Pediatric Liver Transplantation A Clinical Guide

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PEDIATRIC LIVER TRANSPLANTATION: A CLINICAL GUIDE ISBN: 978-0-323-63671-1

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To Sanja, Miran and Nadan
NH

To Kristine, Lukas and Leonie

UB

To my family and mentors

VM
Preface

Does writing books remain relevant in the era of instant This work would not have been possible without the estab-
search engines, strengthening ecology, and lost authorities? lished international pediatric hepatology community where
The three of us strongly believe it is, and the result is here our native institutions and immediate colleagues helped create
for your evaluation. Pediatric liver transplantation is a a stimulating academic atmosphere. Our unique patients and
complex undertaking strongly reflecting the multifaceted their resilient families have always been an endless education
nature of modern medicine, representing a genuine team source of not only medicine but also of simple human feelings
effort. and genuine compassion. Additional thanks must go to our
The initial idea to compile the experience of the current publisher, Elsevier, who has always been sympathetic to our
generation of pediatric hepatologists emerged after one plans, new ideas, and tacit extensions of the production dead-
of the now traditional European Society for Paediatric lines. Finally, our long-suffering families have supported us
Gastroenterology, Hepatology and Nutrition (ESPGHAN) during the long days, untimely teleconferences, late-night
Paediatric Liver Transplantation Schools. The hope was to readings, and abruptly modified social plans.
capture the enthusiasm and professional curiosity of the We hope this book could serve as a reliable point of refer-
increasing number of confident, younger colleagues from ence or a gentle reminder for some of the people who share our
all over the world and match it with the energy and ded- passion for improving the lives of children with liver disease.
ication of the “elders” from the more established transplant
centers. Valerie, Ulli and Dino

vi
List of Contributors

Sergio Assia-Zamora, MD Ana M. Calinescu, MBBS

Senior Clinical Fellow University Center of Pediatric Surgery of Western
Institute of Liver Studies Switzerland
King’s College Hospital FT NHS Trust Division of Pediatric Surgery
London, United Kingdom Geneva University Hospitals
Geneva, Switzerland
Yaron Avitzur, MD
Bicetre Hospital
Associate Professor
Department of Pediatric Surgery
Department of Paediatrics, University of Toronto
Hopitaux Universitaires Paris Sud
Division of Gastroenterology, Hepatology
Le Kremlin-Bicetre, France
and Nutrition
The Hospital for Sick Children Michele Colledan, MD, FEBS
Toronto, ON, Canada Director, Department of Organ Failure and
Transplantation
Ulrich Baumann, MD ASST Papa Giovanni XXIII
Professor of Paediatric Gastroenterology and Hepatology Bergamo, Italy
Hannover Medical School
Department of Kidney, Liver and Metabolic Diseases Vladimir Cousin, MD
Division of Paediatric Gastroenterology Paediatric Intensive Care
and Hepatology Paris South University Hospitals
Hannover, Germany Le Kremlin-Bic
etre, France
Professor of Paediatric Hepatology
University of Birmingham Lorenzo D’Antiga, MD, FEBT
Institute of Immunology and Immunotherapy Director
Edgbaston Child Health
Birmingham, United Kingdom Centre for Paediatric Hepatology,
Gastroenterology and Transplantation
Eliano Bonaccorsi-Riani, MD, PhD Hospital Papa Giovanni XXIII
Department of Abdominal Surgery and Bergamo, Italy
Transplantation
Saint-Luc University Clinics Jemma Day, MD
Universit
e Catholique de Louvain Clinical Psychologist
Brussels, Belgium Liver Transition Service
Institute of Liver Studies
Rachel Mary Brown, BSc, MBChB, FRCPath King’s College Hospital
Department of Cellular Pathology London, United Kingdom
Queen Elizabeth Hospital Birmingham
Histopathology Jean de Ville de Goyet, MD, FRCS, PhD
Birmingham Children’s Hospital Department of Pediatrics
Birmingham, United Kingdom ISMETT UPMC
Palermo, Italy
John C. Bucuvalas, MD
Dominique Debray, MD, PhD
Icahn School of Medicine at Mount Sinai
Pediatric Hepatology Unit
Kravis Children’s Hospital
H^opital Necker-Enfants Malades
New York, NY, USA
Paris, France

vii
viii List of Contributors

Tanguy Demaret, MD Mara Giovanelli, MD

Laboratoire d’H
epatologie P
ediatrique et Th
erapie Department of Organ Failure and Transplantation
Cellulaire (PEDI) ASST Papa Giovanni XXIII
Institut de Recherche Exp
erimentale et Clinique (IREC) Bergamo, Italy
Service de Gastro-Ent
erologie et H
epatologie P
ediatrique
Cliniques Universitaires Saint-Luc Imeke Goldschmidt, MD
Universit
e Catholique de Louvain (UCL) Pediatric Kidney, Liver and Metabolic Diseases
Brussels, Belgium Hannover Medical School
Hannover, Germany
Blossom G. Dharmaraj, BSc, MEd
Division of Pediatric Gastroenterology, Hepatology and Stephen Gottschalk, MD
Nutrition St Jude Children’s Research Hospital
The Hospital for Sick Children Department of Bone Marrow Transplantation and Cellular
Toronto, Canada Therapy
Memphis, TN, USA
Anil Dhawan MD, FRCPCH
Director, Research and Innovation Anish Gupta, MBBS, BSc, FRCA
King’s College Hospital Consultant Anaesthetist
Corporate Medical Director Variety King’s College Hospital
Children’s Hospital London, UK
Director, Paediatric Liver GI and Nutrition
Center and MowatLabs Girish Gupte, MD
King’s College Hospital Consultant Paediatric Hepatologist
London, United Kingdom Liver Unit
Birmingham Women’s and Children’s Hospital
Fabrizio di Francesco, MD, PhD Birmingham, United Kingdom
Department of Pediatrics
Istituto Mediterraneo per i Trapianti e Terapie ad Alta Nedim Hadži
c, MD, MSc, FRCPCH, FAASLD
Specializzazione Professor of Paediatric Hepatology
Palermo, Italy King’s College, London
Consultant in Paediatric Hepatology
Annalisa Dolcet, MD Paediatric Service for Hepatology, Gastroenterology and
Senior Clinical Fellow Nutrition
Institute of Liver Studies King’s College NHS Foundation Trust
Kings College Hospital London, United Kingdom
London, United Kingdom
Winita Hardikar, MBBS, FRACP, PhD
Stephanie Franchi-Abella, MD, PhD Director, Gastroenterology and Clinical Nutrition
Pediatric Radiology Royal Children’s Hospital
Pediatric Liver Transplantation Unit Professor, Department of Paediatrics
National Reference Centre for Rare Pediatric Liver University of Melbourne
Diseases Australia
H^opital Bic^etre, Assistance Publique H^opitaux de Paris
Le Kremlin-Bic^etre Steffen Hartleif, MD
Paris, France University Children´s Hospital T€
ubingen
T€
ubingen, Germany
Daniela Gattini Valdes, MD
Clinical Fellow Jane Hartley, MD
Division of Gastroenterology, Hepatology and Consultant Paediatric Hepatologist
Nutrition Liver Unit
The Hospital for Sick Children Birmingham Women’s and Children’s Hospital
Toronto, ON, Canada Birmingham, United Kingdom

James Gill, MBBS, MSc, FRCA Nigel Heaton MB, BS, FRCS
Consultant Anaesthetist Professor of Transplant Surgery
King’s College Hospital Institute of Liver Studies
London, United Kingdom King’s College Hospital FT NHS Trust
London, UK
 List of Contributors ix

David A. Hobin, BSc, MB, ChB, MRCP, MRCPCH Deirdre Kelly

Department of Paediatric Oncology Professor of Paediatric Hepatology, University of Birmingham
Birmingham Children’s Hospital Consultant Paediatric Hepatologist
Birmingham, United Kingdom Liver Unit
Birmingham Women’s and Children’s Hospital
Simon Horslen, MB, ChB Birmingham, United Kingdom
Division of Gastroenterology, Hepatology Jae Sung Ko, MD, PhD
and Nutrition Professor, Division of Pediatric Gastroenterology and
Seattle Children’s Hospital Nutrition
Seattle, WA, USA Department of Pediatrics
Seoul National University College of Medicine
Evelyn K. Hsu, MD Seoul, Republic of Korea
Division of Gastroenterology Hepatology
and Nutrition Arnaud G. L’Huillier, MD
Seattle Children’s Hospital Department of Pediatrics
Seattle, WA, USA General Pediatrics & Pediatric Infectious
Diseases Unit
Stefan G. H€ ubscher, MB ChB, FRCPath Children’s Hospital of Geneva
Department of Cellular Pathology Geneva University Hospitals and Faculty of Medicine
Queen Elizabeth Hospital Birmingham Geneva, Switzerland
Institute of Immunology and Immunotherapy
University of Birmingham Florence Lacaille, MD
Birmingham, United Kingdom Gastroenterology-Hepatology-Nutrition Unit
H^opital Universitaire Necker-Enfants malades
Kais Hussein, MD Paris, France
Hannover Medical School
Catherine Lombard, PhD
Institute of Pathology
Laboratoire d’H
epatologie P
ediatrique et Th
erapie
Hannover, Germany
Cellulaire (PEDI)
Institut de Recherche Exp
erimentale et Clinique (IREC)
Vandana Jain, BA (Hons), MBBChir
Universit
e Catholique de Louvain (UCL)
Paediatric Liver, GI and Nutrition Centre
Brussels, Belgium
MowatLabs
King’s College Hospital Britta Maecker-Kolhoff, MD
London, United Kingdom Hannover Medical School
Department of Pediatric Hematology and Oncology
Norman Junge, MD Hannover, Germany
Paediatric Gastroenterology and Hepatology
Hannover Medical School George V. Mazariegos, MD
Hannover, Germany Hillman Center for Pediatric Transplantation
Department of Surgery

ski, MD, PhD
Piotr Kalicin UPMC Children’s Hospital of Pittsburgh
Head, Department of Pediatric Surgery & Organ Pittsburgh, PA, USA
Transplantation
Children’s Memorial Health Institute Suzanne V. McDiarmid, MD
Warszawa, Poland Professor of Pediatrics and Surgery
Chief, Division Pediatric Gastroenterology, Hepatology,
Binita M. Kamath, MBBChir, MRCP, MTR and Nutrition
Staff Physician, Division of Gastroenterology, Director, Pediatric Liver Transplantation
Hepatology and Nutrition Medical Director, Upper Extremity Transplantation
The Hospital for Sick Children David Geffen School of Medicine at University of California
Department of Pediatrics Los Angeles, California, USA
University of Toronto
Toronto, ON, Canada Patrick McKiernan, BSc, MB BCh, MRCP
Professor of Pediatrics
Mureo Kasahara, MD, PhD Director of Hepatology
Director of Organ Transplantation Division of Gastroenterology/Hepatology/Nutrition
National Center for Child Health and Development UPMC Childrens, Hospital of Pittsburgh
Tokyo, Japan University of Pittsburgh, Pittsburgh, PA, USA
x List of Contributors

Vale
rie Anne McLin, MD, FAASLD Joanna Pawłowska, MD, PhD

Associate Professor Gastroenterology, Hepatology, Nutritional Disturbances
Department of Pediatrics, Gynecology and Obstetrics and Pediatrics
University of Geneva Medical School The Children’s Memorial Health Institute
Unit Head, Pediatric Gastroenterology, Hepatology Warszawa, Poland
and Nutrition Unit
Medical Director, Swiss Pediatric Liver Center Eva-Doreen Pfister
University Hospitals Geneva Pediatric Kidney, Liver and Metabolic Diseases
Geneva, Switzerland Children’s Hospital
Hannover Medical School
Jordi Miatello, MD, PhD Hannover, Germany
Paediatric Intensive Care
Paris South University Hospitals Gilda Porta, MD, PhD
Le Kremlin-Bic^etre, France Assistant Professor Liver and Transplant Unit
Hospital Menino Jesus/ H. Sírio Liban^es
Giorgina Mieli-Vergani, MD, PhD, FRCP, FRCPCH, São Paulo, Brazil
FAASLD
Emeritus Professor of Paediatric Hepatology Klara M. Posfay-Barbe, MD, MS
Paediatric Liver, GI & Nutrition Centre Department of Pediatrics
MowatLabs General Pediatrics & Pediatric Infectious
King’s College Hospital Diseases Unit
London, United Kingdom Children’s Hospital of Geneva
Geneva University Hospitals and Faculty
Federico Mingozzi, PhD
of Medicine
Spark Therapeutics
Geneva, Switzerland
Philadelphia, PA, USA
Saeed Mohammad, MD Ashwin Rammohan, MCh, FRCS
Medical Director of Hepatology & Liver Transplantation Institute of Liver Disease & Transplantation
Ann & Robert H. Lurie Children’s Hospital of Chicago Dr Rela Institute & Medical Centre
Associate Professor of Pediatrics Chennai, India
Feinberg School of Medicine
Northwestern University Raymond Reding, MD, PhD
Chicago, IL, USA Department of Abdominal Surgery and
Transplantation
Vicky L. Ng, MD, FRCP(C) Saint-Luc University Clinics
Professor of Pediatrics Universit
e Catholique de Louvain
Division of Pediatric Gastroenterology, Hepatology and Brussels, Belgium
Nutrition
Transplant and Regenerative Medicine Center Mohamed Rela, MS, FRCS, DSc
The Hospital for Sick Children Institute of Liver Disease & Transplantation
Department of Pediatrics Dr Rela Institute & Medical Centre
University of Toronto Chennai, India
Toronto, Canada Professor of Transplant Surgery, (ADD)
Institute of Liver Studies
Jean-Bernard Otte, MD King’s College Hospital
Former Director of the Liver Transplant Program London, United Kingdom
Cliniques Universitaires Saint-Luc
Brussels/Universit
e Catholique de Louvain Nathalie Marie Rock, MD
Belgium Swiss Pediatric Liver Center
Pediatric Gastroenterology, Hepatology and
Lars Pape, MD, PhD Nutrition Unit
Professor of Pediatrics Division of Pediatric Specialties
Director, Department of Pediatrics II Department Pediatrics, Gynecology, and Obstetrics
University Hospital of Essen University Hospitals
University of Duisburg-Essen Geneva, Switzerland
Essen, Germany
 List of Contributors xi

Marianne Samyn, MD Roberto Tambucci, MD

Consultant Paediatric Hepatologist Department of Abdominal Surgery and
Clinical Lead for Young Adult Liver Service Transplantation
Senior Clinical Lecturer, King’s College Saint-Luc University Clinics
London, United Kingdom Universit
e Catholique de Louvain
Brussels, Belgium
Alberto Sanchez-Fueyo, MD, PhD
Professor of Hepatology, (ADD)
Alison April Taylor, MBChB, BSc (Hons)
Institute of Liver Studies
Institute of Liver Studies
King’s College Hospital
King’s College Hospital
London, United Kingdom
London, United Kingdom
Sebastian Schulz-Ju €rgensen, MD, PhD
Department of General Pediatrics Pierre Tissieres, MD, DSc
Universit€atsklinikum Eppendorf Paediatric Intensive Care
Hamburg, Germany Paris South University Hospitals
Le Kremlin-Bic^etre, France
Khalid Sharif, FRCS (Paeds), FCPS Paed Surg (PAK)
Consultant hepato-biliary & transplantation Hubert P.J. van der Doef
Department of Paediatric Hepato-biliary and Pediatric Gastroenterology/Hepatology
Transplantation Beatrix Children’s Hospital
Birmingham Children’s Hospital University Medical Center Groningen
Birmingham, United Kingdom University of Groningen
Groningen, The Netherlands
Voytek Slowik, MD
Department of Gastroenterology Hepatology and Shannon M. Vandriel
Nutrition Division of Gastroenterology, Hepatology and Nutrition
Children’s Mercy The Hospital for Sick Children
Kansas City, MO, USA Toronto, ON, Canada
Françoise Smets, MD, PhD Henkjan J. Verkade
Pediatric Gastroenterology and Hepatology Unit Pediatric Gastroenterology/Hepatology
Cliniques Universitaires Saint-Luc Beatrix Children’s Hospital
UCLouvain University Medical Center Groningen
Brussels, Belgium University of Groningen
Etienne Sokal, MD, PhD Groningen, The Netherlands
Professor of Pediatric Hepatology
Laboratoire d’H
epatologie P
ediatrique et Th
erapie Hector Vilca-Melendez, MD, PhD
Cellulaire (PEDI) Institute of Liver Studies
Institut de Recherche Exp
erimentale et Clinique MowatLabs
(IREC) Faculty of Life Sciences & Medicine
Service de Gastro-Ent
erologie et H
epatologie King’s College Hospital
P
ediatrique London, UK
Cliniques Universitaires Saint-Luc
Universit
e Catholique de Louvain (UCL) Sharad I. Wadhwani, MD, MPH
Brussels, Belgium Cincinnati Children’s Hospital Medical Center
Cincinnati, OH, USA
James E. Squires, MD, MS
Assistant Professor of Pediatrics Barbara E. Wildhaber
Division of Gastroenterology/Hepatology/Nutrition Professor
UPMC Children’s Hospital of Pittsburgh University Center of Pediatric Surgery of Western
Pittsburgh, PA, USA Switzerland
Division of Pediatric Surgery
Ekkehard Sturm, MD, PhD Geneva University Hospitals
University Children´s Hospital T€
ubingen Geneva, Switzerland
T€
ubingen, Germany
 SECTION 1
Evolution of Transplantation
Medicine

1
1
Brief History of Pediatric Liver
Transplantation
J E A N - B E R N A R D OT T E

C HA P T E R OU T LI N E enlarged orifices of the recipient suprahepatic veins. Lateral

clamping of the VC avoids the need for decompression of the
Principal Historical Milestones and Breakthroughs
lower part of the body. Decompression of the splanchnic bed
Technical Aspects
during the anhepatic phase is not needed in cirrhotic chil-
Initiation of Clinical Experience dren with portal hypertension because of spontaneous porto-
The National Institutes of Health Statement systemic collaterals. When the liver to be removed has a
Holistic Pediatric Approach normal vascular resistance, like in metabolic diseases and
Technical Variants Addressing Shortage of Full-Size Grafts hepatoblastoma, a swift vascular reconstruction is required.
From Pediatric Donors This technique has become standard also for implantation
Medical Aspects of a segmental graft, both from cadaveric and from living
New Challenges donors.
Shortage of Post Mortem Organ Donors
Portal Vein Reconstruction
Liver Preservation
Withdrawal of Immunosuppression and Tolerance Induction
In children with biliary atresia, which is the most frequent
pediatric liver transplantation (LT) indication, the very fre-
Long-Term Histologic Deterioration/De Novo Post–Liver
Transplantation Autoimmune Hepatitis
quent hypoplasia of the portal vein must be appropriately cor-
rected by portoplasty to avoid post-operative thrombosis.4
Historical Milestones My first trainee in liver transplantation, Jean de Ville de
Goyet, described the meso-Rex shunt for bypassing the
thrombosed portal vein5; this has become the standard in
most centers. This technique could also be used after LT.

Principal Historical Milestones Biliary Drainage

and Breakthroughs Except in larger children where end-to-end biliary recon-
struction is possible, the most reliable technique is an end-
Technical Aspects to-side anastomosis on a Roux-en-Y intestinal loop of suffi-
cient length (50 cm) to prevent reflux.
The basic technique of orthotopic liver transplantation was
developed in dogs by Thomas E. Starzl in the early 1960s;
the dog I watched myself when I was a research fellow with Initiation of Clinical Experience
him in 1965 to 1966 lived for over 13 years under steroids Thomas E. Starzl (Fig. 1.1) performed in Denver, USA, the
and Imuran and served as the proof of concept.1 This original first attempts in children in the 1960s, with the first long-term
technique was successfully transposed to human beings with survival obtained in a child transplanted in 1970 for biliary
minor changes.2 atresia with an incidental hepatocellular arcinoma who sur-
vived over 40 years, off medications for more than10 years.1
The Piggyback Technique In Europe, the first attempts were performed by Roy
To avoid caval occlusion and veno-venous bypass, Tzakis Calne in Cambridge6 in a child with biliary atresia in
described the piggyback technique3: the native liver is excised 1968 (death from cardiac arrest 90 minutes after the sur-
with preservation of the retrohepatic vena cava (VC); the gery). We also tried LT in Brussels7 for the same indication
suprahepatic VC of the donor graft is implanted on the in 1971 (death after 7 weeks from biopsy-related bleeding).

2
 CHAPTER 1 Brief History of Pediatric Liver Transplantation 3

Technical Variants Addressing Shortage

of Full-Size Grafts From Pediatric Donors
To fill the gap between the number of pediatric candidates of
young age and small size and the scarcity of size-matched
pediatric donors, various techniques have been developed
to reduce the graft volume to a certain anatomical part of
an adult donor liver. Reducing the volume of an adult donor
liver to fit into the abdomen of a small-size pediatric recipient
was the first step allowing the real launch of LT.10 Concep-
tually, this approach did not intend to increase the total
number of available liver grafts and was initially considered
to be detrimental for adult recipients. This obstacle was over-
come by the development of the "split" liver concept by R.
Pichlmayer, H. Bismuth, C. Broelsch, and J.B. Otte11 (one
liver for two recipients) and living liver donation. The tech-
• Fig. 1.1 Thomas E. Starzl. nique of liver splitting is based on the dual anatomy of the
biliary and vascular tree of the liver, allowing sharing between
The National Institutes of Health Statement the left lobe adapted to a small child’s abdominal capacity,
whereas an extended right lobe would fit an adult recipient;
The increasing number of successful adult and pediatric liver or between the right and the left hemilivers that would fit
transplants in the United States and Europe led the National two small-size adolescent or adult recipients. The surgical
Institutes of Health (NIH) in 1984 to state that liver trans- splitting can be performed in situ as the first step of a
plantation had become a clinical service.8 This statement multivisceral organ procurement or ex situ on the isolated
triggered the development of several LT programs in the cooled-down liver. This technique has been validated for
United States and Europe. In 1986, a symposium I organized the two options but is surgically more complex and time con-
in Brussels convened four US and three European centers that suming. It is still underused except in countries with an
had started LT in the early 1980s and performed at least 20 intent-to-split policy like the United Kingdom, Switzerland,
cases (Starzl’s team, initially in Denver and later in Pittsburgh, and Italy.
had already performed over 300 cases). The 1-year survival The persisting shortage of cadaveric donors provided the
rates were between 30% and 83%9 (Table 1.1). impetus to develop living-related liver transplantation
(LRLT). After the failed attempts in two children by Raia
Holistic Pediatric Approach in Brazil12 and the first success obtained by Russel Strong in
Success in LT is not limited to the mastering the technique and Australia,13 Broelsch in Chicago in 1989,14 and Tanaka in
adequate immunosuppression. All needs of children requiring Kyoto 199015 standardized the technique, which was imple-
an LT should be covered by a pediatric multidisciplinary mented worldwide later on. My own group has acquired
approach, something which is exemplified in this book. vast expertise with pediatric LRLT, currently exceeding

TABLE Results obtained in eight centers of Europe and the United States and presented during an international
1.1 symposium on Liver Transplantation in Children, Brussels, October 11–12, 1986
% Biliary
Centre Period Number Atresia Patient survival
Cambridge 12/1983–8/1986 35 31 Overall: 60% at 14 months
Boston 1/1984–6/1986 23 55 Actuarial: 59% at 30 months
Brussels 3/1984–10/1986 34 73 Actuarial: 83%at 2 years
Dallas 9/1984–9/1986 44 41 Actuarial: 74% at 1 year
Hannover 6/1978–6/1986 35 48 Actuarial: 57% at 5 years
UCLA 2/1984–9/1986 38 50 Overall: 79%
Minneapolis 4/1984–6/1986 35 60 Actuarial: 65% at 1 year
Denver Pre-CyA, 1967–1979 84 30% at 2 years
Pittsburgh CyA era, 1980–1986 265 51 70% at 2 years

Cyclosporine; Cya. (From Otte JB, Starzl TE, Ascher N, Klintmalm G, Andrews W. Liver transplantation in children. Transplant Proc. 1987;3229-3375.)
4 C HA P T E R 1 Brief History of Pediatric Liver Transplantation

400 cases since 1993.4 Long-term patient survival rates from operations performed shortly after birth. To make
show a significant advantage in favor of living donation: things worse, Bennie’s blood would not clot. The operation
the 15-year patient survival rate was 93% in 254 consecutive could not be completed…"1
LRLT compared with 83% in 236 post mortem grafts We encountered this inextricable situation at the begin-
(P ¼ .002).16 Other potential advantages of living liver ning of our practice. The pediatric surgeons, failing to restore
donation include the optimal quality of the graft; the short- any biliary flow, used to operate again and sometimes again,
ening of the waiting time—reducing nearly to nil the risk of often with the result described by Starzl. The validation of
dying on the waiting list—the possibility to optimize the liver replacement has changed the picture with the descrip-
timing of transplantation, for example, for hepatoblastoma; tion of a standardized sequential treatment, including a sin-
and the possibility of a better immunologic tolerance when gle attempt at hepatoportoenterostomy below the age of
the mother is the donor.4 One-year acute rejection-free sur- 3 months, adequate placement of the abdominal incision
vival was 55.2% for maternal grafts compared with 39.8% in regard of the liver, and prevention of adhesions between
(P ¼ .041) for paternal grafts but only in children with the liver and gastrointestinal tract.18 The overall manage-
biliary atresia.4 ment of a baby with an unsuccessful Kasai operation also
made significant progress with medical measures, including
artificial nutrition, when needed. Fig. 1.2 illustrates the
Medical Aspects
example history of one of my own patients: unsuccessful por-
Indications toenterostomy in 1983, desperate appeal of the mother in
My comments will be limited to biliary atresia. We are com- 1985 when informed about our initial experience with
ing a long way in this area. The first progress in the treatment LT, and a desperate clinical condition with severe malnutri-
of this condition, which when not operated, is always lethal tion and several long bones fractures. We referred the child to
within the first 2 years of life, was achieved by Morio Kasai Claude Ricour, who had developed in Paris a remarkable
(Sendai, Japan), who described the portoenterostomy in the program of parenteral nutrition.19 After that, the child was
late 1970s to reconnect the vestigial bile ducts to the gut.17 successfully transplanted; he is alive 33 years later, fully
Although about one-third of the children having undergone grown up, without any sequelae, and off immunosuppres-
this type of innovative surgery will reach adult life with their sion for several years now.
native liver, another third will derive no benefits, and the
remaining third will develop, sooner or later, biliary cirrhosis. Immunosuppression
For these two latter thirds, LT is the only therapeutic option. Despite its immune privilege, the liver can undergo acute
In 1963, Starzl performed the first LT for biliary atresia in and chronic rejection. Prevention of acute rejection was dra-
a 3-year-old child. He said: "Nothing we had done in the past matically improved by the introduction of calcineurin inhib-
could have prepared us for the enormity of the task. Several itors, cyclosporine and tacrolimus, the latter emerging as
hours were required just to make the incision end enter the the first-choice immune suppressant in most centers.20 This
abdomen. … Bennie’s liver was encased in scar tissue leftover preventive effect is increased by induction with polyclonal

• years after liver transplant performed for biliary atresia in 1985 (photos with patient’s kind permission).
Fig. 1.2 Thirty-three
 CHAPTER 1 Brief History of Pediatric Liver Transplantation 5

(anti-thymocyte globulin) or monoclonal antibodies,21 allow- donors,31 with the recent addition of category V: donation
ing steroid-free immunosuppression.22,23 However, the pre- after euthanasia. In countries where euthanasia has been
vention of acute rejection should not become an obsession. legalized, such as Belgium and the Netherlands, a person
Beside its usual easy control with pulse steroids and, when who requests euthanasia according to the law criteria and
needed, a transitory increase of immunosuppression, acute the standards of the local ethics committee is allowed to
rejection of the liver can possibly facilitate immune donate his or her own organs for transplantation after eutha-
tolerance.24 nasia.32 These potential donors after euthanasia are the
Ductopenic chronic rejection is quite rare in LT; it is patients suffering from neurodegenerative diseases; repre-
often related to poor patient compliance. When progressive, senting about 10% of all cases of euthanasia, they are a sub-
it could be treated by rapamycin.25 stantial source of post mortem organ donations.

Post-transplant Lymphoproliferative Disorder

Most children are Epstein-Barr virus (EBV) negative at the
Liver Preservation
time of transplantation and very soon post-transplant are Recent research pioneered by Peter Friend in Oxford33 is
exposed to the virus, which is widely prevalent in the general close to achieving the old dream to "improve" the liver graft
population. EBV disorders associated with the primary infec- by ex vivo normothermic machine perfusion, allowing a
tion include a wide range of clinical manifestations, post- recovery of the damaged livers.
transplant lymphoproliferative disorder (PTLD) being the
most serious one.26 The highest incidence is during the first
year post-transplant when the immunosuppressive load is the Withdrawal of Immunosuppression
heaviest, mostly when it includes medications that specifi- and Tolerance Induction
cally target T-cell function.27 Treatment of histologically Long-term side effects of immunosuppressants, including
diagnosed PTLD ranges from reduction or cessation of toxicity, infections, and neoplasms, are the main reasons
immunosuppression as the first-line approach (as published for weaning immunosuppression in the long run. The liver
by Starzl in 1984)28 to anti-CD20 antibody (rituximab), is an immunologically privileged organ. Some children and
where CD20-positive B cells are removed, and chemother- adults can become tolerant of their grafts after liver transplant.
apy in the most severe cases. Prevention of EBV-related Occasionally, tolerance has been observed when immune sup-
PTLD is based on the viral load monitoring guiding the pression had to be discontinued, for example, because of
reduction of immunosuppression in patients becoming PTLD. Prospective withdrawal of immunosuppression has
EBV-positive.29 been studied in children in Kyoto34 and in Pittsburgh35 with
very strict selection criteria (long follow-up without rejection,
New Challenges normal liver function tests and histology). In both centers, the
rate of rejection reached 25%, which we consider as unaccept-
Shortage of Post Mortem Organ Donors able in the present absence of reliable biomarkers of tolerance
confirmed in clinical practice.36
The number of pediatric donors is not sufficient to cover the Tolerance induction remains an inaccessible holy grail.
overall needs, with the possible exception of the United Currently, the minimization of immune suppression is a
States. As detailed earlier, the gap is minimized with liver wiser approach, hoping for the development of prope toler-
reduction and splitting, beside the living liver donations. ance, as described by Calne.37
The rate of post mortem organ donation (including brain-
dead donors and deceased cardiac donors) differs largely
between the countries. Within the Eurotransplant area, Long-Term Histologic Deterioration/De Novo
the highest rate is in Belgium, with 28 donors per million Post–Liver Transplantation Autoimmune
people per year, but Croatia is doing even better, with 37 Hepatitis
donors per million people per year, thanks to a very dynamic
policy financially supported by the state. The Netherlands In 1998, the Kings’ College group was the first to describe, in
and Germany are at the bottom. Their combined population 7 (4%) of 180 liver transplant recipients, a late graft dysfunc-
of over 100 million people prevents a fair organ distribution tion that did not result from recognized causes and was asso-
within the Eurotransplant area, to the detriment of smaller ciated with autoimmune features.38
countries such as Belgium. Among European countries out- Histologic chronic hepatitis associated with autoantibody
side the Eurotransplant area, Spain has the highest rate of formation and allograft dysfunction was further described by
post mortem organ donations. the Birmingham group in a cohort of 158 asymptomatic
In Europe, the decreasing availability of brain-dead children with 5-year graft survival who were biopsied 5 to
donors dictated the reactivation of the procurement of 10 years after transplantation. Changes of chronic hepatitis
organs from non–heart beating donors. The Maastricht Clas- with fibrosis and autoantibodies, suggesting immune modu-
sification30 identifies four categories. Practically speaking, lation, were observed in 55% at 5 years post-transplant and
only category III (controlled cardiac death) is a source of 69% at 10 years, with evolution to cirrhosis in 15%.39