities, or the does not reward the efforts and expenses incurred by cen-
administration of potentially damaging pharmacological ters that pursue these option to bring it to the
agents. Criticized at first, this form of expanding the mainstream.
donor pool became widely accepted once the magnitude
of the supply problem was fully appreciated. The use of
marginal donors has become so mainstream that what ORGAN SUPPLY: LIVING DONOR
was once considered marginal is now more often than TRANSPLANTATION
not considered standard.
Several efforts, many often contentious, have been Living donor liver transplantation evolved from the
made to define what constitutes a marginal donor, and reduced liver graft procedures done in deceased donors
how to decide who gets the liver.101 The Donor Risk and involves resecting liver segments (ranging in size
Index was defined by Sandy Feng of the University of from a left lateral segment to an extended right lobe seg-
California, San Francisco, along with colleagues from ment) from volunteer adult donors and transplanting
the University of Michigan102 in 2006. This group used them into a pediatric recipient. The first successful living
powerful statistical techniques and the data pooled donor liver transplant, from an adult to a pediatric recipi-
nationally from large clinical trials and databases to ent, was performed by Russell W. Strong and Stephen V.
identify significant donor parameters. An index was cre- Lynch of the University of Queensland in Brisbane, Aus-
ated that could quantify the risk of a particular donor tralia, in July 1989.108 The living donor transplant opera-
based on these known pretransplant parameters and tion for pediatric recipients was subsequently popularized
quickly provide that risk to the transplant surgeon in by Broelsch and associates from the University of Chi-
real time.102 cago, who reported their experience of living donation
As the organ supply issues become greater, and as the along with their experience of split livers and reduced-
technical capabilities of transplantation and posttrans- size deceased donors at the 1990 American Surgical Asso-
plant management continue to be refined, the question as ciation conference.105
to what defines a marginal donor will invariably be For adult-to-adult living donor transplantation, to
adjusted further. obtain an adequate liver mass, the size of the transected
liver segment was first increased from a left lateral seg-
ment, to a full left lobe, and then to the right lobe opera-
ORGAN SUPPLY: SPLIT-LIVER tion, which is the most common procedure today. This
PROCEDURES first right lobe living donor transplant was carried out by
the program at Kyoto University in Japan,109 when unex-
Split-liver transplantation evolved from the advance- pected anatomical findings were encountered in the
ments of hepatobiliary surgery that have improved donor. The first series of right lobe transplantation in the
parenchymal transection and an improved understand- United States was performed by the team of Igal Kam
ing of liver segmental anatomy. Split-liver procedures from the University of Colorado in 1997.109 Shortly
18 PART I General Considerations

thereafter, several other centers across the United States 1992 and January 1993 using the more phylogenetically
initiated adult-to-adult living donor transplants. Since distant baboon livers.115 The recipients were patients
this time, more than 3500 right lobe transplantations111 with human immunodeficiency virus (HIV) infection and
have been performed in more than 60 U.S. centers, with advanced hepatitis B, specifically chosen because animal
patient and graft survival equivalent to that of whole- livers are refractory to infection by either virus, and they
organ deceased donor transplantation or the various survived for 70 days and 26 days, respectively. In these
kinds of partial liver transplantation, including the adult- baboon xenotransplants, a four-drug immunosuppression
to-child living donor transplant. cocktail was used, and neither cell-mediated nor humoral
Despite its utility, living donor liver transplantation rejection was implicated as the cause of death in the
has been used with caution by many transplant sur- recipients. However, there was evidence of continuous
geons because of concerns of donor mortality. Living complement activation in both, and neither xenograft
donor liver transplant donor deaths have occurred at functioned optimally, with both developing intrahepatic
some of the largest and most experienced living donor cholestasis within the first postoperative week. Because of
liver programs in the United States. These deaths the heavy immunosuppression needed, both patients
occurred under a media microscope that never existed developed infections that led to their deaths, and the first
during the early liver transplant trials of the 1960s, and patient also had a fatal brain hemorrhage at 70 days.115 It
the intense media exposure magnified each event expo- was suspected that synthetic products created from the
nentially. A review of living donor liver transplantation baboon liver might have been incompatible with the
in the United States showed the incidence of early human metabolic environment. Further trials of xeno-
mortality in donors was 0.2%112 with seven liver donors transplantation involving chimpanzees and baboons have
having died in the United States by 2013, during either been avoided because of the anthropometric qualities of
the operative procurement or in the immediate post- the donor and the concerns that these animals pose a high
operative period. risk for zoonotic infections that might enter the human
Although much attention has focused on living population, given the evidence of human diseases that
donation in the United States, most of the later devel- originated from nonhuman primates such as HIV-1 and
opment in the field has occurred in programs through- HIV-2.116
out Asia, largely because of need related to a lack of It has been hoped that lower mammalian donors such
organ supply from deceased donors. Living donor as pigs may be suitable. Studies using the genetic knock-
transplantation flourished early on in Japan, leading to out of clone pigs missing the α1,3-galactosyltransferease
the creation of several very large programs in Fukuoka, gene,117 which is required for the 1,3-galactose sugar
Kyoto, and Tokyo. The greatest success has been in chains that induce human preformed antibodies, show it
Korea, particularly the program of Sung-Gyu Lee at avoided the hyperrejection from the immediate innate
the Asan Medical Center in Seoul, South Korea, which immune response. The first porcine-to-human xeno-
alone performs more living donor liver transplants transplantation was performed by Makowka at the
each year than all of the centers in the United States Cedars-Sinai program in Los Angeles in October 1992.
combined. It was intended as a bridge for a human liver in a patient
with acute liver failure, but the patient died of cerebral
swelling 32 hours after transplant, and 2 hours before
ORGAN SUPPLY: the human transplant was to begin.
XENOTRANSPLANTATION Later trials of porcine-to-human xenotransplantation
have focused on using them ex vivo, as extracorporeal
Xenotransplantation is the transplantation of living tis- support instead of implanting the liver, to bridge sick
sue or organs from one species to another. It has long patients until a human liver becomes available. Marlon
been hoped to be a solution for the supply issues facing Levy at the Baylor University Medical Center in Dallas
liver transplantation. At the same time, xenotransplan- reported the first successful ex vivo porcine xenoperfu-
tation is associated with a number of concerns, includ- sions used in this fashion.118 Nonetheless, concerns of
ing immunological problems and xenogeneic infections, xenogeneic infections have developed out of this situa-
as well as ethical, legal, and social concerns. Regardless tion, because pigs carry an endogenous retrovirus called
of these issues, it is not an area that has had great porcine endogenous retrovirus that is capable of infecting
success human cell lines.113 There have been no reports of por-
The first clinical attempts in xenotransplantation of cine-to-human transmission of porcine endogenous ret-
livers involved chimpanzees between 1966 and 1973.113 rovirus from these ex vivo porcine systems.
There were three attempted transplants of chimpanzee
livers into three children, and all were unsuccessful
with all dying within 14 days of transplant.114 Of inter-
est, the clinical course and histopathological examina-
REGULATORY DEVELOPMENT:
tion of the xenograft livers on autopsy were NATIONAL ORGAN TRANSPLANT ACT
indistinguishable from allotransplantation transplants OF 1984 AND BEYOND
at that time.
With the development of improved immunosuppres- The rapid developments in organ transplantation follow-
sion, two more xenotransplants were attempted by Starzl ing the introduction of cyclosporine, as well as the report
at the University of Pittsburgh program between June from the NIH consensus committee, led to many issues
 1 The History of Liver Transplantation 19

NATIONAL ORGAN TRANSPLANT ACT REGULATORY DEVELOPMENT:

EQUITABLE ORGAN ALLOCATION AND
THE MELD SCORE
HEARING
BEFORE THE As liver transplantation moved from being experimen-
SUBCOMMITTEE ON HEALTH tal to a “clinical service, and as it became more success-
OF THE ful, the increased demand was met with shortages of
COMMITTE ON WAYS AND MEANS organ supply. To help manage this supply-demand
HOUSE OF REPRESENTATIVES mismatch, the transplant field in the United States in
NINETY-EIGHTH CONGRESS
SECOND SESSION
2002 began using the Model for End-Stage Liver Dis-
ON ease (MELD) score, based on an equation using three
H.R. 4080 laboratory-based parameters, to prioritize equitable
TO AMEND THE PUBLIC HEALTH SERVICE ACT TO AUTHORIZE organ allocation. The MELD score was implemented
FINANCIAL ASSISTANCE FOR ORGAN PROCUREMENT in response to the OPTN Final Rule, a mandate to
ORGANIZATIONS, AND FOR OTHER PURPOSES deemphasize waiting time and focus on disease severity
and waiting list mortality.122 Compared to the prior
FEBRUARY 9, 1984
system that used the Child-Turcotte-Pugh score and
Serial 98–64 location of the patient (i.e., home, hospital, intensive
care unit) to allocate organs, the MELD system was
Printed for the use of the Committee on Ways and Means thought to be more standard and equitable, more dif-
ficult to manipulate, less dependent on waiting list, and
FIGURE 1-19 n The National Organ Transplant Act was sponsored instead focusing on the idea of the “sickest first.”
by Representative Al Gore and Senator Orrin Hatch and was Exception points were provided in certain situation
approved on October 19, 1984. The act was important in codify- such as for hepatocellular carcinomas that met the
ing guidelines regarding transplantation, including prohibiting
the sale of human organs. Many of the administrative bodies
Milan criteria.
and tools used today, including the Organ Procurement and The system is not perfect, and its weaknesses have
Transplantation Network, organ procurement organizations, the been widely recognized, including a lack of specificity for
United Network for Organ Sharing, and the Scientific Registry of different liver diseases and particular biases associated
Transplant Recipients, were laid out in the act. with each laboratory parameter. Nonetheless, the MELD
score has set a standard and has allowed for the idea of a
that needed regulation and oversight. Before the passage newer system that reflects these weaknesses to one day be
of the National Organ Transplant Act (NOTA), there incorporated.
was not a clear understanding of property rights for trans-
plant and there were concerns of a developing commer-
cial marketplace for organs.
The NOTA was sponsored by Representative Al
ORGAN PRESERVATION:
Gore and Senator Orrin Hatch (Fig. 1-19), and it was EXTRACORPOREAL MACHINE
approved on October 19, 1984.119 The act provided for PERFUSION SYSTEMS
the establishment of the Task Force on Organ Trans-
plantation, and it outlawed the sale of human organs. Extracorporeal machine perfusion systems are an exam-
Many of the administrative bodies in place today were ple of history repeating itself in the modern day.123
outlined in the act. One mandate was the formation of Machine organ perfusion was part of the first studies of
the Organ Procurement and Transplantation Network organ transplant, before the development of better pres-
(OPTN),120 which would establish and oversee organ ervation solution that allowed cold storage at 4° C.
procurement organizations (OPOs). Another mandate Unfortunately, the organs from marginal donors that
was the development of the Scientific Registry of make up so many of the transplants in today’s transplant
Transplant Recipients (SRTR) with which patient and centers are more susceptible to damage from cold stor-
graft survival could be assessed from center to age. The successful development of hypothermic pulsa-
center.121 tile machine perfusion for kidney allografts, as well as
Following passage of the NOTA, the Department of interest in expanding the use of marginal donors, has led
Health and Human Services awarded the contract to to efforts to create a similar system for livers. James Guar-
administer the OPTN and the OPOs to a private non- rera and colleagues from Columbia University, New
profit organization, the United Network for Organ Shar- York, devised a hypothermic machine perfusion system
ing (UNOS). The SRTR was created in 1987 to support for liver (Fig. 1-20), and the initial trials reported in 2010
ongoing evaluation of the scientific and clinical status of have shown benefit. These machine perfusion systems
solid organ transplant. The SRTR contract was trans- also allow delivery of metabolic substrates and therapeu-
ferred to the University of Michigan–based Arbor tic agents to the allograft and make assessments that can
Research Collaborative for Health in 2000. In 2010 the predict graft function.123,124 The main limitation is devis-
University of Minnesota–based Minneapolis Medical ing a portable system that can accommodate the size and
Research Foundation was awarded the contract for the perfusion demands of a liver. Another machine perfusion
SRTR. strategy involves a normothermic perfusion system that
20 PART I General Considerations

The history of liver transplantation is a complicated

story to tell—but it's a really good one.

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2. Hamilton D. Towards the Impossible. Philadelphia, Lippincott
Bubble 40 m filter Williams & Wilkins. 2002.
chamber (disposable) 3. Busuttil RW, De Carlis LG, Mihaylov PV, et al. The first report
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Closed circuit 4. Staudacher V. Trapianti di organi con anostomosi vascolari.
tubing La Riforma Medica. 1952;66:1060.
5. Welch CS. A note on transplantation of the whole liver in dogs.
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6. Goodrich Jr EO, Welch HF, Nelson JA, et al. Homotransplanta-
tion of the canine liver. Surgery. 1956;39:244-251.
Pump head
A 7. Starzl TE, Marchioro TL, Rowlands DT Jr, et al. Immunosup-
pression after experimental and clinical homotransplantation of
the liver. Ann Surg. 1964;160:411-439.
8. Marchioro TL, Porter KA, Dickinson TC, et al. Physiologic
Left temp probe requirements for auxiliary liver homotransplantation. Surg Gyne-
Right temp probe col Obstet. 1965;121:17-31.
9. Starzl TE, Francavilla A, Halgrimson CG, et al. The origin, hor-
SHIVC effluent cannula monal nature, and action of hepatotrophic substances in portal
IVC venous blood. Surg Gynecol Obstet. 1973;137:179-199.
RLHA
10. Starzl TE, Porter KA, Putnam CW. Intraportal insulin protects
CHA PV from the liver injury of portacaval shunt in dogs. Lancet.
Cho clamp 1975;2:1241-1246.
Portal pressure
11. Woodruff MFA. The Transplantation of Tissues and Organs. Spring-
field, Illinois: Charles C Thomas; 1960. 1-777.
12. Cannon JA. Brief report. Transplant Bull. 1956;3:7.
13. Moore FD, Wheeler HB, Demissianos HV, et al. Experimental
whole organ transplantation of the liver and of the spleen. Ann
Surg. 1960;152:374-387.
B 14. Starzl TE, Kaupp HA Jr, Brock DR, et al. Reconstructive prob-
lems in canine liver homotransplantation with special reference to
the postoperative role of hepatic venous flow. Surg Gynecol Obstet.
FIGURE 1-20 n The successful development of hypothermic pul- 1960;111:733-743.
satile machine perfusion for kidney allografts, as well as interest 15. Moore FD, Smith LL, Burnap TK, et al. One-stage homotrans-
in expanding the use of marginal donors, has led to efforts to plantation of the liver following total hepatectomy in dogs. Trans-
create a similar system for livers. James Guarrera and col- plant Bull. 1959;6:103-110.
leagues from Columbia University, New York, devised a hypo- 16. McBride RA, Wheeler HB, Smith LL, et al. Homotransplanta-
thermic machine perfusion system for liver, and the initial trials tion of the canine liver as an orthotopic vascularized graft. Histo-
reported in 2010 have shown benefit. These machine perfusion logic and functional correlations during residence in the new host.
systems allow delivery of metabolic substrates and therapeutic Am J Pathol. 1962;41:501-515.
agents to the allograft and also allow assessments that can predict
17. Starzl TE, Kaupp HA Jr, Brock DR, et al. Studies on the rejection
graft function. CHA, common hepatic artery; IVC, inferior vena
of the transplanted homologous dog liver. Surg Gynecol Obstet.
cava; PV, portal vein; RLHA, replaced left hepatic artery; SHIVC,
1961;112:135-144.
suprahepatic inferior vena cava; temp, temperature. (From
­Guarrera JV, Henry SD, Samstein B, et al. Hypothermic machine 18. Meyer WH Jr, Starzl TE. The effect of Eck and reverse Eck fis-
preservation in human liver transplantation: the first clinical series. tula in dogs with experimental diabetes mellitus. Surgery.
Am J Transplant. 2010;10:372-381.) 1959;45:760-764.
19. Meyer WH Jr, Starzl TE. The reverse portacaval shunt. Surgery.
1959;45:531-534.
pumps oxygenated blood through the liver at body tem- 20. Starzl TE, Bernhard VM, Benvenuto R, et al. A new method for
one-stage hepatectomy in dogs. Surgery. 1959;46:880-886.
perature,125,126 and initial trials at the program at King's
21. Tzakis A, Todo S, Starzl TE. Orthotopic liver transplantation
College have been very successful.127 with preservation of the inferior vena cava. Ann Surg.
1989;210:649-652.
22. Calne RY, Williams R. Liver transplantation in man. I. Observa-
SUMMARY tions on technique and organization in five cases. Br Med J.
1968;4:535-540.
23. Starzl TE. Experience in Hepatic Transplantation. Philadelphia: WB
The history of liver transplantation is a story that spans Saunders; 1969: 1-553.
more than 6 decades. It is a story of bold clinicians over- 24. Starzl TE. The saga of liver replacement with particular reference
coming obstacles and setbacks, learning from their failures, to the reciprocal influence of liver and kidney transplantation
and through a collaborative effort accomplishing what con- (1955 - 1967). J Am Coll Surg. 2002;195:587-610.
ventional wisdom—and many experts of the day—thought 25. Benichou J, Halgrimson CG, Weil R III, et al. Canine and human
liver preservation for 6 to 18 hours by cold infusion. Transplanta-
was impossible. It is a story of those first brave patients at tion. 1977;24:407-411.
the beginning who were willing to go forward when there 26. Wall WJ, Calne RY, Herbertson BM, et al. Simple hypothermic
were no guarantees of success. And it is now a story of hun- preservation for transporting human livers long distance for
dreds of thousands of lives worldwide that have been saved. homotransplantation. Transplantation. 1977;23:210-216.
Another random document with
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 Streight way so soone as both together met,
Th’enchaunted Damzell vanisht into nought:
Her snowy substance melted as with heat,
Ne of that goodly hew remayned ought,
But th’emptie girdle, which about her wast was wrought.

As when the daughter of Thaumantes faire, xxv

Hath in a watry cloud displayed wide
Her goodly bow, which paints the liquid ayre;
That all men wonder at her colours pride;
All suddenly, ere one can looke aside,
The glorious picture vanisheth away,
Ne any token doth thereof abide:
So did this Ladies goodly forme decay,
And into nothing goe, ere one could it bewray.

Which when as all that present were, beheld, xxvi

They stricken were with great astonishment,
And their faint harts with senselesse horrour queld,
To see the thing, that seem’d so excellent,
So stolen from their fancies wonderment;
That what of it became, none vnderstood.
And Braggadochio selfe with dreriment
So daunted was in his despeyring mood,
That like a lifelesse corse immoueable he stood.

But Artegall that golden belt vptooke, xxvii

The which of all her spoyle was onely left;
Which was not hers, as many it mistooke,
But Florimells owne girdle, from her reft,
While she was flying, like a weary weft,
From that foule monster, which did her compell
To perils great; which he vnbuckling eft,
Presented to the fayrest Florimell;
Who round about her tender wast it fitted well.
Full many Ladies often had assayd, xxviii
About their middles that faire belt to knit;
And many a one suppos’d to be a mayd:
Yet it to none of all their loynes would fit,
Till Florimell about her fastned it.
Such power it had, that to no womans wast
By any skill or labour it would sit,
Vnlesse that she were continent and chast,
But it would lose or breake, that many had disgrast.

Whilest thus they busied were bout Florimell, xxix

And boastfull Braggadochio to defame,
Sir Guyon as by fortune then befell,
Forth from the thickest preasse of people came,
His owne good steed, which he had stolne, to clame;
And th’one hand seizing on his golden bit,
With th’other drew his sword: for with the same
He ment the thiefe there deadly to haue smit:
And had he not bene held, he nought had fayld of it.

Thereof great hurly burly moued was xxx

Throughout the hall, for that same warlike horse.
For Braggadochio would not let him pas;
And Guyon would him algates haue perforse,
Or it approue vpon his carrion corse.
Which troublous stirre when Artegall perceiued,
He nigh them drew to stay th’auengers forse,
And gan inquire, how was that steed bereaued,
Whether by might extort, or else by slight deceaued.

Who all that piteous storie, which befell xxxi

About that wofull couple, which were slaine,
And their young bloodie babe to him gan tell;
With whom whiles he did in the wood remaine,
His horse purloyned was by subtill traine:
For which he chalenged the thiefe to fight.
 But he for nought could him thereto constraine.
For as the death he hated such despight,
And rather had to lose, then trie in armes his right.

Which Artegall well hearing, though no more xxxii

By law of armes there neede ones right to trie,
As was the wont of warlike knights of yore,
Then that his foe should him the field denie,
Yet further right by tokens to descrie,
He askt, what priuie tokens he did beare.
If that (said Guyon) may you satisfie,
Within his mouth a blacke spot doth appeare,
Shapt like a horses shoe, who list to seeke it there.

Whereof to make due tryall, one did take xxxiii

The horse in hand, within his mouth to looke:
But with his heeles so sorely he him strake,
That all his ribs he quite in peeces broke,
That neuer word from that day forth he spoke.
Another that would seeme to haue more wit,
Him by the bright embrodered hedstall tooke:
But by the shoulder him so sore he bit,
That he him maymed quite, and all his shoulder split.

Ne he his mouth would open vnto wight, xxxiv

Vntill that Guyon selfe vnto him spake,
And called Brigadore (so was he hight)
Whose voice so soone as he did vndertake,
Eftsoones he stood as still as any stake,
And suffred all his secret marke to see:
And when as he him nam’d, for ioy he brake
His bands, and follow’d him with gladfull glee,
And friskt, and flong aloft, and louted low on knee.

Thereby Sir Artegall did plaine areed, xxxv

That vnto him the horse belong’d, and sayd;
 Lo there Sir Guyon, take to you the steed,
As he with golden saddle is arayd;
And let that losell, plainely now displayd,
Hence fare on foot, till he an horse haue gayned.
But the proud boaster gan his doome vpbrayd,
And him reuil’d, and rated, and disdayned,
That iudgement so vniust against him had ordayned.

Much was the knight incenst with his lewd word, xxxvi
To haue reuenged that his villeny;
And thrise did lay his hand vpon his sword,
To haue him slaine, or dearely doen aby.
But Guyon did his choler pacify,
Saying, Sir knight, it would dishonour bee
To you, that are our iudge of equity,
To wreake your wrath on such a carle as hee:[273]
It’s punishment enough, that all his shame doe see.

So did he mitigate Sir Artegall, xxxvii

But Talus by the backe the boaster hent,
And drawing him out of the open hall,
Vpon him did inflict this punishment.
First he his beard did shaue, and fowly shent:
Then from him reft his shield, and it renuerst,
And blotted out his armes with falshood blent,
And himselfe baffuld, and his armes vnherst,
And broke his sword in twaine, and all his armour sperst.

The whiles his guilefull groome was fled away: xxxviii

But vaine it was to thinke from him to flie.
Who ouertaking him did disaray,
And all his face deform’d with infamie,
And out of court him scourged openly.
So ought all faytours, that true knighthood shame,
And armes dishonour with base villanie,
From all braue knights be banisht with defame:
For oft their lewdnes blotteth good deserts with blame.

Now when these counterfeits were thus vncased xxxix

Out of the foreside of their forgerie,
And in the sight of all men cleane disgraced,
All gan to iest and gibe full merilie
At the remembrance of their knauerie.
Ladies can laugh at Ladies, Knights at Knights,
To thinke with how great vaunt of brauerie
He them abused, through his subtill slights,
And what a glorious shew he made in all their sights.

There leaue we them in pleasure and repast, xl

Spending their ioyous dayes and gladfull nights,
And taking vsurie of time forepast,
With all deare delices and rare delights,
Fit for such Ladies and such louely knights:
And turne we[274] here to this faire furrowes end
Our wearie yokes, to gather fresher sprights,
That when as time to Artegall shall tend,
We on his first aduenture may him forward send.

FOOTNOTES:
[270] xi 7 Th’other 1596, 1609
[271] 9 th’other 1596, 1609
[272] xix 1 th’azure 1609
[273] xxxvi 8 hee 1596
 Cant. IIII.

Artegall dealeth right betwixt

two brethren that doe striue,
Saues Terpine from the gallow tree,
and doth from death repriue.

Who so vpon him selfe will take the skill i

True Iustice vnto people to diuide,
Had neede haue mightie hands, for to fulfill
That, which he doth with righteous doome decide,
And for to maister wrong and puissant pride.
For vaine it is to deeme of things aright,
And makes wrong doers iustice to deride,
Vnlesse it be perform’d with dreadlesse might.
For powre is the right hand of Iustice truely hight.

Therefore whylome to knights of great emprise ii

The charge of Iustice giuen was in trust,
That they might execute her iudgements wise,
And with their might beat downe licentious lust,
Which proudly did impugne her sentence iust.
Whereof no brauer president[275] this day
Remaines on earth, preseru’d from yron rust
 Of rude obliuion, and long times decay,
Then this of Artegall, which here we haue to say.

Who hauing lately left that louely payre, iii

Enlincked fast in wedlockes loyall bond,
Bold Marinell with Florimell the fayre,
With whom great feast and goodly glee he fond,
Departed from the Castle of the strond,
To follow his aduentures first intent,
Which long agoe he taken had in hond:
Ne wight with him for his assistance went,
But that great yron groome, his gard and gouernment.

With whom as he did passe by the sea shore, iv

He chaunst to come, whereas two comely Squires,
Both brethren, whom one wombe together bore,
But stirred vp with different desires,
Together stroue, and kindled wrathfull fires:
And them beside two seemely damzels stood,
By all meanes seeking to asswage their ires,
Now with faire words; but words did little good,
Now with sharpe threats; but threats the more increast their mood.

And there before them stood a Coffer strong, v

Fast bound on euery side with iron bands,
But seeming to haue suffred mickle wrong,
Either by being wreckt vppon the sands,
Or being carried farre from forraine lands.
Seem’d that for it these Squires at ods did fall,
And bent against them selues their cruell hands.
But euermore, those Damzels did forestall
Their furious encounter, and their fiercenesse pall.

But firmely fixt they were, with dint of sword, vi

And battailes doubtfull proofe their rights to try,
Ne other end their fury would afford,
 But what to them Fortune would iustify.
So stood they both in readinesse thereby,[276]
To ioyne the combate with cruell intent;
When Artegall arriuing happily,
Did stay a while their greedy bickerment,
Till he had questioned the cause of their dissent.

To whom the elder did this aunswere frame; vii

Then weete ye Sir, that we two brethren be,
To whom our sire, Milesio by name,
Did equally bequeath his lands in fee,
Two Ilands, which ye there before you see
Not farre in sea; of which the one appeares
But like a little Mount of small degree;
Yet was as great and wide ere many yeares,
As that same other Isle, that greater bredth now beares.

But tract of time, that all things doth decay, viii

And this deuouring Sea, that naught doth spare,
The most part of my land hath washt away,
And throwne it vp vnto my brothers share:
So his encreased, but mine did empaire.
Before which time I lou’d, as was my lot,
That further mayd, hight Philtra the faire,
With whom a goodly doure I should haue got,
And should haue ioyned bene to her in wedlocks knot.

Then did my younger brother Amidas ix

Loue that same other Damzell, Lucy bright,
To whom but little dowre allotted was;
Her vertue was the dowre, that did delight.
What better dowre can to a dame be hight?
But now when Philtra saw my lands decay,
And former liuelod fayle, she left me quight,
And to my brother did ellope streight way:
Who taking her from me, his owne loue left astray.
She seeing then her selfe forsaken so, x
Through dolorous despaire, which she conceyued,
Into the Sea her selfe did headlong throw,
Thinking to haue her griefe by death bereaued.
But see how much her purpose was deceaued.
Whilest thus amidst the billowes beating of her
Twixt life and death, long to and fro she weaued,
She chaunst vnwares to light vppon this coffer,
Which to her in that daunger hope of life did offer.

The wretched mayd that earst desir’d to die, xi

When as the paine of death she tasted had,
And but halfe seene his vgly visnomie,
Gan to repent, that she had beene so mad,
For any death to chaunge life though most bad:
And catching hold of this Sea-beaten chest,
The lucky Pylot of her passage sad,
After long tossing in the seas distrest,
Her weary barke at last vppon mine Isle did rest.

Where I by chaunce then wandring on the shore, xii

Did her espy, and through my good endeuour
From dreadfull mouth of death, which threatned sore
Her to haue swallow’d vp, did helpe to saue her.
She then in recompence of that great fauour,
Which I on her bestowed, bestowed on me
The portion of that good, which Fortune gaue her,
Together with her selfe in dowry free;
Both goodly portions, but of both the better she.

Yet in this coffer, which she with her brought, xiii

Great threasure sithence we did finde contained;
Which as our owne we tooke, and so it thought.
But this same other Damzell since hath fained,
That to her selfe that threasure appertained;
And that she did transport the same by sea,
 To bring it to her husband new ordained,
But suffred cruell shipwracke by the way.
But whether it be so or no, I can not say.

But whether it indeede be so or no, xiv

This doe I say, that what so good or ill
Or God or Fortune vnto me did throw,
Not wronging any other by my will,
I hold mine owne, and so will hold it still.
And though my land he first did winne away,
And then my loue (though now it little skill,)
Yet my good lucke he shall not likewise pray;
But I will it defend, whilst euer that I may.

So hauing sayd, the younger did ensew; xv

Full true it is, what so about our land
My brother here declared hath to you:
But not for it this ods twixt vs doth stand,
But for this threasure throwne vppon his strand;
Which well I proue, as shall appeare by triall,
To be this maides, with whom I fastned hand,
Known by good markes, and perfect good espiall,
Therefore it ought be rendred her without deniall.

When they thus ended had, the Knight began; xvi

Certes your strife were easie to accord,
Would ye remit it to some righteous man.
Vnto your selfe, said they, we giue our word,
To bide what iudgement ye shall vs afford.
Then for assuraunce to my doome to stand,
Vnder my foote let each lay downe his sword,
And then you shall my sentence vnderstand.
So each of them layd downe his sword out of his hand.

Then Artegall thus to the younger sayd; xvii

Now tell me Amidas, if that ye may,
 Your brothers land the which the sea hath layd
Vnto your part, and pluckt from his away,
By what good right doe you withhold this day?
What other right (quoth he) should you esteeme,
But that the sea it to my share did lay?
Your right is good (sayd he) and so I deeme,
That what the sea vnto you sent, your own should seeme.

Then turning to the elder thus he sayd; xviii

Now Bracidas let this likewise be showne.
Your brothers threasure, which from him is strayd,
Being the dowry of his wife well knowne,
By what right doe you claime to be your owne?
What other right (quoth he) should you esteeme,
But that the sea hath it vnto me throwne?
Your right is good (sayd he) and so I deeme,
That what the sea vnto you sent, your own should seeme.

For equall right in equall things doth stand, xix

For what the mighty Sea hath once possest,
And plucked quite from all possessors hand,
Whether by rage of waues, that neuer rest,
Or else by wracke, that wretches hath distrest,
He may dispose by his imperiall might,
As thing at randon left, to whom he list.
So Amidas, the land was yours first hight,
And so the threasure yours is Bracidas by right.

When he his sentence thus pronounced had, xx

Both Amidas and Philtra were displeased:
But Bracidas and Lucy were right glad,
And on the threasure by that iudgement seased.
So was their discord by this doome appeased,
And each one had his right. Then Artegall
When as their sharpe contention he had ceased,
Departed on his way, as did befall,
To follow his old quest, the which him forth did call.

So as he trauelled vppon the way, xxi

He chaunst to come, where happily he spide
A rout of many people farre away;
To whom his course he hastily applide,
To weete the cause of their assemblaunce wide.
To whom when he approched neare in sight,
(An vncouth sight) he plainely then descride
To be a troupe of women warlike dight,
With weapons in their hands, as ready for to fight.

And in the midst of them he saw a Knight, xxii

With both his hands behinde him pinnoed hard,
And round about his necke an halter tight,
As ready for the gallow tree prepard:
His face was couered, and his head was bar’d,
That who he was, vneath was to descry;
And with full heauy heart with them he far’d,
Grieu’d to the soule, and groning inwardly,
That he of womens hands so base a death should dy.

But they like tyrants, mercilesse the more, xxiii

Reioyced at his miserable case,
And him reuiled, and reproched sore
With bitter taunts, and termes of vile disgrace.
Now when as Artegall arriu’d in place,
Did aske, what cause brought that man to decay,
They round about him gan to swarme apace,
Meaning on him their cruell hands to lay,
And to haue wrought vnwares some villanous assay.

But he was soone aware of their ill minde, xxiv

And drawing backe deceiued their intent;
Yet though him selfe did shame on womankinde
His mighty hand to shend, he Talus sent
 To wrecke on them their follies hardyment:
Who with few sowces of his yron flale,
Dispersed all their troupe incontinent,
And sent them home to tell a piteous tale,
Of their vaine prowesse, turned to their proper bale.

But that same wretched man, ordaynd to die, xxv

They left behind them, glad to be so quit:
Him Talus tooke out of perplexitie,
And horrour of fowle death for Knight vnfit,
Who more then losse of life ydreaded it;
And him restoring vnto liuing light,
So brought vnto his Lord, where he did sit,
Beholding all that womanish weake fight;
Whom soone as he beheld, he knew, and thus behight.

Sir Terpine[277], haplesse man, what make you here? xxvi

Or haue you lost your selfe, and your discretion,
That euer in this wretched case ye were?
Or haue ye yeelded you to proude oppression
Of womens powre, that boast of mens subiection?
Or else what other deadly dismall day
Is falne on you, by heauens hard direction,
That ye were runne so fondly far astray,
As for to lead your selfe vnto your owne decay?

Much was the man confounded in his mind, xxvii

Partly with shame, and partly with dismay,
That all astonisht he him selfe did find,
And little had for his excuse to say,
But onely thus; Most haplesse well ye may
Me iustly terme, that to this shame am brought,
And made the scorne of Knighthod[278] this same day.
But who can scape, what his owne fate hath wrought?
The worke of heauens will surpasseth humaine thought.
Right true: but faulty men vse oftentimes xxviii
To attribute their folly vnto fate,
And lay on heauen the guilt of their owne crimes.
But tell, Sir Terpin, ne let you amate
Your misery, how fell ye in this state.
Then sith ye needs (quoth he) will know my shame,
And all the ill, which chaunst to me of late,
I shortly will to you rehearse the same,
In hope ye will not turne misfortune to my blame.

Being desirous (as all Knights are woont[279]) xxix

Through hard aduentures deedes of armes to try,
And after fame and honour for to hunt,
I heard report that farre abrode did fly,
That a proud Amazon did late defy
All the braue Knights, that hold of Maidenhead,
And vnto them wrought all the villany,
That she could forge in her malicious head,
Which some hath put to shame, and many done be dead.

The cause, they say, of this her cruell hate, xxx

Is for the sake of Bellodant the bold,
To whom she bore most feruent loue of late,
And wooed him by all the waies she could:
But when she saw at last, that he ne would
For ought or nought be wonne vnto her will,
She turn’d her loue to hatred manifold,
And for his sake vow’d to doe all the ill
Which she could doe to Knights, which now she doth fulfill.

For all those Knights, the which by force or guile xxxi

She doth subdue, she fowly doth entreate.
First she doth them of warlike armes despoile,
And cloth[280] in womens weedes: And then with threat
Doth them compell to worke, to earne their meat,
To spin, to card, to sew, to wash, to wring;
 Ne doth she giue them other thing to eat,
But bread and water, or like feeble thing,
Them to disable from reuenge aduenturing.

But if through stout disdaine of manly mind, xxxii

Any her proud obseruaunce will withstand,
Vppon that gibbet, which is there behind,
She causeth them be hang’d vp out of hand;
In which condition I right now did stand.
For being ouercome by her in fight,
And put to that base seruice of her band,
I rather chose to die in liues despight,
Then lead that shamefull life, vnworthy of a Knight.

How hight that Amazon (sayd Artegall)?[281] xxxiii

And where, and how far hence does she abide?
Her name (quoth he) they Radigund doe call,
A Princesse of great powre, and greater pride,
And Queene of Amazons, in armes well tride,
And sundry battels, which she hath atchieued
With great successe, that her hath glorifide,
And made her famous, more then is belieued;
Ne would I it haue ween’d, had I not late it prieued.

Now sure (said he) and by the faith that I xxxiv

To Maydenhead and noble knighthood owe,
I will not rest, till I her might doe trie,
And venge the shame, that she to Knights doth show.
Therefore Sir Terpin from you lightly throw
This squalid weede, the patterne of dispaire,
And wend with me, that ye may see and know,
How Fortune will your ruin’d name repaire,
And knights of Maidenhead, whose praise she would empaire.

With that, like one that hopelesse was repryu’d[282] xxxv

From deathes dore, at which he lately lay,
 Those yron fetters, wherewith he was gyu’d,
The badges of reproch, he threw away,
And nimbly did him dight to guide the way
Vnto the dwelling of that Amazone.
Which was from thence not past a mile or tway:
A goodly citty and a mighty one,
The which of her owne name she called Radegone.

Where they arriuing, by the watchmen[283] were xxxvi

Descried streight, who all the citty warned,
How that three warlike persons did appeare,
Of which the one him seem’d a Knight all armed,
And th’other two well likely to haue harmed.
Eftsoones the people all to harnesse ran,
And like a sort of Bees in clusters swarmed:
Ere long their Queene her selfe, halfe[284] like a man
Came forth into the rout, and them t’array began.

And now the Knights being arriued neare[285], xxxvii

Did beat vppon the gates to enter in,
And at the Porter, skorning them so few[286],
Threw many threats, if they the towne did win,
To teare his flesh in peeces for his sin.
Which when as Radigund there comming heard,
Her heart for rage did grate, and teeth did grin:
She bad that streight the gates should be vnbard,
And to them way to make, with weapons well prepard.

Soone as the gates were open to them set, xxxviii

They pressed forward, entraunce to haue made.
But in the middle way they were ymet
With a sharpe showre of arrowes, which them staid,
And better bad aduise, ere they assaid
Vnknowen perill of bold womens pride.
Then all that rout vppon them rudely laid,
 And heaped strokes so fast on euery side,
And arrowes haild so thicke, that they could not abide.

But Radigund her selfe, when she espide xxxix

Sir Terpin, from her direfull doome acquit,
So cruell doale[287] amongst her maides diuide[288],
T’auenge that shame, they did on him commit,
All sodainely enflam’d with furious fit,
Like a fell Lionesse at him she flew,
And on his head-peece him so fiercely smit,
That to the ground him quite she ouerthrew,
Dismayd so with the stroke, that he no colours knew.

Soone as she saw him on the ground to grouell, xl

She lightly to him leapt, and in his necke
Her proud foote setting, at his head did leuell,
Weening at once her wrath on him to wreake,
And his contempt, that did her iudg’ment breake.
As when a Beare hath seiz’d her cruell clawes
Vppon the carkasse of some beast too weake,
Proudly stands ouer, and a while doth pause,
To heare the piteous beast pleading her plaintiffe cause.

Whom when as Artegall in that distresse xli

By chaunce beheld, he left the bloudy slaughter,
In which he swam, and ranne to his redresse.
There her assayling fiercely fresh, he raught her
Such an huge stroke, that it of sence distraught her:
And had she not it warded warily,
It had depriu’d her mother of a daughter.
Nathlesse for all the powre she did apply,
It made her stagger oft, and stare with ghastly eye.

Like to an Eagle in his kingly pride, xlii

Soring through his wide Empire of the aire,
To weather his brode sailes, by chaunce hath spide
 A Goshauke, which hath seized for her share
Vppon some fowle, that should her feast prepare;
With dreadfull force he flies at her byliue,
That with his souce, which none enduren dare,
Her from the quarrey he away doth driue,
And from her griping pounce the greedy prey doth riue.

But soone as she her sence recouer’d had, xliii

She fiercely towards him her selfe gan dight,
Through vengeful wrath and sdeignfull pride half mad:
For neuer had she suffred such despight.
But ere she could ioyne hand with him to fight,
Her warlike maides about her flockt so fast,
That they disparted them, maugre their might,
And with their troupes did far a sunder cast:
But mongst the rest the fight did vntill euening last.

And euery while that mighty yron man, xliv

With his strange weapon, neuer wont in warre,
Them sorely vext, and courst, and ouerran,
And broke their bowes, and did their shooting marre,
That none of all the many once did darre
Him to assault, nor once approach him nie,
But like a sort of sheepe dispersed farre
For dread of their deuouring enemie,
Through all the fields and vallies did before him flie.

But when as daies faire shinie-beame, yclowded xlv

With fearefull shadowes of deformed night,
Warn’d man and beast in quiet rest be shrowded,
Bold Radigund with sound of trumpe on hight,
Causd all her people to surcease from fight,
And gathering them vnto her citties gate,
Made them all enter in before her sight,
And all the wounded, and the weake in state,
To be conuayed in, ere she would once retrate.
When thus the field was voided all away, xlvi
And all things quieted, the Elfin Knight
Weary of toile and trauell of that day,
Causd his pauilion to be richly pight
Before the city gate, in open sight;
Where he him selfe did rest in safety,
Together with sir Terpin all that night:
But Talus vsde in times of ieopardy
To keepe a nightly watch, for dread of treachery.

But Radigund full of heart-gnawing griefe, xlvii

For the rebuke, which she sustain’d that day,
Could take no rest, ne would receiue reliefe,
But tossed in her troublous minde, what way
She mote reuenge that blot, which on her lay.
There she resolu’d her selfe in single fight
To try her Fortune, and his force assay,
Rather then see her people spoiled quight,
As she had seene that day a disauenterous sight.

She called forth to her a trusty mayd, xlviii

Whom she thought fittest for that businesse,
Her name was Clarin[289], and thus to her sayd;
Goe damzell quickly, doe thy selfe addresse,
To doe the message, which I shall expresse.
Goe thou vnto that stranger Faery Knight,
Who yesterday[290] droue vs to such distresse,
Tell, that to morrow I with him wil fight,
And try in equall field, whether hath greater might.

But these conditions doe to him propound, xlix

That if I vanquishe him, he shall obay
My law, and euer to my lore be bound,
And so will I, if me he vanquish may;
What euer he shall like to doe or say:
Goe streight, and take with thee, to witnesse it,
 Sixe of thy fellowes of the best array,
And beare with you both wine and iuncates fit,
And bid him eate, henceforth he oft shall hungry sit.

The Damzell streight obayd, and putting all l

In readinesse, forth to the Towne-gate went,
Where sounding loud a Trumpet from the wall,
Vnto those warlike Knights she warning sent.
Then Talus forth issuing from the tent,
Vnto the wall his way did fearelesse take,
To weeten what that trumpets sounding ment:
Where that same Damzell lowdly him bespake,
And shew’d, that with his Lord she would emparlaunce[291] make.

So he them streight conducted to his Lord, li

Who, as he could, them goodly well did greete,
Till they had told their message word by word:
Which he accepting well, as he could weete,
Them fairely entertaynd with curt’sies meete,
And gaue them gifts and things of deare delight.
So backe againe they homeward turnd their feete.
But Artegall him selfe to rest did dight,
That he mote fresher be against the next daies fight.

FOOTNOTES:
[274] xl 6 we] were 1596
[275] ii 6 precedent 1609
[276] vi 5 readinesse: thereby 1596
[277] xxvi 1 Turpine 1596
[278] xxvii 7 Knighthood 1609
[279] xxix 1 wont 1609
[280] xxxi 4 clothe 1609
[281] xxxiii 1 (sayd Artegall?) 1596
[282] xxxv 1 repry’ud 1599
[283] xxxvi 1 watchman 1609
[284] 8 selfe halfe, 1596 self, arm’d 1609
[285] xxxvii 1 neare] newe conj. Church
[286] 3 so few] to feare conj. Collier
[287] xxxix 3 doale] doile 1596
[288] diuide] dauide 1596
[289] xlviii 3 Clarind’ 1609 passim
[290] 7 yesterday] yeester day 1596
[291] l 9 emperlance 1609
 Cant. V.

Artegall fights with Radigund

And is subdewd by guile:
He is by her emprisoned,
But wrought by Clarins wile.

So soone as day forth dawning from the East, i

Nights humid curtaine from the heauens withdrew,
And earely calling forth both man and beast,
Comaunded them their daily workes renew,
These noble warriors, mindefull to pursew
The last daies purpose of their vowed fight,
Them selues thereto preparde in order dew;
The Knight, as best was seeming for a Knight,
And th’Amazon, as best it likt her selfe to dight.

All in a Camis light of purple silke ii

Wouen vppon with siluer, subtly wrought,
And quilted vppon sattin white as milke,
Trayled with ribbands diuersly distraught
Like as the workeman had their courses taught;
Which was short tucked for light motion
Vp to her ham, but when she list, it raught
 Downe to her lowest heele, and thereuppon
She wore for her defence a mayled habergeon.

And on her legs she painted buskins wore, iii

Basted with bends of gold on euery side,
And mailes betweene, and laced close afore:
Vppon her thigh her Cemitare was tide,
With an embrodered belt of mickell pride;
And on her shoulder hung her shield, bedeckt
Vppon the bosse with stones, that shined wide,
As the faire Moone in her most full aspect,
That to the Moone it mote be like in each respect.

So forth she came out of the citty gate, iv

With stately port and proud magnificence,
Guarded with many damzels, that did waite
Vppon her person for her sure defence,
Playing on shaumes and trumpets, that from hence
Their sound did reach vnto the heauens hight.
So forth into the field she marched thence,
Where was a rich Pauilion ready pight,
Her to receiue, till time they should begin the fight.

Then forth came Artegall out of his tent, v

All arm’d to point, and first the Lists did enter:
Soone after eke came she, with fell intent,
And countenaunce fierce, as hauing fully bent her,
That battels vtmost triall to aduenter.
The Lists were closed fast, to barre the rout
From rudely pressing to the middle center;
Which in great heapes them circled all about,
Wayting, how Fortune would resolue that daungerous dout.

The Trumpets sounded, and the field began; vi

With bitter strokes it both began, and ended.
She at the first encounter on him ran
 With furious rage, as if she had intended
Out of his breast the very heart haue rended:
But he that had like tempests often tride,
From that first flaw him selfe right well defended.
The more she rag’d, the more he did abide;
She hewd, she foynd, she lasht, she laid on euery side.

Yet still her blowes he bore, and her forbore, vii

Weening at last to win aduantage new;
Yet still her crueltie increased more,
And though powre faild, her courage did accrew,
Which fayling he gan fiercely her pursew.
Like as a Smith that to his cunning feat
The stubborne mettall seeketh to subdew,
Soone as he feeles it mollifide with heat,
With his great yron sledge doth strongly on it beat.

So did Sir Artegall vpon her lay, viii

As if she had an yron anduile beene,
That flakes of fire, bright as the sunny ray,
Out of her steely armes were flashing seene,
That all on fire ye would her surely weene.
But with her shield so well her selfe she warded,
From the dread daunger of his weapon keene,
That all that while her life she safely garded:
But he that helpe from her against her will discarded.

For with his trenchant blade at the next blow ix

Halfe of her shield he shared quite away,
That halfe her side it selfe did naked show,
And thenceforth vnto daunger opened way.
Much was she moued with the mightie sway
Of that sad stroke, that halfe enrag’d she grew,
And like a greedie Beare vnto her pray,
With her sharpe Cemitare at him she flew,
That glauncing downe his thigh, the purple bloud forth drew.
Thereat she gan to triumph with great boast, x
And to vpbrayd that chaunce, which him misfell,
As if the prize she gotten had almost,
With spightfull speaches, fitting with her well;
That his great hart gan inwardly to swell
With indignation, at her vaunting vaine,
And at her strooke with puissance fearefull fell;
Yet with her shield she warded it againe,
That shattered all to peeces round about the plaine.

Hauing her thus disarmed of her shield, xi

Vpon her helmet he againe her strooke,
That downe she fell vpon the grassie field,
In sencelesse swoune, as if her life forsooke,
And pangs of death her spirit ouertooke.
Whom when he saw before his foote prostrated,
He to her lept with deadly dreadfull looke,
And her sunshynie helmet soone vnlaced,
Thinking at once both head and helmet to haue raced.

But when as he discouered had her face, xii

He saw his senses straunge astonishment,
A miracle of natures goodly grace,
In her faire visage voide of ornament,
But bath’d in bloud and sweat together ment;
Which in the rudenesse of that euill plight,
Bewrayd the signes of feature excellent:
Like as the Moone in foggie winters night,
Doth seeme to be her selfe, though darkned be her light.

At sight thereof his cruell minded hart xiii

Empierced was with pittifull regard,
That his sharpe sword he threw from him apart,
Cursing his hand that had that visage mard:
No hand so cruell, nor no hart so hard,
But ruth of beautie will it mollifie.
 By this vpstarting from her swoune, she star’d
A while about her with confused eye;
Like one that from his dreame is waked suddenlye.

Soone as the knight she there by her did spy, xiv

Standing with emptie hands all weaponlesse,
With fresh assault vpon him she did fly,
And gan renew her former cruelnesse:
And though he still retyr’d, yet nathelesse
With huge redoubled strokes she on him layd;
And more increast her outrage mercilesse,
The more that he with meeke intreatie prayd,
Her wrathful hand from greedy vengeance to haue stayd.

Like as a Puttocke hauing spyde in sight xv

A gentle Faulcon sitting on an hill,
Whose other wing, now made vnmeete for flight,
Was lately broken by some fortune ill;
The foolish Kyte, led with licentious will,
Doth beat vpon the gentle bird in vaine,
With many idle stoups her troubling still:
Euen so did Radigund with bootlesse paine
Annoy this noble Knight, and sorely him constraine.

Nought could he do, but shun the dred despight xvi

Of her fierce wrath, and backward still retyre,
And with his single shield, well as he might,
Beare off the burden of her raging yre;
And euermore he gently did desyre,
To stay her stroks, and he himselfe would yield:
Yet nould she hearke, ne let him once respyre,
Till he to her deliuered had his shield,
And to her mercie him submitted in plaine field.

So was he ouercome, not ouercome, xvii

But to her yeelded of his owne accord;
 Yet was he iustly damned by the doome
Of his owne mouth, that spake so warelesse word,
To be her thrall, and seruice her afford.
For though that he first victorie obtayned,
Yet after by abandoning his sword,
He wilfull lost, that he before attayned.
No fayrer conquest, then that with goodwill is gayned.

Tho with her sword on him she flatling strooke, xviii

In signe of true subiection to her powre,
And as her vassall him to thraldome tooke.
But Terpine borne to’a more vnhappy howre,
As he, on whom the lucklesse starres did lowre,
She causd to be attacht, and forthwith led
Vnto the crooke t’abide the balefull stowre,
From which he lately had through reskew fled:
Where he full shamefully was hanged by the hed.

But when they thought on Talus hands to lay, xix

He with his yron flaile amongst them thondred,
That they were fayne to let him scape away,
Glad from his companie to be so sondred;
Whose presence all their troups so much encombred
That th’heapes of those, which he did wound and slay,
Besides the rest dismayd, might not be nombred:
Yet all that while he would not once assay,
To reskew his owne Lord, but thought it iust t’obay.

Then tooke the Amazon this noble knight, xx

Left to her will by his owne wilfull blame,
And caused him to be disarmed quight,
Of all the ornaments of knightly name,
With which whylome he gotten had great fame:
In stead whereof she made him to be dight
In womans weedes, that is to manhood shame,
And put before his lap a napron[292] white,
In stead of Curiets and bases fit for fight.

So being clad, she brought him from the field, xxi

In which he had bene trayned many a day,
Into a long large chamber, which was sield
With moniments of many knights decay,
By her subdewed in victorious fray:
Amongst the which she causd his warlike armes
Be hang’d on high, that mote his shame bewray;
And broke his sword, for feare of further harmes,
With which he wont to stirre vp battailous alarmes.

There entred in, he round about him saw xxii

Many braue knights, whose names right well he knew,
There bound t’obay that Amazons proud law,
Spinning and carding all in comely rew,
That his bigge hart loth’d so vncomely vew.
But they were forst through penurie and pyne,
To doe those workes, to them appointed dew:
For nought was giuen them to sup or dyne,
But what their hands could earne by twisting linnen twyne.

Amongst them all she placed him most low, xxiii

And in his hand a distaffe to him gaue,
That he thereon should spin both flax and tow;
A sordid office for a mind so braue.
So hard it is to be a womans slaue.
Yet he it tooke in his owne selfes despight,
And thereto did himselfe right well behaue,
Her to obay, sith he his faith had plight,
Her vassall to become, if she him wonne in fight.

Who had him seene, imagine mote thereby, xxiv

That whylome hath of Hercules bene told,
How for Iolas sake he did apply
His mightie hands, the distaffe vile to hold,
 For his huge club, which had subdew’d of old
So many monsters, which the world annoyed;
His Lyons skin chaungd to a pall of gold,
In which forgetting warres, he onely ioyed
In combats of sweet loue, and with his mistresse toyed.

Such is the crueltie of womenkynd, xxv

When they haue shaken off the shamefast band,
With which wise Nature did them strongly bynd,
T’obay the heasts of mans well ruling hand,
That then all rule and reason they withstand,
To purchase a licentious libertie.
But vertuous women wisely vnderstand,
That they were borne to base humilitie,
Vnlesse the heauens them lift to lawfull soueraintie.

Thus there long while continu’d Artegall, xxvi

Seruing proud Radigund with true subiection;
How euer it his noble heart did gall,
T’obay a womans tyrannous direction,
That might haue had of life or death election:
But hauing chosen, now he might not chaunge.
During which time, the warlike Amazon,
Whose wandring fancie after lust did raunge,
Gan cast a secret liking to this captiue straunge.

Which long concealing in her couert brest, xxvii

She chaw’d the cud of louers carefull plight;
Yet could it not so thoroughly digest,
Being fast fixed in her wounded spright,
But it tormented her both day and night:
Yet would she not thereto yeeld free accord,
To serue the lowly vassall of her might,
And of her seruant make her souerayne Lord:
So great her pride, that she such basenesse much abhord.
So much the greater still her anguish grew, xxviii
Through stubborne handling of her loue-sicke hart;
And still the more she stroue it to subdew,
The more she still augmented her owne smart,
And wyder made the wound of th’hidden dart.
At last when long she struggled had in vaine,
She gan to stoupe, and her proud mind conuert
To meeke obeysance of loues mightie raine,
And him entreat for grace, that had procur’d her paine.

Vnto her selfe in secret she did call xxix

Her nearest handmayd, whom she most did trust,
And to her said; Clarinda whom of all
I trust a liue, sith I thee fostred first;
Now is the time, that I vntimely must
Thereof make tryall, in my greatest need:
It is so hapned, that the heauens vniust,
Spighting my happie freedome, haue agreed,
To thrall my looser life, or my last bale to breed.

With that she turn’d her head, as halfe abashed, xxx

To hide the blush which in her visage rose,
And through her eyes like sudden lightning flashed,
Decking her cheeke with a vermilion rose:
But soone she did her countenance compose,
And to her turning, thus began againe;
This griefes deepe wound I would to thee disclose,
Thereto compelled through hart-murdring paine,
But dread of shame my doubtfull lips doth still restraine.

Ah my deare dread (said then the faithfull Mayd) xxxi

Can dread of ought your dreadlesse hart withhold,
That many hath with dread of death dismayd,
And dare euen deathes most dreadfull face behold?
Say on my souerayne Ladie, and be bold;
Doth not your handmayds life at your foot lie?