Diseases of the Liver and Biliary System in Children (Kelly, Diseases of Liver and Biliary System in Children)(2nd Edition)

Diseases of the Liver and Biliary System in Children EDITED BY

DEIRDRE A. KELLY MD, FRCP, FRCPI, FRCPCH

The Liver Unit The Birmingham Children’s Hospital NHS Trust Steelhouse Lane Birmingham

FOREWORD BY DAME SHEILA SHERLOCK

SECOND EDITION

Diseases of the Liver and Biliary System in Children EDITED BY

DEIRDRE A. KELLY MD, FRCP, FRCPI, FRCPCH

The Liver Unit The Birmingham Children’s Hospital NHS Trust Steelhouse Lane Birmingham

FOREWORD BY DAME SHEILA SHERLOCK

SECOND EDITION

© 1999 by Blackwell Science Ltd © 2004 by Blackwell Publishing Ltd Blackwell Publishing, Inc., 350 Main Street, Malden, Massachusetts 02148-5020, USA Blackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK Blackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia The right of the Author to be identified as the Author of this Work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. First published 1999 Second edition 2004 Library of Congress Cataloging-in-Publication Data Diseases of the liver and biliary system in children / edited by Deirdre A. Kelly; foreword by Dame Sheila Sherlock. — 2nd ed. p. ; cm. Includes bibliographical references and index. ISBN 1-4051-0660-3 1. Liver — Diseases. 2. Biliary tract — Diseases. 3. Pediatric gastroenterology. [DNLM: 1. Liver Diseases — Child. 2. Liver Diseases — Infant. WS 310 D611 2003] I. Kelly, Deirdre A. RJ456.l5d57 2003 618.92¢362 — dc22 2003016894 ISBN 1-4051-0660-3 A catalogue record for this title is available from the British Library Set in 91/2/12 Palatino by SNP Best-set Typesetter Ltd., Hong Kong Printed and bound in Denmark by Narayana Press, Odder Commissioning Editor: Alison Brown Managing Editor: Rupal Malde Production Editor: Alice Emmott Production Controller: Kate Charman For further information on Blackwell Publishing, visit our website: http://www.blackwellpublishing.com

Contents

List of Contributors, v Foreword, vii Dame Sheila Sherlock Preface, viii

Section 5: Liver Disease in Older Children 8

Chronic Hepatitis, 127 Suzanne Davison

9

Congenital and Structural Abnormalities of the Liver, 162 Ding-You Li, Kathleen B. Schwarz

Acknowledgements, ix 10

Non-alcoholic Steatosis, 183 Eve A. Roberts

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Hepatobiliary Disease in Cystic Fibrosis, 197 Birgitta Strandvik

Section 1: Supporting the Family 1

Supporting the Child and Family, 1 Gill Brook, Jo Hunt, Anne Johnson, Julie Reed Section 2: Investigating the Liver

2 Useful Investigations in the Assessment of Liver Disease, 17 Deirdre A. Kelly 3

Interventional Radiology and Invasive Diagnostic Imaging, 25 Philip John

Section 6: Metabolic Liver Disease 12

Metabolic Liver Disease in the Infant and Older Child, 211 Anupam Chakrapani, Anne Green

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Disorders of Copper Metabolism, 243 Stuart Tanner Section 7: Management of Chronic Liver Disease

Section 3: Neonatal Liver Disease 4

The Jaundiced Baby, 35 Eve A. Roberts

5

The Acutely Ill Baby, 74 Patrick J. McKiernan

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Complications and Management of Chronic Liver Disease, 259 Ross Shepherd Section 8: The Liver and other Organs

Section 4: Acute Liver Disease 6

7

Acute Hepatitis, 92 Suzanne Davison Fulminant Hepatitis and Acute Liver Failure, 107 Peter F. Whitington, Estella M. Alonso

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The Liver in Systemic Illness, 282 Susan V. Beath

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Skin Disorders in Liver Disease, 300 Indra D.M. Van Mourik, Celia Moss

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Dental Care of Children with Liver Disease, 313 Marie-Therese Hosey

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iv

Contents Section 9: Surgical Management of Liver Disease

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Surgical Disorders of the Liver and Bile Ducts and Portal Hypertension, 324 Mark D. Stringer, Edward R. Howard Primary Hepatic Tumours, 363 Bruce Morland, Jean de Ville de Goyet Section 10: Transplantation

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Liver Transplantation, 378 Deirdre A. Kelly, David Mayer

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Small Bowel Transplantation in Children, 402 Jorge Reyes, Kareem Abu-Elmagd Section 11: The Developing World

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Liver Disease in the Developing World, 421 Seng-Hoek Quak, Anupam Sibal, Mei-Hwei Chang Atlas section, 439 Index, 475

List of Contributors

K. ABU-ELMAGD

MD Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh PA 15213, USA

E. M. ALONSO MD Medical Director, Liver Transplantation

P. JOHN MBChB DCH FRCR FRCPC Associate Professor, University of Toronto, Interventional radiologist, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada

Children’s Memorial Hospital, 2300 Children’s Plaza, Chicago, IL 60614-3394, USA

S. V. BEATH BSc MB BF MRCP DTM FRCPCH Consultant Paediatric Hepatologist, The Liver Unit, Birmingham Children’s Hospital NHS Trust, Steelhouse Lane, Birmingham, B4 6NH, UK

A. M. L. JOHNSON Clinical Psychologist, Department of Clinical Psychology, Birmingham Children’s Hospital NHS Trust, Steelhouse Lane, Birmingham, B4 6NH, UK

D. A. KELLY MD FRCP FRCPI FRCPCH Professor of Paediatric Hepatology, The Liver Unit, Birmingham Children’s Hospital NHS Trust, Steelhouse Lane, Birmingham, B4 6NH, UK

G. BROOK CBE RScW RGN Clinical Nurse Specialist, The Liver Unit, Birmingham Children’s Hospital NHS Trust, Steelhouse Lane, Birmingham, B4 6NH, UK

D. LI MD PhD Senior Fellow, Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins Children’s Center, Brady 320, 600 N Wolfe Street, Baltimore, MD 21287, USA

A. CHAKRAPANI MD DCH MRCP MRCPCH Consultant in Inherited Metabolic Disorders, Birmingham Children’s Hospital NHS Trust, Steelhouse Lane, Birmingham, B4 6NH, UK

M. H. CHANG MD Professor, Department of Pediatrics, College of Medicine, National Taiwan University Hospital, No. 7 Chung-Shan S. Road, Taipei, Taiwan

S. DAVISON MB MRCP MRCPCH Consultant Paediatric Hepatologist, Children’s Liver and GI Unit, St James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK

A. GREEN BSc MSc PhD FRCPath FRCPCH FRSC FIBiol Consultant Paediatric Biochemist and Reader in Paediatrics and Child Health (University of Birmingham), Birmingham Children’s Hospital NHS Trust, Department of Clinical Chemistry, Steelhouse Lane,

A. D. MAYER MS FRCS Consultant Surgeon, Queen Elizabeth & Birmingham Children’s Hospital, Birmingham, B15 2TH, UK

P. J. McKIERNAN BSc MRCP FRCPCH Consultant Paediatric Hepatologist, The Liver Unit, Birmingham Children’s Hospital NHS Trust, Steelhouse Lane, Birmingham, B4 6NH, UK

B. MORLAND MBChB, MRCP, DM, FRCPCH Consultant Paediatric Oncologist, Birmingham Children’s Hospital NHS Trust, Steelhouse Lane, Birmingham, B4 6NH, UK

S. H. QUAK MBBS MMed (Paed) FAMS FRCP(Glas) FRCPCH MD Chief and Senior Consultant, Department of Paediatrics, National University Hospital, Lower Kent Ridge Road, Singapore, 119074

Birmingham, B4 6NH, UK

J. REED BSc MPhil Clin Psy D Consultant Clinical Psychologist, M. T. HOSEY BDS FDS RCPS (Glas) MSc (Med Sci) DDS Senior Lecturer in Paediatric Dentistry, University of Glasgow Dental School, 378 Sauchiehall Street, Glasgow, G2 3JZ, UK

Department of Clinical Psychology, Birmingham Children’s Hospital NHS Trust, Steelhouse Lane, Birmingham, B4 6NH, UK

J. REYES MD Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, E. HOWARD MS FRCS (Eng & Ed) formerly Professor of Hepatobiliary Surgery, Department of Paediatric Surgery, King’s College Hospital, Denmark Hill, London, SE5 9RS, UK

J. HUNT Senior Dietician Birmingham Children’s Hospital NHS Trust, Steelhouse Lane, Birmingham, B4 6N6, UK

Pittsburgh, PA 15213, USA

E. A. ROBERTS MD FRCPC Professor of Paediatrics, Medicine and Pharmacology, University of Toronto, Hepatologist, Division of Gastroenterology and Nutrition, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada

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vi

List of Contributors

K. B. SCHWARZ MD Chief, Division of Pediatric

M. S. TANNER MSc FRCP FRCPCH Professor of Child Health

Gastroenterology and Nutrition, Professor of Pediatrics, Johns

and Honorary Consultant Paediatrician, Sheffield Children’s

Hopkins University School of Medicine, Brady 320, 600 N Wolfe Street, Baltimore, MD 21287, USA

Hospital, Western Bank, Sheffield, S10 2TH, UK

I. D. M. VAN MOURIK MRCP MRCPCH R. SHEPHERD MD FRACP FRCP Professor of Pediatrics, St Louis Children’s Hospital, Director, Pediatric Liver Program, Washington University School of Medicine, St Louis, MO 63110, USA

Consultant Paediatric Hepatologist, The Liver Unit, Birmingham Children’s Hospital NHS Trust, Steelhouse Lane, Birmingham, B4 6NH, UK

J. DE VILLE DE GOYET PhD MD FRCS Professor, A. SIBAL Director of Medical Services, Senior Consultant Pediatric Gastroenterologist and Hepatologist, Indraprastha Apollo Hospital, Sarita Vihar, New Delhi 110044, India

B. STRANDVIK MD PhD Professor of Pediatrics, Department

Director of Transplant, Liver and Paediatric Surgery, St Luc University Hospital, Avenue Hippocrate 10, B-1200, Brussels, Belgium

P. WHITINGTON MD Divisional Head of Gastroenterology,

of Pediatrics, Institute of the Health of Women and Childen, Göteborg

Hepatology and Nutrition, Sally B. Searle Professor of Pediatrics and

University, SE-41685 Göteborg, Sweden

Transplantation, Children’s Memorial Medical Center, 2300 Children’s Plaza, Chicago, IL 60614-3394, USA

M. D. STRINGER BSc MS FRCS FRCP FRCPCH Consultant Paediatric Hepatobiliary/Transplant Surgeon and Reader in Paediatric Surgery, Children’s Liver and GI Unit, St James’s University Hospital, Leeds, LS9 7TF, UK

Foreword to the First Edition

Although the Ancient Egyptians believed that the liver had mystic powers of healing and Hippocrates gave a full description of hepatic encephalopathy, modern hepatology has only taken off in the last 50 years. Accelerated progress has followed discovery of the hepatitis viruses, now a virtual alphabet from A to E and beyond. Hepatobiliary imaging and endoscopy have added to the progress. Developments have depended not only on specialist hepatologists but on developments in other related disciplines of medicine, particularly virology, immunology, biochemistry and now, molecular medicine. A huge literature is available describing liver disease in adults but paediatrics has lagged behind. This book covers all the essentials of paediatric hepatology and is therefore particularly timely. The material covered is wide, from such aspects as the psychology of parents of children on transplant waiting lists to the genetic disturbances of bilirubin and bile salt transport in the neonate. The chapter authors have been well

chosen. They are international authorities, active both clinically and in research. They write lucidly from personal experience. Many helpful algorithms and tables are included. The references at the end of each chapter have been carefully selected and are up-to-date. The book concludes with an Atlas of 75 carefully annotated plates. This is virtually a book in itself and covers all paediatric liver diseases. Candidates for higher paediatric examinations will find it particularly useful. This book should be available in every paediatric department. It should be at hand at all times to offer practical advice on any childhood liver disease. General paediatricians will certainly benefit. It would be a suitable gift to reward a trainee. This book fills a real gap in our knowledge of liver disease. It will be a well-deserved success. professor dame sheila sherlock

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Preface

Paediatric hepatology has come of age. The discipline is recognized as an essential component of paediatric gastroenterology, meriting its own curriculum and training programmes in Europe and the USA. Paediatric liver disease is an important cause of morbidity and mortality in both the developed and the developing world. Significant advances, particularly in molecular genetics and the lessons learnt from functional genomics have increased our understanding of the aetiology and pathogenesis of paediatric liver disease, leading to the development of exciting new therapies. The natural history and outcome for many children with liver disease has improved substantially with the combination of modern management and liver transplantation. As survival following liver transplantation is almost assured, the search begins for alternative treatment, such as hepatocyte transplantation and gene therapy.

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The investigation and management of significant paediatric liver disease rightly remains within the remit of specialist or transplant units, but the recognition of the incidence of liver disease, the implications of new therapies, and the necessity for multidisciplinary working is as important for general paediatricians as for paediatric gastroenterologists, surgeons and hepatologists. The second edition of this book summarizes the recent advances of the last five years, and provides a practical approach to the diagnosis and management of paediatric liver diseases, highlighting the importance of multidisciplinary teamworking. New chapters describe the recent phenomenon of fatty liver disease and liver disease in the developing world. It should interest the non-specialist paediatrician and paediatric trainee as well as providing guidance to nurses and allied health professionals. deirdre a. kelly

Acknowledgements

The investigation of paediatric liver disease requires many skills and a multidisciplinary approach. It would not have been possible to write this book without the skill and expertise of many of my colleagues in the Liver Unit and Birmingham Children’s Hospital. I am delighted that I was able to call on so many distinguished contributors worldwide to share their own areas of expertise and learning. I am indebted to many colleagues for help in providing clinical slides and material, particularly, Dr Helen Alton and Dr Rachel Brown. Finally, I am grateful to Jennifer Shervington for all her help in editing and co-ordinating this book.

Dedications First Edition To my sons, Eoin and Lochlinn Parker and My husband, Ian Byatt Second Edition To the memory of my parents Frank and Kathy Kelly who started me on my medical career

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Chapter 1: Supporting the Child and Family GILL BROOK, JO HUNT, ANNE JOHNSON AND JULIE REED

Living with liver disease, 1 The role of the multidisciplinary team, 1 Effective team working, 2 Roles within the multidisciplinary team, 2 Shared-care protocols for patient management, 3 Consent to treatment, 3 Psychological support, 4 Developmental, intellectual and neuropsychological assessment, 4

Treatment adherence, 5 Altered physical appearance, 5 Liver transplantation, 6 Evaluation of the live-related donor, 7 Conclusion, 7 Nutritional support, 7 Chronic liver disease, 8 Cholestatic liver disease, 9 Nasogastric tube feeding, 11 Common problems, 11 Acute liver disease, 11

Living with liver disease ‘In an age and culture in which good health is taken for granted, parents expect their children to be well and survive them. Diseases that threaten children’s autonomy and compromise their life expectancy, challenge our emotions and coping resources to the limit. Childhood disease can turn the world upside down’ (Eiser 1993a). Most liver disease is life limiting. Medical therapy may control symptoms and long-term complications and thus optimize quality of life. However, for many children with liver disease there is no absolute cure and ongoing monitoring with regular hospital visits, for blood tests or admission, is required. Thus, from the time of diagnosis both child and family have to adapt to a life that is different from their expectations in order that the ‘upside down’ world becomes the norm for them. The child (infant–adolescent) with a chronic illness is automatically different to children of a similar age, while parents have an additional workload in caring for their child. ‘Normalizing’ processes within this context should be encouraged, using the knowledge, skills and active support of the different health professionals within the multidisciplinary team (Krulik 1980; Knafl & Deatrick 1986). The child (depending on age) and family pass through numerous processes. First, both parents and child need to come to terms with the shock of the diagnosis as well as, for the parents, the grief of losing their child’s good health. Parents have to take in much information relating to diagnosis and prognosis as well as learning new skills in caring for their child. Ideally information should be shared with the parents and child at their pace, and in the context of their family and social setting.

Liver transplantation, 12 Parenteral nutrition, 12 Conclusion, 12 Adolescence and transition to adult life, 12 Defining adolescence, 12 Moving towards independence, 13 Important information for adolescents and young adults with liver disease, 14 ‘Transition’ to adult services, 14

Parents may find it difficult to accept the unpredictability of their child’s disease and the effect on immediate life plans. If the child’s condition deteriorates, with reduction in physical mobility, increasing symptoms, such as ascites and malnutrition, the intensity of the care required increases exponentially. As a result, the extra time and attention given to the child with liver disease may impact adversely on siblings and other members of the family (Eiser 1993b). As the child’s disease progresses, the parent has to be careful to detect subtle changes in their child’s condition in order to seek appropriate help. As liver disease is relatively uncommon in the child population, many parents, children and young people become ‘experts’ in disease management and often know more about specific aspects of their disease than their local healthcare team. This may be an added concern to the family, and it is vital that efficient communication systems are established with local services. Ideally, the child and family should experience a ‘seamless web’ of care, treatment and support centred on the needs of the child, their siblings and their carers (Department of Health 2000). Multidisciplinary working is an essential feature of this ‘seamless’ care (Heywood 2002).

The role of the multidisciplinary team In order to meet the physical and psychological needs of children and young people with liver disease and to maximize their quality of life, the skills of many appropriately trained health professionals are essential. At the specialist unit, this team includes the medical staff and ward-based nursing team and the following personnel:

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Section 1: Supporting the Family

• social worker • play specialists (for outpatient and inpatient work) • school teacher (hospital based) • clinical nurse specialist • liaison nurses • outpatient clinic coordinator (nursing role) • clinical psychologist • dietician • physiotherapist • pharmacist • secretarial and administrative support. Local health professionals and shared care services will include: • referring paediatrician • general practitioner • community nursing team, preferably children’s community nursing team • local social services • local pharmacist (hospital and local chemist shop). Other professionals who also may be involved are: • school teacher/local home tuition services • community physiotherapist. The resources to support the child and family at home may vary in each geographical area. Early discharge planning and good communication are essential in preparing local care teams to care for the child at home. Effective team working Effective functioning of the multidisciplinary team is achieved by ensuring that there is: 1 A clear vision on how services are to be delivered. 2 Agreement on the philosophy of child and family centred care in which • healthcare meets the needs of the child individually, and as part of a family • the medical, social, spiritual, educational and psychological components of care are considered • information is provided to assist children and their families understand their health problems and available treatments • children have the opportunity to contribute to decisions that affect them, taking into account their age, ability and experience. 3 An understanding of the roles between professionals and the child and family so that there are clear expectations of care. 4 The skills and judgement of all team members are valued. 5 Effective communication and shared decision making. 6 Adequate staff support, as caring for children with life-limiting liver disease can be intensive and stressful. Support may be provided from a clinical psychologist, from colleagues or support groups (Cook 1999).

Roles within the multidisciplinary team Many of the roles within the team are self explanatory, but the following personnel have particular skills and importance. Social worker To many families, the social worker is associated with child protection issues and not with their participation in the psychosocial aspects of care. Many social workers have a practical role by facilitating parents’ support groups and by liaising with community social workers and support organizations. They will also have the detailed knowledge to help the family gain maximum financial support from any benefits provided by central and local government. Play specialist and teacher The play specialist and hospital-based schoolteacher have a crucial role in the psychosocial support of the child (Webster 2000). They provide the ‘normal’ aspects of a child’s life, that of play and education. Using specialist skills, in conjunction with those of the clinical nurse specialist or liaison nurse, they can help children and young people understand how the body works, the nature of their liver disease, and how they may be treated. The play specialist is essential in preparing children for invasive procedures ranging from venesection to transplantation. Liaison nurse and nurse specialist Liaison nurses are usually the ‘key workers’ for a group of children and their families. Their critical activities within the team include: • Provision of information. Children, young people, and their parents and other key family members should be provided with information about liver function, signs and symptoms of the child’s liver disease, the process of diagnosis, disease outcome, and management. The liaison nurse has a central role in the process of assisting children, young people and their parents in making informed decisions about treatment in partnership with the schoolteacher and/or play specialist. The use of written information about specific liver diseases, liver transplantation and other treatments, procedures and medicines is helpful. The development of generic information leaflets (for instance those developed by the Children’s Liver Disease Foundation in partnership with Paediatric Liver centres in the UK) has proved beneficial to parents and families, as information is consistent. • Coordination of discharge planning. The liaison nurse,

Chapter 1: Supporting the Child and Family the social worker, the ward-based team and the family need to plan a safe and effective discharge from hospital. This includes teaching parents and children self-medication and other new skills (their age and ability taken into account) to ensure that they are able to give care safely at home; and liaising with local community teams to ensure resources, information and communication processes are established prior to discharge. It is essential that parents understand the arrangements for care and support at home as well as ongoing management between local and specialist centres. ‘Patient/parent-held records’ are helpful in achieving effective and open communication between all parties. If children have particularly complex care needs a case conference between all relevant professionals may be required. • Continuing care. The liaison nurse or nurse specialist is often the best contact to ensure continuous communication between the family, the specialist centre and local shared-care team regarding any changes in treatment. The liaison nurse or nurse specialist should be easily contactable (by e-mail, telephone or pager) to provide further support and information for the child, family, or other healthcare professionals. It is vital that the child’s local health team are aware of the extent of the child and family’s knowledge in order to care for them appropriately. In Birmingham, a nurse-led telephone consultation service has been developed (Gordon et al. 2002) in order to provide information and advice to patients, their families and medical teams. Advice is provided the same day on the following topics: immunosuppression monitor-ing (38%); information about outpatient appointments and admission dates and processes (16%); medication changes (15%); vaccination requirements (7%); and other issues relating to ongoing treatment (24%). • Transition to adult care. The liaison nurse has a key part to play in the preparation and transfer of the young person to adult care. Establishing close links and working in partnership with the adult liver services in the early stages of transition helps facilitate a smooth and seamless transfer (see later).

Shared-care protocols for patient management The development of shared-care protocols with the local centre makes a significant difference to the care that a child receives. These protocols should outline the management of the liver disease, identifying actions to be taken by the local shared-care team in specific problem situations and providing clear guidelines for referral. These protocols should include: • overview of the liver disease and treatment • potential complications and the medical and nursing management required

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• medication regime and side-effects of relevant drugs, particularly unlicensed drugs • contact information. Copies of the protocol, discharge letter and subsequent correspondence could be given to the parents or young person which can be kept in the ‘parent/patient-held record’.

Consent to treatment It is the right of all children and young people to be informed and have their views taken into account in all matters that affect them as stated in the United Nations Convention on the Rights of the Child of 1989. However, involving children and young people in decision making in relation to their care and treatment requires skill and sensitivity. Gillick (1986) established that children under the age of 16 could give consent (that is they are competent to do so) provided that they have ‘sufficient understanding and intelligence to understand fully what is proposed’. This is known as being ‘Gillick competent’. Although it may be difficult to define when a child or young person is competent, this can be overcome by establishing a clear process of information sharing and opportunity of shared decision making, involving all members of the multidisciplinary team with the child and their parents (Brook 2000). In Birmingham, we have developed a framework to empower children and young people, with their parents, to make choices in their care and treatment (Brook 2000). The objectives of the framework are, for the team: • to gain information of the child’s knowledge, understanding and experience of illness and health care in the context of the child’s life. For the children and young people: • to provide them with an opportunity to increase their knowledge and understanding of their disease and treatments and to express their feelings, fears and expectations • to help them develop confidence in participating in decisions by providing opportunities for them to make choices in their care and treatment. For the parents: • to help them to gain knowledge and understanding of their child’s disease and treatment in order to make informed decisions with their child and as individuals • to enable parents to impart information to their child and siblings • to facilitate sharing information between the child and parent in order to help them make decisions together. The complex issue of defining competence to consent at a practical level is at the centre of this work and is based on children and young people moving from ‘novice to expert’ (Benner 1984; Rushforth 1999) in their ability to make choices in their care and treatment provided they

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Section 1: Supporting the Family

have the opportunity to do so (Alderson 1991; Alderson 1993; Alderson & Montgomery 1996). This depends on their age and cognitive ability, their cultural and family background, their experience of living with liver disease and their wish to participate (Alderson 1991; Alderson 1992; Alderson 1993; Alderson & Montgomery 1996; Alderson 2000). Although children should be encouraged to participate, they should not be burdened with decisions that are too difficult for them to make (Alderson 1991; Alderson 1993). Informed co-operation is vital to the outcome of many treatments, particularly transplantation, as long-term survival is dependent on compliance (Cameron 1996; Fielding & Duff 1999). Many parents wish to protect their child from difficult information and it is important to help them understand that information provided with sensitivity by skilled personnel in an age-appropriate manner is preferable to an unexpected unpleasant experience in which the child has no control (Alderson 1991; Alderson 1993). Many parents require support in this process and should be given strategies to prepare themselves for difficult and emotional questions from their child and sibling(s). In emergency situations, such as transplantation for fulminant liver failure, parents and children need sufficient information to make an informed decision. Time should limit only the quantity of information, not the quality. If the child is too ill to participate in the decision, parents need to be prepared for the child’s anger and grief during their recovery phase. Psychosocial support and information on the necessity of treatment will then be provided retrospectively to the child. The process of information sharing Information sharing between the child, family and healthcare team starts at the point of referral, preferably prior to the initial visit, perhaps by an introductory letter from the liaison nurse. In Birmingham, we attach a short questionnaire with a letter of explanation and activity sheets in order to find out about the child’s wishes and the extent of their understanding about their body and their disease. Plans are then made to meet the needs of the child and family, for example the play specialist may meet them to help with blood tests. The process is continued during the hospital admission with the liaison nurse acting as the key contact for information and communication so that the child’s treatment can be planned accordingly. Information can be provided in a variety of ways using computer teaching sessions or games, innovative books and toys. In addition, the play specialist and nursing team encourage the child/young person to develop an information sheet — ‘Things you need to know about me . . .’. This enables the child to reveal their personal interests, wishes and fears, particularly if they

are undergoing invasive procedures or being prepared for transplantation. In order to make an informed decision, the information provided should include: • the problem to be treated • why the treatment is offered • what the treatment involves • alternative treatment(s) • the risks and benefits. It is crucial to check the child’s understanding by enabling the child to feed back to their parents the information they have received, or to write or draw the information they have remembered in a scrapbook. This multidisciplinary approach relies on effective team working and a shared belief in the importance of allowing children and young people to develop their confidence and competence to make relevant decisions in relation to their health. The emphasis is on working with the parents and children together, helping them to share in decision-making whenever possible, thus parents gain confidence in their child’s ability to manage their own care, which is necessary preparation for adolescence and adult life.

Psychological support The psychologist will be involved in providing psychological support to the child and family, neuropsychological assessment and evaluating psychosocial outcome. Developmental, intellectual and neuropsychological assessment Developmental assessment involves the administration of standardized tests (e.g. Bayley Scales of Infant Development, Griffiths Mental Development Scales) to babies and preschool aged children in order to measure their developmental ability. Intellectual assessment involves the administration of norm-referenced tests (e.g. Wechsler Preschool and Primary Scale of IntelligenceRevised, Wechsler Intelligence Scale for Children III) to preschool and school-aged children in order to measure their general intellectual ability. A neuropsychological assessment involves the administration of standardized tests of intellectual ability, learning, memory and attention and the interpretation of these measures in the light of known brain functioning. Neuropsychological impairment can arise as a direct result of liver disease, e.g. cirrhosis, Wilson’s disease, or as a consequence of treatment, e.g. drug side-effects, transplantation. Assessment of a child’s intellectual or neuropsychological functioning may be clinically indicated where there are concerns about low attainment relative to intellectual potential, specific learning difficulties, problems with memory, attention and concentration.

Chapter 1: Supporting the Child and Family Results of assessments may have important implications for a child’s education, psychological and psychosocial adjustment and professional–patient communication. Neuropsychological assessment may also be carried out as one component of a research protocol to investigate disease progression, effects of drug treatments or outcome after liver transplantation. Research on disease progression suggests that prior to overt signs of encephalopathy, children with chronic liver disease may have specific neuropsychological impairment (visual–spatial skills and attention/concentration), with intact verbal and memory skills. These impairments have been shown in adult patients with nonalcoholic cirrhosis (Tarter et al. 1984) and it is likely that these changes would be at least as significant in the child population. In addition, some liver diseases, such as Wilson’s disease, are associated with decrement in visual–spatial and visual scanning tasks prior to neurological impairment (Tarter et al. 1987). Studies investigating outcome following liver transplantation have been hampered by small heterogeneous samples; difficulties making comparisons between psychometric tests measuring developmental ability and those measuring intellectual functioning; lack of baseline data prior to the onset of end-stage liver disease; absence of comparison groups and a lack of research into specific components of neuropsychological functioning. Nevertheless, these studies suggest that post-transplant intellectual functioning is likely to be at least in the low average range (Stewart et al. 1989; Beath et al. 1993). Children who are under 12 months at the onset of their liver disease may have global intellectual deficits at post-transplant assessment (Stewart et al. 1994) with poor growth being an important mediating factor. If transplantation takes place before 12 months then this leads to improved growth and nutrition and reduces the possibility of developmental delay, with recovery to pretransplant intellectual level, or better, at 2 years post transplant (Van Mourik et al. 2000). Results of a recent longitudinal study suggest that there may be a dip in assessment scores following transplantation, with recovery to pretransplant intellectual level, or better, at 2 years post transplant (Van Mourik et al. 2000). This result requires further investigation but may have important implications for a child’s return to education. In older children, clinical observations and reports from patients suggest that liver transplantation may adversely affect memory, learning processes, attention span and vigilance. In addition, cyclosporin A (until recently the most widely used immunosuppressant drug) is known to have neurological effects (Rubin & Kang 1987) and may affect neuropsychological functioning (Stewart et al. 1994), which has implications for the long-term educational prospects of survivors.

5

Treatment adherence Children with liver disease pre or post transplant need to adhere to drug regimes with negative side-effects, dietary restrictions or repeated invasive procedures. Adherence difficulties are among the most frustrating and perplexing problems for the multidisciplinary team, especially before and after transplantation. Adherence to a specific treatment is affected by a number of interrelated variables including child’s developmental status, disease knowledge, health beliefs, and family support. Interventions to increase medical adherence need to address the immediate positive consequences of nonadherence vs. the delayed benefits of adherence (Schweitzer & Hobbs 1995). Treatment adherence can be particularly problematic during adolescence when patient concerns about not wanting to be ‘different’ are likely to be at their peak. During the teenage years parent support continues to be important, but peer support may have greater influence on a teenager’s adherence. Involving healthy peers or slightly older patients as mentors (e.g. Shroff Pendley et al. 2002) is a new and potentially promising area of research in treatment adherence. Research focusing on children with liver disease is scant, but empirical work with other populations has demonstrated the efficacy of educational programmes (e.g. Beck et al. 1980), behavioural interventions utilizing stimulus control and positive reinforcement (e.g. Lowe & Lutzker 1979), and family support packages (e.g. Satin et al. 1989). While research has focused on quantitative investigations of adherence problems, there have been fewer investigations using qualitative techniques and/or identifying factors associated with good adherence. Treatment adherence is a complex issue and further research is needed to determine which intervention (or combination of interventions) is most suitable for an individual patient and their family (La Greca & Schuman 1995; Bryon 1998). Altered physical appearance Most children with liver disease are likely to experience abnormal changes in their appearance at some stage during their treatment. These changes may be due to disease processes, e.g. jaundice, or as a consequence of medical or surgical treatment, e.g. cushingoid features, scarring. Treatment adherence may be compromised by a patient’s wish to avoid the negative side-effects on physical appearance. There are a number of reasons why it is important to consider the psychological effects of growing up with a distinctive appearance. First, children and adolescents describe themselves and their peers according to their physical appearance, and children as young as 3 years old are able to discriminate between attractive and unattrac-

6

Section 1: Supporting the Family

tive peers (Langlois & Styczynski 1979). Second, from adult studies there is evidence to suggest that individuals with an atypical appearance experience social avoidance (Rumsey et al. 1982), perhaps related to the general public’s conflict over a desire to stare and a desire to adhere to the social norm against staring (Langer et al. 1976). Third, if a child or young person experiences social avoidance from their peers, then this may lead to decreased social competence, teasing and low self-esteem. Children with liver disease may also experience difficulty in establishing peer relationships because of their frequent hospital stays. Social competence in childhood predicts to the formation of adult social relationships and may be seen as a component of an individual’s quality of life. Lack of social competence is a risk factor for social isolation, low self-esteem and depression. There are a number of ways in which psychologists can help patients with abnormal physical appearance. First, it is useful to enable patients to develop age-appropriate ways of explaining their altered appearance. Assistance with social skill development and coping strategies for teasing may also be indicated and role-play with video feedback can be a useful adjunct. For preschool children this work can be carried out with the child’s parents with the expectation that the child will imitate their parents’ behaviour. Second, patients can be involved in preparing photographs, video materials and written text to send to their school prior to their return. Healthy peers will habituate to the patient’s abnormal appearance, have an opportunity to ask questions and their desire to stare is reduced. Third, cognitive therapy may be useful for adolescents whose abnormal appearance is associated with depression, social anxiety or poor treatment adherence. Liver transplantation Liver transplantation presents the child and family with ongoing medical and psychological challenges. As transplant survival rates have risen, transplant teams have become increasingly aware of the need to implement practices that enhance the child’s and their family’s quality of life throughout the transplant process (Burroughs & Rolles 1990). As a consequence, psychologists and other members of the psychosocial team have become involved in pretransplant evaluation of children and their families, and support through the transplant process. Psychological intervention can help ameliorate both the child’s and parents’ distress, reduce the need for drugs, increase adherence to medical regimes, decrease hospital stay, and facilitate adjustment to daily life (Gold et al. 1986; Zitelli et al. 1986; Windsorova et al. 1991; Littlefield et al. 1996). Issues covered by the pretransplant assessment include the child’s cognitive and developmental functioning, coping styles and mental health of the child and family, family

functioning, assessment of adherence, and in the case of live-related donation, evaluation of the donor. Cognitive and emotional development Research has shown that children’s experience of and recovery from medical intervention significantly improves when given age-appropriate information about the procedures (Lewandowski 1984). Consequently, transplant teams need to take into account both a child’s cognitive and emotional development when making decisions about how much, and in what way children should be informed about the disease, transplantation procedure and medical regimen. In addition, in specific cases it can be useful to assess the cognitive functioning of the parents, to determine whether they will require additional support in being able to comprehend and recall details of the child’s medical regimen. Hospital play specialists are trained to educate children about their transplant, guided by an understanding of their cognitive and developmental functioning, through innovative play activities and educational toys and books. Assessment can also reveal anxieties about medical procedures which impact on the transplant process, for example, needle phobia. Psychological techniques have been developed to help children cope with specific medical procedures, including psycho education, play therapy, distraction, relaxation, behavioural therapy and cognitive behavioural therapy (Davis et al. 1988; Kendall 1992; Ollendick et al. 1994; Silverman & Kurtines 1996). Coping styles Assessment of family functioning and coping styles is integral to developing a transplant treatment plan, in order to minimize the impact of stressors on the family through the child’s illness and treatment. Common stressors impacting on the transplant process identified by Uzark (1992) include waiting and competition for a suitable organ (25% of patients die waiting for a donor (Paradis et al. 1988)), uncertainties of rejection, uncertainty of child’s future health and well-being, changes in role within the family, for example, siblings having to become more independent, social isolation, and financial burdens. Clinical experience suggests that families of children who require a second transplant find the process particularly stressful and further research is required to understand the issues that face this patient group. Mental health In the weeks after transplantation children can experience changes of mood, including mild depression and anxiety, which in most cases reaches a peak about a month after the operation (Mowat 1987; Zitelli et al. 1988). These

Chapter 1: Supporting the Child and Family changes in mood are often related to death anxiety, guilt due to perceived and real burdens on the family, survival guilt when other transplant patients have died, changes in family dynamics and body image concerns (Gardner et al. 1977). In addition, Walker et al. (1999) suggested that for some children the duration and severity of their emotional distress meets the diagnostic criteria for Posttraumatic Stress Disorder (PTSD), wherein the acute lifethreat involved in the liver transplantation contributed to the development of PTSD. Consequently, it is important to monitor the child’s mental state from pretransplant to post transplant, enabling early psychological intervention if these symptoms reach clinically diagnostic levels. Family functioning Although not necessarily pathological, changes in the family system are inevitable when a child has a chronic illness such as liver disease and the family are subject to the transplant process, for example, parental role change, increase in care-giving burden, and separation from siblings through hospital stays (Zitelli et al. 1988; Uzark & Crowley 1989). Following transplantation, parents report a departure from practices of infantilization, inconsistent discipline, family social isolation, and resentment of the child by the siblings (Goodheart & Lansing 1996). However, conversely, the parents may become overprotective due to the awareness of the possibility of infection or rejection (Sexson & Rubenhow 1992). The child experiences increasing independence post transplantation, and is expected to engage in activities that have been neglected previously (i.e. school participation) which can induce anxiety and behavioural problems. There are also issues due to difficulties in adjusting to a change in the level of dependence of the child on their parents and their increasing autonomy from the family unit. Therefore, families often require ongoing psychosocial intervention to facilitate the adaptation to the different stages of the transplantation process.

7

Evaluation of the live-related donor When a family decides to consider live-related surgery, the potential donor must undergo extensive assessment. This process may add to the stress of the parents with a child who is seriously ill. Boone et al. (1992) found that common concerns included: possible organ failure, increased risk of two family members undergoing surgery, increased financial burdens, feelings of guilt from nondonating parents and concern for other children. The decision should be interdisciplinary, involving hepatologists, psychologists, social workers, and liaison nurses, to ensure that the donor is making a rational and voluntary decision, based on a good understanding of all the relevant information. The team needs to be aware of the contraindications of living organ donation, for example, pre-existing psychiatric disorders, inadequate parental coping behaviour and disturbed patterns in family functioning (Ozawa et al. 1992). It is important that assessment of a live-related donor programme includes evaluation with particular reference to the quality of life of the family members (i.e. adult donor, partner of donor, siblings of recipient and recipient). Conclusion There is an emerging evidence base to show that psychological input has a positive impact on health outcomes for this group of patients (Roberts 1995).

Nutritional support The need for dietetic support for a child with acute, chronic or metabolic liver disease will depend on the severity of the disease and symptoms (Fig. 1.1). Nutritional problems are multifactorial in origin, and their treatments diverse (Table 1.1; Chapter 14). Inability to provide satisfactory nourishment is distressing for both the families

Table 1.1 Causes of malnutrition in liver disease Inadequate intake

• • • • • •

Anorexia, nausea and vomiting Early satiety due to organomegaly and ascites Recurrent infections and hospitalization Unpalatability of prescribed feeds and diet Behavioural feeding difficulties Taste changes caused by medications and biochemical disturbances

Impaired digestion and absorption of nutrients

• Reduced bile flow causing fat and fat soluble vitamin malabsorption, and and essential fatty acid deficiency • Enteropathy due to portal hypertension • Disease-related pancreatic insufficiency

Increased nutritional requirements

• Hypermetabolism due to infection or trauma • Insufficient protein synthesis and/or accelerated breakdown • Malabsorption

8

Section 1: Supporting the Family On presentation TSF/MAC/weight/height/length/head circumference ( 2 years of age)

Common problems

There are no specialized MCT-containing feeds available for this group of patients. Any paediatric energy supplements, e.g. Paediasure (1 kcal/ml, Abbott) or Fortini (1.5 kcal/ml, Nutricia), or adult supplements, e.g. Ensure Plus (1.5 kcal/ml, Abbott), can be used. Advice on fortifying foods with extra fat, carbohydrate and energy supplements (Table 1.5) can have a huge impact on energy intake. Following ‘healthy eating’ guidelines should be discouraged.

Intensive nutritional support in the ill infant or child may be problematic. A number of common problems are outlined in Table 1.6. Parents of infants/children with liver disease feel immense pressure about feeding their child. They are aware of the importance of good nutrition and growth on prognosis and liver transplantation. They should not be burdened by unrealistic expectations, but should be reassured that the need for extra support and supplementary artificial feeding is often inevitable, particularly in endstage disease. Many children experience difficulty feeding. This may be behavioural, usually as a result of long-term hospitalization, tube feeding when young, delayed weaning or chronic illness, and will require different strategies (Table 1.7). Mealtimes can become a battle ground with both the child and carers using food as emotional manipulation. Often the carer will feel guilty because the child has been ill for so long and that tackling feeding issues is cruel. Resolution of these feeding difficulties will need longterm input from speech therapists, clinical psychologists, dieticians, health visitors, paediatric community nurses, and specialist liaison nurses. Reassurance and practical support are invaluable.

Nasogastric tube feeding Supplementary nasogastric tube feeding should be considered at an early stage for any infant or child who is failing to thrive. Benefits are usually recognized and welcomed by all involved once commenced. These include: • reduction in pressure on parents and child • reduction in force feeding • improved growth • happier mealtimes. Acceptance of tube feeding is enhanced by preparation, explanation and support by the multidisciplinary team before and after it has been instigated. Parents and child (depending on age) should be taught to pass the tube and become familiar with the mechanics of the pump, particularly if enteral feeding is nocturnal. They should be conversant with the mode of feeding (bolus, nocturnal or continuous). Parents should be expert in feed preparation and hygiene. As up to 50–100% of energy requirements may be provided by tube feeding, this may impact on the oral feeding regime. However where possible the regime should

Acute liver disease Dietary treatment will depend on symptoms at presentation, and speed of onset of disease. Initial assessment includes weight and height (length), and anthropometrical measurements such as MAC and TSF. If onset is rapid, the child is likely to be relatively well nourished at presenta-

Table 1.7 Strategies for dealing with behavioural feeding difficulties • Never force/bribe/threaten a child to eat • Try not to show anxiety or annoyance at mealtimes • Reward good behaviour at mealtimes with attention and positive feedback, e.g. smiling, talking to them, and ignore bad behaviour, i.e. leaving the table before they should, throwing meals on the floor, etc. • Encourage family mealtimes, sat at a table for social interaction • Set a realistic time limit for the length of a meal, e.g. 30 min • Encourage a regular meal pattern, which can include nutritious snacks • Offer small portions and offer more when completed • Discourage filling up on drinks between meals • Allow infants to play with food and make a mess; this is part of normal development

12

Section 1: Supporting the Family Continuation of nutritional support post transplant is vital as it is important to maintain an adequate calorie intake (Chapter 20). The diet should normalize unless there are complications such as chronic rejection. Many children will require tube feeding for some time because of previous behavioural feeding problems (Kelly 1997).

tion, but may lose weight rapidly because of anorexia, vomiting or fear of strange surroundings. Children require a high-energy intake, and sufficient carbohydrate to prevent hypoglycaemia. If the child is encephalopathic, then protein reduction (1–2 g/kg) is required for a short period of time only (Table 1.3). Fluid volume should be restricted (50–75% maintenance) to prevent cerebral oedema. Enteral feeding should be continued as long as possible using continuous nasogastric enteral feeding if the child is unable to feed because of drowsiness or the development of hepatic coma. Parenteral nutrition may be required if the child requires transplantation.

Parenteral nutrition TPN is associated with inducing liver disease and the central venous catheters required are a potential source of infection, but may be necessary in children with liver disease if enteral nutrition has failed or there are complications such as feed intolerance or bleeding varices (Chapter 14).

Liver transplantation Children awaiting liver transplantation may need more intensive nutritional support, requiring extra nutritional supplements, enteral tube feeding, or in some circumstances parenteral feeding (Chapters 4 and 20, Fig. 1.1; Table 1.8). Modular enteral feeds may be helpful as this provides the only method of achieving optimal nutritional input, e.g. when electrolytes or protein need to be modified or omitted, or if fluid is restricted (Table 1.4a,b). Modular feeds must be prescribed and supervised by an experienced dietician. Dietary and fluid restrictions should be kept to a minimum. Removing favourite foods from the diet may limit energy intake and is difficult for the child to accept, while prolonged dietary constraints can lead to nutritional deficiencies. Oral nutritional intake should be encouraged in order to maintain feeding skills, even if amounts are of little nutritional benefit.

Conclusion Intensive nutritional support may make a big difference to the quality of life of many children. Skilled intervention by the multidisciplinary team is vital. Useful contact numbers and addresses for infant feed manufacturers are included (Table 1.9).

Adolescence and transition to adult life Defining adolescence Adolescence is best defined as the process of maturity in biological, psychological and social terms (Viner & Keane 1998). Adolescence starts around 10 years and may

Table 1.8 Feed composition commonly used in the treatment of cholestatic children (per 100 ml) Feed

Manufacturer

Energy, kCal (kJ)

Protein, g

Fat, g (% MCT)

Na, mmol

EFAs W6 : W3

Pregestimil (13.5%)

MJ

68 (283)

1.9

3.8 (55%)

1.4

Yes 16.5 : 1

Peptijunior (12.8%)

C+G

66 (280)

1.8

3.6 (50%)

0.9

Yes 64 : 1

Caprilon (12.7%)

S.H.S.

66 (280)

1.5

3.6 (75%)

0.8

Yes 7.5 : 1

Generaid Plus (17–34%)

S.H.S.

75–150

1.9–3.7

3.2–6.5 (35%)

0.5–1.0

Yes 56 : 1

(315–630) MCT Pepdite (15%)

S.H.S.

68 (283)

2

2.7 (75%)

1.5

Yes 6.9 : 1

MCT Pepdite 1+ (20%)

S.H.S.

91 (380)

2.8

3.6 (75%)

1.8

Yes 6.9–1

See individual products

70–200 (290–840)

Flexible

Flexible 50–65%

0–1.5 mmol/kg

Modular Feed

MJ, Mead Johnson; C + G, Cow and Gate; S.H.S., Scientific Hospital Supplies.

No

Chapter 1: Supporting the Child and Family

13

Table 1.9 List of feed manufacturers Company name

Address

Contact No.

Scientific Hospital Supplies (S.H.S.)

SHS International Ltd 100 Wavertree Boulevard Liverpool L7 9PT, UK

Tel: + 44 (0) 151 228 8161 Fax: + 44 (0) 151 228 2650

Cow + Gate (C + G)

Cow + Gate White Horse Business Park Trowbridge, Wiltshire, BA14 0XQ, UK

Tel: + 44 (0) 1225 76 8381 Fax: + 44 (0) 1225 76 8847

Mead Johnson (MJ)

Mead Johnson Nutritionals 141–149 Staines Rd, Hounslow, TW3 3JA, UK

Tel: + 44 (0) 20 8754 3764 Fax: + 44 (0) 20 8569 4091

Nutricia

Nutricia Clinical Care, Nutricia Ltd, White Horse Business Park Trowbridge, Wiltshire BA14 0XQ, UK

Tel: + 44 (0) 1225 71 1677 Fax: + 44 (0) 1225 71 1798

extend to 20 years (Viner & Keane 1998). Using such a wide age range definition highlights the importance of the diversity in individual development, especially in the adolescent phase of life; we may be dealing with a mature 10-year-old and a less mature 20-year-old (KuyKendal 1989; Needham 2000). Adolescence is a transitional stage in which the young person begins to move towards independence, from parents, and towards an increased reliance on peer group acceptance. Adolescents have to learn to accept their developing sexuality and to make choices relating to education, employment and a long-term career. These moves towards adulthood are challenging enough, but to a young person with chronic ill health they can be fraught with difficulties (Schidlow & Fiel 1990). It may be more difficult for them to develop their own autonomy due to the dependence on their parents. Acceptance by peers may be more difficult due to social isolation, missing school or college due to ill health and frequent hospital visits. Also young people with liver disease may look ‘different’ due to drug treatment (e.g. steroids) or the signs and symptoms of liver disease. Puberty may be delayed and growth stunted. The unpredictability of liver disease and treatment may make it difficult for young people and their families to plan realistically for the future. Adolescents are a socially distinct group, not needing the protection and security accorded to children but not yet ready for full independence (Conway 1998). These young people and their parents require the support and guidance of the multidisciplinary team working within the specialist liver centre to help them move into the adult world towards independence. The traditional paediatric model of care focusing on the parent may avoid the important issues of sexual and reproductive health care, substance abuse, risk behaviours, career counselling, and

independent living (Blum et al. 1993). The planning and development of adolescent-friendly services including the transition process must include the views of the young people themselves (Viner & Keane 1998). This group of patients require special provision for: • their overall health care • the psychosocial aspects of illness • education and vocational training • transition to adult care • health promotion. Moving towards independence The multidisciplinary team should positively promote and affirm the ‘moving on’ process in a supportive manner. This may require them to address their own feelings of ‘letting go’ the young people whom they have known for many years. A good way to start is with self-medication (Tomlin 2001). Young people should be helped to take responsibility for medication from an early age as possible. This will include educating children about the reasons for medication as well as the potential side-effects. This information should be in written or another format appropriate to the child’s ability to understand. Parents will require encouragement to enable their child to take on this responsibility. Young people need to take charge of their disease and be informed about effective ways of dealing with medical situations, such as recognizing deterioration in their health and making the appropriate responses. This should include how to seek help from health professionals initially in the paediatric/adolescent service and then in the adult service. Adolescents should also be encouraged to use patient-held records in which they record important medical events (Kurtz & Hopkins 1996).

14

Section 1: Supporting the Family

Important information for adolescents and young adults with liver disease Adolescents will need advice and guidance on: • use of alcohol • body piercing • dental care • sunbathing • sexual health and contraception • pregnancy • healthy diet • promotion of exercise. This information will form part of the general education issues that should be addressed in the preparation for transition to the adult service. ‘Transition’ to adult services Definition of transition: Transition is ‘the purposeful planned movement of adolescents and young adults with chronic physical and medical conditions from child-centred to adultorientated healthcare systems’ (Blum et al. 1993). The optimal goal of transition is ‘to provide healthcare that is uninterrupted, coordinated, developmentally appropriate, psychosocially sound, and comprehensive’ (Blum et al. 1993). Transition is an active process and not a single event. Planning for transition must begin early and be regularly reviewed. It must be age and developmentally appropriate. There appears to be very little ‘hard’ evidence on the most effective model for a transition service. Blum et al. (1993) identify four key elements on which a potentially successful service should be based. These are: • Professional and environmental support. Developing and maturing through adolescence into adulthood requires a service that supports all aspects of growth and development at this time. • Decision making and consent. Young people must be given the opportunity to develop their autonomy and to make choices about their treatment and care with their parents in the early stages of their disease in order to gain confidence and competence in decision making. The parent, once confident in their child’s ability, will find it easier to let go. • Family support. Adolescents require parent support and encouragement to become independent while parents may need the help of health professionals to negotiate boundaries. Each individual transition plan should assist families to adapt their support in order to enable the young person to become more independent. • Professional sensitivity to the psychosocial issues of the disease.

There is an increasing need for health professionals in the adult services to become skilled in the knowledge and management of paediatric health conditions as more children survive into early adulthood and beyond. Young people should not be transferred to adult services until they have the skills to function in the adult service (Conway 1998). The following points highlight some of the important issues to take into account for transition and transfer of adolescence to adult healthcare services (Viner & Keane 1998; Kurtz & Hopkins 1996): • Policy on transition should be established. The establishment of a well-planned and resourced transition programme reflects the strength of belief that chronic disease need not be a handicap (Sawyer 1998). • The timing of transition must depend on the developmental readiness and health status of the adolescent. It is helpful to set a mutually agreed target transfer age for both staff and the young person in preparation for transition to adult care. Early discussion of transfer is essential (around 11 years of age may be an appropriate time, but this will depend on the age at onset of liver disease). • The process of transfer should be coordinated. About a year prior to the agreed transfer date, it is recommended that the young person is provided with information on the adult service. There should be at least one visit to the adult clinic with parents and a trusted paediatric carer or paediatric team. A combined adult–paediatric clinic is very helpful as an introduction for the young person to the adult healthcare team, but this must not replace the coordinated transition process (Court 1993). Evaluation of transition and transfer should be made involving the users of the service (Lightfoot & Sloper 2002). • It is helpful to identify a specific person within both the paediatric and adult teams to take responsibility for transition arrangements, usually the clinical nurse specialist or liaison nurse. • The referring clinicians should provide a combined detailed report on the young person’s disease, treatment and holistic management and support, giving a copy to the adolescent and their parents. • Transition plans must include communication with the local healthcare team. Transition to adult care should be an integrated, smooth, coordinated process. It requires planning, adequate funding, a multidisciplinary patient-centred approach, and willingness by both adult and paediatric healthcare teams to learn and work together to achieve the best quality of life for the young people in their care.

References Alderson, P. (1991) Children’s consent to surgery. Paediatric Nursing December 10–13. Alderson, P. (1992) In the genes or in the stars? Children’s competence to consent. Journal of Medical Ethics 18, 199–204.

Chapter 1: Supporting the Child and Family Alderson, P. (1993) Children’s Consent to Surgery. pp. 142–199. Open University Press, Buckingham. Alderson, P. (2000) The key messages from the evidence and experience. In: Young Children’s Rights. Exploring Beliefs, Principles and Practice, pp. 130–137. Jessica Kingsley Publications Ltd., London. Alderson, P. & Montgomery, J. (1996) Health Care Choices: Making Decisions with Children, pp. 4–22. IPPR, London. Beath, S.V., Brook, G., Kelly, D.A. et al. (1993) Successful liver transplantation in babies under 1 year. British Medical Journal 307, 825–828. Beck, D.E., Tennell, R.S., Yost, R.L. et al. (1980) Evaluation of an educational program on compliance with medication regimens in patients with renal transplants. Journal of Pediatrics 96, 1094–1097. Benner, P. (1984) From Novice to Expert; Excellence and Power in Clinical Nursing. Addison-Wesley, Menlo Park. Blum, R.W., Garell, D., Hodgeman, C.H. et al. (1993) Transition from child centred to adult centred health care systems for adolescents with chronic conditions. Journal for Adolescent Health 14, 570–528. Boone, P., Kelly, S. & Smith, C. (1992) Liver transplantation: living related donation. Critical Care Nursing Clinics of North America 4, 243–248. Brook, G. (2000) Children’s competence to consent. A framework of practice. Paediatric Nursing 12, 31–35. Bryon, M. (1998) Adherence to treatment in children. In: Adherence to Treatment in Medical Conditions (eds. Myers, L.B. & Midence, K.), Harwood Press, Amsterdam. Burroughs, A.K. & Rolles, K. (1990) Liver transplantation. In: Recent Advances in Gastroenterology, 8 (ed. Pounder, R.), Churchill Livingstone, Edinburgh. Cameron, C. (1996) Patient’s compliance; recognising factors involved and suggestions for promoting compliance with therapeutic regimes. Journal of Advanced Nursing 24, 244–250. Chin, S.E., Shepherd, R.W., Cleghorn, G.J. et·al. (1991) Survival, growth and quality of life in children after orthotopic liver transplantation: a 5 year experience. Journal of Pediatric Child Health 27, 380–385. Conway, S.P. (1998) Transition from paediatric to adult centred care for adolescents with cystic fibrosis. Disability and Rehabilitation 20, 209–216. Cook, P. (1999) Supporting the staff. In: Supporting Sick Children and Their Families, Chapter 9, pp. 239–255. Ballière-Tindall, London. Court, J.M. (1993) Issues of transition to adult care. Journal of Paediatrics and Child Health. 29 (Suppl. 1), 553–555. Davis, M., Ribbins-Eshelman, E. & Mckay, M. (1988) The Relaxation and Stress Reduction Workbook, 3rd edn. New Harbinger, Oakland, CA. Department of Health (2000) Core Principle no. 8. The NHS Plan. A Plan for Investment. A Plan for Reform, p. 4. The Stationery Office Ltd, London. Eiser, C. (1993a) Chronic disease. The nature of the challenge. In: Growing Up with Chronic Disease; the Impact on Children and Their Families (ed. Eiser, C.), p. 11. Jessica Kingsley Publishers, London. Eiser, C. (1993b) The impact of chronic disease on sibling relationships. In: Growing Up with Chronic Disease; the Impact on Children and Their Families (ed. Eiser, C.), pp. 175–195. Jessica Kingsley Publishers, London. Fielding, D. & Duff, A. (1999) Compliance with treatment

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protocols; interventions for children with chronic illness. Archives of Disease in Childhood 80, 196–200. Gardner, G.G., August, C.S. & Githens, J. (1977) Psychological issues in bone marrow transplantation. Pediatrics 60, 625–631. Gerber, T. & Schomerus, H. (2000) Hepatic encephalopathy in liver cirrhosis: pathogenesis, diagnosis and management. Drugs 60, 13563–13570. Gillick vs. West Norfolk and Wisbech Health Authority (1986) AC 112;(1985), 3 All ER 402;(1985), 3 WLR 830;(1986), 1 FLR 224. Gold, L.M., Kirkpatrick, B.S., Fricker, F.J. & Zittelli, B.J. (1986) Psychosocial issues in organ transplantation: the parents’ perspective. Pediatrics 77, 738–744. Goodheart, C.D. & Lansing, M.H. (1996) Treating People with Chronic Disease: A Psychological Guide. American Psychological Association, Washington, DC. Gordon, G., Lloyd, C., Gupte, G et·al. (2002) Liver direct — a joined up way to manage long term care? Archives of Disease in Childhood. 86 (Suppl. 1), G130, A46. Heywood, J. (2002) Enhancing seamless care; a review. Paediatric Nursing 14, 18–20. Kelly, D.A. (1997) Posttransplant growth failure in children. Liver Transplantation and Surgery 3, 1–9. Kendall, P. (1992) Coping Cat Workbook. Workbook Publishing, Admore, PA. Knafl, K.A. & Deatrick, J.A. (1986) How families manage chronic conditions — an analysis of the concepts of normalisation. Research in Nursing and Health 2, 215–222. Krulik, T. (1980) Successful normalisation tactics of parents of chronically ill children. Journal of Advanced Nursing 5, 573–578. Kurtz, Z. & Hopkins, A. (1996) Services for Young People with Chronic Disorders in their Transition from Childhood to Adult Life. Royal College of Physicians, London. KuyKendall, J. (1989) Teenage trauma. Nursing Times 85, 26–28. La Greca, A.M. & Schuman, W.B. (1995) Adherence to Prescribed Medical Regimens. In: Handbook of Pediatric Psychology (ed. Roberts, M.C.). Guilford, New York. Langer, E.J., Fiske, S., Taylor, S.E. & Chanowitz, B. (1976) Stigma, staring and discomfort: a novel stimulus hypothesis. Journal of Experimental Social Psychology 12, 451–463. Langlois, J.H. & Styczynski, L. (1979) The effects of physical attractiveness on behavioural attributions and peer preferences of acquainted children. International Journal of Behavioral Development 2, 325–341. Lewandowski, L.A. (1984) Psychosocial aspects of critical care. In: Nursing Care of the Critically Ill Child, (ed. Hazinski, M.F.) Mosby, St Louis. Lightfoot, J. & Sloper, P. (2002) Having a Say in Health. Guidelines for Involving Young Patients in Health Services Development. Social Policy Research Unit, The University of York, York. Littlefield, C., Abbey, S., Fiducia, D. et al. (1996) Quality of life following transplantation of the heart, liver, and lungs. General Hospital Psychiatry 18 (6 Suppl.), 36S–47S. Lowe, K. & Lutzker, J.R. (1979) Increasing compliance to a medical regimen with a juvenile diabetic. Behavior Therapy 10, 57–64. Mowat, A. (1987) Liver Transplantation in Childhood. Butterworths, London. Needham, J. (2000) The nurse specialist role in adolescent health. Paediatric Nursing 12, 28–30.

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Ollendick, T., King, N. & Yule, W. (1994) International Handbook of Phobic and Anxiety Disorders in Children and Adolescents. Plenum, New York. Ozawa, K., Uemoto, S., Tanaka, K. et al. (1992) An appraisal of liver transplantation from living relatives. Annals of Surgery 216, 547–553. Paradis, K.J.G., Freese, D.K. & Sharp, H. (1988) A perspective on liver transplantation. Clinics of North America 35, 409–429. Protheroe, S.M. (1998) Feeding the child with chronic liver disease (Review). Nutrition 14, 796–800. Roberts, M.C. (1995) Handbook of Pediatric Psychology. Guilford, New York. Rubin, A.M. & Kang, H. (1987) Cerebral blindness and encephalopathy with cyclosporin A toxicity. Neurology 37, 1072–1076. Rumsey, N., Bull, R. & Gahagan, D. (1982) The effect of facial disfigurement on the proxemic behaviour of the general public. Journal of Applied Social Psychology 12, 137–150. Rushforth, H. (1999) Practitioner review: communicating with hospitalised children: review and application of research pertaining to children’s understanding of health and illness. Journal of Child Psychiatry 40, 683–691. Satin, W., La Greca, A.M., Zigo, M.A. & Skyler, J.S. (1989) Diabetes in adolescence: effects of multifamily group intervention and parent simulation of diabetes. Journal of Pediatric Psychology 14, 259–276. Sawyer, S.M. (1998) The process of transition to adult healthcare services. In: Diabetes and the Adolescent (eds Wether, G. & Cart, J.), Blackwells, Melbourne. Schidlow, D.V. & Fiel, S.B. (1990) Life beyond pediatrics. Transition of chronically ill adolescents from paediatric to adult healthcare systems. Medical Clinics of North America. 74, 13–20. Schweitzer, J.B. & Hobbs, S.A. (1995) Renal and liver disease: end-stage and transplantation issues. In: Handbook of Pediatric Psychology (ed. Roberts, M.C.), Guilford, New York. Sexson, S. & Rubenhow, J. (1992) Transplants in children and adolescents. In: Psychiatric Aspects of Organ Transplantation (eds Craven, J. & Rodin, A.) Oxford University Press, New York. Shroff Pendley, J., Kasmen, L.J., Miller, D.L., Donze, J., Swenson, C. & Reeves, G. (2002) Peer and family support in children and adolescents with Type 1 diabetes. Journal of Pediatric Psychology 27, 429–438. Silverman, W. & Kurtines, W. (1996) Anxiety and Phobic Disorders: A Pragmatic Approach. Plenum, New York. Stewart, S.M., Kennard, B.D., Waller, D.A. & Fixler, D. (1994)

Cognitive function in children who receive organ transplantation. Health Psychology 13, 3–13. Stewart, S.M., Uauy, R., Waller, D.A., Kennard, B.D., Benser, M. & Andrews, W.S. (1989) Mental and motor development, social competence, and growth one year after successful paediatric liver transplantation. Journal of Pediatrics 114, 574–581. Tarter, R., Hegedus, A., Van Thiel, D., Schade, R., Gavaler, J. & Starzl, T. (1984) Nonalcoholic cirrhosis associated with neuropsychological dysfunction in the absence of overt evidence of hepatic encephalopathy. Gastroenterology 86, 1421–1427. Tarter, R., Switala, J., Carra, J., Edwards, N. & Van Thiel, D. (1987) Neuropsychological impairment in patients with hepatolenticular degeneration (Wilson’s Disease) in the absence of overt encephalopathy. International Journal of Neuroscience 37, 67–71. Teran, J.C. (1999) Nutrition and liver disease (Review). Current Gastroenterology Reports 1: 335–240. Tomlin, S. (2001) Pharmaceutical care: improving practice for children in hospital. Paediatric Nursing 13, 4.25–4.29. Uzark, K. (1992) Caring for families of transplant recipients: psychosocial implications. Critical Care Nursing Clinics of North America 4, 255–261. Uzark, K. & Crowley, D. (1989) Family stresses after heart transplantation. Progress in Cardiovascular Nursing 4, 23–26. Van Mourik, I.D.M., Beath, S.V., Brook, G.A. et al. (2000) Longterm nutritional and neurodevelopmental outcome of liver transplantation in infants aged less than 12 months. Journal of Paediatric Gastroenterology and Nutrition 30, 269–275. Viner, R. & Keane, M. (1998) Youth Matters. Evidence Based Best Practice for the Carer of Young People in Hospital. Action for Sick Children, London. Walker, A.M., Harris, G., Baker, A., Kelly, D. & Houghton, J. (1999) Post-traumatic stress responses following liver transplantation in older children. Journal of Child Psychology and Psychiatry 40, 363–374. Webster, A. (2000) The facilitating role of the play specialist. Paediatric Nursing. 12, 24–27. Windsorova, D., Stewart, S.M., Lovitt, R., Waller, D. & Andrews, W.S. (1991) Emotional adaptation in children after liver transplantation. Journal of Pediatrics 119, 880–887. Zitelli, B., Malatack, J.J., Gartner, C., Urbach, A.H., Williams, L. & Miller, J.W. (1986) Evaluation of the paediatric patient for liver transplantation. Pediatrics 78, 559–565. Zitelli, B., Miller, J., Gartner, C. et al. (1988) Changes in lifestyle after liver transplantation. Pediatrics 82, 173–180.

Chapter 2: Useful Investigations in the Assessment of Liver Disease DEIRDRE A. KELLY

Biochemical liver function tests, 17 Baseline investigations, 17 Second-line investigations, 17 Radiology, 19 X-rays, 20 Ultrasound, 20 Radioisotope scanning, 20 Computed topography (CT), 20 Endoscopic retrograde cholangiopancreatography (ERCP), 20

Endoscopic ultrasound, 21 Percutaneous transhepatic cholangiography (PTC), 21 Angiography, 21 Splenoportography, 21 Magnetic resonance imaging (MRI), 21 Histopathology, 21 Complications of percutaneous liver biopsy, 22

The investigation of the liver relies on a multidisciplinary approach involving clinical chemistry, haematology, radiology, histopathology and microbiology. It is essential to understand the many functions of the liver and to recognize the effects of hepatic dysfunction on other body systems (Table 2.1).

Biochemical liver function tests Baseline investigations Biochemical liver function tests (Table 2.2) reflect the severity of hepatic dysfunction but rarely provide diagnostic information on individual diseases. Conjugated bilirubin is nearly always elevated in liver disease and is a particularly important investigation in the differential diagnosis of neonatal jaundice (Chapter 4). The presence of bilirubin is always abnormal if detected in a fresh urine specimen. Aminotransferases are intracellular enzymes, which are mostly present in liver, heart and skeletal muscle. Increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) indicate hepatic necrosis irrespective of aetiology (Table 2.2). ALT is more liver specific than AST but has a longer plasma half-life. Arise in AST is an early indication of liver damage and is a useful marker of rejection post-liver transplant (Chapter 20). These enzymes may be normal in compensated cirrhosis. Alkaline phosphatase is found in liver, kidney, bone, placenta and intestine. In paediatric liver disease, increases in this enzyme indicate biliary epithelial damage, malignant infiltration, cirrhosis, rejection or osteopenia secondary to vitamin D deficiency. Gamma-glutamyl

Metabolic investigations, 23 Bone marrow aspiration, 23 Skin biopsy, 23 Genetic tests (chromosome and DNA), 23 Endoscopy, 23 Neurophysiology, 23 Ophthalmology, 23 Molecular biology, 23

transpeptidase (GGT) is present in biliary epithelia and hepatocytes. The reference range is age related, with higher levels in neonates. It is elevated in many forms of liver damage, but may be normal in certain forms of intrahepatic cholestasis (e.g. familial intrahepatic cholestasis 1 and 2, Chapter 4). The most useful tests of liver ‘function’ are plasma albumin concentration and coagulation time. Low serum albumin indicates chronicity of liver disease, while abnormal coagulation indicates significant hepatic dysfunction, either acute or chronic. Fasting hypoglycaemia in the absence of other causes (e.g. hypopituitarism or hyperinsulinism) indicates poor hepatic function and is a guide to prognosis in acute liver failure. If these baseline investigations suggest hepatic dysfunction, then more specific investigations for metabolic disease are appropriate to consider (Kelly & Green 1991; Kelly & Hull 1991; McKiernan 2001) (Table 2.3). Second-line investigations (Table 2.3) Hepatic dysfunction may be secondary to sepsis, particularly urinary sepsis, inborn errors of metabolism or endocrine disorders. It is usual to exclude sepsis by performing bacterial culture of the urine, and/or blood cultures if appropriate, and to exclude known causes of viral hepatitis. If the infant is unwell, or has evidence of acute liver failure, then galactosaemia and tyrosinaemia should be excluded (Chapter 5). In neonates, hypopituitarism may be difficult to exclude as thyroid function tests may be equivocal or in the low normal range. It is useful to perform a 09.00 h

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Section 2: Investigating the Liver

Table 2.1 Functions of the liver Function Metabolism/storage Carbohydrate/glycogen Lipid

Protein

Synthesis Albumin Factors II, VII, IX, X Degradation Drugs Oestrogens Toxic products Bile synthesis and excretion

Effect of dysfunction

Assessment

Loss of glucose homeostasis Lipid accumulation in hepatocytes ØOxidation of fatty acids

Hypoglycaemia on fasting/stress High/low cholesterol ≠Lactate ≠Ratio FFA:BOH ≠Acyl carnitine Organic aciduria Low BCAA, urea ≠Ammonia ≠Tyr, -Phe, -Met

≠Catabolism

Loss of muscle mass Coagulopathy Prolonged drug effect, e.g. sedation Telangiectasia Gynaecomastia Encephalopathy Cholestasis Fat malabsorption Fat-soluble vitamin deficiency Pruritus Malnutrition

Low albumin Protein energy malnutrition Prolonged PT/PTT Clinical Clinical Abnormal EEG/clinical signs ≠Conjugated bilirubin ≠GGT ≠ALP ≠cholesterol Anthropometry

ALP, Alkaline phosphatase; BOH, beta-hydroxybutyrate; BCAA, branched chain amino acids; EEG, electroencephalogram; FFA, free fatty acids; GGT, gamma-glutamyl transpeptidase; Met, methionine; Phe, phenylalanine; PT, prothrombin time; PTT, partial thromboplastin time; Tyr, tyrosine.

Table 2.2 Liver function tests Reference range of test

Abnormality

Conjugated bilirubin < 20 mmol/l

Elevated: hepatocyte dysfunction or biliary obstruction

Aminotransferases Aspartate (AST) < 50 U/l Alanine (ALT) < 40 U/l

Elevated: hepatocyte inflammation/damage

Alkaline phosphatase (ALP) < 600 U/l (age dependent)

Elevated: biliary inflammation/obstruction

Gamma-glutamyltransferase (GGT) < 30 U/l (age dependent) Albumin 35–50 g/l

Reduced: chronic liver disease

Prothrombin time (PT) 12–15 s Partial thromboplastin time (PTT) 33–37 s

Prolonged: (i) Vitamin K deficiency (ii) Reduced hepatic synthesis

Ammonia < 50 mmol/l

Elevated: abnormal protein catabolism/urea cycle defect/other inherited metabolic disease

Glucose > 4 mmol/l

Reduced in: acute or chronic liver failure/metabolic disease/hypopituitarism

Chapter 2: Useful Investigations Table 2.3 Investigation of liver disease Baseline investigations

Bilirubin: Conjugated Unconjugated Aspartate aminotransferase Alanine aminotransferase Alkaline phosphatase Gamma-glutamyl transpeptidase Albumin Glucose Full blood count and platelets Prothrombin time Partial thromboplastin time

Second-line investigations

Bacterial culture of blood and urine TORCH screen Hepatitis A, B, C a1-Antitrypsin level and phenotype Abdominal ultrasound

Metabolic investigations

Immunoreactive trypsin Plasma lactate, BOH, FFA Ammonia Acyl carnitine Se iron and ferritin Plasma amino acids Cholesterol, triglyceride Urine: Reducing sugars, organic acids, amino acids, succinylacetone, bile salts

Neonate

Galactose 1-phosphate uridyl transferase Free T4, TSH 09.00 h cortisol Chromosomes/DNA Sweat test (> 4 weeks)

Older child (> 2 years)

Cu, caeruloplasmin, urinary Cu C3, C4, ANF, SMA, LKM Immunoglobulins EBV

If indicated

Radioisotope scan Liver biopsy for: Histology Electron microscopy Enzyme analysis Immunohistochemistry Culture Bone marrow aspirate Endoscopy ERCP PTC MRI

ANF, Antinuclear factor; BOH, b-hydroxybutyrate; C3, C4, complement components 3 and 4; DNA, deoxyribonucleic acid; ERCP, endoscopic retrograde cholangiopancreatography; FFA, free fatty acids; LKM, liver/kidney microsomal antibodies; MRI, magnetic resonance imaging; PTC, percutaneous transhepatic cholangiography; SMA, smooth muscle antibodies; T4, thyroxine; TORCH, toxoplasma, rubella, cytomegalovirus, herpes simplex; TSH, thyroid-stimulating hormone.

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cortisol level at the same time as measuring free thyroxine and thyroid stimulating hormone (TSH) (Spray et al. 2000). a1-Antitrypsin deficiency is the commonest inherited metabolic liver disease and should always be excluded at any age. As a1-antitrypsin is an acute-phase protein, it is necessary to measure both concentration and phenotype in order to differentiate between homozygotes, heterozygotes and an acute-phase response. Although cystic fibrosis is a rare cause of liver disease in the neonatal period, it should be considered in the differential diagnosis of neonatal liver disease, and excluded by performing an immunoreactive trypsin test, a sweat test and mutation analysis if either are positive (Chapter 11). Wilson’s disease rarely presents before the age of 3 years, but may mimic any form of liver disease and should always be excluded in older children (Chapter 13). An autoimmune screen and immunoglobulin levels should detect 75% of children with autoimmune hepatitis (Chapter 8). The development of new technology, such as fast atom bombardment mass spectrometry and tandem mass spectrometry, has permitted the identification of specific metabolites in the urine and blood in a number of rare diseases, e.g. primary bile salt deficiencies (Chapter 4). Other specific tests include measurement of carnitine and acyl carnitine in fatty acid oxidation disorders (Chapter 5). These investigations are essential steps in the differential diagnosis of unresolved neonatal hepatitis. Serum cholesterol is usually elevated in children with severe cholestasis, for example in Alagille’s syndrome or biliary atresia, and provides supporting evidence of these diagnoses. In contrast, low or normal cholesterol is characteristic of bile acid transport disorders, or of terminal liver disease (Chapters 4 and 20). Plasma ammonia and amino acids (particularly phenylalanine, tyrosine and methionine) may be raised in either acute or chronic liver failure and are non-specific indications of hepatic dysfunction. An elevated plasma or urine tyrosine may indicate tyrosinaemia type I, which should be confirmed by measurement of urinary succinylacetone. Definitive diagnosis requires assay of fumarylacetoacetase in skin fibroblasts or mutation analysis (Chapter 5). Primitive hepatic cells synthesize a-fetoprotein. The levels are highest in the newborn (> 1000 mg/l) and fall in the first few months of life. It may be a useful screening test in the diagnosis of tyrosinaemia type I and hepatoblastoma, or for detection of hepatocellular carcinoma in chronic carriers of hepatitis B and C.

Radiology Several radiological techniques provide valuable information in the investigation and diagnosis of paediatric liver disease, while the rapid development of interven-

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Section 2: Investigating the Liver

tional radiology (Chapter 3) has altered the management of many hepatic complications (Saini 1997). X-rays Plain X-ray of the abdomen will give an indication of liver and spleen size but is rarely of diagnostic value and is not a routine investigation. Chest X-ray may show skeletal abnormalities, for example, butterfly vertebrae in Alagille’s syndrome, a dilated heart secondary to fluid overload in end-stage liver disease, or evidence of congenital heart disease. Wrist and knee X-rays will demonstrate bone age and/or the development of osteopenia or rickets.

of biliary excretion in the differential diagnosis of neonatal cholestasis. Under normal conditions biliary excretion is completed within 4 h. Delayed excretion or no excretion after 24 h suggests severe intrahepatic cholestasis or extrahepatic biliary atresia. Delayed biliary excretion or pooling in bile ducts is also a feature of cystic fibrosis liver disease. Radioisotope scanning is of some value in the diagnosis of hepatic vein obstruction (Budd–Chiari syndrome) as poor uptake of isotope is demonstrated in most of the liver except for the caudate lobe, which has a separate venous drainage. It is rarely used now because ultrasound or venography are preferred. Computed tomography (CT)

Ultrasound The development of Doppler ultrasound has been an important advance in the investigation of liver disease. Ultrasonic investigation of the abdomen provides information on the size and consistency of the liver, spleen, pancreas and kidneys, on the size of the gall bladder and on the presence of gallstones. It may identify tumours, haemangiomas, abscesses or cysts within the liver, and allows targeting of lesions for liver biopsy. The gall bladder is best visualized after a 4–6-h fast. A small or absent gall bladder after fasting suggests either severe intrahepatic cholestasis or biliary atresia in the neonate, whereas an enlarged gall bladder may be supporting evidence of primary sclerosing cholangitis. Extrahepatic bile ducts are usually identified but intrahepatic bile ducts are rarely seen unless dilated, secondary to biliary obstruction. Dilated intrahepatic bile ducts are not a feature of extrahepatic biliary atresia in the neonate. Colour-flow Doppler techniques permit rapid evaluation of vascular patency without the use of intravenous contrast material. It is particularly useful in pre- and posttransplant examinations to identify whether the portal vein, hepatic veins and artery, and splenic vessels are patent. Portal hypertension is suggested by the presence of ascites, splenomegaly, and splenic or gastric varices. Radioisotope scanning The development of soluble radioisotopes, Technetium trimethyl 1-bromo imino diacetic acid (TEBIDA) which are taken up well by hepatocytes despite elevated bilirubin levels, have been utilized to demonstrate either hepatic uptake or biliary excretion. Pretreatment with phenobarbitone (5 mg/kg) for 3–5 days prior to the investigation improves hepatic uptake of the isotope. Hepatic uptake is an index of hepatic function and may be patchy in inflammatory conditions, e.g. neonatal hepatitis. Radioisotope scanning is most useful in the assessment

CT scanning of the liver is useful for the identification and biopsy of hepatic tumours or space-occupying lesions of the liver. Intravenous contrast medium causes enhancement of vascular lesions and the wall of abscesses, and may be helpful in differentiating tumours from other solid masses. An important recent advance is the introduction of helical or spiral CT scanning, in which both the table and the X-ray tube move continuously to improve imaging. The use of CT angiography allows non-invasive evaluation of vascular structures. CT scans of the brain are helpful for the detection of cerebral oedema in acute liver failure (Chapter 7) or for cerebral atrophy in certain metabolic conditions (Chapter 5). Endoscopic retrograde cholangiopancreatography (ERCP) In this endoscopic technique a fibreoptic duodenoscope is passed into the first part of the duodenum, the ampulla of Vater is identified, the pancreatic and biliary ducts are cannulated, and radiological contrast is injected. The technique has an 80% success rate in skilled hands and is invaluable for the assessment of extrahepatic biliary disease in older children (e.g. choledochal cysts, primary sclerosing cholangitis) or for the assessment of chronic pancreatitis. Although this technique should be of value in the differential diagnosis of neonatal cholestasis, technical difficulties in the cannulation of bile ducts in small infants may provide equivocal information. The development of a prototype fibreoptic duodenoscope (7.5 mm in diameter) has improved the diagnostic yield in this group of patients. The removal of common bile duct stones, insertion of biliary and pancreatic stents and sphincterotomy are useful therapeutic procedures which can be performed at the same time as the diagnostic procedure, but have limited application in childhood.

Chapter 2: Useful Investigations Endoscopic ultrasound (EUS) Endoscopic ultrasound is a new imaging modality, which visualizes the lower biliary tree. The technique uses mini probes (external diameter 2.6 mm), which are small enough to be passed via the operating channel of conventional paediatric duodenoscopes. The technique is well established in adult practice with a wide range of applications. It is a highly sensitive and specific method of visualizing the lower biliary tree and demonstrating pathology in this area (Scheiman et al. 2001). Although this technique has not yet been evaluated in paediatric practice, it may prove of value in the diagnosis of infants with neonatal cholestasis. Percutaneous transhepatic cholangiography (PTC) This technique is useful for the identification of biliary disease if intrahepatic bile ducts are dilated secondary to obstruction, and an ERCP is impossible or unsuccessful. A thin needle (Chiba) is passed through the liver. The bile ducts or gall bladder are punctured and radiological contrast is injected. External drainage of the biliary tree, dilatation of biliary strictures and the insertion of biliary stents are all possible using this technique. Angiography Visualization of the coeliac access, and hepatic and splenic blood vessels, is obtained by femoral artery catheterization and injection of radiological contrast. This technique has two parts: (i) the arterial phase, which provides information on the coeliac axis, hepatic and splenic artery abnormalities, vascularization and anatomy of hepatic tumours, hepatic haemangiomas or detection of hepatic artery thrombosis; and (ii) the venous phase, which provides information about the patency of the portal, splenic and superior mesenteric veins and the presence of portal hypertension by identification of mesenteric, oesophageal or gastric varices. In skilled hands the investigation can be performed in infants with little risk. Femoral artery spasm or thrombosis is an occasional side-effect, but rarely requires operative treatment. Hepatic artery embolization is now indicated for the treatment of hepatic haemangiomas or in the control of liver haemorrhage from trauma or needle biopsy. Angioplasty for portal or hepatic vein obstruction is also feasible using angiographic techniques. Splenoportography This technique, in which the splenic and portal veins are visualized by the injection of radiological contrast into the spleen, has largely been replaced by hepatic angiography. It may be useful for measuring splenic pulse pres-

21

sures in the evaluation of portal hypertension but carries a small risk of splenic rupture. Magnetic resonance imaging (MRI) MRI scanning has now replaced hepatic angiography as the best way to stage or diagnose hepatic tumours and identify their vascular supply. It may provide valuable information about liver or brain consistency and storage of heavy metals, for example iron in haemochromatosis, and copper in Wilson’s disease and cerebral oedema in acute liver failure. The recent development of MRI cholangiography, in which both intra- and extrahepatic biliary duct abnormalities may be detected, may replace ERCP as a diagnostic investigation (Bearcroft & Lomas 1997). ERCP or PTC will still be required for therapeutic procedures.

Histopathology The diagnosis of most liver diseases requires histological confirmation, thus liver biopsies are a routine procedure in specialist centres. An aspiration technique, using a Mengini needle (or disposable variant), has a complication risk of 1 : 1000 liver biopsies and may be performed under sedation with local anaesthesia. In fibrotic or cirrhotic livers, a Tru-cut needle, which removes a larger core, may be necessary. Transjugular liver biopsies, in which the liver is biopsied through a special catheter passed from the internal jugular vein into the hepatic veins, is now possible for children as small as 6 kg and is the only safe way to perform a biopsy if coagulation times remain abnormal despite support (prothrombin time (PT) > 5 s prolonged over control value) (Furuya et al. 1992) (Chapter 3). The complications of this potentially dangerous procedure (see below) are much reduced if performed in expert hands in specialized units under controlled conditions (Cohen et al. 1992) (Table 2.4). It is essential to have information about liver size and consistency, and the presence of cysts or dilated bile ducts from ultrasound, and if necessary to have a ‘spot’ marked on the abdomen to ensure an accurate biopsy. Correct information about coagulation parameters is vital. Prothrombin time should be within 3 s of control values; platelet count should be > 60 000 m/l ¥ 109/l. The patient’s blood group should be known and it is prudent to crossmatch a unit of blood prior to the procedure. Biopsy specimens should be obtained for routine histopathology, microbiology, electron microscopy, immunohistochemistry, and copper (if appropriate), and snap frozen in liquid nitrogen for enzymatic or metabolic investigations. The interpretation of the histology may be difficult and requires considerable specialist expertise. It is possible to carry out a liver biopsy as a day case procedure in low-risk patients (Vivas et al. 1998) as follows:

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Section 2: Investigating the Liver

Table 2.4 Liver biopsy protocol Establish blood group and save serum for crossmatch Coagulation: prothrombin (PT, normal 12–15 s), partial thromboplastin (PTT, normal 33–37 s) Broad-spectrum antibiotics may be required if cardiac problems or concurrent dental extraction Coagulation support PT: < 3 s prolonged > 3–6 s prolonged > 7 s prolonged FBC and platelets Platelet count: > 80 m/l ¥ 109/l 40–80 m/l ¥ 109/l < 40 m/l Haemoglobin: < 8.0 g/l

No action 15 ml/kg FFP over 2.5 h Correct with FFP; recheck PT/PTT at 1 h Reassess risk/benefit if no correction

No action 10 ml/kg platelet infusion over 1 h 10 ml/kg platelet infusion, recheck Reassess risk/benefit if correction > 80 is impossible Transfuse to Hb > 10 g/l prebiopsy

Procedure and sedation Establish size of liver: +/– mark site by ultrasound Apply local anaesthetic cream to area of maximal dullness between 7th and 9th intercostal space (or ultrasound site) Oral midazolam 2.5 mg < 1 year old 5 mg > 1 year old or Chloral hydrate 75 mg/kg Local anaesthetic Lignocaine 1–2% i.v. sedation Pethidine 1–2 mg/kg Midazolam 0.1–0.75 mg/kg Post-biopsy observations Blood pressure, pulse, respiration and temperature 15 min for 2 h 30 min for 2 h Hourly for 2 h 4-hourly as required Chest X-ray/abdominal ultrasound may be required if bleeding is suspected

• > 1 year old • bilirubin < 200 mmol/l • no other organ dysfunction • no need for coagulation or platelet support • access to emergency facilities for 24 h post procedure. Liver biopsy is contraindicated in the following circumstances: • abnormal coagulation parameters or thrombocytopenia (Table 2.4) • presence of grossly dilated bile ducts or large cysts • angiomatous malformation of the liver • extensive ascites. Under these circumstances, image-guided or transjugular liver biopsies should be performed if the diagnosis will change management (Chapter 3). Complications of percutaneous liver biopsy • The main complication is bleeding and most deaths following a liver biopsy are due to intractable bleeding. However, subclinical bleeding (as evident on ultrasound imaging) is common and intrahepatic and subcapsular

haematomas with no haemodynamic compromise are seen in up to 23% of patients (Minuk et al. 1987; McGill et al. 1990; Sugano et al. 1991). Significant non-fatal bleeding (as seen with evidence of active bleeding, shock and a haemoglobin drop of 2.0 g/l) occurs more frequently in children than adults. In adults significant haemorrhage occurs in 0.3–0.5% of cases whilst bleeding requiring transfusion is seen in up to 2.8% of children (Cohen et al. 1992). Evidence of persistent bleeding following liver biopsy despite medical support and blood transfusion warrants urgent hepatic angiography and embolization (Chapter 3) or surgery. • Pneumothorax or haemopneumothorax which are treated in a standard way. • Infection (particularly if the biopsy is combined with another procedure, e.g. dental extraction). • Perforation of the gall bladder or bile ducts leading to biliary peritonitis and the need for emergency surgery. Adequate monitoring of vital signs post biopsy is essential to detect complications such as haemorrhage or infection (Piccinino et al. 1986; Gonzalez-Vallina et al. 1993) (Table 2.4).

Chapter 2: Useful Investigations

23

Metabolic investigations

Ophthalmology

Many inborn errors of metabolism present with hepatomegaly and/or liver disease. It is essential to screen for these diseases as part of the investigation of liver disease in neonates (Table 2.3) and in older children (Chapter 12).

A number of inherited conditions have associated visual lesions, for example Kayser–Fleischer rings in Wilson’s disease, posterior embryotoxin or optic drusen in Alagille’s syndrome, and cherry-red spot in Niemann– Pick type A. Thus ophthalmological examination may provide valuable diagnostic information and should be part of the assessment process.

Bone marrow aspiration Bone marrow aspiration should be performed in infants with undiagnosed neonatal hepatitis with both hepatomegaly and splenomegaly in order to exclude Niemann–Pick type C or familial haemophagocytosis (Chapters 4 and 5) or at any age if a storage disorder is suspected. Skin biopsy This procedure should be performed if an inborn error of metabolism is being considered (e.g. Niemann–Pick type A, B or C, or tyrosinaemia type I) and the specimen stored frozen for future culture. It may also be necessary to obtain skin biopsies from parents or siblings. Genetic tests (chromosome and DNA) With the rapid development of molecular techniques for diagnosis and detection of genetic diseases, samples for DNA analysis and/or chromosomes from both child and parent is essential.

Endoscopy Upper gastrointestinal endoscopy (gastroscopy) using a flexible fibreoptic endoscope is now the best way to diagnose peptic ulcer disease or oesophageal and gastric varices secondary to portal hypertension. The technique is normally performed under sedation or general anaesthetic. In children with haematemesis, gastroscopy not only provides rapid diagnosis but enables therapy with variceal banding or endoscopic sclerotherapy for bleeding varices or injection of bleeding ulcers with adrenaline or thrombin to be performed.

Neurophysiology Electroencephalography is mostly used in the assessment of hepatic encephalopathy. It will identify abnormal rhythms secondary to encephalopathy due to either acute or chronic liver failure. CT or MRI scans of the brain (see above) may identify cerebral oedema, infarction or haemorrhage.

Molecular biology The development of molecular biology has revolutionized methodology for many complex diagnostic procedures, transforming many techniques into routine laboratory procedures (Worman 1997). Progress in identifying specific genes and DNA sequencing has made possible the diagnosis of many inborn errors of metabolism and inherited disease (e.g. Alagille’s syndrome, Wilson’s disease, tyrosinaemia type I) and led to the identification of mitochondrial disorders. Advances in methodology for gene cloning and molecular cloning methods have been helpful in identifying viruses such as hepatitis C and G, while the polymerase chain reaction has been used to diagnose active infection and monitor patients with many different viral diseases, such as hepatitis C, cytomegalovirus (CMV), and Epstein–Barr virus (EBV). Diagnosis for autoimmune disorders has improved, with specific assays that use recombinant protein antigens (e.g. antinuclear antigens and liver kidney microsome antibodies). The rapid development of molecular techniques is certain to lead to further improvements in diagnostic methods and to a better understanding of paediatric liver disease.

References Bearcroft, P.W. & Lomas, D.J. (1997) Magnetic resonance cholangiopancreatography. Gut 41, 135–137. Cohen, M.B., A-Kader, H.H., Lambers, D. & Heubi, J.E. (1992) Complications of percutaneous liver biopsy in children. Gastroenterology 102, 629–632. Furuya, K.N., Burrows, P.E., Phillips, M.J. & Roberts, E.A. (1992) Transjugular liver biopsy in children. Hepatology 15, 1036–1042. Gonzalez-Vallina, R., Alonso, E.M., Rand, E., Black, D.D. & Whitington, P.J. (1993) Outpatient percutaneous liver biopsy in children. Journal of Pediatric Gastroenterology 17, 370–375. Kelly, D.A. & Green, A. (1991) Investigation of paediatric liver disease. Journal of Inherited Metabolic Disease 14, 531. Kelly, D.A. & Hull, J. (1991) Investigation of prolonged neonatal jaundice. Current Paediatrics 1, 228–230. McGill, D.B., Rakela, J., Zinsmeister, A.R. & Ott, B.J. (1990) A 21year experience with major haemorrhage after percutaneous liver biopsy. Gastroenterology 99, 1396–1400.

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Minuk, G.Y., Sutherland, L.R., Wiseman, D.A., MacDonald, F.R. & Ding, D.L. (1987) Prospective study of the incidence of ultrasound-detected intrahepatic and subcapsular haematomas in patients randomized to 6 or 24 h of bed rest after percutaneous liver biopsy. Gastroenterology 92, 290–293. McKiernan, P.J. (2001) The infant with prolonged jaundice: investigation and management. Current Paediatrics 11, 83–89. Piccinino, F., Sagnelli, E., Pasquale, G. & Guisti, G. (1986) Complications following percutaneous liver biopsy. Journal of Hepatology 2, 165–173. Saini, S. (1997) Imaging of the hepatobiliary tract. New England Journal of Medicine 336, 1889–1894. Scheiman, J.M., Carlos, R.C., Barnett, J.L. etal. (2001) Can endoscopic ultrasound or magnetic resonance cholangiopancreatography replace ERCP in patients with suspected biliary disease? A prospective trial and cost analysis. American Journal of Gastroenterology 96, 2900–2904. Scheimann, A.O., Barrios, J.M., Al-Tawil, Y.S., Gray, K.M. &

Gilger, M.A. (2000) Percutaneous liver biopsy in children: impact of ultrasonography and spring-loaded biopsy needles. Journal of Pediatric Gastroenterology and Nutrition 31, 536–539. Spray, C.H., McKiernan, P., Waldron, K.E., Shaw, N., Kirk, J., Kelly, D.A. (2000) Investigation and outcome of neonatal hepatitis in infants with hypopituitarism. Acta Paediatrica 89, 951–954. Sugano, S., Sumino, Y., Hatori, T., Mizugami, H., Kawafune, T., Abei, T. (1991) Incidence of ultrasound-detected intrahepatic haematomas due to tru-cut needle liver biopsy. Digestive Diseases and Sciences 36, 1229–1233. Vivas, S., Palacio, M.A., Rodriguez, M. etal. (1998) Ambulatory liver biopsy: complications and evolution in 264 cases. Revista Espanola de Enferedades Digestivas 90, 175–182. Worman, H.J. (1997) Molecular biological methods in diagnosis and treatment of liver diseases. Clinical Chemistry 43, 1476–1486.

Chapter 3: Interventional Radiology and Invasive Diagnostic Imaging PHILIP JOHN

Introduction, 25 Diagnostic imaging, 25 Catheter angiography, 25 Procedure for catheterization, 25 Interventional catheterization, 26 Embolization, 26 Thrombolysis, 26 Complications of arterial and venous catheterization, 27

Image-guided liver biopsy, 27 Cholangiography and percutaneous biliary techniques, 28 Aspiration and drainage of fluid collections and abscesses, 29 Congenital vascular anomalies and acquired disorders of the hepatic vasculature, 29 Intractable gastrointestinal bleeding, 30

Variceal bleeding, 30 Gastrointestinal bleeding, 30 Central venous access and related venous occlusive disease, 31 Interventional radiological management of complications following liver transplantation, 31 Vascular problems, 31 Biliary problems, 31

Introduction

Catheter angiography

Interventional radiology has an important role in the modern management of hepatobiliary disorders and provides new treatment options. ‘Key- or pin-hole’ techniques using catheter-based technology carried out under image guidance with X-ray (including computed tomography), ultrasound or magnetic resonance imaging form the basis of interventional radiology and invasive diagnostic imaging.

Although MRI angiography is the technique of choice, conventional catheter angiography may also be required as there are specific limitations with MRI (Gehrke et·al. 2000). Catheter angiography is primarily undertaken in infants and children with the following disorders: 1 Primary hepatic tumours for which complex surgical resection is being considered, e.g. in autotransplantation (Plate 78, Atlas: p. 468). 2 Cavernous transformation of the portal vein (also known as extrahepatic portal vein obstruction) prior to surgical shunting. 3 Portal vein thrombosis in patients being considered for liver transplantation. 4 If intervention is being considered for vascular stenoses or occlusion of the hepatic artery, vein, portal vein or inferior vena cava following liver transplantation or in the Budd–Chiari syndrome. 5 Hepatic vascular anomalies such as life-threatening haemangiomas (Plate 34, Atlas: p. 451), arterioportal fistulae (Plate 73, p. 465), arteriovenous malformations and congenital porto-systemic shunts. 6 Refractory or life-threatening bleeding from gastrointestinal disease or following blunt abdominal trauma or liver biopsy. 7 Invasive diagnostic imaging when angiography is required as part of the procedure such as transvenous (transjugular) liver biopsy, portal vein sampling and arterially stimulated hepatic vein sampling.

Diagnostic imaging The hepatic vasculature may be assessed using either conventional catheter angiography or with non-invasive techniques such as Doppler ultrasound, computed tomography (CT) and magnetic resonance (MR) imaging. MR angiography provides an excellent non-invasive evaluation of hepatic vasculature using different MR angiographic techniques such as the ‘T1-weighted 3D contrast enhanced spoiled gradient-echo pulse sequence’ (Leyendecker et·al. 1997; Lam et·al. 1998; Shirkoda et·al. 1998; Teo et·al. 1999). This is a useful angiographic sequence that can be used throughout infancy and childhood providing excellent arterial and venous phase imaging. Imaging of the hepatic vasculature is required for: • staging and diagnosis of hepatic tumours and planning surgery (Plate 76, Atlas: p. 467) • visualization of hepatic vessels pre- and post-liver transplantation • confirmation of extrahepatic vein obstruction (portal cavernoma) • confirmation of Budd–Chiari syndrome inferior vena cava (IVC) web or obstruction (Plate 74, Atlas: p. 466).

Procedure for catheterization The femoral artery (normally 2 mm in diameter in a term infant) is a common route for arterial access although

25

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Section 2: Investigating the Liver

other vessels, e.g. the brachial artery, can be safely used if the femoral arteries are extremely small secondary to significant shunting through hepatic vascular anomalies. The internal jugular and femoral veins are common routes for venous access. Ultrasound guidance (with up to 10-MHz transducers) helps accurate catheterization and avoids unnecessary ‘cut down’ techniques when vascular access is difficult. For minimizing catheterization times and utilizing small catheters see Freed et·al. 1974; Burrows et·al. 1990 and Young et·al. 2002. A small catheter, e.g. 3 French size (equivalent to 1 mm) outer diameter should be used in babies. Much skill is needed to prevent trauma, spasm or thrombosis during arterial catheterization. Femoral artery thrombosis is a significant risk in infants < 10 kg body weight and should be prevented by appropriate heparinization (unless clotting is deranged). Preservation of vascular access for potential intervention is vital and diagnostic catheter angiography should only be considered when other non-invasive imaging is unable to provide vital information. • General anaesthesia is invariably required. The patient should be prepared as for liver biopsy (see Chapter 2, Table 2.4). Blood should be crossmatched and platelets available for use during and after the procedure. Preventative measure to minimize body heat loss (with Bair Huggers and plastic truncal wrapping) and to minimize pressure injuries (with skin padding) are essential. An indwelling urinary bladder catheter is helpful during long procedures. Fluid and contrast medium volumes are carefully monitored and intravascular iodinated contrast, e.g. Iopamidol 370 (with 370 mg iodine/ml) is restricted to approximately 6 ml/kg at any one session. Interventional catheterization Catheter-delivered techniques enable minimally invasive endovascular procedures to be carried out. Revascularization and devascularization procedures can provide alternatives to invasive vascular surgery for certain conditions. These techniques include: Angioplasty Angioplasty is a technique used to dilate vascular stenoses, usually after liver transplantation (Funaki et·al. 1997; Funaki et al. 2000). Aballoon catheter is inflated temporarily over a guide wire in order to dilate the vessel, but is only successful if the guide wire can traverse the stenosis or if an adequate lumen can be maintained. Stenosis recurrence in the first 24 h after angioplasty is usually due to thrombosis or intimal dissection and repeat angiography is required. Repeated angioplasty may be required if the stenosis recurs or the disease progresses, e.g. the Budd–Chiari syndrome (Plate 74, Atlas: p. 466).

Stent placement A stent is a hollow metal mesh-like tube delivered through a catheter to maintain patency of a blood vessel or transparenchymal liver tract as in TIPS (transjugular intrahepatic porto-systemic shunt) (Plate 486, Atlas: p. 457). A minimal stent diameter of 6 mm is required. Although experience of stents in children is limited, they have been used to create TIPS and after failure of balloon angioplasty (Peters et al. 2000; Lee et al. 2002a,b). Stent thrombosis may be due to low blood flow or small stent diameter and children require long-term antiplatelet/ anticoagulant. Embolization This procedure blocks the vascular bed and reduces the blood supply to organs and tissues. It is required for the management of: • vascular anomalies, e.g. congenital arterioportal fistulae with portal hypertension (Plate 73, Atlas: p. 465) • arteriovenous malformations • hepatic haemangiomas with refractory heart failure (Plate 34, Atlas: p. 451) • bleeding following hepatic trauma, e.g. post-liver biopsy (Mazoit et al. 1985; Fellows et al. 1991) • pre-operative treatment for hepatoblastomas (Tashjian et al. 2002). Common embolic materials include gelatin sponge for temporary vessel occlusion (used for post-biopsy bleeding) and polyvinyl alcohol particles, coils and tissue adhesive (isobutyl-cyanoacrylate) for permanent vessel occlusion. Complications include spillage of embolic material away from the target, right-to-left shunting across a patent foramen ovale in the neonate and lung intolerance to embolic materials with the development of fatal pulmonary hypertension. Thrombolysis Thrombolysis restores flow to occluded blood vessels. In children this is usually iatrogenic due to vascular catheter placement. Systemic administration of recombinant tissue-plasminogen activator (t-PA) (0.5 mg/kg/h for 6 h or by direct clot infusion using a low-dose regime) is now the preferred method and may be effective in up to 84% of femoral artery occlusions (Gupta et al. 2001; Levy et al. 1991). It is less effective in hepatic artery thrombosis postliver transplant and surgical re-exploration is required. Direct clot infusion of thrombolysis is a major undertaking as infants and young children require intensive care support with artificial ventilation to guarantee the targeted arterial delivery of thrombolytics and frequent angiographic monitoring to assess effective lysis.

Chapter 3: Interventional Radiology and Diagnostic Imaging Simultaneous intravenous unfractionated heparin at 20 U/kg/h is recommended. If plasminogen levels are low t-PA will be ineffective and fresh frozen plasma should be given (10–20 ml/kg). Complications of arterial and venous catheterization Complications include: • Arterial thrombosis which is treated by systemic anticoagulation such as intravenous heparin, warfarin or thrombolytics. • Arterial spasm usually resolves spontaneously following catheter and sheath removal. Intra-arterial isosorbide dinitrate (up to 3 mg/kg/dose) can be given as a vasodilator if it persists. 1% lignocaine hydrochloride infiltration into the soft tissues around the artery may reduce spasm. • Puncture site bleeding which usually resolves with pressure. • Limb ischaemia from vessel thrombosis and dissection. • Arterial rupture and haemorrhage may require surgical intervention and support. Following all arterial catheterizations, the child and the catheterized limb should be kept warm to maintain adequate perfusion. A 6-h observation period is recommended to observe limb pulses etc. and detect potential complications. Following venous catheterizations a minimum 2-h observation period is recommended.

Image-guided liver biopsy Image-guided liver biopsies are indicated for those children in whom a liver biopsy is required for diagnosis and management, but a percutaneous biopsy is either unsafe or difficult. The procedure may be performed using the percutaneous route (requiring either intravenous sedation or general anaesthesia) or the transvenous, i.e. transjugular route (requiring general anaesthesia) (Neuberger 1999). They can be safely performed as a day-case investigation (Neuberger 1999). Percutaneous biopsies Image-guided percutaneous biopsies are usually carried out using ultrasound, CT and MR (particularly when lesions cannot be identified on ultrasound). The indications for image-guided biopsy include: 1 To avoid intrahepatic structures, e.g. dilated bile ducts and cysts or extrahepatic structures, e.g. interposed bowel loops following liver transplantation with reduced-sized grafts. 2 To obtain adequate tissue when the liver is small or shrunken and difficult to assess clinically. 3 Post-liver transplantation when liver anatomy is variable, e.g. with reduced-sized grafts.

27

4 To target focal liver lesions and liver ‘nodules’. Preparation is as for closed percutaneous liver biopsy (Chapter 2, Table 2.4). Significant ascites should be drained before biopsy. Discussion with the pathologist to ensure that an adequate and appropriate sample is obtained is useful. It is important to select an appropriate needle size (e.g. 18 gauge) and plan the biopsy route. When a tumour biopsy is taken, it is important to avoid normal liver, as this will reduce the chance of tumour seeding and local recurrence. Ultrasound is used to monitor the infiltration of local anaesthetic into the soft tissues immediately prior to percutaneous biopsy to ensure that the liver capsule is not breached. Automated spring-loaded percutaneous needles give excellent cores (such as the 18-gauge percutaneous Bard ‘Angiomed’ needle). When multiple biopsies are required these can be obtained safely with a coaxial technique (Hoffer 2000). An outer 17-gauge guiding needle is placed percutaneously with image guidance into the liver. Tissue samples can be taken with an 18-gauge cutting needle passed through the outer needle. The advantage of this method is that several samples can be taken with only one capsule puncture. At the end of the procedure the biopsy tract can be easily sealed by injecting autologous blood clot or gelatin sponge through the outer needle as it is withdrawn — the so called ‘plugged technique’ (Hoffer 2000). Image guidance allows a safe route into and through the liver avoiding vascular structures and bile ducts, which may reduce both the complications of a closed percutaneous biopsy and the potential mortality (Chapter 2). Although the mortality in adults is between 0.1 and 0.01% (Neuberger 1999), the rate may be higher in children. Major complications occur in up to 4.5% of children following non-image-guided percutaneous biopsy which include bleeding requiring transfusion, bile leakage, pneumothorax and prolonged drainage of ascites (Cohen et al. 1992). To date there are no available data in children comparing the complications of percutaneous biopsy with and without image guidance. However, in adults ultrasound-guided biopsies using automated needles are safer and more comfortable than ‘blind’ biopsy (Pasha et al. 1998; Farrell et al. 1999; Cadranel et al. 2000). Evidence of persistent bleeding following liver biopsy despite medical support and blood transfusion warrants urgent hepatic angiography and embolization. Transjugular biopsies A transvenous (transjugular) biopsy should be undertaken if there is a high risk of bleeding following percutaneous biopsy, e.g. uncorrectable coagulopathies, dysfunctional platelet abnormalities, significant ascites and following bone marrow transplantation (Ghaleb et al. 1999; Neuberger 1999; Hoffer 2000; Gehrke et al. 2001a).

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Section 2: Investigating the Liver

The procedure is a sterile technique, requiring general anaesthesia and imaging in an angiography suite. The internal jugular vein (usually the right) is accessed. The right/middle hepatic vein is catheterized and a guiding cannula (usually 7 French) is advanced through the right atrium and IVC into the hepatic vein. Venography and hepatic vein pressures are measured. The biopsy needle is advanced through the cannula into the liver and tissue obtained. Most biopsies can be performed with an automated 19-gauge spring-loaded needle. Aspiration type needles (19 and 16 gauge) with a different guiding cannula can be used as an alternative if required. Transjugular liver biopsies may be safely undertaken in infants of 3.5 kg body weight. Complications such as subclinical capsular perforation are reported in between 2.3 and 6.9% of cases.

Cholangiography and percutaneous biliary techniques There are several radiological methods available for evaluating the biliary tree. Non-invasive techniques such as ultrasound, CT, MR and nuclear medicine scans should always be considered before undertaking invasive cholangiographic techniques such as percutaneous transhepatic cholangiography (PTC) and endoscopic retrograde cholangiopancreatography (ERCP). The choice of technique depends on whether the investigation is for diagnosis, to assess function, e.g. biliary excretion, or whether intervention is required. It is essential to have an understanding of biliary anatomy of both the native and transplant liver (Huang et al. 1996; Yoshida et al. 1996; Cheng et al. 1997; Couinaud 1999; Mortelé et al. 2001). Ultrasound and MR are useful for diagnosis and have replaced many diagnostic PTC and ERCP investigations. MRCP (magnetic resonance cholangiopancreatography) specifically evaluates the biliary tree and pancreatic duct (Plate 266, Atlas: p. 448, Plate 386, Atlas: p. 453) (Acrement et al. 2001; Gehrke et al. 2001b; Norton et al. 2002). It is sensitive to bile and other fluids (e.g. in the duodenum) and provides cholangiographic and pancreatic duct images without intravenous contrast. Various MR sequences and short imaging acquisition times of 4 and 17 s using the Single Shot Turbo Spin Echo (SSTSE) thick slab and Half Acquisition Single Shot Turbo Spin Echo (HASTE) multiple thin slice techniques have been successful in all age groups. It is of value in the diagnosis of sclerosing cholangitis, biliary strictures, congenital biliary cystic malformations, intrahepatic calculi and pancreatitis. More recently, functional MRCP imaging with secretin can be undertaken (Manfredi et al. 2002; Vitellas et al. 2002). Both PTC (Plate 83, Atlas: p. 470) and ERCP (Plate 26a, Atlas: p. 448) can be used to define the level of obstruction in dilated bile ducts, determine the aetiology of cholangitis, and demonstrate bile duct leaks. They are required if intervention is being considered, e.g. in evaluating and

treating bile leaks or biliary and pancreatic duct strictures in order to carry out balloon dilatation of biliary strictures or placement of stents and drains. PTC is required following liver transplantation if there is a roux loop, as it does not permit endoscopic access. PTC, using a 22-gauge needle, is performed under general anaesthesia as a sterile procedure with antibiotic cover. Aright lateral approach is used for right duct punctures in native livers and whole liver grafts, an anterior approach for left duct punctures in native livers and whole liver grafts, and a right antero-lateral approach is used for reduced grafts, e.g. a segment 2,3 graft. Preparation is as described above (see Chapter 2, Table 2.4). The 22-gauge needle is passed through the liver parenchyma until an intrahepatic bile duct is punctured, a bile sample is obtained and then iodinated contrast, e.g. Iopamidol 200 (200 mg iodine/ml) is slowly injected outlining the biliary tree under fluoroscopic guidance. Iopamidol 370 (370 mg iodine/ml) may also be used but is less effective for identifying small filling defects in the biliary tree. The success rate is 90–99% for demonstrating dilated bile ducts and 65–75% if the intrahepatic ducts are not dilated (Ferrucci et al. 1977; Hardin et al. 1980). Ultrasound guidance is useful for needle placement into an appropriate duct, particularly when there are dilated ducts and reduces the number of passes. Complications include: • Sepsis, seen in up to 3% cases, is the most frequent significant complication. • Biliary peritonitis, seen in up to 0.6% cases, is usually due to inadvertent puncture of the extrahepatic bile duct/gall bladder. Most patients with bile leakage after PTC remain asymptomatic without biliary peritonitis (Hardin et al. 1980). If there is significant biliary obstruction with dilated intrahepatic ducts the risk of biliary leakage and peritonitis increases to 38% (Nilsson et al. 1983). In this situation an external biliary drainage catheter should be placed at the time of PTC to reduce this complication. • Intraperitoneal haemorrhage following PTC occurs in up to 0.6% of cases with no reported deaths when using a 22-gauge needle (Ariyama et al. 1978). It is interesting that increasing the number of transhepatic passes with a 22gauge needle is not associated with an increase in serious complications. In adult practice there is 3% morbidity and 0.1% mortality from PTC (Hardin et al. 1980). An observation period of up to 6 h is recommended following PTC provided the procedure and post-procedural period are uneventful. A percutaneous cholecystogram, i.e. puncturing the gall bladder and injecting iodinated contrast, is an alternative to PTC if it is difficult to puncture non-dilated intrahepatic ducts, particularly in the neonate. It can be undertaken safely provided the needle is 22-gauge and passes through liver parenchyma before entering the gall bladder to minimize the risk of biliary leakage. This

Chapter 3: Interventional Radiology and Diagnostic Imaging approach may also be used to perform biliary lavage for neonatal cholelithiasis (Pariente et al. 1989). Percutaneous cholecystostomy can be undertaken in those rare cases with unremitting acute calculous or acalculous cholecystitis as a means of providing urgent gall bladder drainage before cholecystectomy (van Sonnenberg et al. 1992). Complications such as haemorrhage and bile leakage are reported in approximately 9% of cases (van Sonnenberg et al. 1992).

Aspiration and drainage of fluid collections and abscesses Aspiration and drainage of fluid collections and abscesses in the peritoneal cavity, liver, spleen, pancreas and retroperitoneum can be performed by percutaneous fine needle aspiration using a 22-gauge needle under image guidance (ultrasound or CT scan) in all age groups (Plate 20, Atlas: p. 445). Complicated fluid collections such as abscesses and pancreatic pseudocysts may require drainage over a period of time. Drainage of an abscess is necessary to control sepsis and prevent the long-term sequelae of chronic sepsis. Percutaneous drainage is performed in sterile conditions under sedation or general anaesthesia with image guidance, either ultrasound/CT or fluoroscopy. Local anaesthesia is used and a 6–14 French pigtail drain inserted and secured appropriately. Aggressive image-guided catheter management is the key to success in treating complicated collections and the catheter (or catheters) must be placed in optimum positions for successful drainage. Drains require constant attention and at least once daily drain evaluation is necessary. Minimal drainage (< 20 ml/24 h) with clinical improvement is the anticipated result within 24–48 h following drainage of uncomplicated abscesses. If the drainage catheter becomes blocked then catheter manipulation and clearing may be necessary. Arepeat ultrasound scan is useful in assessing progress. Continued drainage with clinical improvement usually indicates fistulous communication to the alimentary canal, bile duct, pancreatic duct, urinary tract or lymphatic system. It is important to remove the drains at the correct time. Small bore drains can be removed when there has been clinical improvement, adequate drainage of the collection with no residual cavity and minimal drain output (< 10 ml) over the previous 24-h period.

Congenital vascular anomalies and acquired disorders of the hepatic vasculature The radiologist plays a key role in the management of these rare disorders that may require repeated radiological intervention or combined radiological and surgical management.

29

Successful management of these congenital anomalies is based on a clear understanding of the lesions and their natural history. They include vascular tumours (i.e. haemangiomas which are benign endothelial cell tumours and their variants) and vascular malformations (Chapter 9). Vascular malformations are due to errors in vascular morphogenesis resulting in isolated channel anomalies (capillary/arterial/venous/lymphatic) or combined channel anomalies such as arteriovenous malformations and abnormal connections between vascular channels, e.g. arterioportal fistulae (Enjorlas & Mulliken 1998). They may be high-flow (arteriovenous) or slow-flow (venous) malformations. Approximately 10% of hepatic haemangiomas require specific treatment in infancy as they endanger life from associated cardiac failure and thrombocytopenia. Lesions can be multifocal (which often have consistent imaging appearances) or focal (which have a more variable picture). Infants with high-output cardiac failure presenting at birth tend to have focal lesions while those with mutifocal lesions may present up to several months of age. The angiographic appearance may be variable (Burrows et al. 2001; Kassarjian et al. 2002). It is important to evaluate fully the vascular geography of these lesions as they can be complex and derive an arterial supply from the internal mammary, the phrenic and the intercostal arteries as well as the hepatic artery (Plate 34, Atlas: p. 451). Catheter angiography is carried out in infants with heart failure prior to embolization. Embolization or surgery should be considered in infants requiring mechanical ventilatory support and those with refractory cardiac failure or failure to thrive despite medical support (Boon et al. 1996; Daller et al. 1999). Embolization may need to be repeated if cardiac failure is not controlled, and is not effective for those children with massive haemangiomata who are not in cardiac failure. Hepatic arteriovenous malformations (AVMs) are rare and like hepatic haemangiomata can present with neonatal cardiac failure. In older children or adults hepatic AVMs are found in patients with hereditary haemorrhagic telangiectasia (HHT) (Whiting et al. 2000). They can lead to cardiac failure, hepatic ischaemia and portal hypertension. An MR scan should be undertaken to distinguish a solitary haemangioma from an AVM. Embolization should be undertaken with caution as lesions are invariably diffuse and there is a significant risk of causing hepatic ischaemia and necrosis (Fellows et al. 1991). In the neonate, AVMs are best managed by embolization and surgical resection. Arterioportal fistula (APF) can be intra or extrahepatic and congenital or acquired. Most intrahepatic APF are isolated congenital anomalies and are found in HHT and Ehlers–Danlos syndrome, whilst diffuse APFs are seen in extrahepatic biliary atresia and cirrhosis. Penetrating or blunt trauma may also lead to APFs. The most important clinical manifestation of intrahepatic APF is portal hyper-

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Section 2: Investigating the Liver

tension. A small number of patients will present with high-output cardiac failure if the ductus venosus is patent. Acute closure of the ductus venosus has been implicated in fatal GI bleeding. Most APF have a large intrahepatic varix, which is part of the draining portal vein or a segment of the umbilical vein. The fistula may be a single AV connection or multiple connections with the same varix. These lesions should be treated as soon as they are diagnosed because they may damage the portal vein and bowel. Embolization followed by systemic heparinization to avoid portal vein thrombosis is the treatment of choice (Vauthey et al. 1997) (Plate 73, Atlas: p. 465). Acquired vascular abnormalities rarely present clinically and are often found on non-invasive imaging, e.g. on a liver ultrasound scan performed after a percutaneous liver biopsy. Arterial pseudoaneurysms and arteriovenous fistulae can follow both penetrating and blunt liver trauma and rarely require specific treatment. If lesions increase in size or rupture then urgent catheter embolization should be undertaken . In the Budd–Chiari syndrome, the obstruction to hepatic venous outflow (in native and grafted livers) usually involves the main hepatic veins or the suprahepatic inferior vena cava. The angiographic appearance is variable with coexistent critical stenoses and total occlusion of all hepatic veins. Catheter angiography is the best method to demonstrate the obstruction, measure pressure gradients and to treat. Balloon angioplasty is now recommended as the initial treatment of choice, but other endovascular techniques such as thrombolysis or stenting should be considered if balloon angioplasty fails (Zajko et al. 1989; Kohli et al. 1993; Frank et al. 1994; Xu et al. 1996).

Intractable gastrointestinal bleeding Variceal bleeding Life-threatening oesophageal and gastric variceal bleeding occurs with portal hypertension secondary to liver disease (Chapters 14 and 18). If the bleeding persists despite maximal medical and/or endoscopic therapy, a TIPS can be undertaken (Heyman et·al. 1997; Hackworth et al. 1998) (Plates 48b,c, Atlas: p. 457). A TIPS is a radiologically created intrahepatic porto-systemic shunt between the high-pressure portal vein and the lower pressure hepatic vein. Technological advancements have made this technique possible in paediatric practice (Steventon et al. 1997). The procedure, carried out under general anaesthesia, requires excellent angiographic guidance and is performed by catheterizing the hepatic vein (usually the right) from the internal jugular vein, cutting through the liver and placing a metallic stent between the hepatic and portal veins (usually the right). The stent will hold open the liver parenchyma creating a

shunt, which reduces the portal hypertension. During the procedure venography and venous pressure measurements are carried out and prophylactic antibiotics are given to prevent intrahepatic sepsis. Successful TIPS placements are more difficult in children (78%) than in adults (95%) but can be performed in children weighing 8.6 kg (John et al., presented at the British Society of Interventional meeting, November 1999). Technical failures are usually due to adverse vascular anatomy such as extensive portal vein thrombosis. Control of variceal bleeding is usual in most children following successful TIPS provided the porto-systemic gradient can be reduced to < 12 mmHg. In our own experience, it can stabilize the child by reducing the portal hypertension, halt the bleeding and act as a ‘bridge to transplantation’ by providing time for nutritional rehabilitation. In the emergency situation TIPS compares favorably with surgical shunting. In adults the 30-day mortality following urgent TIPS is 17% compared with surgical shunting of 40–100%, whilst the procedural related mortality for TIPS is < 2%. Early complications such as infection or abscess formation may require removal of the stent, while stent thrombosis is usually treatable. Late complications from shunt stenosis occur in 75% of adults is due to neointimal hyperplasia (NIH) which is seen venographically as narrowing of the shunt lumen. Newer stent designs may halt the development of NIH (Cejna et al. 2001). It is likely that most children with shunts for more than 1–2 years will require re-intervention. In our own experience, 100% 1-year primary assisted patency rate can be achieved with a 1-year primary patency rate of 38%. Follow-up with 6monthly ultrasound and yearly catheter venography is essential to monitor TIPS patency. Venographic evidence of shunt NIH should be treated (either by balloon angioplasty and/or repeat stent placement) before it becomes clinically evident. Gastrointestinal bleeding In children without portal hypertension, gastrointestinal bleeding may be due to peptic ulcer disease, vascular malformations, necrotizing inflammation of the colon or ileum or from surgical anastomoses (Meyerovitz 1984; Racadio et·al. 1999). The bleeding may be extensive and may not be visible endoscopically. Angiography may be useful for the diagnosis, but is only successful if bleeding is brisk (> 1 ml/min) (Meyerovitz et al. 1984). Catheter embolization and the delivery of pharmacological agents, e.g. vasoactive infusions, should be considered in children with persistent gastrointestinal haemorrhage, particularly if they are unstable and/or poor surgical candidates (Gomes et·al. 1986; Defreyne et al. 2001). Bleeding from the stomach, duodenum, liver and pancreas (where there are multiple arterial feeders) can be controlled by

Chapter 3: Interventional Radiology and Diagnostic Imaging catheter embolization using particulate emboli (e.g. autologous blood clot, absorbable gelatin sponge, polyvinyl alcohol particles or coils). Small and large bowel bleeding (where the blood supply is by single regional end-organ vessels with distal branches) can be managed by selective catheter delivery of vasoactive drugs (e.g. vasopressin/octreotide).

Central venous access and related venous occlusive disease Intensive treatment regimes, such as parenteral nutrition, require long-term central venous access, particularly in those undergoing small bowel or combined liver and small bowel transplantation. Interventional radiology is well suited to establishing and maintaining satisfactory central venous line (CVL) access and managing the complications in children of all ages. Radiological percutaneous placement of tunnelled CVL/Hickman lines is consistently more reliable than surgical placement resulting in decreased operative time, lower morbidity, better primary placement success and more accurate positioning (McBride et al. 1997). A radiological percutaneous approach supported by ultrasound and fluoroscopic guidance is ideal for placing subcutaneous venous access ports, haemodialysis lines, peripherally inserted central catheters (PICC) and percutaneous transcaval and transhepatic lines (Donaldson et al. 1995; Crowley et al. 1998; Sharif et al. 2002). General anaesthesia is required for placing tunnelled CVLs and subcutaneous ports and PICC lines in infants. A platelet count of >·75 000 and a prothrombin time 7% of birth weight), maternal diabetes mellitus, bruising, and induction of labour with oxytocin. The severity and duration of jaundice may be increased in infants born prematurely. Infants of Oriental, Inuit, or North American Indian extraction tend to have more severe jaundice, with as many as 24–54% developing serum bilirubin > 200 mmol/l. In general, physiological jaundice peaks on day 3 of life, although hyperbilirubinaemia may persist as long as 2 weeks. The mechanism(s) of such severe physiological jaundice remain uncertain, and while environmental factors cannot be entirely excluded, genetic control of bilirubin production and clearance appears to be most important (Kaplan et al. 2002b). There may be increased bilirubin load due to shortened red blood cell lifespan (Kaplan et al. 2002a), increased activity of the enterohepatic circulation, and inefficient uptake of bilirubin by hepatocytes due to relatively immature expression of ligandin, which mediates uptake of organic anions, in addition to immaturity of hepatic bilirubin glucuronosyl transferase. Infants who have abnormalities in the bilirubin glucuronosyl transferase which cause Gilbert’s syndrome (Burchell & Hume 1999) alone or in addition to glucose-6phosphatase dehydrogenase deficiency (Kaplan et al. 1997; Kaplan & Hammerman 1998) are at greater risk for severe physiological jaundice and breast-milk jaundice. Treatment Treatment may not be necessary in most cases. Phototherapy should be initiated for normal term infants only when serum total bilirubin is > 300 mmol/l. The decision is complex and depends not only on the bilirubin concentration and its rate of increase, but also on the weight and gestational age of the infant, postnatal age, the rate at which bilirubin is generated and the adequacy of bilirubin– albumin binding. Numerous clinical trials have demonstrated the effectiveness of phototherapy for decreasing unconjugated hyperbilirubinaemia (bilirubin > 300 mmol/l) in term infants (Tan 1975; Brown et al.

1985) and in premature babies with serum bilirubin > 200 mmol/l. Body temperature and fluid status must be monitored closely; fluid loss may be excessive, mainly because of increased insensible loss and additionally due to frequent watery stools. Eye patches are required. The baby may be more irritable, especially as normal parental interaction is often interrupted. For babies of ethnic extraction in whom severe unconjugated hyperbilirubinaemia may commonly occur even in the absence of haemolysis, exchange transfusion remains a viable therapy to prevent kernicterus (Yeung 1985), although tinprotoporphyrin treatment has also been used (Rubaltelli et al. 1989; Galbraith et al. 1992). Exchange transfusion may be required to prevent possible kernicterus in any baby with severe unconjugated hyperbilirubinaemia. Breast-milk jaundice Moderately severe unconjugated hyperbilirubinaemia associated with breast feeding is common, occurring in 0.5–2% of healthy newborn babies. Jaundice may develop after the fourth day of life (early pattern) or towards the end of the first week of life (late pattern) and usually peaks around the end of the second week of life. Jaundice may overlap with physiological jaundice or be protracted and last 1–2 months. The aetiology remains uncertain. Contamination of breast milk with steroids such as pregnanediols appears unlikely. Breast milk may contain endogenous substances, such as free fatty acids, which displace bilirubin in the intestinal contents and enhance the enterohepatic circulation of bilirubin, although increased free fatty acids were not found in freshly expressed breast milk from mothers of infants with breast-milk jaundice (Jalili et al. 1985). An alternative hypothesis is that breast milk contains b-glucuronidase, leading to deconjugation of glucuronide moieties from conjugated bilirubin and subsequent reabsorption of bilirubin (Gourley & Arend 1986). Breast-fed babies have less frequent stools and eliminate less bile in faeces than bottle-fed babies (De Carvalho et al. 1985), which may increase bilirubin reabsorption and contribute to hyperbilirubinaemia. More frequent breast feeding may enhance gut motility and stool output. The diagnosis is clinical: an exclusively breast-fed infant with unconjugated hyperbilirubinaemia, normal conjugated bilirubin, haemoglobin and reticulocyte counts, no maternal blood group incompatibility, and a normal physical examination except for jaundice. The diagnosis is supported by a drop in serum bilirubin (≥ 50% in 1–3 days) if breast feeding is interrupted for 48 h (Lascari 1986). Breast-milk jaundice lasting 1–2 months requires surveillance by the physician to exclude liver disease, although pale stools, if noted, are highly suggestive of important liver disease.

Chapter 4: The Jaundiced Baby Systemic disease Unconjugated hyperbilirubinaemia is frequently associated with systemic disease. Haemolysis of any aetiology increases the bilirubin load and includes: rhesus and ABO incompatibility with Coombs’ positivity; glucose-6phosphate dehydrogenase deficiency; erythrocyte membrane defects; and spherocytosis. Severe haemolytic disease of any aetiology can result in severe jaundice associated with kernicterus and requires aggressive treatment with phototherapy and/or exchange transfusion. Bruising, haemorrhage into brain or lung tissue, and neonatal polycythaemia also increase the bilirubin load. The association of unconjugated hyperbilirubinaemia with congenital hypothyroidism is based on early observations (Weldon & Danks 1972). The mechanism of jaundice is not known, but thyroid function should be evaluated in any neonate with jaundice. Unconjugated hyperbilirubinaemia is also found with pyloric stenosis and other forms of upper intestinal obstruction, which resolves rapidly after pyloric myotomy (Bleicher et al. 1979). The mechanism remains uncertain. Alikely explanation is that these infants have Gilbert syndrome and develop unconjugated hyperbilirubinaemia due to reduced oral intake (Labrune et al. 1989; Trioche et al. 1999). Other pathological conditions associated with unconjugated hyperbilirubinaemia include sepsis, hypoxia, hypoglycaemia, galactosaemia and fructose intolerance.

Inherited disorders Crigler–Najjar syndromes Crigler–Najjar syndromes type 1 and 2 are autosomal recessive conditions which lead to unconjugated hyperbilirubinaemia due to a deficiency of the enzyme bilirubin uridine diphosphate glucuronosyl transferase (UDPGT). In Crigler–Najjar type 1 there is effectively no UDPGT present; in type 2 the defect is partial. The genetic basis for these diseases has been elucidated since the structure of the human bilirubin glucuronosyl transferase gene has been established (Owens & Ritter 1992; Ritter et al. 1992, 1993). Humans have two such genes (B-UGT1 and B-UGT2); B-UGT2 appears to play little if any role in bilirubin glucuronidation and is not responsible for induction of enzyme activity in Crigler– Najjar type 2 due to phenobarbital. B-UGT1 and 2 are members of a glucuronosyl transferase superfamily. In these genes exon 1 relates to substrate specificity, for example, for bilirubin, exons 2–5 code for the carboxyterminal domains common to all glucuronosyl transferases. The clinical phenotype of Crigler–Najjar type 1 can result from mutations in exons 2–5, resulting in a trun-

37

cated non-functional enzyme, or in exon 1, resulting in complete loss of substrate recognition for bilirubin. Genetic heterogeneity in this condition has been striking (Aono et al. 1993; Labrune et al. 1994). The genetic defect in Crigler–Najjar type 2 is somewhat subtler. Mutations leading to Crigler–Najjar type 2 appear to change the affinity of the enzyme for its substrate (Seppen et al. 1994; Guldutuna et al. 1995). Clinical features and diagnosis Both conditions present early in the perinatal period with a rapid rise in bilirubin despite phototherapy. Kernicterus may develop in the perinatal period, particularly if treatment is delayed or if associated with dehydration or sepsis. Type 1 is much more severe than type 2, with peak serum bilirubin levels at 250–850 mmol/l. In Crigler–Najjar type 2 serum bilirubin is lower (200–300 mmol/l) and may reduce by ~40% when phenobarbitone is administered. Liver function tests, including conjugated bilirubin, are normal. Liver histology is normal except for occasional bile plugs. Confirmation of the diagnosis may be obtained by detection of the enzyme deficiency in liver or estimation of bilirubin mono- and diglucuronides in bile aspirates. Bilirubin diglucuronides are not present in bile in type 1 but can be found in type 2 (Sinaasappel & Jansen 1991). Management Treatment for Crigler–Najjar type 1 consists of aggressive use of measures to remove bilirubin with either phototherapy or exchange transfusion. Effective phototherapy depends on delivering radiant energy from light of wavelength 400–500 nm to the skin. Irradiance is not related to the brightness of the lights; the quantity of irradiation is inversely related to the distance between the lights and the infant. Skin pigmentation does not influence effectiveness of treatment. The development of lighted mattresses (Hughes-Benzie et al. 1993) has facilitated treatment and permitted early discharge from hospital. The use of tin-protoporphyrin has been advocated as an alternative treatment, which works by interfering with the generation of bilirubin from haem (Kappas et al. 1988; McDonagh 1988). The aim of therapy is to maintain bilirubin levels low enough (< 300 mmol/l) to prevent kernicterus, which may require up to 15 h of phototherapy a day. Intercurrent infections with rapid increases in bilirubin should be managed with plasmapheresis or exchange transfusions. Liver transplantation, including auxiliary transplantation, is a long-term option if damage to the nervous system has been avoided (Chapter 20) and may improve quality of life. It is the only effective method for preventing kernicterus. Hepatocyte transplantation has limited success (Fox et al. 1998). In Crigler–Najjar type 2 prolonged treatment with phenobarbitone (5–10 mg/kg/day) may provide cos-

38

Section 3: Neonatal Liver Disease

metic improvement, but treatment is not usually required as kernicterus is rare. Outcome Sudden late neurological deterioration in Crigler–Najjar type 1 may occur even if management of hyperbilirubinaemia has been meticulous. Late intrahepatic cholestasis has been reported. The outcome following liver transplantation is excellent. Gilbert’s syndrome This condition manifests with mild variable unconjugated hyperbilirubinaemia, with total serum bilirubin levels ranging from 30 to 90 mmol/l. It is a heterogeneous condition in which the responsible gene defect in has been identified: the presence of an extra TA tandem repeat in the promoter region of the bilirubin UDP glucuronosyl transferase 1 gene (Bosma et al. 1995). Instead of having the normal six repeats, seven are present. Although this promoter region abnormality is the prevailing abnormality in individuals of European extraction, a different genetic picture exists in Asians in whom mutations within the coding region of bilirubin UDP glucuronosyl transferase 1 gene have been found associated with Gilbert’s syndrome (Burchell & Hume 1999). Clinical features There is mild jaundice which is exacerbated by dehydration, intercurrent illness or fatigue. Patients often complain of vague abdominal pain, lethargy and general malaise for which no good cause has been found. It is more common in males than females; most children present in adolescence. Serum aminotransferases are normal and biopsy is unnecessary. Infants homozygous for the genetic abnormality of Gilbert syndrome have a greater increase in jaundice in the first 2 days of life than heterozygotes or non-affected infants (Bancroft et al. 1998; Monaghan et al. 1999; Roy-Chowdhury et al. 2002). Asian infants with Gilbert’s syndrome associated with coding region mutations in the bilirubin glucuronosyl transferase gene are also more prone to physiological or breast-milk jaundice (Akaba et al. 1999; Maruo et al. 1999, 2000; Sutomo et al. 2002). Treatment No treatment is required, but families often require reassurance.

Conjugated hyperbilirubinaemia Conjugated hyperbilirubinaemia nearly always indicates liver disease, which may be due to the neonatal hepatitis syndrome, biliary atresia or duct paucity syndromes. The nomenclature for neonatal liver disease is problematic. The term ‘neonatal jaundice’ causes confusion with physiological jaundice, while ‘neonatal cholestasis’ is imprecise. In the first 3–4 months of life every infant has

some degree of neonatal cholestasis on a physiological basis, which is multifactorial. Hepatocellular pathways of bile acid conjugation and biliary secretion are immature, and uptake of bile acids and other organic anions by hepatocytes is inefficient, leading to high concentrations of bile acids in blood; the circulating bile acid pool is contracted, and ileal uptake of bile acids is underdeveloped (Suchy et al. 1981; Balistreri et al. 1983). The term ‘neonatal hepatitis’ is inadequate because hepatic inflammation is not prominent in every condition. The term ‘neonatal hepatitis syndrome’ (NHS) is now used as it conveys the similarity of the clinical illness in infants and suggests a broad spectrum of causative disease processes.

Neonatal hepatitis syndrome (NHS) The neonatal hepatitis syndrome is now the term given to non-specific hepatic inflammation, which develops secondary to many different aetiologies, including intrauterine infection, endocrine disorders and inborn errors of metabolism. Causes of the neonatal hepatitis syndrome and diagnostic approach are summarized in Fig. 4.1 and Table 4.1. Treatment is summarized in Table 4.5. (p. 61). Clinical features Conjugated hyperbilirubinaemia may present at any time after birth. If detected in the first 24 h of life infection is usually the cause. Most causes of the neonatal hepatitis syndrome have a similar presentation: • Jaundice, which may not be obvious at first. • Dark urine and pale yellow stools. Abnormal stool colour, though suggestive of liver disease, is neither a specific nor a reliable feature. • Infants may be small for gestational age, especially those with Alagille’s syndrome, metabolic liver disease and intrauterine infection (see Plate 1, Atlas: p. 440). • Failure to thrive or poor feeding. • Dysmorphic features in trisomy 18, trisomy 21, Alagille’s syndrome, Zellweger syndrome, and with certain congenital infections. • Hypoglycaemia in metabolic liver disease, hypopituitarism or severe liver disease. • Hepatomegaly. • Splenomegaly (the spleen may also be palpated in healthy babies 1–2 cm below left costal margin). An impalpable spleen in an infant with severe cholestatic jaundice may suggest extrahepatic biliary atresia with polysplenia. • Ascites is rarely evident except in metabolic liver disease (Chapter 5). • Cardiac murmurs or neurological abnormalities are associated with specific congenital syndromes. • Bleeding from vitamin K deficiency or thrombocytopenia.

Chapter 4: The Jaundiced Baby

39

Conjugated hyperbilirubinaemia

TORCH α-1-antitrypsin level and phenotype RBC galactose-6-phosphate uridyl transferase Plasma amino acids, cholesterol, triglyceride, cortisol, thyroid function tests Serum: ferritin, TIBC, total bile acids, GGT, karyotype Urine: amino acids, organic acids, reducing sugars Bile acid intermediates Succinylacetone2

Ultrasound of bile ducts

Abnormal

Normal/absent or concentrated gall bladder

Hepatobiliary (TEBIDA) scan

Cholangiography

Excretion within 4 hours

Delayed/no excretion within 24 hours

Choledochal cyst

Liver biopsy

Liver biopsy

Surgery

Neonatal hepatitis

Biliary atresia

Bile duct paucity

Alagille gene testing

ERCP/operative cholangiogram

Laparotomy

Fig. 4.1 Investigation of conjugated hyperbilirubinaemia in the neonate. TORCH, Serology for toxoplasma, other, rubella, cytomegalovirus and herpes simplex viruses; TIBC, total ironbinding capacity; GGT, gamma-glutamyl-transpeptidase; TEBIDA, Technetium trimethyl-1-bromo imino diacetic acid; ERCP, endoscopic retrograde, cholangiopancreatography.

Investigations The following investigations and findings are used in determining a diagnosis of neonatal hepatitis syndrome:

• The cardinal feature is conjugated hyperbilirubinaemia of any degree. Even a mildly elevated conjugated bilirubin (≥ 20 mmol/l) in the absence of unconjugated hyperbilirubinaemia may indicate significant hepatic disease. • Serum aminotransferases are frequently elevated 2–4 times normal, but they may be within normal limits for age. Higher elevations suggest an infectious process. • Serum alkaline phosphatase may be normal or only mildly elevated. Higher levels may indicate biliary atresia or rickets.

40

Section 3: Neonatal Liver Disease

Table 4.1 Neonatal liver disease syndrome: differential diagnosis and diagnostic approach Disease

Major diagnostic strategy

Congenital infection Toxoplasmosis Rubella Cytomegalovirus Herpes simplex Syphilis Human herpesvirus-6, herpes zoster Hepatitis B Hepatitis C Human immunodeficiency virus Parvovirus B19 Syncytial giant cell hepatitis Enteric viral sepsis (echoviruses, Coxsackie A and B viruses, adenoviruses)

IgM-specific antibodies IgM-specific antibodies Urine for viral culture, IgM antibodies EM/viral culture of vesicle scraping STS, VDRL, FTA-ABS, long-bone films Serology, PCR HBsAg, anti-HBc (IgM), HBV DNA HCV RNA by RT-PCR Anti-HIV, immunoglobulins, CD4 count IgM antibodies Giant cell hepatitis on liver biopsy Appropriate serology, CSF for viral culture

Genetic Trisomy 18, (21), cat-eye syndrome

Karyotype

Endocrine Hypopituitarism (septo-optic dysplasia) Hypothyroidism

Low cortisol, TSH and T4 High TSH titre; low T4, free T4, T3

Structural Extrahepatic biliary atresia Caroli cyst, choledochal cyst Neonatal sclerosing cholangitis Hair-like bile duct syndrome Spontaneous perforation of CBD Inspissated bile syndrome

Delayed or absent excretion on hepatobiliary scan, biliary obstruction on histology Ultrasound, cholangiography Cholangiogram Cholangiogram Ultrasound, paracentesis, biliary ascites Coombs’ test, other evidence for haemolysis, dilated bile ducts

Duct paucity syndromes Alagille syndrome Non-syndromic duct paucity

Echocardiogram, posterior embryotoxon, CXR for ‘butterfly vertebrae’ Bile duct paucity on histology

Metabolic a1-Antitrypsin (AAT) deficiency Cystic fibrosis Galactosaemia Tyrosinaemia Hereditary fructosaemia Glycogen storage disease, type IV Niemann–Pick, type A Niemann–Pick, type C Wolman disease Primary disorders of bile acid synthesis Byler disease Zellweger syndrome

Serum AAT concentration, PI type Sweat chloride, immunoreactive trypsin Galactose-1-6-phosphate uridyltransferase Serum tyrosine, methionine, alpha-fetoprotein, urine succinylacetone Liver biopsy: EM, enzyme activities Liver biopsy Bone marrow aspirate, sphingomyelinase Storage cells in BM aspirate, liver, rectal Bx Abdominal X-ray of adrenal glands Urinary bile acid intermediates by FAB-MS GGT, genetic testing Very-long-chain fatty acid studies

Immune Neonatal lupus erythematosus NH with autoimmune haemolytic anaemia

Anti-Ro and anti-La antibodies (in infant and mother) Coombs’ test, giant cell hepatitis

AAT, a1-antitrypsin; Bx, biopsy; CBD, common bile duct; CXR, chest X-ray; EM, electron microscopy; FAB-MS, fast-atom bombardment-mass spectroscopy; FTA-ABS, fluorescent treponemal antibody, absorbed; GGT, gamma-glutamyl transpeptidase; HBV, hepatitis B virus; HCV, hepatitis C virus; PI, protease inhibitor; PCR, polymerase chain reaction; RT-PCR, reverse transcriptase-polymerase chain reaction; STS, standard test for syphilis; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone; VDRL, Venereal Disease Research Laboratory.

Chapter 4: The Jaundiced Baby • Serum gamma-glutamyl transpeptidase (GGT) may be elevated, but reference values for GGT change during the first 3 months of life and may be difficult to gauge. It does not reliably distinguish bile duct obstruction from hepatocelllar injury in the infant. Normal or low GGT suggests Byler disease or progressive familial intrahepatic cholestasis (see below). • Blood glucose may be normal or low. Hypoglycaemia suggests metabolic liver disease, hypopituitarism or poor hepatic reserve. • Serum albumin is usually normal unless there is severe prenatal disease. • Prothrombin and partial thromboplastin times are usually normal unless there is associated vitamin K deficiency (haemorrhagic disease of the newborn) or severe liver disease. • Bilirubin is present in urine. • Screening investigations for known causes of neonatal hepatitis syndrome may be diagnostic (Fig. 4.1). • Abdominal ultrasound scan (after 4-h fast) to detect gall bladder size. Usually present unless there is severe intrahepatic cholestasis or biliary atresia (see Plate 2, Atlas: p. 440). • Radioisotope scan to demonstrate hepatic uptake (may be reduced in NHS) and biliary excretion (may be delayed more than 4–6 h in NHS if there is severe cholestasis, and more than 24 h, or indefinitely, in biliary atresia) (see Plate 3, Atlas: p. 440). • Liver biopsy. This is frequently the most informative investigation in neonatal hepatitis syndrome (Lichtman et al. 1987). If the liver is difficult to palpate, or if situs inversus abdominis is present, an ultrasound-guided biopsy should be performed. Information provided by liver biopsy includes: the severity of hepatocellular injury and extent of fibrosis; evidence for infiltrative or storage disease; and type of biliary damage (bile ductular proliferation vs. small duct paucity). Care should be taken to obtain a large enough specimen with adequate numbers of portal tracts to assess changes in the small bile ducts. Histological findings vary depending on the aetiology. Most diseases will have conspicuous cholestasis with bile staining within the hepatocytes, and bile plugs within bile canaliculi and bile ductules. Hepatocytes may demonstrate a variable degree of multinucleated giant cell transformation and rosette formation on the hepatocytes. There may be a degree of extramedullary haematopoiesis. Although biliary ductular proliferation is said to be prominent in bile duct obstruction, it also occurs in children with a neonatal hepatitis syndrome, particularly those with a1-antitrypsin deficiency, cystic fibrosis and endocrine deficiency. Paucity of bile ducts is a feature in Alagille’s syndrome (see Plates 4 and 6, Atlas: pp. 441 and 442, respectively).

41

Infection Toxoplasmosis, rubella, cytomegalovirus, herpes simplex (‘TORCH’) infections Congenital infections grouped under the acronym ‘TORCH’ often have very similar clinical features: hepatosplenomegaly, jaundice, pneumonitis, petechial or purpuric rash, and a tendency to prematurity or poor intrauterine growth. A presentation with fulminant hepatic failure in the newborn period is common with herpes simplex infection. Whenever possible, direct identification of viral infection or measurement of specific IgM antibodies should be sought for rapid diagnosis; relying on conventional TORCH titres is less preferable. Toxoplasmosis Congenital toxoplasmosis is comparatively rare. Maternal infection in the third trimester is more likely to cause fetal infection than infection earlier in pregnancy. Neonatal hepatitis is an important feature but may be less obvious than central nervous system involvement with chorioretinitis (with large pigmented scars), hydrocephaly or microcephaly. Intracranial calcification is usually prominent, leading to convulsions, nystagmus and evidence of increased intracranial pressure. Liver biopsy may demonstrate a non-specific hepatitis or portal fibrosis with biliary ductule proliferation. Spiramycin therapy may prevent progression of central nervous system and liver disease. Prognosis depends on the extent of neurological or optic disease. Rubella Congenital infection with rubella virus is now rare because of immunization. It may cause intrauterine growth retardation, anaemia/thrombocytopenia, congenital heart disease (patent ductus arteriosus or pulmonary artery stenosis), cataracts, chorioretinitis (‘salt and pepper’ appearance), mental retardation and sensorineural deafness. Hepatosplenomegaly is usual. Liver histology shows typical giant-cell hepatitis. The disease may be self-limited or progress to cirrhosis. Cytomegalovirus Cytomegalovirus is the most commonest cause of congenital infection, affecting 1–2% of newborns, most of whom are asymptomatic. Those with evident disease may have intrauterine growth retardation or be premature (Hart et al. 1991). Fetal ascites (Binder et al. 1988; Sun et al. 1990) may occur. Cytomegalovirus rarely causes acute liver failure in the newborn. Clinical findings include: petechial rash, hepatosplenomegaly, and jaundice in 60–80%. Cytomegalovirus infection often affects the central nervous system, producing microcephaly, intracranial calcification, and chorioretinitis; progressive sensorineural deafness or cerebral palsy may develop later in childhood. Primary infection in the second and third trimesters ap-

42

Section 3: Neonatal Liver Disease

pears to cause more severe fetal disease than recurrent infection. Liver biopsy demonstrates a giant cell hepatitis; the classical inclusion bodies are rarely seen in neonatal infection. In a study of liver tissue in infants with neonatal hepatitis or extrahepatic biliary atresia, Chang et al. (Chang et al. 1992) found cytomegalovirus DNA in 23 of 50 infants with neonatal hepatitis by polymerase chain reaction, but in only two of 26 with extrahepatic biliary atresia, and in none of control specimens. Although differentiation from biliary atresia is usually easy, cytomegalovirus may be associated with extrahepatic biliary atresia. In one report of fraternal twins, both had congenital cytomegalovirus infection: one had hepatitis only and the other presented with ‘late’ pattern extrahepatic biliary atresia (Hart et al. 1991). In addition, 25% of infants with extrahepatic biliary atresia were found to have cytomegalovirus infection and were referred later than those without cytomegalovirus infection (Tarr et al. 1996). Cytomegalovirus is a candidate virus for causing ‘late’ presentation extrahepatic biliary atresia as it can infect bile duct epithelial cells directly and increase expression of MHC class II antigens (Arnold et al. 1992; Domiati-Saad et al. 2000). Infants with congenital cytomegalovirus infection and persisting conjugated hyperbilirubinaemia should have extrahepatic biliary atresia excluded. Conclusive diagnosis requires cytomegalovirus to be cultured from the infant within the first 4 weeks of life. Serological studies and clinical features provide support for the presence of cytomegalovirus infection but do not distinguish congenital from early postnatal infection (Table 4.1). In most children cytomegalovirus hepatitis is mild and resolves completely. A few children develop hepatic fibrosis (Zuppen et al. 1986; Le Luyer et al. 1990) or noncirrhotic portal hypertension (Ghishan et al. 1984). Intrahepatic calcification has been reported (Alix et al. 1978). Cirrhosis with chronic cholestasis necessitated liver transplantation in one child. Persisting neurodevelopmental abnormalities become the main problem in the majority of patients (Conboy et al. 1987). Herpes simplex In the newborn this virus causes a severe multisystem disorder with encephalitis, severe hepatitis, or acute liver failure (Miller et al. 1970; Benador et al. 1990) due to either type 1 or type 2 virus, although type 2 virus shed from the infected cervix at birth is more common. Liver biopsy shows areas of necrosis with viral inclusions in intact hepatocytes; however, profound coagulopathy may preclude biopsy. Scrapings from vesicular skin lesions reveal herpes simplex virus, but these typical herpetic skin, mouth or eye lesions may not be present in neonates. Antiviral treatment with acyclovir should be administered to avert the otherwise high mortality.

Syphilis Congenital syphilis is now rare in the developed world. It causes a multisystem illness, which may include intrauterine growth retardation and subsequent failure to thrive, severe anaemia and thrombocytopenia, nephrotic syndrome, periostitis, nasal discharge (‘snuffles’), skin rash, diffuse lymphadenopathy, and hepatomegaly. Jaundice may be present within 24 h of birth or develop after treatment (Long et al. 1984). Jaundice may be severe (Wolf et al. 1997). Some babies with congenital syphilis never develop jaundice but present with a typical rash on palms and soles or only with fever, as well as prominent hepatomegaly (Dorfman & Glaser 1990). Central nervous system involvement occurs in up to 30% of infants. Liver histology in untreated congenital syphilis may reveal numerous treponemes in hepatic tissue, but after treatment with penicillin, giant-cell hepatitis without detectable treponemes is the usual finding. Diagnosis involves serological testing, including the Venereal Disease Research Laboratory (VDRL) test and confirmatory testing for specific antitreponemal antibodies. Radiographs of long bones may show typical bony abnormalities in the first 24 h of life and aid rapid diagnosis (Table 4.1). Varicella Varicella may occur in newborn infants if maternal infection occurs within 14 days of delivery. It tends to be more severe in premature infants and is mild in term infants after 10 days of age. Early presentation or protracted disease in an infant of any gestational age may lead to a fatal outcome. This severe disease is characterized by jaundice, and extensive skin and multisystem involvement, especially pneumonia. In fatal cases hepatic parenchymal involvement can be demonstrated (Brunell 1983; Feldman 1986). Hepatotropic viruses: hepatitis A, B and C In general, infection with hepatotropic viruses in neonates does not cause jaundice unless there is acute liver failure or severe hepatitis. Neither hepatitis A nor B have been associated with NHS or biliary atresia (Balistreri et al. 1980). Hepatitis A Hepatitis A is rare in the neonate but congenital infection may occur if the mother is infected 1–2 weeks before delivery (Watson et al. 1993). The typical picture in the early neonatal period is a non-specific diarrhoeal illness, as shown by rare outbreaks of transfusion-related hepatitis in premature infants (Klein et al. 1984; Noble et al. 1984).

Chapter 4: The Jaundiced Baby Hepatitis B Vertical hepatitis B infection is subclinical in the neonatal period; prompt administration of both hepatitis B immune globulin and hepatitis B immunization provides protection against chronic infection in 93% of infants at risk. Infants who fail this regimen may have been infected transplacentally. Without immunoprophylaxis, infants may become chronic carriers or develop acute hepatitis B or fulminant hepatic failure after a 3- to 4-month incubation period (Dupuy et al. 1975; Mollica et al. 1977; Shiraki et al. 1980; Delaplane et al. 1983) (Chapter 7). Hepatitis C Hepatitis C is not a cause of neonatal hepatitis syndrome. A study of 33 infants with either idiopathic neonatal hepatitis or extrahepatic biliary atresia revealed only one (with extrahepatic biliary atresia) positive for anti-hepatitis C virus (anti-HCV) antibodies and for virus by reverse transcriptase-polymerase chain reaction (RTPCR) (A-Kader et al. 1994). Similar studies in Taiwan, where hepatitis C is endemic, found no anti-HCVpositive infants among 42 with neonatal hepatitis and 11 with extrahepatic biliary atresia, by second-generation enzyme-linked immunoassay (Chang et al. 1993). Vertical transmission of hepatitis is less common than in hepatitis B viral infection. Jaundice does not occur. Human immunodeficiency virus (HIV) infection Although infants with congenital HIV infection may present with hepatosplenomegaly, conjugated hyperbilirubinaemia in the neonatal period is rare. A case of neonatal hepatitis was attributed to HIV infection despite concomitant congenital cytomegalovirus infection (Witzleben et al. 1988); an increased incidence of congenital cytomegalovirus infection has subsequently been found in HIV-infected infants. Congenital HIV infection may present clinically as hepatitis with jaundice although later than in the neonatal period, typically at ~6 months of age (Persaud et al. 1993). Parvovirus B19 infection Congenital parvovirus B19 infection may cause profound anaemia leading to hydrops (Essary et al. 1998) and fetal death. The spectrum includes conjugated hyperbilirubinaemia, hepatomegaly, severe coagulopathy, dermal erythropoiesis (‘blueberry muffin’ rash), anaemia and perinatal distress (Silver et al. 1996). Liver biopsy showed diffuse sinusoidal fibrosis, siderosis, little giant-cell transformation of hepatocytes but excessive extramedullary haematopoiesis (Metzman et al. 1989; Langnas et al. 1995; White et al. 1995). Despite features of early hepatic insufficiency, serum aminotransferases may be low or near normal. Diagnosis is made by PCR for presence of parvovirus 19, although placental histology may suggest prenatal

43

parvovirus infection. Outcome depends on severity of infection. Human herpesvirus-6 (HHV-6) infection Human herpesvirus-6 causes exanthem subitum, a common but usually benign febrile illness in infants; other HHV-6 infections are common and self-limited without a rash. Acute liver failure has been reported (Asano et al. 1990; Aita et al. 2001). Syncytial giant-cell hepatitis ‘Syncytial giant-cell hepatitis’ denotes severe liver disease attributed to paramyxovirus infection. The clinical liver disease varies with the age of the patient: in children, fulminant hepatic failure is common, while rapidly progressive chronic hepatitis occurs in adults. Infants may have features of a chronic active hepatitis or autoimmune haemolytic anaemia. In neonates, syncytial giant-cell hepatitis is associated with a severe hepatitis, which does not meet the criteria for fulminant liver disease (Chapters 5 and 7). Hepatitis with moderately elevated serum aminotransferases progresses to chronic cholestasis and decompensated cirrhosis over 6–12 months. Liver histology and electron microscopy show both the characteristic syncytial-type giant cells and viral inclusions consistent with the morphology of paramyxoviruses (Phillips et al. 1991; Sussman et al. 1994; Hicks et al. 2001). Formation of giant multinucleated hepatocytes is a characteristic response of infantile hepatocytes to injury, which is not often seen in hepatitis in adults. Syncytial giant cells differ from the giant cells of neonatal hepatitis because the outline of the liver cell plates remains evident, with indistinct, ‘smudged’ borders between the cells. They may form because of cell fusion secondary to paromyxovirus, in the same way as other viruses such as respiratory syncytial virus and measles virus. Spontaneous recovery is uncommon. Treatment with the antiviral agent ribavirin appeared efficacious in one case (Roberts et al. 1993). Most babies require liver transplantation before the end of the first year of life. Enteric viral sepsis (echovirus, Coxsackie viruses, adenoviruses) The enteroviruses cause systemic viral infection in the newborn period, and severe hepatitis with acute liver failure may be a prominent feature. Incidence is greatest at the seasonal peak incidence of echovirus infections (late summer to early autumn). The infant’s mother may relate development of abdominal pain just prior to onset of labour. Vertical infection near the time of birth is associated with more severe disease in the infant. Most infants

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with enteric viral sepsis present between 1 and 5 weeks old. The infant is lethargic and jaundiced, with very high serum aminotransferases and severe coagulopathy; meningitis is usually present. Echovirus serotypes 3, 6, 7, 9, 11, 14, 19 and 21 have all been reported in severe infections with hepatitis (Modlin 1980; Gillam et al. 1986; Modlin & Kinney 1986). Echovirus serotype 11 appears to be most virulent for newborns. Coxsackie A and B viruses are capable of causing an identical clinical picture, although myocarditis or heart failure suggests Coxsackie virus infection. Adenoviruses (Matsuoka et al. 1990) and herpes simplex infection (either type 1 or 2) also cause the same severe hepatitis (Benador et al. 1990). Mortality with acute liver failure is of the order of 85–90%. Meticulous supportive care is essential (Chapter 14). Infants who recover may develop severe cholestatic jaundice. Subsequent hepatic function in survivors appears entirely normal.

more common. Newborn infants may be infected by aspirating infected amniotic fluid or cervical secretions at the time of delivery. Practical criteria for diagnosis are a proven tuberculous infection in a newborn baby with at least one of the following: lesions in the first week of life; primary hepatic complex or caseating granulomas in the liver; tuberculous infection of the placenta or maternal genital organs; and exclusion of postnatal infection by investigation of contacts (Cantwell et al. 1994). Hepatomegaly is common in infants with tuberculosis, but jaundice is rare and indicates severe disease. Respiratory distress, poor feeding and fever are frequent. Mortality approaches 30%; a quadruple antitubercular antibiotic regimen excluding ethambutol is recommended. A high index of suspicion appears to be required for diagnosis, as tuberculosis in this age group often has atypical clinical features (Gogus et al. 1993).

Bacterial infection outside the liver

Endocrine disorders

Conjugated hyperbilirubinaemia may occur with sepsis or localized extrahepatic infection, such as a urinary infection, that is inapparent (Hamilton & Sass-Kortsak 1963; Franson et al. 1985; Garcia & Nager 2002). Serum aminotransferases may be slightly elevated; hepatosplenomegaly is uncommon. Jaundice may also occur with streptococcal and staphylococcal infections and Gram-negative bacterial septicaemia. Infants with galactosaemia may present initially with jaundice and Gram-negative septicaemia, often due to Escherichia coli or Klebsiella species. Other typical features of galactosaemia may not be obvious. Galactosaemia should be investigated in any infant with conjugated hyperbilirubinaemia associated with sepsis by measuring erythrocyte galactose-1-phosphate uridyl transferase.

Hypothyroidism

Listeriosis Congenital infection with Listeria monocytogenes typically involves the liver. Although meningitis is the predominant clinical feature of the systemic disease, infants have hepatosplenomegaly and are sometimes jaundiced. Pneumonia is usually present. A history of maternal illness is common. Liver biopsy may reveal simply a diffuse hepatitis or, more commonly, diffuse areas of focal necrosis. Diagnosis is made by isolating the organism from blood, cerebrospinal fluid (CSF) or liver. Treatment is with penicillin. Tuberculosis Congenital tuberculosis is rare, but since the prevalence of tuberculosis in women of child-bearing age has risen in the past few years, tuberculosis in infants may become

Hypothyroidism is usually associated with an unconjugated hyperbilirubinaemia but may be associated with the neonatal hepatitis syndrome and should be excluded in every patient (Fig. 4.1). Hypopituitarism Pituitary–adrenal dysfunction is associated with neonatal hepatitis syndrome in 30–70% of patients (Herman et al. 1975; Leblanc et al. 1981b; Kraehe et al. 1992; Sheehan et al. 1992; Ellaway et al. 1995). The cause of the hypopituitarism is variable. It is due to hypothalamic dysfunction in some; deficiency of anterior and/or posterior pituitary function may be present; a child with adrenal insensitivity to adrenocorticotropin was also described (Lacy et al. 1993). Clinical features include: conjugated hyperbilirubinaemia; hypoglycaemia in the perinatal period, which is usually symptomatic and persistent; and septo-optic dysplasia, which is a neuro-optical malformation that includes ventral midline developmental defect (absence of the septum pellucidum or corpus callosum) and hypoplasia of one or both optic nerves which is associated with hypopituitarism. There may also be midline facial abnormalities, nystagmus and microgenitalia in boys (see Plate 5, Atlas: p. 441). The diagnosis is confirmed by detecting an extremely low random or 09.00 h cortisol in association with a low thyroid-stimulating hormone (TSH) and thyroxine (T4). Liver biopsy usually reveals typical giant-cell hepatitis, but severe cholestasis may be present with dilated bile canaliculi and hepatocellular necrosis. There may be delayed excretion on radioisotope scanning (Kumura et al.

Chapter 4: The Jaundiced Baby 1987). Hormone replacement is essential and includes thyroxine, corticosteroids and occasionally growth hormone. Progression of the disease to cirrhosis and portal hypertension has been reported in those children who had delayed or no hormone replacement. Chromosomal disorders Trisomy 18 Trisomy 18 is associated with growth retardation, skeletal abnormalities and complex congenital heart disease. Both giant-cell hepatitis and extrahepatic biliary atresia have been reported (Alpert et al. 1969; Ikeda et al. 1999). In one infant with trisomy 18 serial liver biopsies suggested late evolution of neonatal hepatitis to extrahepatic biliary atresia. Other cytogenetic abnormalities, including trisomy 13, deletion of the short arm of chromosome 18 and 49 XXXXY (Silveira et al. 1991), have been reported in association with extrahepatic biliary atresia. Trisomy 21 The association between trisomy 21 and neonatal cholestasis or extrahepatic biliary atresia (Henriksen et al. 1981) is not well substantiated. Recently, severe hepatic fibrosis associated with transient myeloproliferative disorder has been reported with Down’s syndrome (Ruchelli et al. 1991; Becroft 1993), raising the possibility that hepatic fibrogenesis might be due to high concentrations of growth factors derived from megakaryocytes.

45

bilirubinaemia before 3 months of age, no aetiology is found, and these infants are considered to have idiopathic neonatal hepatitis. If cholestasis is severe, differentiation from extrahepatic biliary atresia and other cholestatic conditions is important. Infants with idiopathic neonatal hepatitis are more likely to be premature or small for gestational age than those with extrahepatic biliary atresia (Mowat et al. 1976), perhaps reflecting a genetic disorder or an intrauterine infection. An important subset of idiopathic neonatal hepatitis includes instances where more than one child in a single family is affected, accounting for 5–15% of cases in most series. Liver biopsy shows an extensive giant-cell transformation of hepatocytes with inflammation, but bile ducts appear generally normal. A few infants with histologically severe inflammation also have small bile duct paucity. In general, it may not be easy to differentiate between severe idiopathic neonatal hepatitis and extrahepatic biliary atresia. An intraoperative cholangiogram may be required, and there is no evidence that diagnostic laparotomy for assessment of the extrahepatic biliary tree is adverse for infants with idiopathic neonatal hepatitis. The prognosis is generally good. Mortality is 13–25% (Deutsch et al. 1985; Chang et al. 1987; Suita et al. 1992). Predictors of poor prognosis include: prolonged severe jaundice (beyond 6 months of age); acholic stools; familial occurrence; persistent hepatomegaly; and severe inflammation on biopsy. Peak bilirubin level is not necessarily predictive of outcome, and the prognostic importance of ductopenia has not been rigorously investigated. Septic complications may lead to decompensation. The longterm outlook for infants surviving the first year of life with little evidence of chronic liver disease is very good.

Cat-eye syndrome Cat-eye syndrome is a highly variable malformation syndrome associated with a small supernumerary bisatellited marker chromosome derived from duplicated regions of chromosome 22. Major features may include coloboma of the iris and other facial malformations involving the eyes, anal atresia with fistula, complex congenital heart disease and renal malformation. There is considerable phenotypical variability. Extrahepatic biliary atresia has been reported in association with this disorder. A candidate responsible gene in this condition has recently been identified as the human homologue of CECR1, which is an insect gene encoding growth factors. The expression pattern of hCECR1 in heart, cranial nerves and notochord and later in fetal liver, lung and kidney implicates it as leading to cat-eye syndrome when it is overexpressed (Riazi et al. 2000). Idiopathic neonatal hepatitis In up to 25% of infants presenting with conjugated hyper-

Neonatal hepatitis in preterm infants Idiopathic neonatal hepatitis does occur in preterm babies, some of whom will have cholestasis due to immaturity of the biliary tree. They may be prone to hypoglycaemia and have a functionally immature gastrointestinal tract resulting in difficulties with feeding. It is important to differentiate this condition from other known causes of NHS and, in particular, extrahepatic biliary atresia. The prognosis is generally good.

Structural abnormalities Extrahepatic biliary atresia Extrahepatic biliary atresia (EHBA) is the cause of liver disease in ~25% of infants presenting with neonatal hepatitis syndrome and is the most important differential diagnosis. Early diagnosis is vital as the Kasai portoenterostomy is less likely to be successful the later it is performed (Mieli-Vergani et al. 1989; Chardot et al. 1999).

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Section 3: Neonatal Liver Disease

EHBA involves a progressive destruction of the extrahepatic bile ducts, with scarring, obliteration and concomitant damage to small and medium-sized intrahepatic bile ducts. The disease is classified according to the extent of damage at diagnosis. In type 1, damage is limited to the distal common bile duct (also known as ‘correctable’); in type 2 damage is limited to the common hepatic duct; in type 3, which is the most common, the entire extrahepatic biliary tree is involved. Type 1 accounts for ~10% of EHBA, and type 2 is extremely rare (Chapter 18). EHBA is found worldwide in all racial groups, with an incidence of 1 in 8000–15 000 live births. For discussion of aetiology and pathogenesis see Chapter 18.

The clinical presentation of EHBA is unremitting, progressive jaundice in an infant who usually looks well. The main features are: • Normal birth weight and gestational age in the majority. Preterm infants can have EHBA. • Jaundice, which is present from shortly after birth, continuous with physiological jaundice. There may be some variability in intensity; however, jaundice can be readily identified in affected infants by 4 weeks of age. • Yellow or dark urine with increasingly pale stools, which eventually become acholic. Initially there may be variation in stool colour, which may be confusing. • Hepatomegaly is always present; the liver is usually firm. • Splenomegaly is a late sign and implies some degree of hepatic fibrosis. • Failure to thrive despite adequate feeding. • Cardiovascular anomalies (ventricular or atrial septal defects) in 30%. • Polysplenia syndrome; this includes preduodenal portal vein, situs inversus, absence of inferior vena cava and malrotation (Chapter 18). • Bleeding from vitamin K-responsive coagulopathy, which is more common in breast-fed infants who did not receive vitamin K at birth. • Ascites and pruritus are late complications indicating progression to cirrhosis.

• Serum alkaline phosphatase is usually elevated (range 500–800 iU/l) due to biliary damage or rickets. • Gamma-glutamyl transpeptidase is usually elevated (¥ 10 normal). • Serum albumin is usually normal. • Cholesterol may be elevated but triglycerides are normal. • Prothrombin time is normal although 5–10% of cases present with vitamin K-responsive coagulopathy. • Blood glucose is usually normal. • Hepatic ultrasound, after a 4-h fast, may not demonstrate a gall bladder or only a contracted gall bladder (see Plate 2a, Atlas: p. 440); it rarely shows a dilated extrahepatic biliary tree, consistent with distal, ‘correctable’ atresia; dilated intrahepatic bile ducts are uncommonly found. Abnormal vascular anatomy consistent with the polysplenia syndrome may be seen. • Hepatobiliary scanning, using TEBIDA, following phenobarbitone pretreatment (5 mg/kg/day for 3–5 days) fails to demonstrate passage of the radiolabelled substance into the intestinal tract over a 24-h period (see Plate 3b, Atlas: p. 440). Although hepatobiliary scanning has high sensitivity, scanning may appear normal if performed very early in the disease process in late-pattern extrahepatic biliary atresia (Clarke et al. 1997; Gilmour et al. 1997). It may also fail to show bile drainage in severe idiopathic neonatal hepatitis or bile duct paucity syndromes. • Percutaneous liver biopsy is essential and has high diagnostic specificity. Features of bile duct obstruction (bile ductular proliferation, bile plugs in small bile ducts, portal tract oedema) are usually obvious, along with variable fibrosis and some giant-cell transformation (see Plate 4b, Atlas: p. 441). The earlier the liver biopsy is performed, the more difficult it may be to interpret. When the hepatobiliary scan shows no drainage and the liver histology is ambiguous, close clinical surveillance is required to determine the evolution of disease. • Uncertain cases require cholangiography, usually intraoperative, although endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography (PTC), and MR cholangiography are possible alternatives (Derkx et al. 1994; Norton et al. 2002) (Chapter 18).

Diagnosis

Management

A diagnosis of EHBA involves the following investigations and findings: • Serum conjugated bilirubin at presentation ranges from 40 to 200 mmol/l. • Serum aminotransferases are always abnormal: concentrations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are typically in the range of 80–200 iU/l.

Therapy consists of nutritional and family support. Palliative surgery, the Kasai portoenterostomy, should be carried out, if possible, to establish biliary drainage. See Chapter 18 for operative details and postoperative management. Optimally, the diagnosis of EHBA must be established before the infant is 5–7 weeks old, so that the Kasai portoenterostomy can be performed by 6–8 weeks of age. The

Clinical features

Chapter 4: The Jaundiced Baby operation should not be withheld from infants of 10–12 weeks of age because successful palliation can be achieved in one-third of patients. It is probably not indicated after 14 weeks of age, but every child should have a laparotomy to confirm the diagnosis and exclude unusual anatomy that might be amenable to surgical reconstruction. In one series there was no improvement in outcome associated with very early (before the infant is 40 days old) operation (Davenport et al. 1997). Contrary to initial impressions, the presence of the polysplenia syndrome does not in itself predict that the Kasai operation is likely to fail (Karrer et al. 1991; Vasquez et al. 1995). Complications and outcome The complications include recurrent cholangitis, malnutrition secondary to malabsorption, and progression to cirrhosis and portal hypertension. Patients with a wellfunctioning portoenterostomy appear to have some risk of recurrent cholangitis at any age despite prophylaxis. In one series, children with correctable atresia appeared unusually susceptible to septicaemia, presumably due to bacterial cholangitis. Since damage to intrahepatic bile ducts is progressive irrespective of whether or not bile drainage is reestablished, even children with a successful Kasai operation may be expected to develop biliary cirrhosis. Portal hypertension with variceal haemorrhage occurs in many long-term survivors, and endoscopic injection sclerotherapy or band ligation may be required. In ~40% of children, a Kasai portoenterostomy fails to establish biliary drainage. These children remain cholestatic and develop the complications of fat malabsorption with subsequent protein-energy malnutrition, and should be referred immediately for liver transplantation (Chapter 20). Five-year survival after Kasai portoenterostomy is 40–60% (Houwen et al. 1989). Patients in Japan (Nio et al. 1996) and elsewhere (Davenport et al. 1997) have survived 20 years or more after a portoenterostomy without liver transplantation: most are well and asymptomatic, with normal growth and psychosocial development, but have evidence of chronic liver disease. A few women have had babies after apparently uncomplicated pregnancies. The majority of children will require liver transplantation at some stage, especially if the Kasai portoenterostomy has not been successful. Choledochal cyst Choledochal cyst refers to a group of congenital malformations of the biliary system. There are five major forms (Todani et al. 1977). Choledochal cysts may be identified

47

in the fetus by prenatal sonography (Bancroft et al. 1994; Stringer et al. 1995; Burnweit et al. 1996) (see also Chapter 18). Clinical features and diagnosis The triad of symptoms associated with choledochal cyst consists of jaundice, abdominal mass and pain, but this is an unusual presentation in the neonatal period. There is female predominance (female : male is 5 : 1). Most affected infants have jaundice, abdominal mass or distension, and acholic stools (Stringer et al. 1995; Todani et al. 1995), and differentiation from biliary atresia or choledocholithiasis is important. The diagnosis is made by identifying the choledochal cyst by ultrasound examination of the liver in a jaundiced infant (see Plate 2b, Atlas: p. 440). Cholangiography, either percutaneous or endoscopic, confirms the diagnosis (see Plate 3c, Atlas: p. 440). Hepatobiliary scanning has limited utility for diagnosis. Liver function tests are compatible with biliary obstruction. Treatment and outcome Treatment is aimed at removing the cyst as much as possible (Chapter 18). Excision of the cyst with hepaticoenterostomy offers the best outcome (Lipsett et al. 1994; Miyano & Yamataka 1997; Yamataka et al. 1997). Complications are less with early surgical intervention. Surgery should be performed promptly in infants diagnosed prenatally who have conjugated hyperbilirubinaemia. If the infant remains free of jaundice, elective surgical resection of the choledochal cyst may be postponed until the infant is ~1 month old, but it should not be greatly delayed. Although ~50% of infants with prenatally identified bile duct dilatation have hepatic fibrosis, and a few have cirrhosis, most of these infants do well. A minority of infants may have correctable biliary atresia, and close follow-up is warranted. Caroli disease Caroli disease (also known as type 5 choledochal cyst) denotes congenital saccular dilatations of the intrahepatic bile ducts, without hepatic fibrosis or portal hypertension. It is often associated with autosomal recessive polycystic kidney disease. Caroli disease is rarely evident in infancy, but associated jaundice may be due to acute cholangitis. Some newborn infants with severe autosomal recessive polycystic kidney disease have extensive cystic bile duct changes, but renal insufficiency dominates the clinical picture. Ultrasound of the liver is often adequate for diagnosing Caroli disease; cholangiography is confirmatory. Outcome is related to the severity of renal disease (Chapter 9).

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Congenital hepatic fibrosis, often associated with these same bile duct abnormalities (Caroli syndrome), may present in infancy with hepatomegaly and either autosomal recessive polycystic kidney disease or systemic hypertension. Jaundice and abnormal serum aminotransferases are uncommon (Alvarez et al. 1981). Outcome is variable and depends on the progression of hepatic and renal disease (Chapter 9). Cholelithiasis and choledocholithiasis Choledocholithiasis was reported in four of 62 children with neonatal hepatitis syndrome (Lilly 1980). Two of these infants had structural abnormalities of the extrahepatic bile ducts (correctable biliary atresia in one and choledochal cyst in the other). Stones were of the bilirubinate type. The stones were removed without difficulty by standard methods once the diagnosis was secured. Subsequent reports indicate that choledocholithiasis is not rare in infants (Debray et al. 1993; Bohle 1995; Rescorla 1997). Haemolysis, fasting and total parenteral nutrition may be contributing factors, in addition to anatomical abnormalities. The obstructing gallstone may not contain enough calcium to be seen on a plain abdominal X-ray, but ultrasound usually (though not consistently) identifies the gallstone or shows dilatation of the biliary tree due to obstruction. Treatment may not be required if the stones are asymptomatic or pass into the duodenum without intervention (Monnerie & Soulard 1995). Prolonged obstruction or cholangitis require surgery (Ishitani et al. 1996; Wilcox et al. 1997). Alternatives to surgical treatment include ursodeoxycholic acid (20 mg/kg/day); and percutaneous drainage after percutaneous transhepatic cholangiogram with lavage of the bile ducts and ERCP combined with sphincterotomy in older infants (Wilkinson 1996). Adequate antibiotic treatment is required to avoid bacterial cholangitis (Chapter 18). Inspissated bile syndrome ‘Inspissated bile syndrome’ is the term traditionally given to conjugated hyperbilirubinaemia complicating severe jaundice associated with haemolysis, usually due to rhesus factor or ABO incompatibility or erythrocyte membrane abnormalities. A multifactorial cause cannot be entirely excluded as these infants are often premature and present complex medical problems. Intrahepatic cholestasis is found on liver biopsy, and cholestasis may be due to direct hepatocellular toxicity of unconjugated bilirubin. The outlook is generally good, although early reports showed cirrhosis in some infants. Obstruction of the extrahepatic biliary system with dried-out highly viscous bile has been reported in cystic fibrosis (Davies et al. 1986; Evans et al. 1991). Diagnosis is

usually made by demonstrating dilated bile ducts on ultrasound or cholangiography. Treatment includes ursodeoxycholic acid (20 mg/kg/day) or surgical or percutaneous lavage (Chapter 18). Spontaneous perforation of the common bile duct This condition usually presents as a severe acute illness resembling acute peritonitis with abdominal pain and distension, jaundice and fever, but may present as neonatal hepatitis syndrome with abdominal distension in addition to jaundice and acholic stools (Stringel & Mercer 1983). Biliary ascites is pathognomonic. Bacterial superinfection greatly increases the morbidity of this condition. Hepatobiliary scan may indicate the site of leakage and typically shows no drainage into the intestinal tract. In some cases perforation is associated with distal choledocholithiasis. Surgical repair is usually curative (Lloyd & Mickel 1980) (Chapter 18). Neonatal sclerosing cholangitis Neonatal sclerosing cholangitis (NSC) was first reported in 1987 with a few subsequent reports (AmedeeManesme et al. 1987; Sisto et al. 1987; Maggiore et al. 1988; Mulberg et al. 1992; Baker et al. 1993). The aetiology of this condition is unknown but may have a genetic basis (Baker et al. 1993). Currently the true nature of neonatal sclerosing cholangitis remains uncertain, although scepticism as to whether the entity exists seems unwarranted. In one case non-specific autoantibodies were detected (Bar Meir et al. 2000). NSC is distinguished from childhood primary sclerosing cholangitis by the presentation in early infancy with conjugated hyperbilirubinaemia which then resolves. The clinical picture includes: • Jaundice, which subsides within 3–6 months (AmedeeManesme et al. 1987). Although some children with childhood primary sclerosing cholangitis present as infants (Wilschanski et al. 1995), they have not had early cholestatic jaundice. • Recurrent hyperbilirubinaemia develops 1–2 years later or in mid childhood (8–10 years old). • Development of hepatosplenomegaly, biliary cirrhosis and portal hypertension. Laboratory investigations indicate obstructive biliary disease with elevated serum alkaline phosphatase and gamma-glutamyl transpeptidase. Endoscopic or percutaneous cholangiography demonstrates beaded irregularity of medium to large intrahepatic bile ducts in all patients and in extrahepatic ducts in 80%. Liver histology shows portal fibrosis with ductal proliferation developing into biliary cirrhosis. Surgical treatment with Kasai portoenterostomy is not indicated and nutritional and supportive management is

Chapter 4: The Jaundiced Baby required. The majority of children require liver transplantation at some stage. Hair-like bile duct syndrome This very rare disorder is known as extrahepatic biliary hypoplasia (Krant & Swenson 1973; Lilly 1976) or ‘hairlike bile duct syndrome’. Infants present with conjugated hyperbilirubinaemia and features suggesting extrahepatic biliary atresia, but are found at laparotomy to have an intact but disproportionately small extrahepatic biliary tree. In some reports the extrahepatic bile duct was described as thickened. The clinical course is similar to that of neonatal sclerosing cholangitis: resolution of jaundice, development of biliary cirrhosis, progressive cholestasis with recurring jaundice, portal hypertension, and hepatic insufficiency. A Kasai portoenterostomy is not indicated for these children. Bile duct paucity syndromes Alagille’s syndrome Alagille’s syndrome (syndromic duct paucity, Watson–Miller syndrome, arteriohepatic dysplasia) is a genetic disorder with autosomal dominant transmission but highly variable expression. Alagille’s syndrome was identified in the early 1970s (Watson & Miller 1973; Alagille et al. 1975) because of the unusual association of congenital heart disease, usually peripheral pulmonary artery stenosis, with neonatal cholestasis. Alagille’s syndrome is thought to be rare, occurring in 1 in 100 000 live births. This is probably a gross underestimate, reflecting only those with disease severe enough to be recognized clinically. Genetic basis The genetic basis for Alagille’s syndrome has been determined. Analysis of multiple kindreds indicates autosomal dominant inheritance, with essentially complete penetrance but highly variable expression. There is no evidence for anticipation or imprinting in the pattern of expression. The proportion of new mutations is uncertain, estimated at 15% to ≥ 50% (Dhorne-Pollet et al. 1994; Elmslie et al. 1995). The gene defect has been localized to the human JAG1 gene which is on the short arm of chromosome 20 (20p12) (Li et al. 1997; Oda et al. 1997). JAG1 is the human homologue of the rat gene Jagged 1. It codes for a ligand of Notch 1, which is one of four members in a family of transmembrane proteins with epidermal growth factor (EGF)-like motifs. Alagille’s syndrome is the first childhood disorder identified with a mutation in a ligand for a Notch protein. The expression of Notch 1 and its ligand includes many of the organs potentially abnormal in Alagille’s syndrome. JAG1 is expressed in adult heart and kidney; it is not expressed in adult liver, but it is

49

in fetal liver (Li et al. 1997; Pollet et al. 1997). Haploinsufficiency of JAG1 causes Alagille’s syndrome. Dosage of Notch ligands is critical in development, and this may contribute to the clinical diversity of Alagille’s syndrome. Mutations result in truncated and thus inactive proteins; residual gene expression cannot compensate, leading to the phenomenon of haploinsufficiency (Spinner et al. 2001). Many mutations are sporadic. No clear relationship between genotype and phenotype has been found, although the Delta/Serrate/Lag-2 (DSL) domain in the JAG1 protein may influence the severity of liver disease (Crosnier et al. 1999; Colliton et al. 2001; Crosnier et al. 2001; Yuan et al. 2001). Clinical features Alagille’s syndrome is fairly benign in the majority of children. The majority of patients with clinically important Alagille’s syndrome have conjugated hyperbilirubinaemia in the neonatal period (Deleuze et al. 1995; Emerick et al. 1999). The main clinical features are as follows (see Plate 6, Atlas: p. 442): • Cholestasis, which may be sufficiently severe to produce acholic stools and dark urine. • Characteristic facies, which consists of a broad forehead, deep-set eyes, mild hypertelorism, straight nose and small pointed chin. The facies may not be evident in the first months of life and the classic childhood appearance differs from the adult form. • Skeletal abnormalities, which include ‘butterfly’ vertebrae due to failure of fusion on the anterior arch of the vertebral body, are commonly found in the thoracic spine (Sanderson et al. 2002). There may also be a decrease in the interpedicular distance in the lumbar spine, spina bifida oculta, short distal phalanges and fifth finger clinodactyly, and short ulna. • Eye findings may be very diverse (Hingorani et al. 1999). Posterior embryotoxon, an abnormal prominence of Schwalbe’s line (junction of Descemet’s membrane with the uvea at the angle of the anterior chamber), is most common and requires slit-light examination for detection. It is not pathognomonic since it occurs in 8–15% of normal persons. Optic disc drusen, which are calcific deposits in the extracellular space of the optic nerve head, are common in Alagille’s syndrome and are not found in other cholestatic conditions. They are detected by ocular ultrasound examination (Nischal et al. 1997). Abnormal retinal pigmentation without evidence of functional retinal degeneration may occur. Strabismus, ectopic pupil and hypotrophic optic discs with or without abnormal retinal vessels have also been reported. • Cardiac disease includes peripheral pulmonary artery stenosis, severe hypoplasia of the pulmonary artery branches (Silberbach et al. 1991; McElhinney et al. 2002), Fallot’s tetralogy, pulmonary valve stenosis, aortic stenosis, ventricular septal defect, atrial septal defect and anomalous pulmonary venous return. The severity of

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Section 3: Neonatal Liver Disease

cardiac disease varies between patients and careful assessment is required, particularly if liver transplantation is contemplated. • Chronic cholestasis with pruritus, fat malabsorption, occasionally exacerbated by exocrine pancreatic insufficiency. • Failure to thrive in association with intrauterine retardation. • Severe malnutrition present in ~50% of patients may be part of the syndrome or secondary to fat malabsorption or gastroesophageal reflux. Minor features Apart from the main aspects of Alagille’s syndrome outlined above, a number of other features may be present. These are: • Renal disease, which includes defects in urinary concentrating function, nephrolithiasis, or structural abnormalities such as small kidneys or congenital single kidney, or renal cystic disease. Histological examination may reveal a membranous nephropathy or lipid accumulation in the kidney (mesangiolipidosis). • Delayed puberty or hypogonadism. • Abnormal cry or voice. • Mental retardation, learning difficulties or antisocial behaviour. • Vascular anomalies, including decreased intrahepatic portal vein radicals, coarctation of the aorta and other arterial abnormalities, and Moya Moya disease (Connor et al. 2002). • Neurological abnormalities, such as peripheral neuropathy, may be related to vitamin E deficiency from severe chronic cholestasis. • Hypothyroidism and pancreatic insufficiency. • Recurrent otitis media (Quiros-Tejeira et al. 1999). • Recurrent chest infections, perhaps secondary to gastrointestinal reflux and aspiration pneumonia. • Xanthomata secondary to hypercholesterolaemia. Diagnosis The diagnosis of Alagille’s syndrome is based on the characteristic clinical features, but laboratory investigations may indicate: • Conjugated hyperbilirubinaemia in neonates, which may improve with age. • Aspartate aminotransferase and alkaline phosphatase concentrations are usually elevated (¥ 10 normal). • Gamma-glutamyl transpeptidase concentration elevated 3–20 times normal. • Serum cholesterol and triglyceride may be raised to values three times the upper limit of normal. • Serum albumin and prothrombin time are normal except in decompensated disease. • Abdominal ultrasound may be normal or show a small contracted gall bladder. • Radioisotope scanning may show delayed or no excretion if intrahepatic cholestasis is severe.

• Liver biopsy classically shows reduced numbers of small (i.e. portal) bile ducts and in neonates there may be giant-cell transformation and cholestasis. In some infants (up to 20%) ongoing damage to small bile ducts may be found, or bile ductular proliferation suggestive of extrahepatic bile duct obstruction. The diagnostic histological findings may become obvious only with age (Deutsch et al. 2001). Alternatively, the number of portal tracts may be reduced. Periportal or centrilobular fibrosis is usually absent in infancy but progressive disease with biliary cirrhosis develops in 15–20% of patients. Differentiation from extrahepatic biliary atresia may be difficult on histological grounds alone, particularly if there is significant bile ductular proliferation (see Plate 6, Atlas: p. 442). Management It is essential to exclude extrahepatic biliary atresia, which may be difficult in infants with severe cholestasis, acholic stools and non-excreting hepatobiliary scanning. Endoscopic or operative cholangiography may identify a patent extrahepatic biliary tree. Portoenterostomy is not indicated as this rarely improves bile flow and may increase portal fibrosis because of recurrent cholangitis. Specific management of Alagille’s syndrome is dependent on the distribution and severity of associated disease. Severe cholestasis requires supportive management (see p. 60–3). Nutritional support with feeding via a gastric tube may be highly effective (Duche et al. 1999). Hypercholesterolaemia usually responds to a modified fat diet; gastroesophageal reflux requires standard medical or surgical management. Cardiac anomalies may require corrective surgery, with balloon dilatation or surgical correction of pulmonary valve or pulmonary artery stenosis. Children with Alagille’s syndrome are prone to bleeding episodes without necessarily having definite abnormalities of coagulation (Berard & Triolo 2000; Lykavieris et al. 2003). Special caution must be exercised with respect to head trauma. Renal disease requires specific management as indicated. Outcome The outcome of Alagille’s syndrome depends on the hepatic and extrahepatic disease. The majority of children have a benign course. Most estimates put overall mortality at 20–30%, due to cardiac disease, intercurrent infection or progressive liver disease (Hoffenberg et al. 1995; Emerick et al. 1999; Lykavieris et al. 2001). Early reports of outcome minimize the role for liver transplantation. Liver transplantation should be reserved for patients with hepatic failure, intolerable pruritus unresponsive to medical treatment, and severe growth failure. Liver transplantation can be complicated by associated heart disease, renal impairment or vascular anomalies. Catch-up growth after transplantation often occurs (Cardona et al. 1995; Holt et al. 1997; Quiros-Tejeira et al. 2000) (Chapter 20).

Chapter 4: The Jaundiced Baby Non-syndromic duct paucity In a full-term neonate with small bile duct paucity in whom Alagille’s syndrome has been excluded, various disorders may cause portal ductopenia (small duct paucity), known as ‘non-syndromic duct paucity’. These disorders (Table 4.2) fall into the broad categories of infection, genetic (with chromosomal abnormalities), and metabolic diseases (Kahn et al. 1986). When idiopathic neonatal hepatitis is clinically severe, bile duct paucity may also be present. Among congenital infections cytomegalovirus is the most important cause (Finegold & Carpenter 1982; Dimmick 1993) and cytomegaloviral inclusions may be found in bile duct epithelial cells. Chromosomal abnormalities associated with duct paucity include trisomy 18 and 21. Metabolic disorders associated with duct paucity in the infant are diverse and include a1-antitrypsin deficiency (usually indicates more severe liver disease and a poor prognosis), Byler syndrome, and rarely cystic fibrosis or Zellweger syndrome. Duct paucity may also develop in late stages of extrahepatic biliary atresia following a Kasai portoenterostomy or in primary sclerosing cholangitis. Small bile duct paucity may develop in infants as a result of graft vs. host disease (Shulman et al. 1988) or other immunological injury complicating allogeneic bone marrow transplant or a stem-cell transplant in the perinatal period. Occasionally this develops without features of graft vs. host disease (Wulffraat et al. 1997). Where no specific associated condition can be found, Table 4.2 Causes of non-syndromic paucity of bile ducts in infants Prematurity Infection Cytomegalovirus (CMV) Rubella Syphilis Hepatitis B Metabolic a1-antitrypsin deficiency Cystic fibrosis Zellweger syndrome Byler syndrome Ivemark syndrome Prune belly syndrome Hypopituitarism Genetic: chromosomal disorders Trisomy 18, 21 Partial trisomy 11 Monosomy X Immune-related: graft vs. host disease Severe idiopathic neonatal hepatitis Isolated/idiopathic

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then isolated non-syndromic bile duct paucity can be diagnosed. These children are supposed to have a less favourable outlook than children with Alagille’s syndrome, with persistent severe cholestasis and progressive liver damage. The relationship of childhood nonsyndromic duct paucity to idiopathic adult ductopenia, which has recently been described and may be familial, remains uncertain (Ludwig et al. 1988; Bruguera et al. 1992).

Metabolic liver disease a1-Antitrypsin deficiency This autosomal recessive condition is the most common inherited cause of neonatal hepatitis syndrome. Deficiency occurs in 1 in 1600–2000 live births in North American and European populations, but it is less common in people of other ethnic backgrounds. The protease inhibitor, a1-antitrypsin, is a glycoprotein that is mainly produced in the liver. Only a small proportion of individuals with a1-antitrypsin deficiency ever develop liver disease, but it is the main cause of emphysema in early adulthood. Aetiology and genetics Amember of the serpin superfamily, a1-antitrypsin binds and inactivates leucocyte elastase. More than 75 variants have been reported. The deficiency status is caused by a mutation in the gene at the PI locus on chromosome 14. There is impaired secretion of the mutant gene product, which can be demonstrated in the hepatocyte (periodic acid–Schiff (PAS)-positive diastase-resistant granules). The most common deficiency variant is ‘Z’, a slowmoving protein on electrophoresis, with a point mutation resulting in a single amino acid substitution (lysine replacing glutamic acid at position 342). Some variants such as MMalton and MDuarte show only subtle differences from the normal ‘M’ electrophoretically and may be difficult to recognize. Structural variants of a1-antitrypsin are classified according to the protease inhibitor (PI phenotype) system. More than 75 variants have been reported, most of which are not associated with clinical disease. Liver disease is associated with PI ZZ in the majority of cases. It may occur with PI SZ at a relatively young age and with PI FZ and PI MZ later in adulthood (Gourley et al. 1989; Primhak & Tanner 2001). The pathogenesis of liver disease is unknown, although studies in transgenic mice indicate that liver injury is caused by the intracellular accumulation of the abnormal a1-antitrypsin gene product (Carlson et al. 1989). The Z mutation causes abnormal folding of the a1antitrypsin molecule so that it is caught in the endoplasmic reticulum (Lomas et al. 1992; Perlmutter 1996). Since

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not everyone with PI ZZ a1-antitrypsin develops liver disease, additional factors such as increased production and decreased removal of abnormal a1-antitrypsin within hepatocytes might accelerate liver damage. One possible mechanism involves the serpin–enzyme complex (SEC), which is activated by a1-antitrypsin–elastase complexes and by inflammatory mediators such as substance P (Perlmutter 1994). When activated, it increases a1antitrypsin synthesis. Since a1-antitrypsin is an acutephase reactant, any inflammatory process might increase its production. Defects in hepatocellular proteasome action or other mechanisms for removing abnormal proteins from the endoplasmic reticulum might account for excessive accumulation of abnormal a1-antitrypsin in hepatocytes. New treatments are envisioned based on these mechanisms, including administration of chemical chaperones (Burrows et al. 2000; Perlmutter 2002). Clinical features Neonates with a1-antitrypsin deficiency who develop liver disease present with • Conjugated hyperbilirubinaemia (see Plate 1, Atlas: p. 440). • Intrauterine growth retardation. • Severe cholestasis with totally acholic stools; differentiation from extrahepatic biliary atresia may be difficult. The rare infant has been reported with both a1antitrypsin deficiency and extrahepatic biliary atresia (Nord et al. 1987). • Hepatomegaly is usual at presentation, but splenomegaly is unusual unless significant hepatic fibrosis develops. Approximately 2% of infants present with a vitamin Kresponsive coagulopathy, which is more likely in those infants not given prophylactic vitamin K at birth or who are breast fed. The coagulopathy may be obvious, with bruising and bleeding from the umbilicus, or the initial presentation may be an intraventricular haemorrhage. There is a rapid response to intravenous vitamin K (Hope et al. 1982). Diagnosis Biochemical evaluation demonstrates a mixed hepatocellular/obstructive pattern with raised aminotransferases, alkaline phosphatase and gamma-glutamyl transpeptidase. Radiological investigation may demonstrate severe intrahepatic cholestasis with a contracted gall bladder on abdominal ultrasound and delayed or absent excretion of radioisotope on hepatobiliary scanning. In homozygotes the diagnosis is confirmed by demonstrating low serum a1-antitrypsin levels (normal > 1.0 g/l) and determining the phenotype (PI) by isoelec-

tric focusing. Confusion may occasionally arise if a1antitrypsin levels are increased secondary to hepatic inflammation because it is an acute-phase reactant, but in practice this is rarely a problem with homozygotes. Liver biopsy typically demonstrates a giant-cell hepatitis in which the characteristic PAS-positive diastaseresistant (PASD) granules are detected in the hepatocytes, often noted as early as 6–8 weeks (see Plate 6, Atlas: p. 441). Occasionally PASD-positive inclusions are found in individuals without the Z allele because of an M variant associated with hepatocellular a1-antitrypsin retention (Roberts et al. 1984). Management Management consists of nutritional support, fat-soluble vitamin supplementation, treatment of pruritus and cholestasis as required (see p. 60–3). Patients and parents should not be permitted to smoke, and phenotype inhibitor zz (PIZZ) individuals should be protected from secondary smoke. It is usual to offer family screening for families wishing to have further children. Parents are obligate heterozygotes, thus there is a 25% chance of each subsequent fetus being affected. Antenatal diagnosis by chorionic villus sampling is now available using synthetic oligonucleotide probes specific for the M and Z gene or by restriction fragment length polymorphism (Povey 1990). Prognosis The prognosis is varied. The long-term outlook for many infants with a1-antitrypsin deficiency is good, although a certain proportion of infants with early jaundice develop chronic liver disease (Moroz et al. 1976; Odievre et al. 1976; Ghishan & Greene 1988; Volpert et al. 2000). The outcome falls into four general categories (Psacharopoulos et al. 1983). Approximately half do well: of these infants, half are entirely normal and the other half have mildly abnormal serum aminotransferases but no progression of liver disease. The other half do poorly. Of the infants with poor prognosis, half develop persisting cholestasis with progressive hepatic decompensation and may die or require live transplantation in the first year of life. In the other half, jaundice resolves but serum aminotransferases are abnormal; the liver and spleen remain enlarged. These infants develop cirrhosis with eventual hepatic insufficiency. The small group of children with a1-antitrypsin deficiency who present later in infancy or in childhood with hepatomegaly, without neonatal jaundice, usually have early cirrhosis and a poor prognosis. Early prognostication of individual infants with a1antitrypsin deficiency is difficult. Standard indicators of hepatic decompensation, such as persistent or recurring jaundice, hepatosplenomegaly, prolonged prothrombin

Chapter 4: The Jaundiced Baby time (PT), and elevated serum aminotransferases, are only helpful later in the course of disease (Nebbia et al. 1983). A retrospective analysis of 85 children with neonatal hepatitis and a1-antitrypsin deficiency showed that very elevated serum alanine aminotransferase, prolonged PT, and very low serum a1-antitrypsin concentration at presentation were associated with poor outcome; girls generally had a worse outcome than boys (Ibarguen et al. 1990). In another study of children with neonatal hepatitis, persisting elevation of serum aminotransferases and serum GGT through 6–12 months of age, or presence of bile ductular proliferation, bridging fibrosis or cirrhosis on the initial liver biopsy presaged rapidly progressive liver disease (Francavilla et al. 2000). Infants in whom jaundice or hepatomegaly resolves before the age of 6 months are likely to have a good outcome, but those with prolonged jaundice, cirrhosis or bile duct paucity pursue a downhill course. Infants whose liver disease appears to resolve should still be monitored for development of splenomegaly, as this may herald advancing hepatic fibrosis. Children with a1-antitrypsinassociated cirrhosis may remain stable for some time but may decompensate precipitously. Evaluation for liver transplantation should be considered early for these children. They tolerate liver transplantation well, although attention to potential kidney disease associated with a1antitrypsin deficiency is required through the early postoperative period (Prachalias et al. 2000).

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usually without conjugated hyperbilirubinaemia, and paucity of small (portal tract) bile ducts. The clinical presentation is with jaundice, hepatomegaly, failure to thrive and extrahepatic biliary tract obstruction similar to extrahepatic biliary atresia due to plugging of the common bile duct by abnormal bile (Davies et al. 1986). Early studies suggested that infants with severe liver disease had meconium ileus, which is supported by more recent data obtained at autopsy in patients similar with respect to pulmonary function, nutritional status and Schwachman score (Maurage et al. 1989). Children with cirrhosis had a statistically significant relationship between incidence of mucous plugs in liver tissue histologically and meconium ileus in infancy or distal intestinal obstruction syndrome later in life. Occurrence of neonatal hepatitis syndrome in itself does not necessarily predict early development of cirrhosis. Another rare lesion in cystic fibrosis in infancy is paucity of intrahepatic bile ducts (‘non-syndromic duct paucity’) (Furuya et al. 1991), raising the possibility that there is an inherent abnormality in the small bile ducts in cystic fibrosis. Severe hepatic steatosis has been reported in infants with cystic fibrosis who are typically not jaundiced. In one case, carnitine deficiency was found, and the steatosis improved with carnitine supplementation (Treem & Stanley 1989). Primary disorders of bile acid synthesis

Cystic fibrosis Abnormalities of liver function tests or hepatic pathology are found in one-third of infants with cystic fibrosis (Chapter 11). The spectrum of hepatic pathology includes: giant-cell hepatitis; extrahepatic bile duct obstruction by inspissated bile; massive hepatic steatosis

Inherited defects in the enzymes involved in bile acid synthesis lead to neonatal hepatitis syndrome or to chronic cholestasis later in childhood. A number of new entities have been identified (Table 4.3), largely facilitated by fast atom bombardment-mass spectroscopy (FAB-MS) of urine to identify unusual intermediates arising from

Table 4.3 Primary disorders of bile acid synthesis Enzyme

Cellular location

Features

Treatment

3b-Hydroxy-D5-C27-steroid dehydrogenase/isomerase

Endoplasmic reticulum (‘microsomal’)

Severe neonatal hepatitis; normal serum GGT; low serum total bile acid concentrations; no pruritus

Cholic acid ± UDCA initially

D4-3-Oxosteroid 5b-reductase

Cytoplasm (‘cytosolic’)

Severe cholestasis, coagulopathy; elevated serum total bile acid concentrations

Cholic acid

24,25-Dihydroxy-cholanoic cleavage enzyme

Endoplasmic reticulum

Severe giant-cell hepatitis; normal serum GGT; elevated serum cholesterol; low serum total bile acid concentrations

Cholic acid

C27-Hydroxylase

Mitochondria

Cerebrotendinous xanthomatosis: No liver disease

–

GGT, Gamma-glutamyl transpeptidase; UDCA, ursodeoxycholic acid.

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Section 3: Neonatal Liver Disease

deranged bile acid synthesis. Although rare, these diseases can be treated by supplementation of critical bile acids if the diagnosis is made early in the course of disease. Aetiology Bile acid synthesis involves the conversion of cholesterol to the primary bile acids, cholic and chenodeoxycholic acid. This takes place in hepatocytes, and enzymes in the process are variously located in the endoplasmic reticulum (‘microsomal’), the cytoplasm (‘cytosolic’), mitochondria or peroxisomes. The initial, and rate-limiting, step is a change in the steroid nucleus: hydroxylation of cholesterol at the C7 position by the microsomal enzyme 7a-hydroxylase. Further modifications can then be categorized as involving the steroid nucleus or the side chain. Side-chain abnormalities are found mainly with mitochondrial or peroxisomal disorders. Cerebrotendinous xanthomatosis is due to deficiency of the mitochondrial enzyme C27-hydroxylase, leading to abnormal side-chain modifications; neonatal cholestasis and jaundice do not occur in this disease. Autosomal recessive mutations in two enzymes associated with steroid nucleus modifications at early stages of bile acid synthesis have been associated with severe neonatal liver disease. Two other inborn errors of bile acid metabolism have been described in single patients presenting with neonatal liver disease. An infant with NHS progressing rapidly to biliary cirrhosis with a low–normal serum GGT was found to have oxysterol 7a-hydroxylase deficiency: the liver disease did not improve with cholic acid treatment and required liver transplantation (Setchell et al. 1998). Rather mild NHS with profound fat-soluble vitamin deficiencies was found with deficiency of peroxisomal 2-methylacyl-CoA racemase (Setchell et al. 2003). The bile acid profile was similar to that found with Zellweger syndrome (alligator bile), and treatment with cholic acid was effective. NHS with a defect in bile acid conjugation (ligase deficiency) has also been observed (Bove 2000). 3b-Hydroxy-D5-C27-steroid dehydrogenase/isomerase deficiency This microsomal enzyme is the second in the bile acid synthetic pathway. Infants lacking it present with jaundice and acholic stools in the first few days of life (Buchmann et al. 1990); neonatal hepatitis may be histologically severe (Clayton et al. 1987) or the cholestatic disease may be somewhat more indolent, resembling progressive intrahepatic cholestasis and therefore presenting later in childhood (Horslen et al. 1992; Jacquemin et al. 1994b). One patient was reported with rickets and fat-soluble vitamin deficiencies in the absence of jaundice (Akobeng et al. 1999). Typically affecting infants and children, this deficiency produces excessive amounts of C24bile acids with a 3b-hydroxy-D5 structure. Biochemically they have normal serum GGT and low serum total bile

acid concentrations, and clinically have no pruritus. Treatment with chenodeoxycholic acid (Ichimiya et al. 1990; Horslen et al. 1992) or ursodeoxycholic acid (Jacquemin et al. 1994b) has been reported, but the preferred treatment stategy is cholic acid with or without ursodeoxycholic acid. This may improve bile flow and prevent cirrhosis and hepatic decompensation. D4-3-Oxosteroid 5b-reductase deficiency D4-3-Oxosteroid 5breductase is an important cytosolic enzyme in the bile acid synthetic pathway. The original description of this disorder included two infants with early severe cholestasis and coagulopathy (Setchell et al. 1988); subsequent reports have included infants with a clinical presentation resembling perinatal haemochromatosis (Shneider et al. 1994; Siafakas et al. 1997). In this disorder D4-3-oxo bile acids are overproduced and may be hepatotoxic. Serum GGT is usually, but not invariably, normal. Liver biopsy may reveal abnormal bile canaliculi in a focal, ‘mosaic’ pattern. Treatment with cholic acid (with or without ursodeoxycholic acid) appears beneficial in patients without iron overload (Daugherty et al. 1993). There is a diagnostic subtlety in identifying patients with this genetic disorder because hepatocellular levels of D4-3-oxosteroid 5b-reductase drop with progressive severe liver disease (Clayton 1994). Thus for diagnostic reasons, as well as therapeutic ones, diagnostic testing should be performed as early as possible. 24,25-Dihydroxycholanoic cleavage enzyme deficiency Infants have been described with a defect in the 25hydroxylase pathway (Clayton et al. 1995) and excess production of a bile alcohol with an abnormal, eightcarbon side chain. Jaundice and hepatomegaly were noted in the first week of life; serum GGT was normal but alkaline phosphatase and cholesterol were elevated; biliary and serum bile acid concentrations were low; hepatobiliary scanning showed no drainage; pruritus later developed. Liver biopsy revealed severe giant-cell hepatitis with cholestasis. Treatment with chenodeoxycholic plus cholic acid appeared beneficial. Treatment Treatment consists of nutritional support, therapy for cholestasis and with specific bile salts aimed at compensating for a defective synthetic pathway. Byler disease (progressive familial intrahepatic cholestasis) Byler disease was originally described as a disorder of intrahepatic cholestasis in an American Amish kindred named ‘Byler’: clinical features included pruritus, steatorrhoea, poor growth and inexorable progression to

Chapter 4: The Jaundiced Baby cirrhosis in early childhood (Clayton et al. 1969). NonAmish children were later reported with similar clinical characteristics (Tazawa et al. 1985; Maggiore et al. 1987; Winklhofer-Roob et al. 1992; Whitington et al. 1994; Bourke et al. 1996). A prominent finding was a low or normal serum GGT, which was discordant with the severe cholestasis. Low or normal serum cholesterol is also characteristic and may identify patients reported prior to 1969 (Gray & Saunders 1966). Nomenclature is problematic, especially as Byler disease is itself clinically somewhat variable and is probably only one of several diseases with progressive intrahepatic cholestasis that are clinically similar but mechanistically different. The term ‘progressive familial intrahepatic cholestasis’ (PFIC) has the advantage of being more general, but it is not strictly applicable until there are at least two affected children in a family. Genetics Recent genetic studies, mainly using a shared segment strategy for identifying a common mutation, have identified a group of diseases with progressive intrahepatic cholestasis in childhood with low GGT (PFIC-1 and PFIC2) and one variant with high GGT (PFIC-3). Other highGGT disorders exist and require further definition genetically (Chen et al. 2001). Most patients with Byler disease have a mutation on chromosome 18q21-22 in the FIC1 gene (Bull et al. 1998). FIC1 encodes a P-type ATPase (ATP8B1) involved in aminophospholipid transport between membrane leaflets. FIC1 is expressed in numerous tissues including the gastrointestinal tract, pancreas and lung. Mutations in FIC1 are also responsible for Greenland Eskimo cholestasis (Ornvold et al. 1989; Klomp et al. 2000). Mutations in FIC1 are often the cause of benign recurrent intrahepatic cholestasis, a disease mainly of adults but sometimes symptomatic in childhood (Carleton et al. 1995; Bull et al. 1997; van Ooteghem et al. 2002). Clinical features Byler disease (PFIC-1) presents with conjugated hyperbilirubinaemia in the first 3–6 months of life. The degree of jaundice may vary. Hepatomegaly persists, although progression to cirrhosis is variable. Fat-soluble vitamin deficiencies, including rickets, may be severe. Pruritus is problematic and refractory to most treatment. Growth retardation may not be evident initially. Children with Byler disease have persistent diarrhoea with fat malabsorption and protein loss, bouts of pancreatitis, and poor growth leading to short stature. Sensorineural hearing loss may occur. Cirrhosis usually develops in early childhood and liver transplantation is required. After liver transplant, pancreatitis may still occur, and the diarrhoea may get worse.

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Diagnosis The serum GGT is repeatedly normal, as is serum cholesterol. The total serum bile acid concentration is elevated. However, the concentration of chenodeoxycholic acid in bile from these patients is extremely low (Tazawa et al. 1985; Jacquemin et al. 1994a). Sweat chloride may be elevated (Lloyd-Still 1981). Liver biopsy shows little inflammation but has canalicular bile plugs of distinctive colour on routine histochemical staining, with a characteristic granular appearance on electron microscopy. Small duct paucity may be found. The main differential diagnosis is from an inborn error of bile salt metabolism (see above). PFIC-2 Some children with intrahepatic cholestasis and normal serum GGT do not have this 18q mutation. Instead they have a mutation in a gene found on chromosome 2q24 (Strautnieks et al. 1997). These children differ from those with Byler disease in some respects: they do not have pancreatitis or diarrhoea. There is evidence of inflammation with giant-cell hepatitis, fibrosis and ductular proliferation on liver biopsy. The PFIC-2 gene has now been identified as encoding a bile canalicular transporter, the human bile salt export pump (BSEP, ABCB11), an ATP-binding cassette transporter formerly known as sister of P-glycoprotein (SPGP) (Strautnieks et al. 1998; Jansen et al. 1999). A variety of functional disturbances in bile salt excretion due to different mutations leads to clinical disease (Wang et al. 2002). PFIC-3 A further group of children has been identified with progressive intrahepatic cholestasis but elevated serum GGT (Jacquemin et al. 1997). Onset may occur later in childhood, but presentation in infancy is common. In children with PFIC-3 jaundice may be less prominent than pruritus; despite the clinical appearance of biliary tract obstruction, imaging reveals a normal biliary tree. Portal fibrosis with or without bile ductular proliferation is prominent on liver biopsy. Mutations in the Pglycoprotein MDR-3 gene (ABCB4) have been identified, and mutations resulting in a truncated protein appear to be associated with more severe disease than missense mutations (Jacquemin et al. 2001). The affected protein is the bile canalicular membrane translocator of phospholipids, and PFIC-3 patients have bile phospholipid concentrations which are < 15% of normal. Most children with severe disease require liver transplantation. Treatment and outcome Treatment is as for other cholestatic disorders (see below). Treatment with ursodeoxycholic acid appears to be beneficial in many, if not most, patients with any PFIC disorder. Some children may have relief of pruritus following biliary diversion (Melter et al. 2000) provided it is per-

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formed prior to development of significant hepatic fibrosis. Liver transplantation is indicated for those children with decompensated disease. Aagenaes syndrome Aagenaes syndrome is a very rare disorder with cholestasis and lower limb oedema. It was initially reported in a Norwegian kindred but has also been reported in children of Norwegian descent and in other ethnic groups (Aagenaes et al. 1968; Sharp & Krivit 1971; Vajro et al. 1984; Morris et al. 1997; Aagenaes 1998). The principal features are neonatal hepatitis syndrome evolving to a chronic cholestatic condition and a lymphatic disorder perhaps due to abnormal development of hepatic lymphatics. The lymphatic abnormalities may present clinically later than the jaundice and include localized lower limb lymphoedema like Milroy disease, a more subtle disorder with generalized oedema despite normal serum albumin, or haemangioma(s) and/or lymphangioma(s). The neonatal hepatitis evolves into a cholestatic problem with pruritus and fat-soluble vitamin deficiencies which require treatment. While the initial cholestasis resolves in early childhood, recurrent bouts of cholestasis, similar to benign recurrent cholestasis, and lymphoedema become a prominent problem in adulthood. Chronic liver disease with portal hypertension has not been reported. Abnormal development of hepatic lymphatics has been postulated as part of the pathogenesis of this condition. The genetic basis of this familial cholestatic disorder remains unknown, but the genetic locus has been mapped to chromosome 15q (Bull et al. 2000). North American Indian familial cirrhosis Chronic cholestatic liver disease was described in 14 North American Indians living in north-western Quebec, Canada. Familial clustering of disease incidence was prominent and consanguinity a possible factor. Nine of the 14 presented with neonatal conjugated hyperbilirubinaemia, and in these infants jaundice disappeared during the first year of life. Chronic cholestatic disease was similar in all 14: hepatosplenomegaly, pruritus, facial telangiectasia, and eventually portal hypertension. Serum aminotransferases, alkaline phosphatase and bile acids were elevated, but serum cholesterol was normal in most patients. Serum gamma-glutamyl transpeptidase data were not reported. Electron microscopy revealed widening of the pericanalicular microfilament cuff, not unlike changes due to phalloidin intoxication (Weber et al. 1981). A subsequent report indicated most had moderate elevation of serum cholesterol and elevated GGT (Drouin et al. 2000). Liver disease typically progresses to biliary cirrhosis in this disorder, although liver transplantation is often not required in the first decade of life. The gene

mutated in this disorder has recently been identified: it is FLJ14728, conventionally called cirhin, on chromosome 16q22, and it encodes a protein of unknown function which localizes to mitochondria (Chagnon et al. 2002). It may be appropriate to classify this disorder as one of the PFIC disorders (e.g. PFIC-4). A second apparently different cholestatic disease has been described in North American Indians from various regions of Ontario, Canada (Phillips et al. 1996). Most belong to a single extended kindred and presented as infants with conjugated hyperbilirubinaemia and hepatomegaly; in some jaundice was transient and chronic cholestatic disease developed later in childhood. Two unrelated North American Indian children appeared to have extrahepatic biliary atresia clinically and at laparotomy. Increased concentrations of zinc were found in hepatic parenchyma obtained at the time of liver transplantation in all patients. The pathogenesis of this zincoverload cholestatic liver disease remains to be determined. Zellweger syndrome Zellweger syndrome is the prototype of the peroxisomal biogenesis disorders, characterized by multiple abnormalities of peroxisome function. The molecular and cell biology of these disorders is complex, involving multiple PEX genes which encode peroxins, proteins required for peroxisome assembly. Zellweger syndrome is most often associated with mutations in PEX1 and PEX6 (Moser 1999; Gould & Valle 2000; Preuss et al. 2002). Bile acid synthesis is abnormal because of selective or generalized deficiency of the peroxisomal enzymes involved in sidechain modification. In Zellweger syndrome C27 bile acids accumulate: principally, trihydroxycoprostanic acid (THCA) and dihydroxycoprostanic acid (DHCA). These would ordinarily undergo side-chain modification in the peroxisome to chenodeoxycholic acid and cholic acid. It is a rare disorder with an incidence of 1 in 100 000. Sexes are affected equally. Clinical features and diagnosis Multiple systems besides the liver are affected: features include profound hypotonia, facial dysmorphism with a high forehead and large fontanelles, developmental delay, seizures, bony abnormalities such as epiphyseal calcifications, and cystic malformations in the brain and kidneys (see Plate 7, Atlas: p. 442). Failure to thrive and feeding difficulties are common. In the first 3 months of life, hepatic involvement may not be prominent, although some babies have persistent conjugated hyperbilirubinaemia (Naidu et al. 1988). Fifty percent of infants are not jaundiced but have hepatosplenomegaly with evidence of poor hepatic synthetic function.

Chapter 4: The Jaundiced Baby The diagnosis is confirmed by demonstrating abnormal bile salt metabolites using FAB-MS or the detection of very long-chain fatty acids in serum. Hepatic histology may be normal, although there may be excess iron deposition. Hepatic fibrosis is typical. Paucity of the small (portal) bile ducts may be found. Electron microscopic studies of liver reveal the absence of peroxisomes in hepatocytes. Mitochondria may appear abnormal. These infants may develop cirrhosis, although extrahepatic features of the syndrome typically overshadow the hepatic disease. Treatment and outcome Treatment is supportive, as death is inevitable. Liver transplantation is contraindicated because of the multisystem disease. Attempts to produce peroxisomes with hypolipaemic drugs were not successful (Lazarow et al. 1985). Primary bolus therapy with cholic and chenodeoxycholic acid may produce some initial improvement but does not prolong life (Setchell et al. 1992). Niemann–Pick disease, type A or type C There are two types of Niemann–Pick disease (A and C) associated with neonatal liver disease. Type B is defined as a juvenile-adult form of sphingomyelinase deficiency without neurological features (see also Chapter 12). Niemann–Pick type A This is due to lysosomal sphingomyelinase deficiency. Clinical features include hepatosplenomegaly, failure to thrive and progressive neurological deterioration. Jaundice is unusual. Fetal ascites has been reported (Meizner et al. 1990). Niemann–Pick type C Niemann–Pick type C is secondary to a disorder of cholesterol esterification (Pentchev et al. 1985). There are two subtypes characterized by different mutations (Millat et al. 1999; Naureckiene et al. 2000). Correlation of genotype with phenotype is complex (Millat et al. 2001a,b). The gene product of NPC1 appears to mediate trafficking of sterols and various other substrates out of lysosomes to other subcellular compartments (Neufeld et al. 1999). Numerous animal models exist for type C Niemann–Pick disease. Recent studies in a mutant mouse strain suggest that in addition to abnormal cholesterol homeostasis, peroxisomal function is impaired. This appears to develop at an early stage of the disease and may influence disease progression (Schedin et al. 1997). Some infants may have a similar pattern of disease (Sequeira et al. 1998).

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Clinical features and diagnosis Two-thirds of infants present with prolonged cholestasis, hepatomegaly and a particularly prominent splenomegaly; some may have fetal ascites (Maconochie et al. 1989; Kelly et al. 1993). They appear neurologically normal at birth, although subsequent motor and speech development may lag (Semeraro et al. 1986; Kelly et al. 1993). In one Indo-Pakistani kindred, type C Niemann–Pick disease was associated with extrahepatic biliary atresia and meconium ileus in two of three affected infants (Adam et al. 1988). The remainder of affected children present with isolated splenomegaly with or without neurological symptoms. Liver biopsy shows a histologically severe neonatal hepatitis, pericellular fibrosis and pseudoacinar formation (Rutledge 1989). The diagnosis is confirmed by identifying the characteristic PASD-resistant material in Kupffer cells and hepatocytes, which may be difficult to identify in neonates. It may be easier to detect the foamy storage cells in bone marrow aspirate. Neuronal storage is usually present at birth and may be demonstrated in the ganglion cells of a suction rectal biopsy, which demonstrate typically pleomorphic lamella cytoplasmic inclusions (Kelly et al. 1993) (see Plate 8, Atlas: p. 442). Studies of cholesterol esterification in the patient’s cultured fibroblasts are definitive. Management and prognosis In most infants liver disease resolves and jaundice disappears in the first year of life. Neurological symptoms become obvious by 5 years of age. Most children develop loss of upward gaze due to vertical supranuclear ophthalmoplegia, which is regarded as a pathognomonic sign. Other neurological complications include ataxia, convulsions, developmental delay and dementia. Most children die in early adolescence from bronchial pneumonia rather than liver failure. There is no specific treatment, although a low-cholesterol diet has been suggested. Liver and bone marrow transplantation are ineffective. Genetic counselling is essential and antenatal diagnosis is available by chorionic villus biopsy (Vanier et al. 1989) or by gene analysis (Vanier 2002). Wolman disease Wolman disease, and the associated milder disease, cholesterol ester storage disease, are both due to deficiency of lysosomal acid lipase (also known as acid esterase, cholesterol esterase, or sterol esterase). Inheritance is autosomal recessive; some mutations in the lysosomal acid esterase gene capable of causing severe functional deficiency have been identified (Anderson et al. 1994). Babies with Wolman disease are not usually jaundiced but have deranged liver function, hepatosplenomegaly, persistent diarrhoea and poor growth; calcified adrenal glands are found radiologically. The majority die in early infancy.

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Citrullinaemia, type II Citrullinaemia is due to deficiency of argininosuccinate synthetase. The classic form of citrullinaemia (type I) presents in infancy or childhood as a urea cycle disorder with hyperammonaemia. Jaundice is rare. The disorder is due to mutations in the argininosuccinate synthetase gene on chromosome 9q34. A second form of citrullinaemia has been described, which occurs mainly in adults, who present with fatty liver, hepatitis and iron accumulation. Type II citrullinaemia is due to a deficiency in citrin, a carrier protein of unknown function associated with the urea cycle, encoded by the gene SLC25A13. Several mutations in this gene have been identified in adults with the type II citrullinaemia. Recently infants with NHS were found to have type II citrullinaemia, confirmed by genetic analysis (Tazawa et al. 2001; Ben-Shalom et al. 2002; Saheki & Kobayashi 2002; Tamamori et al. 2002). A distinguishing feature was the presence of steatosis and iron deposition histologically. Liver disease was severe enough in one infant to require liver transplantation.

Toxic injury Total parenteral nutrition-associated cholestasis Progressive cholestasis in infants receiving total parenteral nutrition without any enteral nutrition occurs mainly in critically ill, often premature infants. Aetiology Total parenteral nutrition-associated cholestasis is more likely to develop with increasing degree of prematurity and longer duration of exclusive dependence on total parenteral nutrition to meet nutritional needs. The setting of severe gastrointestinal disease (such as recurrent necrotizing gastroenteritis, gastroschisis or intestinal atresias), which may lead to recurrent bouts of sepsis or require surgical resection(s), or a short gut syndrome signals an especially difficult situation as these infants often cannot avoid protracted use of total parenteral nutrition. The more premature the infant is, the more underdeveloped are hepatocellular mechanisms of bile formation, leading to the development of total parenteral nutritionassociated cholestasis. Factors which amplify this physiological inefficiency by interfering with enterohepatic circulation of bile acids may contribute to the pathogenesis of total parenteral nutrition-associated cholestasis. Depending on gestational age, fetal patterns of bile acid biosynthesis may persist: synthesis of the toxic bile acid, lithocholic acid, may be higher than in older infants. Fasting interrupts the enterohepatic circulation, diminishes the output of gut hormones needed for normal

hepatobiliary function, and may promote small bowel overgrowth by bacteria that are capable of producing endotoxin or modifying endogenous bile acids to more toxic chemicals. Bacterial translocation may occur. All these mechanisms are compounded by systemic factors such as hypoxia or hypoperfusion, localized infection or septicaemia, and medications used to treat these sick infants. Specific nutritional deficiencies may also play a role: lack of taurine, essential fatty acids, carnitine, and antioxidants such as vitamin E, selenium and glutathione (Sokol et al. 1996). It is not clear whether specific components in the total parenteral nutrition solution are toxic. High concentrations of amino acids do not necessarily promote more rapid protein synthesis and may be toxic to hepatocytes. Lipid preparations are probably not toxic as such, although some sources of lipid may be tolerated better than others; however, accumulation of lipofuscin in Kupffer cells appears to be due mainly to the lipid component. Clinical features and diagnosis Most infants present with conjugated hyperbilirubinaemia and hepatomegaly in the context of prolonged parenteral nutrition. Cholestasis may be so severe that extrahepatic biliary tract obstruction is mimicked with acholic stools. Serum aminotransferases, alkaline phosphatase and GGT are usually elevated, whereas albumin and coagulation times are usually normal unless affected by extrahepatic disease. The diagnosis is relatively straightforward. A careful history mapping out feeding history, all other medications and intercurrent illnesses is essential. Other causes of neonatal hepatitis syndrome should be considered and excluded. Abdominal ultrasound may be normal or demonstrate a contracted gall bladder. If cholestasis is severe, there may be delayed excretion on a hepatobiliary scan. Liver biopsy shows cholestasis with hepatocellular necrosis, abundant lipofuscin, some fatty infiltration, mild giant-cell transformation, portal inflammatory infiltrate, and some bile ductular proliferation with or without portal fibrosis. Electron microscopy may reveal cholesterol crystals in hepatocytes. Treatment Treatment continues to be empirical. If possible, some oral nutrition should be introduced: even dextrose in water given in very small boluses (2–5 ml) every few hours is beneficial. Oral or nasogastric feeding with a highly digested formula may be commenced concurrent with continued total parenteral nutrition. The components of the total parenteral nutrition solution should be reviewed carefully to be sure that amino acid requirements are being met but not exceeded and that essential

Chapter 4: The Jaundiced Baby fatty acids and trace metals are supplied. Taurine and carnitine can be supplemented. Protecting the total parenteral nutrition solution from light, and cycling total parenteral nutrition administration are other simple strategies. Extreme care to avoid central venous catheter sepsis is critically important. There may be benefit from treating small bowel overgrowth with metronidazole, although no controlled trials are available; metronidazole is preferable to gentamicin. Once some oral intake is established, ursodeoxycholic acid (20 mg/kg/day) may promote bile flow and improve cholestasis, but there are few reports in children (Cocjin et al. 1993). In general, recovery is slow, unless parenteral nutrition can be discontinued. Infants totally dependent on total parenteral nutrition because of massive bowel dysfunction due to severe inherited disorders of motility or short gut syndrome will develop progressive liver disease, cirrhosis and portal hypertension, which may be exacerbated by intercurrent portal vein thrombosis. Cirrhosis may be averted by either innovative bowel surgery or successful intestinal transplantation, and this should be considered at an early stage before a combined liver– intestine transplant may be needed (Chapter 21). Other complications of total parenteral nutrition Other complications of total parenteral nutrition include: generation of ‘biliary sludge’ (material appreciated by sonography as echogenic, resembling a stone but without typical acoustic shadowing) (Matos et al. 1987); cholelithiasis (Whitington & Black 1980; Roslyn et al. 1983); or acalculous cholecystitis (Thurston 1986) (Chapter 18). Extensive abdominal surgery leading to short gut syndrome or resection of the ileocaecal valve as well as longer duration of parenteral nutrition may predispose to biliary tract disease. Regular ultrasound examination of the biliary tree at 4- to 6-week intervals during prolonged use of total parenteral nutrition may be of value in such patients. Spontaneous resolution of gallstones sometimes occurs in infancy, and thus surveillance of the asymptomatic infant is often appropriate, instead of immediate surgery (Debray et al. 1993). Drug-induced hepatotoxicity Drug hepatotoxicity as a cause of neonatal hepatitis syndrome is poorly documented. Prolonged chloral hydrate administration is associated with conjugated hyperbilirubinaemia in newborns, without other signs of liver toxicity (Lambert et al. 1990). Drug exposure might occur via breast milk, which has been reported for carbamazepine (Merlob et al. 1992; Frey et al. 2002). Cholelithiasis in infants has been attributed to certain drug therapies including prolonged use of frusemide (Whitington & Black 1980; Callahan et al. 1982) or various

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antibiotics such as ceftriaxone (Schaad et al. 1988). Without choledocholithiasis, jaundice is unusual.

Immune causes Neonatal lupus erythematosus Neonatal lupus erythematosus is due to passage of maternal anti-Ro and anti-La antibodies across the placenta leading to damage to fetal tissues, which express Ro and La antigenic determinants. The heart, skin and liver are most likely to be involved, rarely with thrombocytopenia and leukopenia (Silverman & Laxer 1997). Congenital heart block is the most dramatic cardiac manifestation. A rash resembling discoid lupus erythematosus may be present in the newborn period or develop some weeks later. Hepatic involvement, evident in ~10%, is often limited to elevated serum aminotransferases, but neonatal hepatitis syndrome is found (Laxer et al. 1990; Evans & Gaskin 1993). Occasionally this is severe enough to mimic extrahepatic biliary tract obstruction, with acholic stools and non-draining hepatobiliary scan (Rosh et al. 1993). In severe cases a clinical phenotype of neonatal haemochromatosis may be found (Schoenlebe et al. 1993). Deposits of associated antobodies (anti-Ro and/or anti-La) may be found in affected liver tissue by immunofluorescence (Selander et al. 1998). Transient unexplained isolated conjugated hyperbilirubinaemia in the perinatal period and later presentation at 2–3 months old with transient elevations of serum aminotransferases are other possible clinical presentations (Lee et al. 2002). In most infants the liver disease resolves completely between 6 and 12 months of age, as the maternal antibodies are degraded. Mild fibrosis was found in one child on repeat liver biopsy. The diagnosis of neonatal lupus erythematosus is difficult in the child who does not have congenital heart block, a typical skin rash or a history of maternal systemic lupus erythematosus or Sjögren’s syndrome. The risk of neonatal lupus erythematosus in subsequent pregnancies appears variable, estimated at 10–50%. Autoimmune haemolytic anaemia with giant-cell hepatitis This condition is rare and poorly defined as only about 10 children with this complaint have been reported in the English language literature. Most are infants aged 6–24 months or more. Pallor, jaundice and hepatosplenomegaly are the important clinical findings. The autoimmune haemolytic anaemia is Coombs’ positive, but autoantibodies typical of autoimmune hepatitis are not present (Bernard et al. 1981). Viral studies are generally negative, although it is possible that the disease is related to syncytial giant-cell hepatitis attributed to paramyxoviral infection (Phillips et al. 1991). Liver biopsy

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reveals extensive giant-cell transformation with fibrosis. Some patients have responded to treatment with prednisolone and azathioprine (Brichard et al. 1991), but the disease has frequently been refractory to immunosuppressive treatment and may recur following liver transplantation.

Miscellaneous causes Vascular disorders Budd–Chiari syndrome Budd–Chiari syndrome is rarely diagnosed in infants (Jaffe & Yunis 1983; McClead et al. 1986; Gentil-Kocher et al. 1988) but may be due to endophlebitis from a venous catheter or associated with neoplasia, septicaemia or fungal infection (Brocart et al. 1974); membranous obstruction of the inferior vena cava probably represents previous thrombosis of the vessel. A prothrombotic disorder may be present (Dahms et al. 2002). Hepatic vein thrombosis may rarely occur due to other intraabdominal congenital abnormalities (Yonekura et al. 1998). Affected children usually have hepatomegaly, splenomegaly or ascites; jaundice is more common in infants. Budd–Chiari syndrome must be differentiated from veno-occlusive disease, where the vascular blockage is at the level of terminal hepatic venules, as opposed to larger hepatic veins. Veno-occlusive disease is rarely reported in infants, although an infant with congenital leukaemia developed veno-occlusive disease after treatment with antineoplastic drugs. Severe congestive heart failure The role of chronic passive congestion, or functional hepatic venous obstruction, in neonatal hepatitis syndrome is difficult to assess. Babies with severe chronic congestive heart failure may develop moderate hepatomegaly or hepatosplenomegaly, as well as ascites. Jaundice is uncommon (Chapter 15). Infants with acute circulatory failure associated with severe congenital heart disease or shock may develop elevated serum aminotransferases, coagulopathy and jaundice with mild to moderate conjugated hyperbilirubinaemia (Jacquemin et al. 1992), which resolves rapidly once hepatic perfusion is restored. Neonatal asphyxia Neonatal conjugated hyperbilirubinaemia with mild elevations of aminotransferases is associated with severe neonatal asphyxia (Vajro et al. 1997; Jacquemin et al. 1998). Conjugated hyperbilirubinaemia jaundice developed within 6 days of birth, and was protracted. Hepatobiliary

scanning showed bile drainage. Spontaneous resolution typically occurs. Neoplasia Primary hepatic neoplasms rarely present with the neonatal hepatitis syndrome, although mesenchymal hamartoma may present with hyperbilirubinaemia in the neonatal period (Chapter 19). Rhabdomyosarcoma of the biliary tree rarely presents in infancy, but jaundice and acholic stools are the major clinical features. Any neoplasm which obstructs bile flow may cause jaundice (Finegold 1994). Langerhans cell histiocytosis is associated with sclerosing cholangitis in children and may present in early infancy with jaundice (Leblanc et al. 1981a). Jaundice rarely occurs with neuroblastoma, erythrophagocytic lymphohistiocytosis, or neonatal leukaemia.

Consequences of cholestasis Many infants with neonatal liver disease will have a mild self-limiting disease, but those children with progressive disease, or following unsuccessful Kasai portoenterostomy, will develop significant fat malabsorption with consequent protein malnutrition. It is important to establish baseline anthropometric examinations in order to detect and prevent early malnutrition. This is best evaluated by using a combination of weight (may be imprecise because of fluid retention), height (may be useful for assessing chronic malnutrition), triceps skin fold (to evaluate fat stores), and mid-arm muscle area (to evaluate protein stores). Mid-arm circumference is a reliable marker of malnutrition in children under 5 years old. The effects of chronic cholestasis are extensive: failure of biliary excretion of bilirubin, bile salts and cholesterol leads to jaundice, pruritus and xanthomata; decreased bile salts in the intestine leads to malabsorption of longchain triglycerides and consequent fat malnutrition. Malabsorption of fat-soluble vitamins is inevitable (Table 4.4). If cirrhosis develops, then protein malnutrition and muscle wasting are likely.

Management of neonatal liver disease Management should be supportive and, whenever possible, definitive. Disorders for which specific medical or surgical therapies are available are summarized in Table 4.5. Nutritional support The main aim of nutritional support is to provide sufficient calorie intake to reverse or prevent fat malabsorption and protein malnutrition. In extrahepatic biliary

Chapter 4: The Jaundiced Baby atresia resting energy expenditure runs ~30% higher than in normal infants of the same age and sex (Pierro et al. 1989). Thus an aggressive approach to feeding is required, including nasogastric supplementation if oral feeding cannot meet caloric needs (Kaufman et al. 1987). Infants with severe cholestatic jaundice require special

Table 4.4 Consequences of chronic cholestasis and cirrhosis Aetiology

Clinical manifestations

Reduced excretion of bilirubin, bile acids Fat malabsorption Essential fatty acid deficiency Vitamin A deficiency

Pruritus, jaundice

Vitamin E deficiency

Vitamin D deficiency Vitamin K deficiency Hypercholesterolaemia Increased protein catabolism

Steatorrhoea, loss of fat stores Peeling skin rash Conjunctival and corneal drying, abnormal retinal function, night blindness Peripheral neuropathy, ophthalmoplegia, ataxia, haemolysis Osteopenia, rickets, fractures Bruising, epistaxis, coagulopathy Xanthomata Muscle wasting, motor development delay, growth failure

formulas to ensure that calorie intake is 120–150% EAR (estimated average requirement) using either a standard infant formula with appropriate supplements or a modular feed in which individual constituents can be added according to requirement. A nearly elemental formula containing medium-chain triglycerides, which can be absorbed regardless of luminal concentrations of bile acids, is preferable. Caloric density can be increased further by concentrating the formula or adding starch powder (glucose polymer). If the infant is satisfactorily breast-feeding this should be encouraged with supplementation using a highly digestible high-caloric-density formula. Fat-soluble vitamin supplementation All infants with chronic cholestasis, whether jaundiced or not, require supplementation with fat-soluble vitamins. These can be provided as water-soluble preparations of vitamins A, D, E and K given orally (Kaufman et al. 1987), or less commonly, as parenteral supplementation (Alagille 1985) (Table 4.6). Vitamin levels should be monitored to ensure adequate absorption and prevent toxicity. Vitamin AThis is provided in a water-soluble preparation. Toxic levels may lead to hepatic fibrosis or pseudotumour cerebri.

Table 4.5 Neonatal liver disease syndrome: specific treatments Disease

Major diagnostic strategy

Infection Toxoplasmosis Cytomegalovirus Herpes simplex Syphilis Bacterial infection elsewhere (sepsis) Tuberculosis Syncytial giant-cell hepatitis

Spiramycin Gancyclovir, if severe Acyclovir Penicillin Appropriate antibiotic(s) Quadruple antitubercular therapy (not ethambutol) Ribavirin (unproven benefit)

Endocrine Panhypopituitarism (septo-optic dysplasia)

Corticosterone, thyroxine, growth hormone

Structural Extrahepatic biliary atresia Choledochal cyst Choledocholithiasis Spontaneous perforation of CBD

Kasai portoenterostomy before 8–12 weeks old Surgical resection Surgical removal Surgical repair

Metabolic Primary disorders of bile acid synthesis

Bile acid supplementation

Toxic TPN-associated cholestasis Drug-induced

Enteral feeding; metronidazole; ursodeoxycholic acid Stop causative drug

Immune Neonatal hepatitis with autoimmune haemolytic anaemia

Prednisolone + azathioprine

CBD, Common bile duct; TPN, total parenteral nutrition.

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Table 4.6 Oral regimens for supplementation of fat-soluble vitamins in infants with chronic cholestasis Vitamin

Regimen

Features of toxicity

A

Water-soluble preparation 5000–25 000 units/day

Hepatotoxicity; pseudotumour cerebri; dermatitis

D

Vitamin D 800–5000 units/day or 25-hydroxyvitamin D3 3–5 mg/kg/day

Hypercalcaemia: lethargy, cardiac arrhythmia, nephrocalcinosis

E

TPGS 15–25 IU/kg/day or a-tocopheryl 25–200 iU/d/day

(None known) (Polyethylene glycol: hyperosmolarity if renal impairment)

K

2.5 mg twice per week 5 mg daily

(Clotling diathesis?)

TPGS, Tocopheryl polyethylene glycol succinate.

Vitamin D This is usually provided as alfacalcidol (1,25-dihydroxy-vitamin D), although the administration of 25-hydroxy-vitamin D may be more effective (Heubi et al. 1989). Vitamin D production in the skin can be enhanced through sunlight or sunlamp exposure, even for babies who are jaundiced (Kooh et al. 1989). Absorption of water-soluble vitamin D may be enhanced by simultaneous administration of alpha tocopheryl polyethylene glycol succinate formulation of vitamin E (Argao et al. 1992). Vitamin E Vitamin E transferred via the placenta to the fetus may keep the infant replete until the age of 3 months, but the sufficiency of maternal stores varies from baby to baby. Most babies require supplementation after 2 months of age or earlier if the baby was born preterm. Vitamin E linked to polyethylene glycol 1000 through a succinate linkage, alpha tocopheryl polyethylene glycol succinate (TPGS), has the best bioavailability in severe cholestasis (Sokol et al. 1987a,b) as its absorption depends on simple passive absorption of polyethylene glycol independent of bile acids in the intestinal lumen. This formulation is not universally available and the more traditional oral supplement vitamin E acetate may not be as quickly absorbed. Coagulation should be monitored closely in all infants with cholestasis, who should receive oral vitamin K prophylactically. Infants receiving rifampicin for pruritus should receive extra vitamin K. Other dietary measures It is reasonable to place an infant with conjugated hyperbilirubinaemia on lactose-free formula until the results of testing for galactosaemia are known; however, interrupting breast feeding is problematic. Brief use of a more restrictive diet is sometimes justifiable: an infant with severe neonatal hepatitis syndrome might be placed on a lactose-free/low-protein formula (to minimize aromatic amino acid intake) until the results of tests for both galac-

tosaemia and hereditary tyrosinaemia type I are available. Special diets are used life-long for children with inborn errors of carbohydrate and amino acid metabolism. Supplementation with specific bile acids may arrest liver damage in inborn errors of bile acid metabolism (Suchy 1993). Pruritus Pruritus due to severe cholestasis interferes with the infant’s sleep and compromises quality of life. It is often difficult to treat; local measures such as non-perfumed skin cream may help. For infants with some duct patency and bile flow medical therapy includes: • Cholestyramine (1–4 g daily) is effective but is unpalatable. The mechanism of action is to bind bile salts in the intestinal lumen, thus interrupting the enterohepatic circulation and reducing bile salt concentration. Sideeffects include malabsorption of fat-soluble vitamins and drugs, folic acid deficiency, constipation and acidosis. Cholestyramine can cause intestinal obstruction or hypernatraemia in small infants; adequate fluids must be given with it. • Ursodeoxycholic acid (UDCA) may be effective when given in a dose of 15–30 mg/kg/24 h. It is thought to have a choleretic action but is not universally effective. UDCA may transiently increase pruritus. • Phenobarbitone (5–10 mg/kg/day) may stimulate bile salt-independent bile flow and decrease jaundice and control pruritus. However, it is relatively ineffective, causes sedation and may exacerbate rickets. • Biliary diversion may be effective in some conditions, including PFIC and Alagille’s syndrome (Emerick & Whitington 2002). • Rifampicin (5–10 mg/kg/day) relieves pruritus in at least 50%, producing a significant improvement in the remainder (Yerushalmi et al. 1999). Results are variable and experience in young infants limited (Banks et al. 1989;

Chapter 4: The Jaundiced Baby Gregorio et al. 1993). Rifampicin inhibits uptake of bile acids by hepatocytes and alters their metabolism (Hoensch et al. 1985; Wietholtz et al. 1996). Side-effects include hepatotoxicity in 5–10% and thrombocytopenia. The urine may turn an orange–red colour. • Phototherapy with infrared or ultraviolet radiation may improve pruritus if given for 3–10 min daily. • Antihistamines are largely ineffective but as they cause drowsiness may be useful at night. Toxic side-effects include cardiac dysrhythmias. Family and psychological support Specific attention to the infant’s developmental needs is often beneficial. Physiotherapy may improve gross motor development while infant stimulation programmes enhance the mental development for infants who require frequent hospitalization. Family education and support are essential, particularly for children with progressive illness requiring liver transplantation. Indications for liver transplantation The indications for liver transplantation are severe cholestasis, decompensated liver disease and intractable pruritus (Chapter 20). Orthotopic liver transplant is often the only definitive treatment for severe infantile liver disease and can be performed safely in the first year of life (Casavilla et al. 1994; Colombani et al. 1996; Bonatti et al. 1997), especially if nutrition has been maintained well. In those who are malnourished, catch-up growth occurs after liver transplantation, including patients with Alagille’s syndrome (Holt et al. 1997; D’Antiga et al. 2002). The role of gene transfer therapies for genetic disorders causing the neonatal hepatitis syndrome requires further clarification.

Inherited disorders of bilirubin conjugation These rare disorders are characterized by benign conjugated hyperbilirubinaemia and an unexplained abnormality of coproporphyrin metabolism. Clinical features include jaundice, which may be exacerbated by stress, intercurrent illness, pregnancy and oral contraceptives. There are no other clinical or laboratory features of liver disease. The diagnosis is made as described below. Dubin–Johnson syndrome Dubin–Johnson syndrome is due to mutations in the human gene MRP2, which encodes the bile canalicular membrane transporter for anion conjugates (Kartenbeck et al. 1996; Paulusma et al. 1997). (Some initial reports used the terminology ‘canalicular multispecific organic anion

63

transporter’, or cMOAT, for this transporter.) Numerous mutations have been described, most of which cause functional deficits though defects in protein maturation and localization (Hashimoto et al. 2002; Keitel et al. 2003). Neonatal hepatitis syndrome has been reported rarely in Dubin–Johnson syndrome (Shieh et al. 1990; Regev et al. 2002). Treatment of severely affected neonates with ursodeoxycholic acid may be beneficial. Diagnosis is hampered by the difficulty in recognizing the typical melanin-containing pigment in the liver during infancy as little accumulates until later in childhood. Bromosulphophthalein sodium retention in the serum at 45 min is generally between 10 and 20%. Coproporphyrin excretion in urine is normal, but the ratio of coproporphyrin III to coproporphyrin I is is reversed, with coproporphyrin I accounting for > 75% of the total urinary coproporphyrins (Haimi-Cohen et al. 1998). Abdominal computed tomography scan showing high attentuation in the liver may provide important supporting evidence for the diagnosis in an infant (Shimizu et al. 1997). Liver histology in older children demonstrates a typical melanincontaining pigment, which is found predominantly in the centrolobular region. Rotor syndrome Rotor syndrome is also characterized by conjugated hyperbilirubinaemia without cholestasis but does not have pigment accumulation in the liver. The pathogenesis of Rotor syndrome remains unclear but is related to a defect in bilirubin secretion. Neonatal hepatitis syndrome has not been reported in infants with Rotor syndrome. The diagnosis is made by estimating the bromosulphophthalein sodium retention in serum, which is 30–50% at 45 min after injection, or by measuring urinary coproporphyrin excretion, which is generally increased, with a particular increase in coproporphyrin I. No treatment is required for either disorder apart from reassurance.

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of a new category of metabolic liver disease. Hepatology 18, 1274–1277. Suchy, F.J., Balistreri, W.F., Heubi, J.E., Searcy, J.E. & Levin, R.S. (1981) Physiologic cholestasis: elevation of the primary serum bile acid concentrations in normal infants. Gastroenterology 80, 1037–1041. Suita, S., Arima, T., Ishii, K., Yakabe, S. & Matsuo, S. (1992) Fate of infants with neonatal hepatitis: pediatric surgeons’ dilemma. Journal of Pediatric Surgery 27, 696–699. Sun, C.-C.J., Keene, C.L. & Nagey, D.A. (1990) Hepatic fibrosis in congenital cytomegalovirus infection: with fetal ascites and pulmonary hypoplasia. Pediatric Pathology 10, 641–646. Sussman, N.L., Finegold, M.J., Barish, J.P. & Kelly, J.H. (1994) A case of syncytial giant-cell hepatitis treated with an extracorporeal liver assist device. American Journal of Gastroenterology 89, 1077–1082. Sutomo, R., Laosombat, V., Sadewa, A.H. et al. (2002) Novel missense mutation of the UGT1A1 gene in Thai siblings with Gilbert’s syndrome. Pediatrics International 44, 427–432. Tamamori, A., Okano, Y., Ozaki, H. et al. (2002) Neonatal intrahepatic cholestasis caused by citrin deficiency: severe hepatic dysfunction in an infant requiring liver transplantation. European Journal of Pediatrics 161, 609– 613. Tan, K.L. (1975) Comparison of the effectiveness of phototherapy and exchange transfusion in the management of non-hemolytic neonatal hyperbilirubinemia. Journal of Pediatrics 87, 609–612. Tarr, P.I., Haas, J.E. & Christie, D.L. (1996) Biliary atresia, cytomegalovirus, and age at referral. Pediatrics 97, 828–831. Tazawa, Y., Kobayashi, K., Ohura, T. et al. (2001) Infantile cholestatic jaundice associated with adult-onset type II citrullinemia. Journal of Pediatrics 138, 735–740. Tazawa, Y., Yamada, M., Nakagawa, M., Konno, T. & Tada, K. (1985) Bile acid profiles in progressive intrahepatic cholestasis: absence of biliary chenodeoxycholate. Journal of Pediatric Gastroenterology and Nutrition 4, 32–37. Thurston, W.A. (1986) Acute acalculous cholcystitis in a premature infant treated with parenteral nutrition. Canadian Medical Association Journal 135, 332–334. Todani, T., Urushihara, N., Morotomi, Y. et al. (1995) Characteristics of choledochal cysts in neonates and early infants. European Journal of Pediatric Surgery 5, 143–145. Todani, T., Watanabe, Y., Narusue, M., Tabuchi, K. & Okajima, K. (1977) Congenital bile duct cysts. Classification, operative procedures, and review of thirty-seven cases including cancer arising from choledochal cyst. American Journal of Surgery 134, 263–269. Treem, W.R. & Stanley, C.A. (1989) Massive hepatomegaly, steatosis, and secondary plasma carnitine deficiency in an infant with cystic fibrosis. Pediatrics 83, 993–997. Trioche, P., Chalas, J., Francoual, J. et al. (1999) Jaundice with hypertrophic pyloric stenosis as an early manifestation of Gilbert syndrome. Archives of Disease in Childhood 81, 301–303. Vajro, P., Amelio, A., Stagni, A. et al. (1997) Cholestasis in newborn infants with perinatal asphyxia. Acta Paediatrica 86, 895–898. Vajro, P., Romano, A., Fontanella, A., Oggero, V., Vecchione, R. & Shmerling, D.H. (1984) Aagenaes’s syndrome in an Italian child. Acta Paediatrica Scandinavica 73, 695–696. Vanier, M.T. (2002) Prenatal diagnosis of Niemann–Pick diseases types A, B and C. Prenatal Diagnosis 22, 630–632. Vanier, M.T., Rousson, R.M., Mandon, G., Choiset, A., Lake,

Chapter 4: The Jaundiced Baby B.D. & Pentchev, P.G. (1989) Diagnosis of Niemann–Pick disease type C on chorionic villus cells. Lancet 1, 1014–1015. Vasquez, J., Lopez Gutierrez, J.C., Gamez, M. et al. (1995) Biliary atresia and the polysplenia syndrome: its impact on final outcome. Journal of Pediatric Surgery 30, 485–487. Volpert, D., Molleston, J.P. & Perlmutter, D.H. (2000) Alpha1antitrypsin deficiency-associated liver disease progresses slowly in some children. Journal of Pediatric Gastroenterology and Nutrition 31, 258–263. Wang, L., Soroka, C.J. & Boyer, J.L. (2002) The role of bile salt export pump mutations in progressive familial intrahepatic cholestasis type II. Journal of Clinical Investigation 110, 965–972. Watson, J.C., Fleming, D.W., Borella, A.J., Olcott, E.S., Conrad, R.E. & Baron, R.C. (1993) Vertical transmission of hepatitis A resulting in an outbreak in a neonatal intensive care unit. Journal of Infectious Diseases 167, 567–571. Watson, G.H. & Miller, V. (1973) Arteriohepatic dysplasia. Familial pulmonary arterial stenosis with neonatal liver disease. Archives of Disease in Childhood 48, 459–466. Weber, A.M., Tuchweber, B., Yousef, I. et al. (1981) Severe familial cholestasis in North American Indian children: a clinical model of microfilament dysfunction? Gastroenterology 81, 653–662. Weldon, A.P. & Danks, D.M. (1972) Congenital hypothyroidism and neonatal jaundice. Archives of Disease in Childhood 47, 469–471. White, F.V., Jordan, J., Dickman, P.S. & Knisely, A.S. (1995) Fetal parvovirus B19 infection and liver disease of antenatal onset in an infant with Ebstein’s anomaly. Pediatric Pathology 15, 121–129. Whitington, P.F. & Black, D.D. (1980) Cholelithiasis in premature infants treated with parenteral nutrition and furosemide. Journal of Pediatrics 97, 647–649. Whitington, P.F., Freese, D.K., Alonso, E.M., Schwarzenberg, S.J. & Sharp, H.L. (1994) Clinical and biochemical findings in progressive familial intrahepatic fibrosis. Journal of Pediatric Gastroenterology and Nutrition 18, 134–141. Wietholtz, H., Marschall, H.U., Sjovall, J. & Matern, S. (1996) Stimulation of bile acid 6 alpha-hydroxylation by rifampin. Journal of Hepatology 24, 713–718. Wilcox, D.T., Casson, D., Bowen, J., Thomas, A. & Bruce, J. (1997) Cholelithiasis in early infancy. Pediatric Surgery International 12, 198–199.

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Wilkinson, M.L. (1996) Sphincterotomy for jaundice in a neonate. Journal of Pediatric Gastroenterology and Nutrition 23, 507–509. Wilschanski, M., Chait, P., Wade, J.A. et al. (1995) Primary sclerosing cholangitis in 32 children: clinical, laboratory, and radiographic features, with survival analysis. Hepatology 22, 1415–1422. Winklhofer-Roob, B.M., Shmerling, D.H., Soler, R. & Briner, J. (1992) Progressive idiopathic cholestasis presenting with profuse watery diarrhea and recurrent infections (Byler’s disease). Acta Paediatrica 81, 637–640. Witzleben, C.L., Marshall, G.S., Wenner, W., Piccoli, D.A. & Barbour, S.D. (1988) HIV as a cause of giant cell hepatitis. Human Pathology 19, 603–605. Wolf, M.J., Beunen, G., Casaer, P. & Wolf, B. (1997) Extreme hyperbilirubinaemia in Zimbabwean neonates: neurodevelopmental outcome at 4 months. European Journal of Pediatrics 156, 803–807. Wulffraat, N.M., Haddad, E., Benkerrou, M. et al. (1997) Hepatic GVHD after HLA-haploidentical bone marrow transplantation in children with severe combined immunodeficiency: the effect of ursodeoxycholic acid. British Journal of Haematology 96, 776–780. Yamataka, A., Ohshiro, K., Okada, Y. et al. (1997) Complications after cyst excision with hepaticoenterostomy for choledochal cysts and their surgical management in children versus adults. Journal of Pediatric Surgery 32, 1097–1102. Yerushalmi, B., Sokol, R.J., Narkewicz, M.R., Smith, D. & Karrer, F.M. (1999) Use of rifampin for severe pruritus in children with chronic cholestasis. Journal of Pediatric Gastroenterology and Nutrition 29, 442–447. Yeung, C.Y. (1985) Kernicterus in term infants. Australian Paediatrics Journal 21, 273–274. Yonekura, T., Kubota, A., Hoki, M. et al. (1998) Intermittent obstruction of the inferior vena cava by congenital anteromedial diaphragmatic hernia: an extremely rare case of Budd–Chiari syndrome in an infant. Surgery 124, 109–111. Yuan, Z.R., Okaniwa, M., Nagata, I. et al. (2001) The DSL domain in mutant JAG1 ligand is essential for the severity of the liver defect in Alagille syndrome. Clinical Genetics 59, 330–337. Zuppen, C.W., Bui, H.D. & Grill, B.G. (1986) Diffuse hepatic fibrosis in congenital cytomegalovirus infection. Journal of Pediatric Gastroenterology and Nutrition 5, 489–491.

Chapter 5: The Acutely Ill Baby PATRICK J. MCKIERNAN

Approach to diagnosis and management, 74 Infection, 76 Fetal and neonatal ascites, 76 Galactosaemia, 77 Neonatal screening, 77 Infantile liver failure, 77 Neonatal haemochromatosis (NNH), 78 Disorders of mitochondrial energy metabolism, 79 Deficiencies of the electron transport chain enzymes, 79

Mitochondrial DNA depletion syndrome, 80 Tyrosinaemia type I, 80 Familial haemophagocytic lymphohistiocytosis, 82 Inborn errors of metabolism associated with hepatic enzyme deficiency, 83 Urea cycle disorders, 83 Defects in fatty acid oxidation, 84 Carnitine palmitoyl transferase 1 deficiency, 85 Multiple acyl-coenzyme A

The majority of patients presenting with liver disease in infancy will have either cholestatic liver disease (Chapter 4) or acute liver failure with multisystem disease. Recent advances in biochemical techniques and molecular genetics have dramatically improved the diagnosis of many of these conditions whilst significant developments in therapy have altered management and outcome. This chapter outlines the clinical presentation and approach to diagnosis and management for infants presenting with an acute illness.

Approach to diagnosis and management Infants and neonates have limited responses to severe illness irrespective of aetiology, but important diagnostic information may be obtained from simple clinical and laboratory observations obtained at the time of presentation. Age at presentation is important, with three risk periods recognizable: at birth, in the neonatal period, and later in infancy. Conditions presenting at birth imply an intrauterine process, while early neonatal presentation may imply a toxic process, often infective or metabolic in origin (Table 5.1). In establishing aetiology, the clinical history should enquire about preceding symptoms and precipitants. In infants presenting soon after birth, information about pregnancy and delivery is of obvious relevance. In all age groups, a dietary history is crucial, with particular attention being paid to symptoms on weaning or on fasting, and recent changes in diet. In neonates the first sign

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dehydrogenase defect (glutaric acidaemia type 2), 86 Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, 86 Organic acidaemias, 86 Propionic acidaemia, 86 Methylmalonic acidaemia, 87 Other organic acidaemias, 88 Screening for inborn errors of metabolism, 88 Mutation detection, 88 Hepatocyte transplantation, 88

of altered consciousness may be difficulty in feeding, whereas in older infants vomiting is a frequent accompaniment of encephalopathy. A history of consanguinity or of any previously affected siblings should be sought. Clinical assessment should first concentrate on the Airway–Breathing–Circulation of resuscitation, followed by a complete physical examination. Particular attention should be paid to the presence of hepatomegaly, neurological abnormalities, tachypnoea and unusual odours. It is important to recognize intercurrent illnesses such as pneumonia, septicaemia or congenital heart disease, which may have precipitated the acute episode and will require specific treatment. Table 5.2 lists the investigations that are required immediately. Additional samples of each biological fluid should be separated and frozen, with subsequent analysis depending on the results of the initial screen. An algorithm for diagnosis of the acutely ill infant is given in Fig. 5.1, with appropriate second-line investigations outlined in Table 5.3. Until the diagnosis is established, management is supportive with correction of hypoglycaemia, acid–base imbalance, electrolyte imbalance and coagulopathy as required (Chapter 7). It is prudent to exclude galactose, fat and protein from the diet during the first 24 h of acute illness while awaiting specific diagnostic information, but restriction should be for as short a time as possible. Parenteral empirical broad-spectrum antibiotic treatment should be commenced once initial samples have been obtained and continued until sepsis has been excluded.

Chapter 5: The Acutely Ill Baby Table 5.1 Differential diagnosis of acutely ill infants Conditions presenting at birth Hydrops fetalis Lysosomal storage disease Conditions presenting in neonatal period Infection: Coxsackie A or B Herpes simplex Adenovirus Cytomegalovirus Parvovirus Echovirus Neonatal haemochromatosis Mitochondrial cytopathy Galactosaemia Organic acidaemia Urea cycle defects Disorder of fatty acid oxidation

Table 5.3 Second-line investigations following initial assessment Phenotypic group

Second-line investigations

Liver failure

Fe, transferrin, ferritin Cholesterol and triglycerides Galactose-1-phosphate uridyl transferase Plasma amino acids Urinary organic acids and succinyl acetone Specific urine and stool viral culture Respiratory chain enzymes

Mitochondrial energy disorders*

Pre-/post-prandial plasma lactate, glucose FFA and 3-OH Plasma carnitine, acylcarnitine Plasma amino acids, creatine kinase Urinary organic acids CSF lactate Muscle biopsy for RCE Brain MRI EEG and visual evoked potentials

Urea cycle disorders*

Plasma amino acids Carnitine and acylcarnitines Lactate, glucose, FFA, and 3-OH Creatine kinase Urinary amino, organic and orotic acids

Fat oxidation defects*

Carnitine and acylcarnitines; lactate, glucose, FFA, 3-OH Creatine kinase Urinary organic acids

Gluconeogenetic defects

Lactate, glucose FFA, 3-OH Creatine kinase, urate, cholesterol, triglycerides Urinary organic acids and oligosaccharides Specific enzyme assays (see text)

Organic acidaemias*

Plasma amino acids Carnitine and acylcarnitines Urinary organic acids

Hypopituitarism

09.00 h cortisol, thyroid function tests, growth hormone, IGF-1

Conditions presenting later in infancy Tyrosinaemia type 1 Glycogen storage disease Hereditary fructose intolerance

Table 5.2 Initial investigations in the acutely ill infant Blood* Bacterial culture Prothrombin time, partial thromboplastin time, fibrinogen, D-dimers Bilirubin, alkaline phosphatase, transaminases, albumin, GGT Acid–base balance Glucose Lactate Ammonia, amino acids Full blood count and film Urea, sodium, potassium, calcium Acylcarnitine profile Urine* pH Microscopy and culture Reducing substances Ketones Organic acids Amino acids CSF (if coagulation and neurological state allow) Gram stain and culture Protein, glucose Lactate Radiology Chest and wrist X-ray Echocardiography

*Store plasma, serum and urine samples for further investigations (see Table 5.3). GGT, Gamma-glutamyl transpeptidase.

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CSF, Cerebrospinal fluid; EEG, electroencephalogram; Fe, iron; FFA, free fatty acids; IGF-1, insulin growth factor-1; MRI, magnetic resonance imaging; 3-OH, 3-hydroxybutyrate; RCE, respiratory chain enzyme. *Fibroblast culture for specific enzymatic diagnosis.

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Coagulopathy +/- encephalopathy +/- hypoglycaemia +/- liver dysfunction

Yes

Liver failure

No Encephalopathy? Yes No

Hyperammonaemia?

Lactate increased? Yes

Yes

Hypoglycaemia? Yes

Metabolic acidosis or Lactate increased? No

Gluconeogenetic defects

No Hypoglycaemia

No Mitochondrial energy disorders

Hypopituitarism

Yes

Hypoglycaemia? No

Ketosis? Yes

Urea cycle disorders

No

Fat oxidation defects

Mitochondrial disorders Organic acidaemias

Table 5.4 Causes of neonatal ascites Congenital infection Cytomegalovirus Toxoplasmosis Syphilis Metabolic Lysosomal storage disorders: Salla disease Sialidosis type II Niemann–Pick type C GMI gangliosidosis Mucopolysaccharidosis VII Wolman’s disease Gaucher’s disease Tyrosinaemia type 1 Neonatal haemochromatosis Carbohydrate deficient glycoprotein syndrome Other Cardiac disease Hepatoblastoma Haemangioendothelioma Mesenchymal hamartoma

Fig. 5.1 Algorithm for the initial investigation/diagnosis of the acutely ill infant. The bold boxes represent phenotypic groups. For each phenotypic group second-line investigations are summarized in Table 5.3.

Yes

Infection Intrauterine or postnatal infection is an important and common cause of acute illness in the neonate; it is fully discussed in Chapters 4, 6 and 7 (see also Tables 5.1 and 5.2).

Fetal and neonatal ascites Fetal or neonatal ascites is a rare presentation that occurs in about 1 in 3000 pregnancies and is associated with intrauterine infection, inborn errors of metabolism or rhesus haemolytic disease. As the rate of fetal loss is high, few infants present with this complication. The widespread use of anti-D immunoglobulin has reduced the incidence of haemolytic disease and the majority of cases are now secondary to disorders of cardiac structure or rhythm, or haematological, gastrointestinal or genitourinary disease. Hepatic and metabolic causes account for about 4% of cases, with lysosomal storage disorders being the commonest of this group (Table 5.4). They are particularly important to recognize as all are autosomal recessive, and early prenatal diagnosis may be possible (Stone & Sidransky 1999). A number of pathogenic mechanisms may contribute to the development of ascites: cardiac failure; anaemia

Chapter 5: The Acutely Ill Baby due to infiltration of the reticuloendothelial system; hepatic infiltration or insufficiency producing hypoalbuminaemia; or mass effects resulting in vascular and lymphatic obstruction. The diagnosis may be suspected on antenatal ultrasound or shortly after birth because of abdominal distension. Hepatosplenomegaly is usually present. Investigation It is necessary to exclude the commoner infective, cardiovascular and haematological causes, and search for storage disorders as follows: • blood film for vacuolated lymphocytes • bone marrow aspirate for storage cells • plasma transferrin electrophoresis for carbohydratedeficient glycoprotein syndrome • urinary oligosaccharidases and glycosaminoglycans • white cell or fibroblast culture for lysosomal enzymes. Treatment This should be started prenatally, if possible, with close obstetrical liaison regarding the mode and place of delivery. Resuscitation may require immediate paracentesis and transfusion in the labour suite. Subsequent management and prognosis depend on the aetiology. The prognosis is poor for storage diseases presenting in this manner. Symptomatic relief may be gained by the use of spironolactone (3 mg/kg/day), fluid restriction (50–75% maintenance) and 4.5% albumin transfusion (5–10 ml/kg).

Galactosaemia This autosomal recessive disorder is caused by deficiency of galactose-1-phosphate uridyl transferase and has an incidence of ª1 in 45 000. Several different allelic variants with varying degrees of residual activity have been recognized (Reichardt 1992). The commonest mutation (Q188R) accounts for > 70% of abnormal alleles while N314D is associated with a milder form, the Duarte variant (Elsas et al. 1995). Much more rarely, a defect of the epimerase enzyme can occur with similar clinical presentation (Walter et al. 1999). Acute illness results from the accumulation of galactose-1-phosphate (Gal-1-P) and galactitol following the introduction of milk feeds. Clinical presentation and diagnosis Infants may present with collapse with hypoglycaemia and encephalopathy in the first few days of life, or with progressive jaundice and liver failure. Vomiting, diarrhoea, jaundice and poor weight gain are common in early infancy. Cataracts (characteristically ‘oil-drop’) are present shortly after birth and may be associated with intraocular haemorrhage and retinal detachment. There

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is a high incidence of Gram-negative sepsis, which is usually associated with a severe coagulopathy. Renal tubular dysfunction is common. The diagnosis is classically suggested by the detection of urinary reducing substances without glycosuria, but urinary tests are neither sensitive nor specific. An associated proximal renal tubular defect may result in aminoaciduria and glycosuria while reducing substances in the urine are a frequent non-specific finding in other forms of neonatal liver disease (Vajro et al. 1991). Alternatively, galactosuria may not be detected in an infant with galactosaemia who is severely ill and no longer taking a lactose-containing formula. The diagnosis should be confirmed by demonstration of reduced enzyme activity in blood. Misleading results may be obtained if the baby has been transfused (false negative) or in glucose-6-phosphate dehydrogenase deficiency (false positive). Where there is confusion, other diagnostic options include measuring erythrocyte Gal-1-P, testing for the Q188R mutation or measuring parental-erythrocyte galactose-1-phosphate uridyl transferase. Hepatic pathology initially demonstrates fatty change, periportal bile duct proliferation and iron deposition with extramedullary haematopoiesis (Plate 10, Atlas: p. 443). If galactose ingestion persists, hepatic fibrosis and cirrhosis may develop, although cirrhosis may be present at birth (Holton 1996). Management and prognosis Liver function improves within days following exclusion of galactose from the diet unless liver failure or cirrhosis is already established. Cataracts may improve if treatment is started early enough. Galactose elimination should be lifelong but long-term complications such as mental disability, speech defects, ovarian failure and neurological syndromes are common despite dietary treatment (Honeyman et al. 1993). This may result from endogenous synthesis of galactose-1-phosphate rather than dietary indiscretion (Berry et al. 1995). Neonatal screening Neonatal screening for galactosaemia is not universally available but leads to early detection except in those babies who present with fulminant hepatitis. Antenatal diagnosis is possible by chorionic villus sampling.

Infantile liver failure Acute liver failure in infancy usually presents with multisystem involvement (see Plate 9, Atlas: p. 443). The diagnosis may initially be difficult as jaundice may be a late feature. Infants may be small for gestational dates or have intrauterine growth retardation. The clinical pre-

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sentation includes hypotonia, hypoglycaemia and hypotension. Coagulopathy is invariable in association with liver dysfunction and moderate hyperammonaemia. Encephalopathy is frequent but not inevitable in infants and may be difficult to recognize (Chapter 7). Neurological problems such as nystagmus and convulsions may be secondary to cerebral disease or encephalopathy. Renal tubular acidosis or lactic acidosis is common. Physical examination and investigations should be directed at identifying and excluding multiorgan disease and pathology. General measures include intravenous dextrose to maintain blood glucose > 4 mmol/l, prophylactic antibiotics, antifungal therapy, intravenous ranitidine to prevent gastric bleeding, correction of coagulopathy with fresh frozen plasma and/or exchange transfusions (Chapter 7). Once baseline and essential investigations have been conducted (Table 5.2) it is wise to exclude galactose and protein from the diet until diagnosis is confirmed. As spontaneous recovery is unlikely, all children should be assessed for liver transplantation unless there is irreversible multiorgan disease. Neonatal haemochromatosis (NNH) This disorder, also known as perinatal haemochromatosis or neonatal iron storage disease, is the commonest cause of acute liver failure in the neonate. The disease is characterized by prenatal liver disease combined with hepatic and extrahepatic siderosis with sparing of the reticuloendothelial system (Knisely 1992). The pathogenesis is uncertain. It is unclear whether it is due to a primary disorder of fetoplacental iron handling, or a secondary manifestation of fetal liver disease. Reports of fetal liver disease preceding extrahepatic siderosis in familial cases favour the latter model. This is unlikely to be a single disorder, but rather a syndrome developing as a common endpoint to a range of potential disease processes (Witzleben & Uri 1989). There does not appear to be a permanent systemic defect of iron storage, as surviving children do not have reaccumulation of iron following successful liver transplantation. Inheritance Familial occurrence of this disease is well recognized, but inheritance is non-Mendelian. There is no association with mutations in the genes for hereditary haemochromatosis or juvenile haemochromatosis (Feder et al. 1996; Kelly et al. 2001; Roetto et al. 1999). NNH is extremely rare in first pregnancies, and once one affected child has been born the risk of recurrence in subsequent pregnancies is > 70%. Of seven reported cases where half-siblings were born to the same mother, NNH occurred in both sibships in six (Verloes et al. 1996). This suggests that in at

least some cases a maternal factor, possibly isoimmune, is contributory. In some cases, there has been an association with maternal anti-Ro and anti-La antibodies (Schoenlebe et al. 1993). Presentation and diagnosis Intrauterine growth retardation is common and the majority of affected infants are delivered prematurely. Children present with hypoglycaemia, jaundice and coagulopathy, often on the first day of life, although the presentation may be delayed until up to 3 months of age (Knisely 1992; Silver et al. 1987). Ascites may be present. Encephalopathy is variable and may present with irritability and drowsiness. The clinical course is usually rapidly progressive, with most infants dying in the first month of life. Laboratory features include: • mild elevation of transaminases • low albumin • elevated conjugated bilirubin • prothrombin time grossly elevated (> 50 s) • serum iron high with hypersaturation of iron-binding capacity (95–105%) • grossly elevated ferritin levels (2000–3000 mg/l). These laboratory features, including iron status markers, are sensitive but non-specific, being found in neonatal liver failure of any cause (Lee et al. 2001). For definitive diagnosis, liver biopsy is rarely feasible in life but extrahepatic siderosis can be safely demonstrated in minor salivary glands obtained by lip biopsy (Knisely et al. 1988). Magnetic resonance imaging (MRI) may also provide evidence of excess hepatic and extrahepatic iron. Where feasible, liver histology demonstrates pericellular fibrosis, giant-cell transformation, ductular proliferation and regenerative nodules. The distribution of siderosis is similar to hereditary haemochromatosis, with characteristic sparing of the reticuloendothelial system (Knisely 1992) (see Plate 11, Atlas: p. 443). Management and outcome Infants should be managed in a Neonatal Intensive Care setting in a transplant centre. In addition to the usual supportive regime for acute liver failure (Chapter 7) an antioxidant cocktail should be commenced once the diagnosis is suspected. This includes three antioxidants: • N-acetyl cysteine (140 mg/kg by mouth or nasogastric tube as a loading dose; then 70 mg/kg every 4 h to a total of 17–21 doses) • selenium (3–2 mg/kg/day intravenously over 24 h) • Alpha tocopheryl polyethylene glycol succinate (20–30 iU/kg/day orally in two divided doses) • Prostaglandin E1 given as a continuous intravenous infusion (0.4–0.6 mg/kg/h daily for 2–4 weeks)

Chapter 5: The Acutely Ill Baby • Desferrioxamine (30 mg/kg/day as an intravenous infusion over 8 h until serum ferritin is < 500 mg/l). Response to the antioxidant cocktail is variable. Of eight patients treated with the antioxidant cocktail in the USA, seven died or required liver transplantation (Sigurdsson et al. 1998). In Birmingham we have treated five children with the antioxidant cocktail, two of whom recovered completely without liver transplantation and without recurrence of the disease (Flynn et al. 2002). The antioxidant cocktail is more effective if begun within 24–48 h of birth and in infants with a less severe phenotype. Even in children who do not completely respond to treatment the use of this cocktail may produce sufficient stabilization of their condition to allow liver transplantation (Shamieh et al. 1993; Sigurdsson et al. 1998). Children who survive without liver transplantation develop an inactive fibrosis or cirrhosis (Colletti & Clemmons 1988). Liver transplantation remains the definitive treatment. It is usually appropriate to list children for transplantation while continuing the antioxidant cocktail as suitable donor organs are scarce in this age group and the major cause of mortality is progressive liver failure while awaiting transplantation. Recent reports have demonstrated how liver transplantation is successful in this group of infants despite technical difficulties (Muiesan et al. 1995; Sigurdsson et al. 1998; Noujaim et al. 2002). Transient recurrent siderosis may occur in the transplanted liver, presumably reflecting mobilization of extrahepatic iron stores (Rand et al. 1992). In only one case has there been clinically significant recurrence (Egawa et al. 1996). Antenatal diagnosis Early antenatal diagnosis is impossible, but later in pregnancy ultrasound may detect non-specific abnormalities such as hydrops fetalis or growth retardation. Maternal anti-Ro and anti-La antibodies may be associated with the development of fetal heart block and subsequent neonatal haemochromatosis (Flynn et al. 2002). MRI has been used to detect prenatal iron accumulation, as has fetal blood sampling for iron status (Hayes et al. 1992). Antenatal diagnosis facilitates the prospective use of the antioxidant regime from birth, but early delivery to limit fetal iron accumulation is not currently appropriate as complications of prematurity and small size may preclude liver transplantation. Experimental protocols have been established to examine the effect of maternal immunoglobulin administration during affected pregnancies. Provisional reports suggest that the disease is ameliorated rather than prevented. For subsequent siblings we suggest immediate postpartum measurement of iron status (iron, iron-binding capacity and ferritin) and liver synthetic function to facilitate early use of the antioxidant cocktail in affected cases (Flynn et al. 2002).

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Disorders of mitochondrial energy metabolism This rare group of disorders presents with acute liver failure and multiorgan disease. There is a wide range of clinical phenotypes with any mode of inheritance — autosomal recessive, autosomal dominant or transmission through maternal DNA. The pathological effects are secondary to dysfunction of the electron transport chain resulting in cellular ATP deficiency and the generation of toxic free radicals. Clinical symptoms are variable depending on the nature of the primary defect, its tissue distribution and abundance, and the importance of aerobic metabolism in the affected tissue. The constituent proteins of the electron transport chain are encoded by autosomally inherited nuclear DNA (nDNA) and by mitochondrial DNA (mtDNA), which is maternally inherited (Munnich et al. 1996). In the acutely ill infant, two entities are most relevant: isolated deficiencies of the electron transport chain enzymes and mtDNA depletion syndromes. Deficiencies of the electron transport chain enzymes The most common isolated defect involves complexes IV and I, although multiple deficiencies have been reported. Infants present with multisystem involvement and a severe metabolic acidosis (Cormier-Daire et al. 1997). Clinical presentation The clinical presentation is varied, and the onset may be prenatal with structural brain abnormalities. Non-specific dysmorphic features are not uncommon. Neurological features are prominent, and lethargy and hypotonia are almost invariable. Cardiac involvement includes hypertrophic cardiomyopathy, and there may be proximal renal tubulopathy. Hepatic involvement is unpredictable and includes isolated hepatomegaly; neonatal cholestasis; and acute liver failure with coagulopathy. Diagnosis The diagnostic hallmark of these disorders is elevated blood lactate, but even this may be intermittent and is non-specific. Useful secondary investigations to identify the cause of lactic acidosis include: • increased plasma 3-OH-butyrate/acetoacetate ratio (> 2) • increased plasma lactate ± ketone bodies either postprandially or following a glucose load (2 g/kg) • detection of specific organic acids such as urinary 3methylglutaconic acid or other Krebs cycle intermediates (Poggi-Travert et al. 1996). A comprehensive evaluation is required, including renal tubular function, ECG and echocardiography,

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electroretinography and visual evoked potentials. Elevated cerebrospinal fluid (CSF)/plasma lactate ratio or elevated CSF protein suggest central nervous system involvement. Hepatic pathology is characterized by both micro- and macrovesicular steatosis, with hepatocyte degeneration and micronodular cirrhosis (see Plate 12a, Atlas: p. 443). Electron microscopy may reveal abnormal structure or number of mitochondria, although this is not invariable. Muscle histology usually shows increased lipid droplets with variation in fibre size; the presence of ragged red fibres on the Gomori stain are strongly suggestive of mtDNA abnormalities (see Plate 12b, Atlas: p. 443). The definitive diagnosis is based on demonstrating dysfunction of electron transport chain function in affected tissue by histochemistry and direct measurement of enzyme activity. Deficiencies of some respiratory chain subunits can be detected by immunocytochemistry. It is helpful to identify whether or not these defects are encoded in mtDNA or nDNA as this facilitates genetic counselling. The most useful tissue to sample is usually muscle, as it is easily accessible with well-established normal ranges. In the presence of liver failure demonstration of extrahepatic involvement will preclude liver transplantation. Management and prognosis Supportive management for acute liver failure may be the only therapeutic option. Dichloroacetate may lower lactate concentrations, but clinical benefit has not been established and there are concerns about side-effects. Liver transplantation may be successful if the defect is confined to the liver (Goncalves et al. 1995; Dubern et al. 2001), which is highly unusual if the presentation is with liver failure. Transplantation is contraindicated if multisystem involvement is demonstrated, as neurological deterioration continues post-transplant with eventual death (Thomson et al. 1998). Antenatal diagnosis Inheritance is generally assumed to be autosomal recessive, but in individual families it is impossible to exclude spontaneous mutations. Antenatal diagnosis is occasionally possible if the underlying mutation is known (Ruitenbeek et al. 1996; Amiel et al. 2001). Mitochondrial DNA depletion syndrome Mitochondria normally contain 2–10 copies of mtDNA. Replication of mtDNAis regulated by a number of factors encoded by nuclear genes. Presumed mutations in these nuclear genes lead to reduction in copy numbers of mtDNA resulting in mitochondrial DNA depletion with autosomal recessive inheritance. The underlying nuclear

genetic defect has only been found in a few cases to date. In these cases mutations have been found in genes encoding the mitochondrial enzymes DNApolymerase gamma (Naviaux 1998), thymidine kinase (Saada et al. 2001) and deoxyguanosine kinase (Taanman et al. 2002). Clinical presentation and diagnosis The clinical presentation includes acute liver failure and fasting hypoglycaemia in the newborn period or infancy (Morris et al. 1998). Presentation in later childhood has been occasionally reported. In the newborn form, metabolic or lactic acidosis in association with jaundice may be presenting features, whereas in the infantile form, vomiting and hypoglycaemia develop in the first month of life. Biochemical liver function tests may demonstrate a disproportionately elevated gamma-glutamyl transpeptidase (GGT) compared with aspartate aminotransferase (AST) and alanine aminotransferase (ALT). There may be urinary dicarboxylic aciduria and lactic acidosis. In all hepatic variants, hepatic pathology demonstrates micronodular cirrhosis, microvesicular steatosis and increased iron deposition. Electron microscopy may demonstrate proliferation of mitochondria with abnormalities of content and morphology. Tissue measurement of electron chain activities typically shows deficiencies in complexes I, III and IV, although activity may be normal (Gray et al. 1997). The diagnosis is confirmed by demonstrating an abnormally low ratio of mtDNA/nDNA in affected tissue (Tritschler et al. 1992). Management and prognosis Treatment is supportive with prevention of fasting hypoglycaemia using either continuous feeds or uncooked corn starch (1 g/kg). Carnitine (100 mg/kg/ day), multivitamins supplemented with coenzyme Q (4 mg/kg/day), riboflavin (50–100 mg/day) and niacin (10–25 mg/day) have been used anecdotally. Liver transplantation is usually contraindicated due to multisystem involvement, but liver isolated forms have been documented (Ducluzeau et al. 2002). Most cases have been fatal, and invariable where presentation has been in infancy. Documented reports of spontaneous recovery suggest some caution should be exercised in prognostication where the presentation is after infancy. Antenatal diagnosis is not currently possible in the majority of cases (Blake et al. 1999). Tyrosinaemia type I Tyrosinaemia type I is an autosomal recessive disorder due to a defect of fumaryl acetoacetase (FAA), which is the terminal enzyme in tyrosine degradation. Intermediate metabolites such as maleyl- and fumaryl-acetoacetate

Chapter 5: The Acutely Ill Baby

81

Tyrosine

4-OH phenylpyruvate

4-OH phenylpyruvate deoxygenase

NTBC (2-(2-nitro-4-trifluoromethylbenzoyl) -1,3-cyclohexenedione)

–ve

Porphyrin synthesis pathway

Maleylacetoacetate

5-aminolaevulinic acid

Fumarylacetoacetate

Succinylacetone

–ve

PBG synthase

Fumarylacetoacetase (deficient in TT1)

Fig. 5.2 Metabolic pathway for tyrosine metabolism. TT1, Tyrosinaemia type 1; 4-OH, 4-hydroxybutyrate.

Fumarate + acetoacetate

are highly reactive compounds that are locally toxic and mutagenic within the liver. The secondary metabolite succinylacetone has local and systemic effects (Fig. 5.2) including inhibition of porphobilinogen synthase, accounting for the porphyria-like neurological crises seen. The gene for FAA is on the short arm of chromosome 15. More than 40 mutations have been described to date (St-Louis & Tanguay 1997; Heath et al. 2002), although in some populations a single mutation may be prevalent (Grompe et al. 1994; Rootwelt et al. 1996). Ahallmark of the condition is the extremely high lifetime risk of developing hepatocellular carcinoma, which historically is at least 40% (Weinberg et al. 1976). Clinical presentation The disease is found worldwide but is particularly common in the Saguenay-Lac St. Jean region of Canada (incidence 1 : 500) (De Braekeleer & Larochelle 1990) and in parts of Pakistan and northern Europe. In Birmingham, the incidence is 1 : 20 000, reflecting the mixed ethnic population (Hutchesson et al. 1996). Clinical presentation is heterogeneous even within the same family (van Spronsen et al. 1994). Acute liver failure is a common presentation in infants between 1 and 6 months of age; these patients present with mild jaundice, coagulopathy, encephalopathy and ascites with inguinal hernias. Hypoglycaemia is common and may be secondary to liver dysfunction or hyperinsulinism due to pancreatic islet cell hyperplasia (Baumann et al. 1996). In older infants, failure to thrive, coagulopathy, he-

Porphobilinogen

patosplenomegaly, hypotonia and rickets are common. Older children may present with chronic liver disease, cardiomyopathy, renal failure or a porphyria-like syndrome with self-mutilation (Plate 13a,b, Atlas: p. 444). Neurological symptoms include muscle weakness, particularly respiratory muscle weakness. Renal tubular dysfunction and hypophosphataemic rickets may occur at any age. Diagnosis Investigations and diagnostic findings include: • mildly elevated bilirubin • mildly abnormal transaminases (100–200 iU/l) • elevated alkaline phosphatase (> 600 iU/l) • low albumin (< 30 g/l) • prolonged prothrombin time (> 20 s) • grossly elevated a-fetoprotein levels (40 000–70 000 mg/l) • increased plasma tyrosine, phenylalanine and methionine (3 ¥ normal depending on age) • significant urinary succinyl acetone is a pathognomonic but not an invariable finding, but this compound should be estimated to exclude a non-specific elevation of amino acids secondary to liver dysfunction • increased urinary delta-aminolaevulinic acid • proximal tubular dysfunction with phosphaturia and aminoaciduria is invariable • echocardiography may reveal a hypertrophic cardiomyopathy • radiological evidence of rickets.

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Hepatic histology is non-specific with steatosis and siderosis. Cirrhosis is almost always established at the time of clinical presentation. Hepatocyte dysplasia is a common finding that increases with age, and is regarded as a premalignant change (see Plate 14, Atlas: p. 444). The diagnosis is confirmed by measuring FAA activity in fibroblasts or lymphocytes or by mutation analysis in informative families.

transplantation (Mohan et al. 1999), which prevents the development of hepatocellular carcinoma and allows resumption of a normal diet. Current indications for liver transplantation include: • the development of acute or chronic liver failure unresponsive to NTBC • the development of hepatocellular carcinoma • poor quality of life due to dietary restriction.

Management

Prognosis

Initial management is with a phenylalanine- and tyrosine-restricted diet, which may improve overall nutritional status and renal tubular function, but alone has little effect on the progression of liver disease. The recent introduction of NTBC (2-(2-nitro-trifluoromethylbenzoyl)-1,3-cyclohexenedione), which prevents the formation of toxic metabolites (Fig. 5.2), has changed the natural history of this disease in childhood (Lindstedt et al. 1992). Treatment with NTBC (1 mg/kg/day) in addition to dietary restriction leads to rapid reduction of toxic metabolites within days, with disappearance within 1 month. Over 200 patients world-wide have been treated with NTBC, with normalization of renal tubular function, complete control of porphyria-like crises, and improvement in both nutritional status and liver function (Holme & Lindstedt 2000). In Birmingham we have treated 16 children with NTBC. Eight of these children presented with acute liver failure and seven responded to NTBC with correction of coagulopathy and encephalopathy. All responders showed an improvement in prothrombin time within 1 week of treatment and the single nonresponder underwent successful liver transplantation. NTBC therapy requires close monitoring of plasma amino acids. Tyrosine levels should be kept < 600 mmol/l, with the phenylananine level within normal range. NTBC clearly protects against the development of hepatocellular carcinoma, but not absolutely (see Plate 15, Atlas: p. 444). To date, a single patient treated in infancy with NTBC has developed hepatocellular carcinoma (DionisiVici 1997) and eight children who were more than 2 years old at treatment have developed hepatocellular carcinoma. This has usually been early in treatment, suggesting that malignancy was already established and was associated with abnormal a-fetoprotein levels (Holme & Lindstedt 2000). Due to the risk of hepatocellular carcinoma we suggest that a-fetoprotein levels are monitored every 3 months, abdominal ultrasound every 6 months and hepatic MRI annually (unless ultrasound is abnormal). A sustained rise of a-fetoprotein is an indication for liver biopsy to identify hepatic dysplasia, and or consideration of liver transplantation. The definitive treatment for tyrosinaemia remains liver

Infantile presentation with liver failure has an 80% mortality with supportive treatment alone and a high lifetime risk of hepatocellular carcinoma. The long-term outcome for children with tyrosinaemia type I treated with NTBC, and particularly the risk of hepatocellular carcinoma, is as yet unknown (Lindstedt et al. 1992; Grompe et al. 1995). Palliation of features such as hypertrophic cardiomyopathy occurs with both NTBC and following liver transplantation (Arora et al. 2001). Liver transplantation has an 80% 5-year survival with good quality of life (Perez-Cerda et al. 1993; Paradis 1996). It results in a functional ‘cure’ although renal production of succinylacetone continues. Renal dysfunction is more likely in patients transplanted for this indication due to the combined effect of renal succinyl acetone production and nephrotoxic immunosuppressive drugs (Laine et al. 1995; Wijburg et al. 1995). Screening Neonatal screening programmes have been established in populations with relatively high incidences of tyrosinaemia. Sensitivity is achieved by using a sufficiently low blood tyrosine cut-off, with specificity maintained by using secondary tests such as porphobilinogen synthetase, or mutation detection in homogeneous populations. Prospective dietary treatment decreases the risk of infantile liver failure. There is surprisingly little information on the prospective use of NTBC. I have treated only one sibling prospectively and at 1 year the infant is clinically and biochemically normal. Antenatal diagnosis Antenatal diagnosis is possible either by chorionic villus sampling to measure FAA directly or from mutation analysis if the genotype is known. Alternatively, succinylacetone can be measured in amniotic fluid.

Familial haemophagocytic lymphohistiocytosis This rare autosomal recessive disorder is a class II histiocytosis that may be due to a defect in immunomodula-

Chapter 5: The Acutely Ill Baby tion. It is characterized by development of clonal T-cell lymphocyte populations with resulting abnormal cytokine production (Hirst et al. 1994; Kimura et al. 2001). The disease appears to be genetically heterogeneous. In some families mutations in the perforin gene have been described (Stepp et al. 1999). If the disease presents in later infancy or in older childhood the distinction between familial and virally induced haemophagocytic syndrome may be extremely difficult to make.

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accumulation of ammonia and glutamine. These defective enzymes are: • carbymyl phosphate synthetase (CPS) • ornithine transcarbamylase (OTC) • arginosuccinic acid synthetase (citrullinaemia) • arginosuccinate lyase (ASA). These disorders are autosomal recessive apart from OTC, which is X-linked. Females with OTC may be heterozygotes and have varying degrees of deficiency and clinical involvement (Nyhan et al. 1991).

Clinical presentation and diagnosis Infants present with malaise, jaundice, hepatosplenomegaly, relapsing fever and skin rash. Laboratory investigations show: • consumptive coagulopathy with hypofibrinogenaemia • pancytopenia • elevated plasma triglycerides • increased serum ferritin and LDH • low albumin • hyponatraemia • erythrophagocytosis in bone marrow, liver or CSF lymphocytic infiltration (see Plate 16, Atlas: p. 444). Treatment and prognosis Treatment is supportive. Etoposide and steroids may induce remission but relapse is frequent. Cyclosporin and anti-T-lymphocyte globulin may be helpful in maintaining remission. HLA-identical bone marrow transplantation has produced survival rates of 66%, but as < 20% of patients have a disease-free identical sibling this option is restricted. Matched unrelated and related non-identical marrow transplantation has shown encouraging results in a few cases (Jabado et al. 1997). Liver transplantation is contraindicated and inappropriate (Parizhskaya et al. 1999).

Inborn errors of metabolism associated with hepatic enzyme deficiency There are a number of inborn errors of metabolism associated with defective hepatic enzymes, which are characterized by profound acidosis, hyperammonaemia or disorders of fatty acid oxidation. The relevance of these disorders is that presentation is usually in the neonatal period with an acute illness, which may be associated with abnormal liver function tests or hepatomegaly. A brief overview of these disorders is provided. Urea cycle disorders There are four main disorders in which defects in enzymes of the urea cycle lead to neurotoxicity from an

Clinical features and diagnosis There is a wide range of clinical features, which are associated with increased plasma ammonia. Hepatomegaly and abnormal transaminases may be present. Neonates present shortly after birth and are extremely ill, with vomiting, lethargy, seizures and coma. The diagnosis may be suspected if there is a low urea, alkalosis and an intraventricular haemorrhage. Females with OTC may present later in infancy or even in adult life. Clinical features include episodic vomiting with neurological dysfunction, which may be precipitated by intercurrent infection or ingestion of protein. A history of natural avoidance of high-protein foods is common. Investigations include: • hyperammonaemia • plasma amino acids, which demonstrate abnormal citrulline levels: elevated in citrullinaemia; low in ASA, and undetectable in OTC and CPS • argininosuccinic acid is also high in citrullinaemia • orotic aciduria is present in OTC, ASA and citrullinaemia • glutamine and alanine concentrations may also be elevated • prothrombin time may be increased. The diagnosis is confirmed by measuring specific enzyme activity in liver tissue for CPS and OTC. The main differential diagnoses for an elevated ammonia in the newborn periods include poor sampling, organic acidaemia, liver dysfunction or acute liver failure (Chapter 7), or transient hyperammonaemia of the newborn (Green 1988). Treatment Emergency management of hyperammonaemia The initial aim of treatment is to reduce ammonia as quickly as possible to prevent further neurotoxicity. Dietary protein should be withdrawn. Initial management is pharmacological (Table 5.5), with dialysis if hyperammonaemia is severe. Intravenous dextrose, in combination with insulin, is provided to minimize catabolism. Phenylbutyrate and sodium benzoate form conjugates

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Section 3: Neonatal Liver Disease

Table 5.5 Emergency management of hyperammonaemia

Table 5.6 Recognized defects of fatty acid oxidation

Stop all dietary protein

Fatty acid transporter Carnitine transporter Carnitine palmitoyl transferase 1 Acylcarnitine translocase Carnitine palmitoyl transferase 2 Very long-chain acyl-CoA dehydrogenase Medium-chain acyl-CoA dehydrogenase Short-chain acyl-CoA dehydrogenase Long-chain 3-hydroxyacyl-CoA dehydrogenase (trifunctional protein) Short-chain 3-hydroxyacyl-CoA dehydrogenase Multiple acyl-CoA dehydrogenases (electron transport flavoprotein and electron transport flavoprotein dehydrogenase) Riboflavin-responsive multiple acyl-CoA dehydrogenase

If ammonia > 200 mmol/l 1. Intravenous dextrose 10% 2. Sodium benzoate: Loading dose 250 mg/kg Continuous infusion 250 mg/kg/day 3. Arginine in 10%: Loading dose 350 mg/kg over 2 h Continuous infusion 350 mg/kg/day If ammonia > 400·mmol/l or rising despite treatment 1. Dialysis 2. Continuous infusion of sodium phenylbutyrate (250 mg/kg/day) 3. Repeat loading dose of sodium benzoate and arginine

with glutamine and glycine, respectively, which are excreted in the urine and provide an alternative route for elimination of nitrogenous compounds. Arginine, which corrects the arginine deficiency resulting from the block in the urea cycle, also acts as a source of ornithine for reconstitution of the cycle if there is residual activity. Continuous venovenous haemodialysis is more rapidly effective than haemofiltration or peritoneal dialysis, especially in the newborn period (Schaefer et al. 1999). Dialysis should be continued until ammonia is < 150 mmol/l. The intravenous dextrose and insulin is continued until the ammonia is < 100 mmol/l and the child is neurologically normal. Protein can slowly be reintroduced at this stage. Maintenance treatment This consists of dietary restriction of protein (0.7 g/kg) supplemented with essential amino acids and a high-calorie diet sufficient to allow normal growth. Oral sodium benzoate (0.1–0.25 g/kg/day) and/or phenylbutyrate (0.25–0.6 g/kg/day) are given. Frequent nutritional assessment and monitoring of plasma ammonia and amino acids are required. Plasma glutamine should be maintained at < 800 mmol/l to minimize risk of acute decompensation. The need for protein restriction may be less severe in children with ASA and citrullinaemia, and arginine rather than benzoate is used for maintenance treatment. Due to the poor prognosis and severity of the nutritional regimen, liver transplantation is indicated and has been successful in selected cases with OTC, CPS and citrullinaemia. Selection of candidates is difficult, but intact survivors of neonatal presentation, those at risk of future neurological damage and those in whom dietary management is ineffective should be considered for transplantation. Liver transplantation results in complete functional correction of the defect, although some

residual biochemical abnormalities may persist (Brady et al. 1998). Prognosis and outcome Without treatment the disease is usually fatal and most children still die during the acute neonatal illness. The most important determinant of outcome is the duration of neonatal coma–coma lasting longer than 5 days is always associated with severe neurological abnormality. Children remain at lifelong risk of hyperammonaemic coma, either during intercurrent illness or following dietary indiscretion. Families and patients should be taught an emergency regimen and have open access to hospital treatment. Defects in fatty acid oxidation Fatty acid oxidation provides an important source of energy during fasting, especially in childhood when glycogen stores are limited. Hepatic fatty acid oxidation produces ketone bodies, which are an important secondary energy source for many tissues, including the brain. Defects in any of the 17 proteins in this pathway may lead to diseases, and 13 individual defects have been recognized to date (Table 5.6). All have autosomal recessive inheritance. The principles of pathophysiology, diagnosis and treatment will be discussed. Pathophysiology The first step in fatty acid metabolism is lipolysis in response to fasting, resulting in circulating free fatty acids (FFA). Fatty acids are then transported across the plasma membrane and are transformed to coenzyme A (CoA) esters in the cytosol before entry to the mitochondria for further metabolism. Long-chain acyl-CoA esters are

Chapter 5: The Acutely Ill Baby transported into the mitochondrion by a three-step carnitine-dependent pathway. Defects in each of these steps and in carnitine uptake have been recognized. Within the mitochondria acyl-CoA esters undergo boxidation. This is a four-step cyclical process where fatty acids are sequentially degraded to acetyl-CoA, with a molecule of acetyl-CoA being released at each step. boxidation results in a continuous flow of electrons to the electron transport chain by electron transfer flavo protein (ETF) and its dehydrogenase (ETF-DH). The first two cycles of b-oxidation of long-chain fatty acids take place at the inner mitochondrial membrane using very long-chain acyl-CoA dehydrogenase (VLCAD) and the associated trifunctional protein (which contains the other three enzymes needed to complete a cycle, including long-chain 3-hydroxy-acyl-CoA dehydrogenase, LCHAD). Shorter chain fatty acids are oxidized within the mitochondrial matrix by length-specific enzymes. Within the liver acetyl-CoA is used for ketone body synthesis. Defects at any stage in the pathway will result in failure of energy production and inadequate ketone body production. Moreover, when b-oxidation is defective, FFA undergo w-oxidation in microsomes producing dicarboxylic acids. Clinical features and diagnosis These disorders are characterized by hypoketotic hypoglycaemia, which may become evident on weaning or in association with the increased metabolic needs of intercurrent infection. Other clinical features include: • hypotonia • cardiomyopathy • rhabdomyolysis • metabolic acidosis • maternal fatty liver of pregnancy or HELLP (haemolysis, elevated liver enzymes, and low platelets). The most dramatic presentation may be with a Reyeslike syndrome or an apparent sudden infant death syndrome, but patients may be clinically and biochemically normal between episodes. The best diagnostic yield will be from blood acylcarnitine profile and urinary organic analysis at the time of decompensation. Biochemical investigations reveal: • elevated aminotransferases • low plasma carnitine • abnormal acyl carnitine profile, especially during decompensation or following a controlled fast • elevated ratio of free fatty acids : 3-hydroxybutyrate • increased urinary ratio of dicarboxylic acids : 3-hydroxybutyrate • mild to moderate hyperammonaemia • metabolic acidosis • elevated plasma creatinine kinase.

85

Confirmation of specific defects may be difficult due to the variety of potential enzyme defects. In selected patients, loading tests with medium-chain or long-chain triglyceride may be helpful. In medium-chain acyl-CoA dehydrogenase deficiency and LCHAD common single mutations make the diagnosis simpler (Ijlst et al. 1996). All recognized defects are expressed in skin fibroblasts. In vitro analysis with labelled myristate, palmitate and oleate are useful for diagnostic screening and in vitro acylcarnitine profiling can provide very specific diagnostic information (Roe et al. 2001). A fascinating aspect of this group of disorders is the association with maternal illness during pregnancy. This association was first noted when a mother with acute fatty liver of pregnancy delivered an infant with LCHAD deficiency (Ijlst et al. 1996). Recently it has become clear that this association is not limited to fetal LCHAD deficiency but may occur in trifunctional protein deficiency (Chakrapani et al. 2000) or other fatty acid oxidation defects. The maternal illness may be part of a spectrum ranging from acute fatty liver to the HELLP syndrome. The mechanism of the maternal illness is unclear but presumably results from limited ability to detoxify metabolites produced by the fetus in an obligate heterozygote. The incidence of fatty acid oxidation defects in unselected pregnancies complicated by HELLP is low, but recognition of susceptible infants is important as prospective treatment can be offered to the affected infant and the maternal illness may recur in future pregnancies (Ibdah et al. 2000). Treatment and prognosis The primary aim of treatment is to avoid excess fasting and suppress lipolysis. This may require the use of overnight nasogastric tube feeds or nocturnal uncooked cornstarch. In some disorders of long-chain fat oxidation, dietary long-chain fat should be restricted with mediumchain triglyceride supplementation. Routine carnitine supplementation is controversial (100 mg/kg/day) but should be used during acute episodes. The prognosis for infants with a neonatal presentation is poor, with overall mortality in the first episode as high as 60%. In patients who survive to diagnosis, the prognosis is good. Physical and intellectual development are usually normal as long as acute crises can be avoided. Carnitine palmitoyl transferase 1 deficiency This disorder is due to a defect in the carnitine palmitoyl transferase enzyme at the outer mitochondrial membrane. This defect prevents mitochondrial uptake of long-chain fatty acyl-CoA, the rate-limiting step in fat oxidation. Presentation is usually in the first year of life with

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Section 3: Neonatal Liver Disease

acute hypoketotic hypoglycaemia following an episode of fasting or intercurrent illness. Hepatomegaly, renal tubular acidosis, convulsions and coma are reported. Investigations demonstrate the typical features of fat oxidation defect (see above) except: • plasma carnitine may be normal or increased • acylcarnitine profile is normal • liver histology demonstrates microvesicular and macrovesicular steatosis • muscle biopsy may show accumulation of glycogen and lipid. The diagnosis is confirmed by demonstrating impaired oxidation of palmitate in fibroblast culture. Treatment consists of the avoidance of fasting and provision of a low-fat diet with medium-chain triglyceride supplements. The prognosis is good and normal growth and development can be achieved. Multiple acyl-coenzyme A dehydrogenase defect (glutaric acidaemia type 2) This rare disease is due to a deficiency of electron transfer flavoprotein (ETF) or its dehydrogenase (ETF-DH), which interferes with the function of all acyl-CoA dehydrogenases. Distinguishing features include: • severe neonatal illness with profound metabolic acidosis • congenital malformations, including polycystic kidneys, defects in the anterior abdominal wall and genital abnormalities • dysmorphic features, including low-set ears, high forehead, rocker-bottom feet, single palmar creases, and defects in the anterior abdominal wall. Biochemical investigations and diagnostic findings include: • increased urinary organic acids, including ethylmalonic and adipic acids • hypoglycaemia without ketonuria • mild to moderate elevation of ammonia • metabolic acidosis • hepatic dysfunction with elevated bilirubin and transaminases • plasma lactate is usually elevated. Diagnosis is confirmed by demonstrating the enzyme deficiency in fibroblast cultures. Treatment consists of providing a diet low in protein and fat. Patients who present later should be assessed for riboflavin responsiveness, and treated with 100–300 mg/day riboflavin. Carnitine (100–200 mg/kg/day) may be helpful and should be used in acute episodes. Most infants with structural abnormalities die within the first week of life. Some respond to initial treatment but often succumb to cardiomyopathy in infancy.

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency The enzyme long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) is a component of the trifunctional protein of the inner mitochondrial membrane and has optimal activity for C12 to C16 chain length fatty acids. A common mutation (G1528C) has been recognized, accounting for 70% of abnormal alleles (Ijlst et al. 1996). The clinical presentation is similar to other disorders of fatty acid oxidation with infantile hypoketotic hypoglycaemia, sudden infant death syndrome or a Reyes-like illness. Distinguishing features include: • severe cardiomyopathy • marked hypotonia • diarrhoea and failure to thrive • peripheral neuropathy and retinitis pigmentosa • neonatal cholestasis or acute liver failure • hepatic histology demonstrates microvesicular steatosis but progression to cirrhosis is frequent (Tyni et al. 1997a). Diagnosis is confirmed either by mutation detection or by specific enzymatic diagnosis from cultured fibroblasts. As in other fatty acid oxidation defects, fasting should be avoided. Long-chain fat should be restricted with the addition of medium-chain triglycerides. Riboflavin (100 mg/day) and carnitine (100 mg/kg/day) have also been used. Previously many children have died in crises (Tyni et al. 1997b), but with early recognition and treatment medium-term survival can be expected (Morris et al. 1997). The neuropathy and retinopathy do not appear to respond to dietary treatment (Lawlor & Kalina 1997). Maternal acute fatty liver of pregnancy may develop when a heterozygote mother carries a fetus with LCHAD deficiency, particularly if the fetus carries the G1528C mutation (Treem et al. 1996).

Organic acidaemias Inborn errors of organic acid metabolism produce lifethreatening illness early in life. They should be suspected in any patient with metabolic acidosis. Propionic acidaemia (PA) and methylmalonic acidaemia (MMA) are the commonest of the organic acidaemias. Propionic acidaemia Propionic acidaemia is due to an autosomal recessive defect in the enzyme propionyl-CoA carboxylase. The gene has been cloned and mapped to chromosome 13q32 and (a-subunit) 3913.3-22 (b-subunit). Anumber of mutations have been defined with some genotype–phenotype correlation (Kennerknecht et al. 1990; Perez-Cerda et al. 2000).

Chapter 5: The Acutely Ill Baby Most propionate is derived from catabolism of the essential amino acids valine and isoleucine, and to a lesser extent from threonine and methionine. Odd-chain fatty acids are synthesized from the 3-carbon propionyl-CoA and subsequently act as a propionate source when they are oxidized during catabolism or fasting. Anaerobic bacterial metabolism contributes ª20% of propionate turnover. Biotin is a coenzyme for this pathway. Methylmalonic acidaemia Methylmalonic acidaemia is part of a group of disorders with abnormal metabolism of branch-chain amino acids due to defective activity of methylmalonyl-CoA mutase. The gene has been localized to chromosome 6q12-21.2, and more than 20 mutations have been identified (Adjalla et al. 1998). The methylmalonyl-CoA mutase enzyme has a vitamin B12-derived cofactor, 5¢deoxyadenosylcobalamin. There is considerable genetic heterogeneity as some patients are B12-responsive due to defects in the synthesis of the cofactor, while unresponsive patients have defects in the mutase enzyme itself. Clinical presentation and diagnosis Both disorders have a wide clinical spectrum of severity. The most severely affected present in the newborn period with encephalopathy, hypotonia, hepatomegaly and subsequent coma. Some children present later with recurrent illness characterized by bouts of lethargy, abnormal behaviour and altered consciousness, or occasionally with a slowly progressive form with failure to thrive and developmental delay. In general patients are more susceptible to infection. First-line investigations demonstrate: • metabolic acidosis and ketosis (arterial pH < 6.9; serum bicarbonate < 10 mEq/l) • neutropenia and thrombocytopenia • hyperammonaemia, which may be profound • plasma amino acids show hyperglycinaemia (> 600 mmol/l) • urinary organic acids reveal either the characteristic propionyl-CoA derivatives, including glycine and carnitine conjugates, methyl citrate and 3-hydroxypropionate, or urinary methylmalonate. The definitive diagnosis is achieved by demonstrating the relevant enzyme defect in cultured fibroblasts. Liver histology may show fatty change or mild biliary changes. Management and prognosis Initial management of the acute crisis involves intravenous 10% dextrose and sodium bicarbonate and dietary protein restriction. Carnitine (200 mg/kg/day)

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and metronidazole (20 mg/kg/day) help to detoxify and decrease production of propionate, respectively. Insulin may be useful, especially if hyperglycaemia occurs. Hyperammonaemia requires specific treatment with sodium benzoate or dialysis (see ‘Urea cycle disorders’ above). In MMA higher fluid intakes are necessary and all patients should have a trial of pharmacological doses of vitamin B12 (1 mg/day). Maintenance treatment consists of an individually titrated low-protein high-calorie diet with overnight nasogastric tube feeding. Amino acid supplementation may be necessary. Carnitine supplementation is continued. Metronidazole may be used continuously or intermittently as required. Sodium benzoate is useful in those with a recurrent hyperammonaemia (Nyhan et al. 1991). In B12-responsive MMA treatment should be lifelong with little need for dietary restriction. With the exception of those patients with MMA who respond to B12, patients remain at risk of recurrent metabolic decompensation, often in association with intercurrent illness. The outlook for patients with neonatal presentation is poor. Neurological abnormalities are common, with severe hypotonia, progressive neurodevelopmental delay and learning difficulties. Basal ganglia damage and stroke-like symptoms are common in patients who presented early, but all affected patients are vulnerable to neurological damage (Nicolaides et al. 1998). Nutritional progress is difficult and systemic complications such as pancreatitis, cardiomyopathy and osteoporosis occur. Tubulointerstitial nephritis with progressive renal impairment occurs in MMA and may lead to renal failure in adolescence. Appreciation of this poor outlook has led to early consideration of liver transplantation to correct the defect. Initial experience demonstrates that liver transplantation results in useful partial correction of PA. Diet is normalized, with decreased metabolite excretion and nutritional and developmental catch-up. There is complete protection against recurrent crises (Schlenzig et al. 1995). Our own experience has confirmed that successful liver transplantation improves the quality of life for affected children and their families. However, the risks of early liver transplantation in those with neonatal presentation are very high. In this group transplantation is best deferred until at least early childhood when the risks of perioperative instability are less (Leonard et al. 2001). The situation is not as clear in severe MMA. Although liver transplantation also results in a useful functional correction of the metabolic defect, this may be less than in PA. In addition, transplantation does not appear to prevent vulnerability to neurological damage, particularly the development of metabolic stroke (Chakrapani et al. 2002; Nyhan et al. 2002).

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Section 3: Neonatal Liver Disease

Antenatal diagnosis

Mutation detection

Prenatal diagnosis is possible for both conditions by enzymatic measurement in cultured amniocytes or amniotic fluid measurement of methylcitrate or methylmalonate. DNA analysis from chorionic villi is feasible in families with known mutations. In adenosylcobalamin synthetic defects, prenatal B12 treatment may be given.

The number of proven pathogenic mutations recognized in individual disorders continues to increase. In disorders where there are common mutations, or where a mutation is known within a family, this is often the best way to confirm or refute the diagnosis and to establish carrier status. As methods techniques improve these techniques will have a wider application.

Other organic acidaemias Isovaleric acidaemia and multiple carboxylase deficiency are rarer organic acidaemias due to deficiencies in isovaleryl-CoA dehydrogenase and holocarboxylase synthetase, respectively. Clinical presentation and diagnosis Both conditions present with severe neonatal illness, with similar presentation to other organic acidaemias. Distinguishing features include a ‘sweaty feet’ odour in isovaleric acidaemia. Diagnostic biochemical features include elevated plasma isovaleric acid and urinary isovalerylglycine in isovaleric acidaemia, and urinary 3-methylcrotonylglycine and 3-hydroxyvaleric acid in multiple carboxylase deficiency. Enzymatic diagnosis is confirmed in cultured fibroblasts in both disorders.

Hepatocyte transplantation In disorders characterized by severe metabolic instability in the neonatal period the outlook remains poor. Liver transplantation remains the definite treatment for hepatic disorders. Neonatal liver transplantation is a formidable challenge and many potential recipients succumb before a suitable organ becomes available. The infusion of reconstituted cryopreserved human hepatocytes via the umbilical vein may partially correct the defect and maintain metabolic stability until definitive treatment is possible. Initial attempts with this technique have had limited success but improvements in cryopreservation techniques and increased experience with the transfusion procedure will permit more definite progress in this area in the near future.

References Management and prognosis Emergency management is similar to the other organic acidaemias. Most patients with multiple carboxylase deficiency are responsive to pharmacological doses of biotin (10 mg/day) and in the majority no other treatment is required other than an ‘emergency regimen’ for use during intercurrent illness. In isovaleric acidaemia a low-protein high-calorie diet should be used in combination with glycine supplementation. Screening for inborn errors of metabolism Tandem mass spectrometry has the potential to detect more than 30 inborn metabolic disorders simultaneously from a single blood spot. At present 12 amino acid disorders, 14 organic acidaemias and eight fat oxidation defects can be detected. However, the potential technical, logistical and ethical difficulties posed by application of this technique to mass screening programmes should not be underestimated. The technique has to date been validated in only a small number of individual disorders and the challenge in the coming years will be to learn how to harness the potential of this technique for mass neonatal screening. Its role in the diagnosis of liver disease has yet to be established.

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Hirst, W.J., Layton, D.M., Singh, S. et·al. (1994) Haemophagocytic lymphohistiocytosis: experience at two UK centres. British Journal of Haematology 88, 731–739. Holme, E., & Lindstedt, S. (2000) Nontransplant treatment of tyrosinemia. Clinis in Liver Disease 4, 805–814. Holton, J.B. (1996) Galactosaemia: pathogenesis and treatment. Journal of Inherited Metabolic Disease 19, 3–7. Honeyman, M.M., Green, A., Holton, J.B., Leonard, J.V. (1993) Galactosaemia: results of the British Paediatric Surveillance Unit Study, 1988–90. Archives of Disease in Childhood 69, 339–342. Hutchesson, A.C.J., Hall, S.K., Preece, M.A. & Green, A. (1996) Screening for tyrosinaemia type I. Archives of Disease in Childhood 74, F191–F194. Ibdah, J.A., Yang, Z., & Bennett, M.J. (2000) Liver disease in pregnancy and fetal fatty acid oxidation defects. Molecular Genetics and Metabolism 71, 182–189. Ijlst, L., Ruiter, J.P., Hoovers, J.M., Jakobs, M.E. & Wanders, R.J. (1996) Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alphasubunit gene. Journal of Clinical Investigation 98, 1028–1033. Jabado, N., de Graeff-Meeder, E.R., Cavazzana-Calvo, M. et·al. (1997) Treatment of familial hemophagocytic lymphohistiocytosis with bone marrow transplantation from HLA genetically nonidentical donors. Blood 90, 4743–4748. Kelly, A.L., Lunt, P.W., Rodrigues, F. et·al. (2001) Classification and genetic features of neonatal haemochromatosis: a study of 27 affected pedigrees and molecular analysis of genes implicated in iron metabolism. Journal of Medical Genetics 38, 599–610. Kennerknecht, L., Suormala, T., Barbi, G. & Baumgartner, E.R. (1990) The gene coding for the alpha-chain of human propionyl-CoA carboxylase maps to chromosome band 13q32. Human Genetics 86, 238. Kimura, N., Ishii, E., Sako, M. et·al. (2001) Effect of chemotherapy and stem cell transplantation on T lymphocyte clones in familial haemophagocytic lymphohistiocytosis. British Journal of Haematology 113, 822–831. Knisely, A.S. (1992) Neonatal hemochromatosis. Advances in Pediatrics 39, 383–403. Knisely, A.S., O’Shea, P.A., Stocks, J.F. & Dimmick, J.E. (1988) Oropharyngeal and upper respiratory tract mucosal-gland siderosis in neonatal hemochromatosis: an approach to biopsy diagnosis. Journal of Pediatrics 113, 871–874. Laine, J., Salo, M.K., Krogerus, L., Karkainen, J., Wahlroos, O. & Holmberg, C. (1995) The nephropathy of type I tyrosinaemia after liver transplantation. Pediatric Research 37, 640–645. Lawlor, D.P. & Kalina, R.E. (1997) Pigmentary retinopathy in long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. American Journal of Ophthalmology 123, 846–848. Lee WS, McKiernan PJ, Kelly DA. (2001) Serum ferritin level in neonatal fulminant liver failure. Archives of Diseases in Childhood 85, F226. Leonard, J.V., Walter, J.H., & McKiernan, P.J. (2001) The management of organic acidaemias: the role of transplantation. Journal of Inherited Metabolic Disease 24, 309–311. Lindstedt, S., Holme, E., Lock, E.A., Hjalmarson, O. &

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hepatitis with galactosemia-like presentation. Clinical Pediatrics 30, 191–193. Verloes, A., Temple, I.K., Hubert, A.F. et·al. (1996) Recurrence of neonatal haemochromatosis in half sibs born of unaffected mothers. Journal of Medical Genetics 33, 444–449. Walter, J.H., Roberts, R.E., Besley, G.T. et·al. (1999) Generalised uridine diphosphate galactose-4-epimerase deficiency. Archives of Diseases in Childhood 80, 374–376. Weinberg, A.G., Mize, C.E. & Worthen, H.G. (1976) The occurrence of hepatoma in the chronic form of hereditary tyrosinemia. Journal of Pediatrics 88, 434–438. Wijburg, F.A., Reitsma, W.C., Sloof, M.J et·al. (1995) Liver transplantation in tyrosinaemia type I: the Groningen experience. Journal of Inherited Metabolic Disease 18, 115–118. Witzleben, C.L. & Uri, A. (1989) Perinatal hemochromatosis: entity of end result? Human Pathology 20, 335–340.

Chapter 6: Acute Hepatitis SUZANNE DAVISON

Acute infective hepatitis, 92 Acute viral hepatitis, 93 Hepatitis A virus, 93 Hepatitis B, C and D infection, 96 Hepatitis E, 96 Hepatitis F, 96 Hepatitis G, 96 Transfusion transmissible virus, 96 Non A-E hepatitis, 97

Measles, 97 Rubella, 97 Parvovirus B19, 97 Herpesviruses, 97 Adenovirus, 100 Enteroviruses, 100 Viral haemorrhagic fever, 100 Yellow fever, 100 Dengue haemorrhagic fever, 100

Acute hepatitis is characterized by inflammation and necrosis of the liver. The underlying trigger for the inflammatory process may be toxic, autoimmune, infective or metabolic. Noninfective causes, which may produce a wider spectrum of liver disease than acute inflammation, are considered elsewhere. The scope of this chapter will be acute infective disorders of the liver: • viral hepatitis • bacterial, protozoal and helminth infection • hepatic abscess (amoebic and pyogenic).

• • • • • • • • • •

Lassa fever, 101 Marburg and Ebola viruses, 101 Nonviral causes of hepatic infection, 101 Leptospirosis, 101 Bartonella infection, 101 Other bacterial infections, 102 Toxoplasmosis, 102 Helminthic infections, 102 Liver abscesses, 103

a prodrome of malaise anorexia nausea vomiting fever tender hepatomegaly splenomegaly lymphadenopathy rash jaundice

Differential diagnosis of acute infective hepatitis

Acute infective hepatitis Acute infection of the liver may be due to a wide range of pathogens. The outcome of the infection is dependent not only on the cause but on the host immune response: complete recovery depends on elimination of the infecting agent, resolution of the inflammatory changes and prevention of reinfection by effective antibody production. Viruses are the major cause of acute infective hepatitis. Viral hepatitis may be due to infection with hepatotropic viruses (Table 6.1), causing disease primarily affecting the liver, or with viruses predominantly associated with extrahepatic manifestations (Table 6.2). Nonviral causes of hepatitis (Table 6.3) are less common, but must be considered in the differential diagnosis.

A clinical picture resembling acute infective hepatitis may be the presenting illness of both non-infective acute liver disease and underlying chronic disease, including: • metabolic liver disease • drug-induced hepatitis • autoimmune hepatitis. The presence of the following risk factors for an infective cause should be considered: • immunosuppression • extrahepatic sepsis • foreign travel • local epidemics • household contacts • parenteral acquisition • recreational activity • pets.

Clinical features Clinical presentation is varied according to the infecting organism, the presence of extrahepatic disease and host immunocompetence. Typical symptoms may include:

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Laboratory investigation Specific features are discussed with each infection, but some investigations are of general application.

Chapter 6: Acute Hepatitis Table 6.1 Hepatotropic viruses

Table 6.3 Nonviral causes of hepatic infection

Virus

Family

Type

Route of spread

Disease

HAV HBV HCV HDV HEV HFV

Picornavirus Hepadnavirus Flavivirus Incomplete virus Calicivirus Not yet characterized Flavivirus

RNA DNA RNA RNA RNA –

Orofaecal Parenteral Parenteral Parenteral Orofaecal –

Acute Acute/chronic Acute/chronic Acute/chronic Acute –

RNA

Parenteral

Not established

HGV

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Bacteria Bartonella henselae/quintana Brucella melitensis Legionella pneumophilia Leptospira ictohaemorrhagica Listeria monocytogenes Mycobacterium tuberculosis Salmonella typhi Protozoa Toxoplasma gondii Helminths (worms) Cestodes (tapeworms): Echinococcus multilocularis Echinococcus granulosus

HAV, Hepatitis A virus; HBV, hepatitis B virus; etc.

Table 6.2 Non-hepatotropic viruses associated with hepatocellular damage RNA viruses

DNA viruses

Paramyxovirus (measles) Togavirus (rubella) Enteroviruses Echovirus Coxsackie virus Flaviviruses Yellow fever flavivirus Dengue fever flavivirus Filoviruses Marburg virus Ebola virus Arenavirus (Lassa fever)

Parvovirus B19 Adenovirus Herpesviruses: Herpes simplex type 1 Herpes simplex type 2 Varicella zoster virus Cytomegalovirus Epstein–Barr virus Human herpes virus 6

Biochemical features The main biochemical finding of hepatitis is typically raised aminotransferases. Serum bilirubin may be normal despite significant inflammation. Hepatic synthetic function, measured by serum albumin and coagulation, is normal unless there is extensive hepatocellular necrosis, underlying chronic disease or disseminated intravascular coagulation. Full blood count The blood count may be normal or reveal pancytopenia (viral infection), eosinophilia (helminth infection) or polymorph leucocytosis (bacterial infection, hepatic abscess). Microbial diagnosis Specific microbial diagnosis is available for almost all infecting agents, either in blood or affected tissue, by: • specific antibody detection in serum • viral antigen detection or genome detection • virus culture or visualization by electron microscopy • bacterial culture from blood/liver/other affected tissue • detection of helminth ova in faeces.

Nematodes (roundworms): Ascaris lumbricoides Toxocara canis/T. catis Trematodes (flukes): Schistosoma mansoni Schistosoma japonicum Fasciola hepatica

Note: See Table 6.4 for causes of abscesses.

Histology Histological assessment of liver tissue may reveal non-specific features of acute hepatitis (see Plate 17, Atlas: p. 445) or helpful diagnostic features including: • granulomata • inclusion bodies • detection of viral products by immunohistochemistry.

Acute viral hepatitis The hepatotropic viruses constitute a heterogeneous group (Table 6.1) with differing modes of transmission and clinical manifestations. Viruses which are not predominantly hepatotropic (Table 6.2) may lead to hepatic inflammation as part of a more widespread disease process. Infection may occur more frequently, severely or atypically in the presence of immunosuppression or according to the age of the host. The diagnosis may be suggested by typical non-hepatic manifestations (e.g. in measles), and for most viruses may be confirmed by specific antibody detection. Hepatitis A virus Introduction Hepatitis A is the most common form of acute viral hepatitis in much of the world (Koff 1998). Hepatitis A virus (HAV) usually gives rise to an asymptomatic infection, with less than 5% of infected people having an identifiable illness. Due to its high prevalence world-wide,

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however, HAV alone accounts for 20–25% of clinically apparent hepatitis. The likelihood of symptomatic infection increases with age of acquisition, with most children under 6 years of age being asymptomatic (Bell 2000). The HAV-associated mortality of 0.2–0.4% of symptomatic cases is increased in individuals older than 50 years or less than 5 years of age at acquisition. The significant morbidity and mortality of HAV infection in childhood are due to its world-wide prevalence, the development of fulminant hepatic failure and hepatic and extrahepatic complications. Virology/pathophysiology HAV belongs to the family of picornaviridae, and is classified in its own genus ‘hepatovirus’ (Francki et al. 1991). Man appears to be the only natural reservoir of infection for HAV, which is maintained predominantly by oral– faecal transmission. Following acquisition by a susceptible individual, HAV gains access to the liver via the intestinal tract. The liver is the only organ to be directly infected. Although HAV is not known to be directly cytopathic to hepatocytes, it is likely that the cell-mediated immune response of the host leads to necroinflammatory damage. Following replication within the hepatocyte, HAV is then excreted via the biliary tract and shed in faeces (Koff 1998).

associated HAV is rare, but has been reported in patients exposed to factor concentrates (Mannucci et al. 1993). There is no evidence for perinatal transmission. Clinical features HAV infection has an incubation period of 2–6 weeks, following which symptoms become evident. A prodromal illness is characterized by non-specific symptoms including anorexia, nausea, malaise and fever. In children, gastrointestinal symptoms such as diarrhoea and vomiting may predominate. Within a few days to a week, jaundice, pale stools and dark urine become apparent, and the prodromal symptoms usually subside. There may be tender hepatic enlargement, splenomegaly and posterior cervical lymphadenopathy. Rarely, extrahepatic manifestations such as arthritis, and vasculitis may accompany the acute illness. The infectivity of HAV due to faecal shedding typically begins during the prodromal phase, peaks at the onset of symptoms, then rapidly declines. However, faecal shedding of HAV RNA may persist for up to 3 months with therefore a prolonged risk of transmission (Yotsuyanagi et al. 1996). Furthermore, HAV RNA may be detected in blood during the incubation period and up to 30 days after the onset of the illness (Fujiwara et al. 1997). Precautions to minimize transmission are therefore advisable during this period.

Risk factors The majority of cases in the UK are sporadic, and not associated with any known risk factor. However, risk of sporadic HAV acquisition is increased by: • Travel abroad: Hepatitis A is the most frequently diagnosed form of hepatitis imported from the developing world (Steffen et al. 1994), with 36% of imported cases occurring in children (Bell 2000). • Household contact with HAV infection: Household spread is the predominant route of transmission: symptomatic secondary cases occur in up to 50% of household members (Koff 1998). Young children are important sources of infection in both household and communityacquired infection. Crowding, poor social hygiene and mixing of children in institutions such as day care centres and schools increase the risk of community outbreaks. No significant increased risk was identified however in nursery nurses, child-minders, healthcare workers or teachers (Maguire et al. 1995). Outbreaks may also occur following exposure of large groups to a common source such as contaminated drinking water or food, particularly bivalve molluscs. Parenteral acquisition is uncommon. Acquisition by individuals with high-risk behaviour such as intravenous drug abuse may relate to poor hygiene and crowding in addition to exposure to infected blood. Transfusion-

Diagnosis Biochemical indices of HAV infection are non-specific and include elevated conjugated bilirubin and aminotransferase enzymes (ALT and AST). The degree of elevation does not correlate with the severity of the illness or likelihood of complications. Ultrasound examination is not essential in uncomplicated HAV infection if the diagnosis is not in doubt. Ultrasound features include hepatomegaly with periportal echogenicity, periportal lymphadenopathy and splenomegaly. The gall bladder may be distended with a thickened wall. Confirmation of the diagnosis relies on the serological detection of circulating hepatitis A-specific IgM antibody: • Anti-HAV IgM is indicative of recent infection. Peak levels occur during the acute illness or early convalescent phase. IgM persists for 4–6 months after infection. • Anti-HAV IgG appears early, peaks during the convalescent phase and persists lifelong, conferring protection. Management and outcome The majority of symptomatic children will have an uncomplicated course with complete resolution of infection.

Chapter 6: Acute Hepatitis Supportive treatment with rest, analgesia and ensuring adequate hydration is needed during the acute phase. Complete recovery is usual within 3–6 months. However, the course may be complicated by: • fulminant hepatic failure • prolonged cholestasis • recurrent hepatitis • extrahepatic manifestations • pre-existing chronic liver disease. Fulminant hepatic failure This affects approximately 0.1% of symptomatic infected children. Deterioration in liver function may not be apparent clinically, and may occur either rapidly following the onset of symptoms or after an interval of several weeks. Frequent vomiting or deterioration in conscious level, even if only intermittent, should prompt careful clinical assessment and evaluation of hepatic function. Those with a rapid onset of liver failure from the onset of jaundice are most likely to undergo spontaneous recovery. In children with encephalopathy, the predictors of a poor outcome are bilirubin > 400 mmol/l or a significantly elevated prothrombin time, irrespective of the grade of encephalopathy (Debray et al. 1997). Children with fulminant HAV infection should be transferred to a centre where liver transplantation is available. Prolonged cholestasis In a series of nine adults with prolonged cholestasis due to HAV infection, mean duration of cholestasis was 77 days (range 30–120) and mean bilirubin level of 265 mmol/l (range 51–560) (Corpechot et al. 1994). Histological features were intralobular cholestasis and portal tract infiltrates, associated with dystrophy and paucity of bile ducts. A course of corticosteroids may shorten the duration of cholestasis, but spontaneous recovery is usual. Fat-soluble vitamin supplementation should be provided, together with antipruritic treatment. Recurrent hepatitis A biphasic or relapsing course may occur in up to 25% of symptomatic cases and may be associated with extrahepatic manifestations. A complete recovery is usual: hepatitis A infection does not give rise to chronic liver disease. Extrahepatic manifestations Extrahepatic manifestations rarely occur, but include: • Neurological involvement: Guillain–Barré syndrome, transverse myelitis, postviral encephalitis and mononeuritis multiplex. • Renal disease: acute interstitial nephritis, mesangioproliferative glomerulonephritis, nephrotic syndrome and acute renal failure. • Acute pancreatitis: described in children in both the acute and convalescent phase.

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• Haematological disorders: autoimmune haemolytic anaemia, red cell aplasia and thrombocytopenia purpura. Hepatitis A infection in chronic liver disease Acute HAV infection in children with pre-existing chronic liver disease may lead to a more severe acute hepatitis, with an increased risk of fulminant hepatic failure and increased mortality. This has been reported in both chronic hepatitis B (Keeffe 2000) and C (Vento et al. 1998) infection. Immunization is recommended in all patients with chronic liver disease (see below). Prevention Global strategies to minimize epidemics of HAV infection include improving sanitation and providing education to improve standards of basic hygiene. Prevention of HAV acquisition in an individual may be conferred by either active or passive immunization. Widespread immunization of children has been introduced in areas with a high incidence (see Chapter 22). Active immunization A formaldehyde-inactivated vaccine is now available containing one of two strains of HAV (GBM and HM 175). Vaccination is recommended for: • travellers to areas of high endemicity • laboratory personnel working with HAV • patients with chronic liver disease • staff and residents of institutions. The recommended regimen is a single dose of 1440 ELISA units in adults and 720 ELISA units in children. In 90% of those vaccinated, protective levels of antibodies are achieved and persist for at least 1 year. A second dose given after an interval of 6–12 months may increase the duration of protection to up to 10 years. Post-vaccination testing is not indicated: antibody assays are not sufficiently sensitive to detect the low but protective level of antibody (Bell 2000). The vaccine is not licensed for children < 2 years of age: passively transferred maternal antibody may lead to suboptimal response to the vaccine. HAV vaccine can be given concurrently with passive immunization. HAV vaccine is both safe and immunogenic for protection of patients with underlying chronic liver disease (Keeffe 2000). A combination vaccine for protection against both hepatitis A virus and hepatitis B virus is available (Twinrix) and compares favourably with the monovalent vaccine. Although currently recommended as a three-dose schedule, a two-dose schedule, separated by 6 months, is being investigated in children (Van Damme & Van der Wielen 2001). Passive immunization Human normal immunoglobulin, given by intramuscular injection, offers up to 3–6 months

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of protection against HAV. It is effective if given within 2–3 weeks of exposure and should be considered for: • household contacts of infected cases • those at greatest risk during an outbreak • travellers staying less than 3 months in endemic area (alternative to vaccination). Hepatitis B, C and D infection These are considered in Chapter 8 (Chronic hepatitis). Hepatitis E Hepatitis E virus (HEV) infection resembles HAV infection and should be considered in the differential diagnosis of acute hepatitis. It is the cause of 50% of cases of acute viral hepatitis in young to middle-aged adults in the developing world (see Chapter 22). Although less common in children, outbreaks have been described (Arora et al. 1999). HEV is a single-stranded RNA virus, provisionally classified in the family Caliciviridae, genus Calicivirus (Cubitt et al. 1995). The genome of HEV has been fully sequenced, and classification into genotypes according to nucleotide homology has emerged. Two main strains are the Burmese strain (genotype 1) and the Mexican strain (genotype 2). A third strain (genotype 3), identified in the USA, is genetically similar to swine HEV. There is evidence that suggests that HEV may be transmitted from animals to primates (Meng et al. 1998). Other genotypes are increasingly being assigned, as isolates are sequenced in other countries, including the UK (Wang et al. 2001).

HEV inpatients with chronic liver disease may cause severe decompensation (Hamid et al. 2002). Diagnosis Serological diagnosis is made by detecting IgG and IgM antibodies to recombinant or synthetic HEV antigens by enzyme immunoassay (EIA). IgM appears during the early phase of symptoms and disappears after 4–5 months (Favorov et al. 1992). IgG appears soon after IgM, and the titre continues to increase into the convalescent phase, and may remain high for several years. HEV genome sequences may also be detected in the stool and serum by polymerase chain reaction (PCR). Management Management, as for HAV, is supportive. A vaccine has been developed by recombinant technology and is undergoing phase III clinical trials (Hyams 2002). Hepatitis F Particles resembling togavirus have been isolated from the explanted livers of children and adults undergoing liver transplantation for fulminant-non-A-non-B hepatitis (Fagan et al. 1989, 1992). Recurrence after transplantation was demonstrated in several cases. Not all cases were associated with foreign travel. Although initially deemed a possible candidate for acute non-A-E hepatitis, and thus termed hepatitis F, its role has not been clearly established.

Transmission and clinical features

Hepatitis G

HEV is oral-faecally transmitted, usually by contaminated water. Epidemics most frequently occur in developing countries, particularly after the rainy season. Sporadic cases also occur: although initially described in endemic areas and in travellers, sporadic cases in people with no history of travel abroad or other risk factors have been reported, including five cases in the UK (McCrudden et al. 2000, Levine et al. 2000). A striking and unexplained feature is the severity of HEV infection in pregnant women, with a mortality rate as high as 20%. Vertical transmission has been described with significant perinatal morbidity and mortality (Khuroo et al. 1995). The incubation period for HEV is 2–9 weeks, with symptomatic illness lasting up to 4 weeks. The disease resembles HAV infection and is usually mild and selflimiting, especially in children. Fulminant hepatitis, anicteric hepatitis and prolonged cholestasis have also been observed. Chronic liver disease and persistent viraemia have not been observed. The frequency of secondary cases in household members is low. Superinfection with

Hepatitis G virus (HGV) or GBV-C is a transfusiontransmissible agent (Linnen et al. 1996). It has a high prevalence in those at risk from parenteral acquisition and may coexist with HCV. Vertical transmission has also been described (Lin et al. 1996). Although HGV infection is described in association with acute, fulminant and chronic hepatitis, its precise role in causing liver disease is not established. In the majority of infected people there is no biochemical evidence of liver disease (Alter 1996). In children, the prevalence of HGV infection is unknown. In a series of paediatric liver transplant recipients, HGV prevalence was 30% and infection was persistent, although not associated with chronic graft hepatitis (Davison et al. 1998). Transfusion transmissible virus Transfusion transmissible virus (TTV), a circular DNA virus, has also been proposed as a causative agent of acute

Chapter 6: Acute Hepatitis non-A-E hepatitis. It may be spread parenterally and by the faecal–oral route. It is however highly prevalent in the general population, and its role in causing otherwise unexplained acute hepatitis is not established (Kanda et al. 1999). Non A-E hepatitis It is apparent that there are other, currently unidentified viruses that may cause acute hepatitis. This diagnosis of exclusion, previously termed non-A, non-B hepatitis, has now been re-named non-A-E hepatitis or non-A-G hepatitis. Although there may be more than one infectious agent to account for non-A-E hepatitis, a characteristic clinical picture has emerged. Children and young adults are predominantly affected, the hepatitic illness is usually severe and there is a low rate of spontaneous recovery. Non-A-E hepatitis is the commonest viral cause for fulminant hepatic failure requiring liver transplantation in children in the UK and the USA (see Chapter 7). It may be further complicated by transient bone marrow suppression or aplastic anaemia: in one series of 32 children and young adults who underwent liver transplantation for non-Anon-B hepatitis, 28% developed aplastic anaemia (Tzakis et al. 1988). Furthermore, in a series of eight children with both acute liver failure and bone marrow failure, two had parvovirus B16 infection, and six non-A-C hepatitis (Tung et al. 2000). Management is supportive, with early consideration of liver transplantation in view of the poor chance of spontaneous recovery. Measles Hepatic involvement with measles is more common in adolescents and adults than in children. Measlesassociated hepatobiliary disease has been described in 27 patients ranging in age from 9 to 59 years (Khatib et al. 1993) with two distinct patterns emerging: • asymptomatic hepatocellular dysfunction with aminotransferase elevation occurring early in measles infection and resolving within days • cholestasis and jaundice, becoming apparent as measles resolves and persisting for 2 weeks or longer. In children hospitalized with measles, hepatic dysfunction with elevated aminotransferase enzymes is described in 5–11% of cases (Makhene & Diaz 1993, Papadopoulou et al. 2001), and is usually subclinical with spontaneous and rapid resolution. Type 1 autoimmune hepatitis occurring within 3 months of measles infection has been reported, with measles virus being proposed as the viral trigger (Vento et al. 1996).

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Rubella Rubella is associated with liver disease in children following intrauterine infection, as part of the congenital rubella syndrome (Chapter 4). Hepatic involvement in congenital rubella may range from a mild hepatitis with focal necrosis to severe disease with massive necrosis, and progression to cirrhosis may occur. In acquired rubella infection, acute hepatitis has been described. Parvovirus B19 Human parvovirus (HPV) B19 infection in childhood typically presents with erythema infectiosum or in the presence of an underlying haemolytic anaemia leads to an aplastic crisis. Infection during pregnancy may lead to hydrops fetalis. HPV B19 infection is, however, becoming increasingly associated with a wide range of systemic manifestations, including hepatic dysfunction. • Raised hepatic aminotransferase enzymes — median aspartate aminotransferase (AST) 865 iU/l, alanine aminotransferase (ALT) 993 iU/l — associated with HPV B19 infection are described in seven children, three of whom had erythema infectiosum, with complete biochemical recovery occurring within 3 weeks (Yoto et al. 1996). • Fulminant liver failure (with and without aplastic anaemia) in association with HPV B19 is described (Naides et al. 1996, Tung et al. 2000), with evidence of productive HPV B19 infection in the liver. The haematological and fetal effects of HPV B19 infection are due to the erythrocyte P antigen, present on erythroid and fetal liver cells, acting as a receptor for the virus (Brown et al. 1993). The pathogenesis of hepatocellular damage is not known. It is proposed that a non-structural protein of HPV B19 may be hepatotoxic or that a specific defect in the immune response may contribute. Immunemediated destruction of the hepatocytes is thought unlikely due to the lack of cellular infiltration seen in affected liver tissue (Naides et al. 1996). Herpesviruses The herpesviruses are a family of icosahedral doublestranded DNA viruses, all of which may cause acute hepatitis. They have a propensity to latency, persisting in the host after primary infection despite high levels of neutralizing antibody. Reactivation may occur particularly in the presence of immunosuppression. Replication by herpesvirus DNA polymerase may be inhibited by antiviral agents, providing effective therapy for severe disease (see below).

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Herpes simplex viruses 1 and 2 Herpes simplex virus (HSV) hepatitis is very rare outside the neonatal period in an immunocompetent host. In perinatally acquired infection, a severe, disseminated disease typically manifests at day 4 or 5 of life and may be associated with severe hepatic dysfunction. In 90% of cases this is due to HSV type 2, with a clear history of maternal herpetic vulvovaginitis, though occasionally type 1 HSV is implicated. HSV may be detected in affected tissue by electron microscopy (EM) or specific anti-HSV antibody by immunoassay. Varicella zoster virus Varicella zoster (VZV) infection typically causes chickenpox with a characteristic rash. Dissemination may occur in the first week of infection, particularly in the immunocompromised host, to involve the lungs, brain and liver. The prognosis is determined by the lung involvement: varicella hepatitis in the absence of pneumonitis usually resolves. Diagnosis may be made by specific serology or by detecting VZV in vesicle fluid by EM. Cytomegalovirus Cytomegalovirus (CMV) infection is usually a mild illness in childhood, but is of great significance following congenital infection, and in the immunocompromised host (Chapters 4, 20 and 21). In the immunocompetent, acquired infection is usually asymptomatic or associated with mild non-specific symptoms. In less than 1% a clinically apparent syndrome that resembles infectious mononucleosis may occur. Hepatic involvement is frequent and usually mild, with raised transaminases, alkaline phosphatase and bilirubin. It has a good prognosis and a chronic course is unusual. Treatment is usually not required. In the presence of immunosuppression, there may be more diffuse and severe disease involving in particular the respiratory system, gastrointestinal tract and central nervous system. In liver transplant recipients, the transplanted liver is the most frequent site of CMV disease, with the donor organ the likely mode of transmission (see Chapter 20). Diagnosis Acute CMV infection is characterized by specific IgM production, and reactivation by a fourfold increase in IgG titre or by IgM production. CMV early antigen may be detected in infected urine, peripheral blood leucocytes, serum, sputum or other tissue by immunofluorescence or latex agglutination. Viral genome detection by PCR is now widely available, leading to a more rapid diagnosis, and quantitative PCR allows the

course of infection or disease and its resolution or treatment response to be monitored. Histology Histological features of CMV infection may be diagnostic (Plate 18, Atlas: p. 445). Cytomegalovirus is so named because following infection it leads to a characteristic cytopathic effect with the appearance of: • cellular enlargement • enlarged rounded nuclei with prominent rim • intranuclear ‘owl’s eye’ inclusion bodies • cytoplasmic granules. Immunostaining of biopsy material using monoclonal antibody and in situ DNA hybridization may permit a rapid and specific diagnosis, even in the absence of suggestive histological changes. Inflammatory changes, especially in the immunocompetent, may be mild. Epstein–Barr virus The severity of Epstein–Barr virus (EBV) infection depends on the age of acquisition and the immune status of the host. In early childhood, EBV infection is frequent and usually asymptomatic or associated with mild non-specific symptoms. Primary infection occurring in adolescence or early adulthood, however, is typically associated with acute infectious mononucleosis (IM) or ‘glandular fever’. IM is characterized by pharyngitis and malaise. Splenomegaly and lymphadenopathy are present in almost 50%, liver enlargement in up to 20% and jaundice in 5%. Although elevated aminotransferase enzymes (up to 5 times normal) are detected in up to 80%, hepatitis is usually mild with a complete recovery likely. Though predominantly infecting B-lymphocytes, the manifestations of EBV seen in IM are due to T-cell proliferation and infiltration of lymphoid tissue. Treatment is supportive. Fulminant liver failure associated with ‘sporadic fatal infectious mononucleosis’ (SFIM) occurs in »1/3000 cases of IM (Markin 1994), with a median age at presentation of 13 years. Clinical presentation initially resembles that of IM, and treatment for acute liver failure is required (see Chapter 7). In the presence of immunodeficiency or immunosuppression, proliferation of EBV-infected B-cells is not controlled by the specific T-lymphocyte response. Clinical syndromes associated with unchecked B-cell proliferation range in severity from benign lymphoid hyperplasia to malignant monoclonal lymphoma (see Chapters 20 and 21). Histology Features of acute infectious mononucleosis are (Markin 1994): • mild predominantly lymphocytic portal inflammation • mild hepatocellular ballooning

Chapter 6: Acute Hepatitis • prominent hepatocellular mitoses • panlobular canalicular cholestasis. In SFIM, hepatic involvement is characterized by prominent portal lymphocytic infiltration, hepatocellular necrosis and occasionally bile duct damage with intracellular lymphocytes (Markin 1994). Diagnosis Diagnosis of EBV rests on serological assays, as virus culture is difficult. The pattern of antibody detection in acute and previous infection is as follows: • Antibody to viral capsid antigen (VCA): IgM is positive in early acute infection, IgG is usually present at clinical presentation, then declines but persists for life. • Antibody to Epstein–Barr nuclear antigen (EBNA) increases during convalescence, persists for life and may increase during reactivation. • Antibody to early antigen (EA) transiently increases during infection and reactivation. The Paul–Bunnell test demonstrates acute non-specific antibody production in response to EBV infection. Unlike in adults where the Paul–Bunnell test is usually diagnostic of IM, in up to 50% of children and also in the presence of immunosuppression the heterophile antibodies are not detectable. Detection of EBV-encoded products including latent membrane protein (LMP), nuclear antigen (EBNA) and EBV encoded RNA (EBER) by immunohistochemistry, and detection of EBV genome by in situ hybridization, permits specific detection of EBV in infected tissues, and these techniques are currently used as research tools. PCR detection and quantification of EBV RNAallow the monitoring of viral load, which is of particular value in organ transplant recipients, so that immunosuppressive therapy can be tailored appropriately. Human herpesvirus 6 Most children are infected with human herpesvirus 6 (HHV6) in the first year of life (Kimberlin 1998). The only disease for which a causal link is definitely established is roseola infantum (exanthem subitum), characterized by a fever for 3–5 days, which subsides as a rose-pink macular rash becomes apparent. Liver dysfunction in association with HHV6 infection is described, and includes an infectious mononucleosislike syndrome, isolated hepatitis and fulminant hepatic failure (Dubedat & Kappagoda 1989; Asano et al. 1990; Sobue et al. 1991). Serological diagnosis is made by the appearance of specific HHV6 IgM antibody or a fourfold rise in IgG titre. Treatment of herpesvirus infections Antiviral therapy is effective against the herpesviruses

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by inhibition of viral DNA synthesis (Bean 1992). As the majority of infections in the immunocompetent host are mild and self-limiting, specific treatment is only warranted in certain circumstances where disease is likely to be severe or disseminated, or in the presence of immunosuppression. Antiviral agents effective against herpes viruses include: • acyclovir and valacyclovir • ganciclovir and valganciclovir • cidofovir • famciclovir. Acyclovir Acyclovir, a nucleoside analogue, is safe and relatively non-toxic and has the best therapeutic index of all currently available antiviral agents. Its activation by phosphorylation to acyclovir triphosphate is catalysed by a virus-encoded thymidine kinase, and thus only occurs in infected cells. Acyclovir triphosphate has a higher affinity for viral DNA polymerase than the natural substrate, and when incorporated into DNA terminates replication. Susceptibility of herpesviruses to acyclovir is as follows: • HSV 1 and 2: very susceptible. • VZV: less effective phosphorylation of acyclovir occurs by VZV thymidine kinase, but with intravenous administration adequate antiviral activity is achieved and may prevent dissemination. • CMV: limited susceptibility as CMV has no thymidine kinase: ganciclovir is a more effective alternative (see below). • EBV: acyclovir is effective against EBV replication, but has no effect on latent virus. It may therefore reduce viral shedding in infectious mononucleosis but has no effect on symptoms or course. • HHV6: resembles CMV in its susceptibility, being relatively resistant to acyclovir. Valacyclovir This is an ester of acyclovir with valine, with good absorption and bioavailability. Following oral administration, valacyclovir may achieve levels equivalent to intravenous acyclovir. Its safety profile appears to be similar to acyclovir. Pharmacokinetic studies in children support the use of oral valacyclovir instead of intravenous acyclovir for mucositis in immunosuppressed children, but clinical application is limited by palatability and the lack of an oral suspension (Eksborg et al. 2002). Cidofovir Cidofovir has been successfully used for CMV disease with resistance to ganciclovir or foscarnet (Ljungman et al. 2001). It has significant nephrotoxicity and is therefore not recommended as first-line treatment. It has also been used for other herpes infections in immuno-

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suppressed patients when there is resistance to first-line agents (LoPresti et al. 1998; Bryant et al. 2001) and for adenovirus infection (Ribaud et al. 1999, Hoffman et al. 2001, Legrand et al. 2001). Ganciclovir Ganciclovir is 100 times more active than acyclovir in its action against CMV replication. It is activated by phosphorylation in CMV-infected cells despite the lack of viral thymidine kinase. It is more toxic than acyclovir, with 25% of patients experiencing reversible bone marrow suppression, and intravenous therapy (5 mg/kg/dose i.v. twice daily for 2–3 weeks) should therefore be reserved for specific indications, which include: • prophylaxis against CMV in organ transplant recipient • CMV disease in immunocompromised host. Ganciclovir resistance due to lack of phosphorylation is rare, but emergence of resistant strains may be facilitated by prolonged ganciclovir use. The role of ganciclovir in congenital CMV infection or acquired neonatal hepatitis is not established. Oral ganciclovir is poorly absorbed and has poor bioavailability, but in appropriate dose may be as effective as i.v. treatment. In a study in children with HIV infection, 30 mg/kg/dose tds was well tolerated and achieved similar drug levels to the effective adult dose of 1 g/dose tds (Frenkel et al. 2000). High-dose oral ganciclovir has been successful in the management of symptomatic CMV infection in a child with acute lymphoblastic leukaemia (Castagnola et al. 2002). Valganciclovir As for acyclovir, ganciclovir linked to the amino acid valine increases its bioavailabiliy 10-fold. Its role in children is not well documented, but it has the potential to allow oral treatment of CMV disease. Foscarnet Foscarnet acts by directly binding to pyrophosphate binding sites of DNA polymerases, leading to noncompetitive inhibition (Bean 1992). As it does not require activation by cellular or viral kinases it is of value in ganciclovir-resistant CMV disease. Its usefulness, however, is limited by its toxicity, with major adverse effects being renal impairment, electrolyte disturbance and seizures.

Enteroviruses Echoviruses and Coxsackie viruses (Aand B) are the most frequent causes of viral meningitis, and Coxsackie B virus may cause myocarditis. Hepatitis due to these enteroviruses, however, is also described. Coxsackie B viruses, particularly B1, may be acquired in the newborn period and cause acute hepatitis (Chou et al. 1995) associated with thrombocytopenia. The spectrum of disease may range from a mild non-specific illness, to overwhelming multiorgan involvement with fulminant hepatic failure. Diagnosis may be made by virus detection in throat swabs, stool or cerebrospinal fluid using immunofluorescence with monoclonal antibody. Coxsackie B-specific IgM assay is a rapid but less sensitive method of diagnosis (Haddad et al. 1993). Treatment is supportive. Viral haemorrhagic fever Imported viral haemorrhagic fevers are characterized by fever, circulatory collapse and haemorrhage. There may be diffuse organ involvement with severe hepatocellular necrosis. Yellow fever This is due to a flavivirus, which is transmitted to man, the main animal reservoir, by mosquitoes. It is endemic in West and Central Africa and may also occur in South America. The incubation period is between 3 and 6 days. In endemic areas symptoms may be mild with fever, proteinuria, leucopenia and occasionally jaundice. In the severe form, after 3–4 days of fever, rigors and headache there is a transient improvement for less than 24 h before the onset of cutaneous and gastrointestinal haemorrhage and renal failure. Jaundice may become apparent during recovery. Treatment is supportive. Mortality is in the order of 5%, death usually occurring 7–10 days after the onset of symptoms. Immunization with a live attenuated vaccine is required for entry into some countries, either for all travellers or those arriving from infected areas (HMSO 1996).

Adenovirus Adenovirus is a double-stranded DNA virus which typically causes pharyngitis and conjunctivitis. It has been implicated in both sporadic hepatitis and fulminant hepatic failure occurring in the presence of immunosuppression. Diagnosis is by immunoassay to detect virus in stool, respiratory tract or throat swabs. Treatment is supportive, but the new antiviral agent Cidofovir (see above) may be of value, particularly in immunosuppressed children.

Dengue haemorrhagic fever The distribution of this infection is South-East Asia, the Pacific islands, India and the Caribbean. Children are most frequently infected. After 4–8 days’ incubation there is either a mild febrile illness or a more severe infection with generalized aches, especially arthralgia, nausea, vomiting, painful eye movements and depression, accompanied by petechiae and often tender hepatomegaly. Fever subsides after 3 days, to recur 1–2 days later accom-

Chapter 6: Acute Hepatitis panied by circulatory collapse. Treatment is supportive, with improvement usual after 48 h. Lassa fever This arenavirus infection is endemic in rats, and is transmitted by water contaminated with their urine or saliva. In endemic areas infection may be limited to a mild febrile illness. In others after 7–17 days’ incubation there is persistent fever, pharyngitis with tonsillar exudate, lethargy, gastrointestinal symptoms and maculopapular rash. In the second week encephalopathy, circulatory collapse and diffuse haemorrhage into skin and organs may develop. Diagnosis is by isolation of virus from the throat, urine or blood, or by detection of specific Lassa antibodies — present in the second week of illness — by immunofluorescence. Infected patients must be treated in strict isolation. Intravenous ribavirin may be effective in reducing mortality (McCormick et al. 1986). Marburg and Ebola viruses These are endemic in Africa. After an initial flu-like illness, massive hepatocellular necrosis and disseminated intravascular coagulation (DIC) occur, with a high mortality rate of up to 90%.

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Table 6.4 Bacterial causes of hepatic abscess Common

Uncommon

Escherichia coli Klebsiella pneumoniae Other coliforms Streptococcus milleri Anaerobic streptococci

Mycobacterium tuberculosis Actinomycosis Brucella melitensis Salmonella typhi Yersinia enterocolitica Bacteroides spp. Listeria monocytogenes Staphylococcus aureus (common in chronic granulomatous disease)

severity relating to the number of infecting organisms and the immune status of the host. In less than 10% of symptomatic cases, severe systemic disease, Weil’s disease, occurs. Symptoms are due to damage to the endothelium of small vessels and to seeding of the leptospires in meninges, liver or kidneys. They include: • fever, headache, myalgia • extensive vasculitic rash and circulatory collapse • renal failure • myocarditis • pneumonitis • hepatitis: jaundice and hepatomegaly are characteristic, and transaminases are only mildly elevated.

Nonviral causes of hepatic infection Nonviral hepatic infections (Table 6.3) may be manifest by: • hepatitis with inflammatory destruction of hepatocytes, resembling acute viral hepatitis • invasion and infiltration leading to hepatomegaly (e.g. hydatid disease) • abscess formation, either single or multiple, which may be secondary to extrahepatic sepsis (Table 6.4).

Diagnosis Diagnosis is made by: • demonstrating leptospires by dark-ground microscopy in: blood during the bacteraemic phase urine during phase of organ involvement • detecting in serum specific IgM antibody or rising titre of IgG antibody.

Leptospirosis

Treatment

Leptospira ictohaemorrhagica is a spirochaete that is carried in the kidneys of both wild and domestic animals, particularly the rat, with contamination of streams and rivers occurring through infected urine. Human exposure occurs in vets and farm workers, and by swimming in contaminated water. Transmission occurs via skin abrasions or mucous membranes, with person-to-person spread being rare.

Treatment with penicillin G (200 000–250 000 U/kg/day i.v. in six divided doses for 1 week) may have a favourable effect on the illness if given in the first 4–7 days. Tetracycline or erythromycin are also effective. Most patients recover without long-term sequelae.

Clinical features Following an incubation period of 1–2 weeks, bacteraemia is established and leads in the majority to a subclinical infection or a mild flu-like illness with fever and myalgia. Symptoms usually persist for 1 week, with their

Bartonella infection Bartonella henselae or B. quintana infection leading to hepatic disease is described in both immunosuppressed and immunocompetent children (Liston & Koehler 1996). Almost all reported cases in children are linked to likely transmission from cats by bites or scratches. Two histopathological types are described: vascular proliferative disease with cystic blood-filled spaces and

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foci of necrosis within the liver and spleen, and a necrotizing granulomatous type. In both, ultrasonography reveals low-attenuation lesions within the liver and spleen. A giant, solitary hepatic granuloma, mimicking a hepatic tumour, has also been described (Murano et al. 2001). The diagnosis may be confirmed by serological (EIA) testing for antibodies to B. henselae or B. quintana, or by specific stains applied to biopsy material or culture. Outcome is good, with a dramatic response to erythromycin or doxycycline. Listeria monocytogenes Almost all cases of hepatic involvement with Listeria infection occur in the presence of immunosuppression. A hepatitic illness with fever, raised transaminases and jaundice may occur, diagnosis being confirmed by isolating listeria organisms from blood cultures. Treatment with antibiotics (ampicillin 200–400 mg/kg/day i.v. for 14 days) is usually effective. Hepatic abscess formation due to L. monocytogenes infection has also been described (see below). Other bacterial infections Legionella pneumophilia has also been associated with a hepatitic illness in the immunosuppressed host, and Salmonella typhi infection may give rise to hepatitis which clinically resembles viral hepatitis. Brucellosis and tuberculosis may give rise to a granulomatous hepatitis with fever and hepatosplenomegaly in which jaundice is uncommon, transaminases are only mildly elevated but alkaline phosphatase is typically raised. Toxoplasmosis Toxoplasma gondii is a protozoan parasite whose animal reservoir is the cat. Excretion of cysts by cats contaminates the soil and leads to infection in other animals, particularly sheep. Infection in man occurs following ingestion of meat contaminated by toxoplasma cysts, or due to prenatal acquisition (Chapter 4). The majority of acquired infections are asymptomatic and unrecognized. Symptomatic acute infection is manifest by fever, fatigue and lymphadenopathy, resembling infectious mononucleosis, and may be accompanied by hepatitis. Lymph node biopsy may be characteristic and may permit isolation of the parasite. Recovery can be prolonged over several weeks but is usually complete. Treatment is only indicated in the immunocompetent with acquired infection if there is clinically overt visceral involvement or severe or persistent symptoms (Craft & Ruff 1988). A good response is made to pyrimethamine 2 mg/kg/day given orally in two divided doses, for 2–3 days, then 1 mg/kg/day, with

sulphadiazine 100 mg/kg/day in two divided doses. The optimal duration of therapy is not determined, but should be from 1 to 4 months, until symptoms resolve. Folinic acid (5–10 mg every 1–2 days) should be given to prevent significant bone marrow suppression occurring due to pyrimethamine. Helminthic infections Helminths, or parasitic worms, lead to a wide range of liver disease, the type and severity of which depends not only on the type of worm but also on the intensity of the infection and the host response. Simultaneous infection with more than one type of worm may occur. Children are particularly at risk, as infection may occur following close contact with infected animals, ingestion of infected soil or contaminated food. Echinococcus multilocularis (alveolar echinococcosis) and E. granulosus (hydatid disease) The primary host for the adult Echinococcus tapeworm is the dog. Ova are excreted in faeces, and although sheep are the usual intermediate host, man may become infected following close contact with infected dogs. In the UK, hydatid disease is most prevalent in Wales. Following ingestion of ova, the embryo develops and penetrates the stomach wall, reaching the liver via the portal venous circulation. Hydatid disease In hydatid disease, cysts develop most frequently within the lungs and liver. Hepatic cysts are usually slow growing and lead to asymptomatic hepatomegaly, but may become manifest due to secondary infection or because of their size. Aspiration of the cysts is hazardous due to risk of dissemination and hypersensitivity to the daughter cysts contained within the fluid-filled parent cysts. Serological diagnosis is highly sensitive. Treatment is by careful surgical excision if the cysts lead to symptoms, or with mebendazole 50–100 mg/kg/day for at least 3 months. Alveolar echinococcosis In alveolar echinococcosis, the cysts resemble a slow-growing tumour, with symptoms due to local pressure and parenchymal infiltration. As growth is slow, clinical symptoms may be delayed for decades, but presentation in childhood is reported and may be associated with immunodeficiency (Sailer et al. 1997). Metastatic spread to the lung and brain may occur. Ultrasound reveals a typical solid, heterogeneous mass, which may resemble a malignant lesion, with a necrotic centre. If complete surgical excision is not possible, mebendazole 40 mg/kg/day may arrest growth of the lesion (Keystone 1988).

Chapter 6: Acute Hepatitis Ascaris lumbricoides Ascaris has a world-wide distribution and often may cause no symptoms. Heavy infestation may lead to intestinal obstruction. Migration into the biliary tree, gall bladder and liver may lead to obstructive jaundice and secondary pyogenic infection with cholangitis and abscess formation. Diagnosis is made following recognition of Ascaris eggs or mature worms in infected faeces. Treatment is with a single dose of albendazole (200 mg) or mebendazole (200 mg), levamisole (3–5 mg/kg) or piperazine (75 mg/kg) and is effective in 90% of cases (Pawlowski 1988). Toxocara canis and T. catis Adult worms of Toxocara are found in the intestine of dogs (T. canis) or cats (T. catis). Infection in man follows ingestion of ova due to food contaminated by infected faeces. Larvae develop in the small intestine, invade the portal circulation and lead to tissue damage with granulomata in the liver and other organs. Infection is characterized by fever, hepatosplenomegaly and eosinophilia: ‘visceral larva migrans’. Diagnosis is presumptive or by serology. Treatment is with thiabendazole 25 mg/kg/day for 5 days or diethylcarbamazine 6 mg/kg/day for 21 days (Pawlowski 1988). Schistosoma mansoni (Middle East and Africa) and S. japonicum (Far East) (see Chapter 22) The ova of these flukes infect snails, emerge in water as cercariae which then gain access to man as the intermediate host by penetrating the skin. Following invasion into the circulation, ova may embolize to the liver, become impacted in presinusoidal portal veins and give rise to a granulomatous hepatitis with progressive fibrosis and portal hypertension. Diagnosis is made by detection of the ova in stools or in rectal biopsy material. Treatment is with praziquantel 20 mg/kg/dose, given twice for S. mansoni, three times for S. japonicum, for 1 day (Markell 1988). Fasciola hepatica This sheep liver fluke inhabits large bile ducts. The eggs, after excretion in faeces, hatch in water and infect snails. Cercariae emerge from the snail and thus contaminate water and vegetation such as watercress. Human infection is common where watercress is eaten. Following ingestion, F. hepatica may invade the biliary tree by migration through the gastrointestinal mucosa, peritoneal cavity and hepatic parenchyma. This may be accompanied by fever, tender hepatic enlargement, anorexia, nausea and vomiting and with allergic symp-

103

toms, urticaria and eosinophilia. Severe infection may lead to biliary tract involvement including hyperplasia, necrosis, dilatation and inflammation. Diagnosis is by recognition of the ova in infected faeces. Serological tests are also of value. Treatment is with Bithionol 30–50 mg/kg given on alternate days for a total of 10–15 doses (Markell 1988). Recovery is usually complete. Liver abscesses Abscess formation within the hepatic parenchyma may be due to pyogenic or amoebic infection (Table 6.4). As symptoms may be non-specific, a high index of suspicion, particularly in those with underlying risk factors (see below) is needed. Clinical features Symptoms and signs present in a series of 48 adults with pyogenic hepatic abscesses included the following (Barnes et al. 1987): • fever (77%) • abdominal pain (66%) • nausea (62%) • chest pain/cough (51%) • vomiting (43%) • right upper quadrant tenderness (42%) • right upper quadrant pain (27%) • hepatomegaly (25%) • jaundice (22%). Duration of symptoms was less than 2 weeks in 63% of cases. Patients with amoebic abscesses were more likely to have abdominal pain (90%), nausea (85%), right upper quadrant tenderness (67%) and a short duration of symptoms (86%) and were less likely to have respiratory symptoms (24%). Predisposing factors for pyogenic abscess Various conditions increase the likelihood of a pyogenic abscess developing in the liver. These include: • complications of prematurity • intra-abdominal sepsis (e.g. appendicitis, pancreatitis, Crohn’s disease, penetrating trauma) • diabetes (especially Klebsiella pneumoniae) • primary haemochromatosis (Yersinia enterocolitis is an iron-dependent bacteria, requiring high iron for growth) • haemoglobinopathy • immunodeficiency, including chronic granulomatous disease. Laboratory features Although there may be no detectable abnormality, the

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majority of patients with either pyogenic or amoebic abscesses have: • raised serum alkaline phosphatase • reduced serum albumin • mildly elevated aminotransferase enzymes (40– 100 U/l) • leucocytosis. Radiology Ultrasonography may permit detection of abscesses of at least 1 cm diameter within the hepatic parenchyma. The typical appearance is of a hypoechoic area with ring enhancement (see Plate 19, Atlas: p. 445). Computed tomography, where necessary, permits confirmation and more precise localization of the lesion (see Plate 20, Atlas: p. 445). Lesions which may mimic an abscess include malignant metastatic disease and the necrotizing hepatic lesions of fulminant herpes hepatitis (Wolfsen et al. 1993). There are no reliable ultrasonographic features to distinguish amoebic from pyogenic abscess (Barnes et al. 1987). Microbiology Aspiration of the abscess will yield the causative organism in almost all cases of pyogenic infection, with almost 50% of infected patients having the same organism isolated from peripheral blood culture (Barnes et al. 1987; Doerr et al. 1994). Amoebic abscess may be diagnosed by negative bacteria culture and positive serology, with antibody to Entamoeba histolyticum detectable by indirect haemagglutination assay, complement fixation or indirect fluorescence. Neonatal pyogenic abscess Hepatic abscesses occurring in the neonatal period are usually solitary and associated with underlying predisposition due to (Doerr et al. 1994): • prematurity • umbilical vessel catheterization • necrotizing enterocolitis. Signs and symptoms may be absent or non-specific, with irritability and a mildly distended, tender abdomen. Fever may be absent. Liver function may remain normal, leucocytosis is not invariable and abdominal X-ray may be unhelpful. Diagnosis rests on a high index of suspicion and ultrasonography (see above). In Doerr’s review of 18 cases, the following bacteria were identified, being isolated from the abscess in the majority: • Gram-negative coliforms • staphylococcal species

• streptococcal species. In 24% of cases there were multiple pathogens isolated. Treatment Percutaneous aspiration and drainage of the abscess cavity should be performed, and intravenous antibiotic therapy administered for 2–4 weeks. Antimicrobial treatment should be directed against the most likely organisms, and thus include a penicillin, aminoglycoside and metronidazole. Amoebic abscesses usually respond to metronidazole. Serial ultrasonography should be performed to document a reduction in size of the abscess cavity prior to stopping antibiotic therapy. Complete resolution over a few months, with eventual calcification of the lesion, can be expected with no long-term sequelae.

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Chapter 7: Fulminant Hepatitis and Acute Liver Failure PETER F. WHITINGTON AND ESTELLA M. ALONSO

Definition, 107 Aetiology, 107 Infectious disease, 107 Infection with viruses other than hepatitis viruses, 109 Non-viral hepatitis, 109 Drug and toxin-related hepatic injury, 109 Autoimmune hepatitis, 110 Inherited and metabolic diseases, 110 Pathology, 110

Hepatic necrosis, 110 Hepatocellular degeneration, 110 Recovery, 111 Chemical biochemistry, 111 Pathogenesis, 111 Clinical manifestations and differential diagnosis, 112 Management, 113 General measures, 114 Fluid balance, 114

Fulminant hepatic failure is a rare but often fatal disease. It is a heterogeneous condition with many different aetiologies in which the pathophysiology is unclear, preventing substantial advances in therapy. Therapy consists of supportive measures, with a focus on prevention or treatment of complications and early consideration for liver transplantation. Recent general reviews of the subject include (Lee 1993; Bhaduri & Mieli-Vergani 1996; Lee & Schiodt 1999; Whitington et al. 2001; Sanyal & Stravitz 2003).

Definition The broadest definition of fulminant hepatic failure (FHF) is the development of hepatic necrosis leading to acute loss of liver function occurring within weeks or a few months of the onset of clinical liver disease (Williams 1996). The currently accepted narrow definition includes the onset of hepatic encephalopathy and coagulopathy (which defines failure of liver function) within 8 weeks of the onset of liver disease and the absence of pre-existing liver disease in any form (Trey & Davidson 1970). It is important to realize that there are several problems with this definition in children. First, some patients with acute hepatocellular disease develop encephalopathy later than 8 weeks into the course of the illness and are defined as having subacute hepatic failure, subacute hepatic necrosis, or late-onset hepatic failure (Bernuau et al. 1986). Second, acute liver failure may be the first presentation of a previously unrecognized autoimmune or metabolic liver disease, e.g. Wilson’s disease or tyrosinaemia type 1. Third, most hepatic failure in neonates is secondary to an inborn metabolic error or an intrauterine insult, which, by defini-

Other therapy, 115 Antibiotic therapy, 115 Nutritional support, 115 Central nervous system monitoring, 115 Prevention and management of complications, 116 Specific therapies, 121 Family support, 122 Prognosis, 122 Outcome, 123

tion, are pre-existing diseases. In addition, encephalopathy may be difficult to detect in infants and small children and be less severe than coagulopathy (Chapter 5). Finally, some important paediatric disorders such as Reye’s syndrome and inborn errors of metabolism mimicking Reye’s syndrome, produce a syndrome similar to fulminant hepatic failure in which the encephalopathy is not secondary to acute liver failure.

Aetiology The aetiology of fulminant hepatic failure is age-dependent (Table 7.1) (Sokol 1990; Durand et al. 2001). While acute viral hepatitis is most common in all series, there is a distinct geographical impact on the frequency of diagnosis, particularly regarding the frequency with which hepatitis A and B infections are implicated. Table 7.2 and Fig. 7.1 provide data on 86 patients included in the ongoing US National Institutes of Health Acute Liver Failure study (NIH ALF study, personal communication, Dr R. Squires). This study provides the most up to date view of the epidemiology of acute liver failure in children. Infectious disease Hepatitis virus infection Viral hepatitis accounts for the largest proportion of fulminant hepatic failure in children of all age groups. Comprehensive reviews of the subject have recently been published (Williams & Riordan 2000; Whitington & Alonso 2001). In a series of 31 children with fulminant hepatic failure in London (Psacharopoulos et al. 1980) 26

107

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Section: 4: Acute Liver Disease is a frequent cause of fulminant hepatic failure in reports from developing countries but also paediatric series from developed countries (Psacharopoulos et al. 1980; Debray et al. 1997). In the USA, HAV generally causes < 5% of fulminant hepatic failure. Only one of the 86 cases in the NIH ALF study was due to HAV. The prevalence of acute hepatitis B virus (HBV) infection in large series of fulminant hepatic failure ranges from 25 to 75%, making it the commonest cause worldwide (Bernuau et al. 1986; Schiodt et al. 1999; Teo et al. 2001). The overall rate of fulminant hepatic failure in acute HBV infection is estimated to be about 1%. It is uncommon to document HBV infection in children with acute liver failure from Western Europe and the USA, as demonstrated in the NIH ALF study, except in infants born to HBV-positive, HbeAg-negative mothers (Beath et al. 1992), while in endemic areas it plays a much greater

(84%) had presumed viral hepatitis, and all 33 children reported from Cape Town (Saunders et al. 1972) had viral hepatitis. In the NIH ALF study, 63% of cases in children under 2 years of age and 35% of cases in children over 2 years old were viral or presumed viral hepatitis. Acute hepatitis A virus (HAV) infection is a relatively frequently diagnosed cause of fulminant hepatic failure; the prevalence of HAV among patients of all ages with fulminant hepatic failure in published series has varied from as low as 1.5% to as high 31%. Not surprisingly, HAV

Table 7.1 Causes of fulminant hepatic failure (FHF) in children. Aetiology Neonates Infectious Metabolic*

Ischaemia

Older children Infectious Drugs Toxins Metabolic* Autoimmune Ischaemia

Other

Disease

Incidence

Herpesviruses, echovirus, adenovirus, HBV Galactosaemia*, tyrosinaemia*, neonatal haemochromatosis*, mitochondrial disease Congenital heart disease, cardiac surgery, myocarditis, severe asphyxia

Frequent

HAV, HBV, NA-G, herpesviruses, sepsis*, other Valproate, isoniazid, paracetamol, carbamazepine, halothane Amanita phalloides, carbon tetrachloride, phosphorus Hereditary fructose intolerance*, Wilson’s disease† Hepatitis Congenital heart disease, cardiac surgery, myocarditis, severe asphyxia, Budd–Chiari syndrome Malignancy

Frequent

Moderately frequent

Table 7.2 Data from the NIH ALF study: aetiology of acute liver failure by age*.

Rare

Indeterminate Acetaminophen Metabolic Autoimmune Medication related Shock Budd–Chiari Hepatitis A Wilson’s disease Epstein–Barr virus Cytomegalovirus Congenital leukaemia Neonatal iron storage Other Total

Moderately frequent Rare Rare Rare Rare

Rare

HAV, Hepatitis A virus; HBV, hepatitis B virus; NA-G, non-A-G virus. *Diseases do not fulfil definition of FHF. †Rare under 3 years.

£ 2 years

≥ 2 years

Total

19 (63) 0 5 (17) 2 (7) 0 0 0 0 0 0 0 1 3 (10) 0 30

19 (34) 14 (25) 1 4 (7) 7 (13) 1 1 1 2 1 1 0 0 4 56

38 (44) 14 (16) 6 (7) 6 (7) 7 (8) 1 (1) 1 (1) 1 (1) 2 (2) 1 (2) 1 (2) 1 (1) 3 (3) 4 (5) 86 (100)

Percentages are given in parentheses. *Personal communication, Dr R. Squires, National Institutes of Health, Acute Liver Failure Study.

25

20

15

10

5

0

1000 IU/l), or may have fallen precipitously since their last measurement (in concert with a decreasing liver size, reflecting severe necrosis and collapse of hepatic mass). • Plasma ammonia is usually 2–8 times elevated (> 100 µmol/l). • Serum creatinine may be elevated secondary to renal complications, while the urea may be high (renal dys-

function, increased production from blood in the GI tract, dehydration) or low (failure of hepatic synthesis). • Hypoglycaemia may be present and difficult to correct. • Arterial blood gas analysis may show a wide spectrum of abnormalities from respiratory alkalosis to mixed respiratory and metabolic acidosis, usually in association with hypoxaemia. • Electrolyte abnormalities are associated with vomiting and dehydration. • Coagulation profiles demonstrate deficiencies of clotting factors and often evidence of consumptive coagulopathy. • The platelet count is often reduced, due to consumption or reduced production (aplastic anaemia). • The white blood cell count varies from high (stress response, secondary bacterial infection) to low (aplastic anaemia). Diagnosis The diagnosis is established by the combination of clinical and biochemical features and specific diagnostic tests (see below and Table 7.4). Ahistological diagnosis by liver biopsy is not critical for patient management and may be dangerous because of the abnormal coagulation. The risk of biopsy can only be justified when atypical clinical features exist. Transjugular biopsy to reduce the risk of bleeding is technically possible in children other than infants.

Differential diagnosis Viral hepatitis Pyrexia is more likely in HAV than in other forms of hepatitis. Diagnosis is confirmed by detecting IgM antibodies to HAV. Family members should be screened and offered HAV vaccine or immunoglobulin. HBV occurs in three clinical situations: 1 In non-vaccinated infants of HBV carrier mothers who have recently seroconverted to anti-‘e’ antibody (Chapter 8). 2 In chronic carriers who have been coinfected with delta or other viruses. 3 Rarely, in healthy unimmunized children following blood transfusions or drug or sexual abuse. The diagnosis is made by detecting IgM anticore antibodies to HBV, as other serological markers may be absent. Polymerase chain reaction for HBV DNA may be confirmatory. Adenovirus FHF is characterized by severe prolonged fever, liver failure and neutropenia. Diagnosis is made by viral culture, electron microscopy or immunohistochemistry of the liver. EBV hepatitis may be associated with lymphadenopathy and aplastic anaemia, while parvovirus may demonstrate the classic facial rash and haemolysis or aplasia. Diagnosis is confirmed by serological tests or a rise in viral titres (Chapter 8).

Chapter 7: Fulminant Hepatitis and Liver Failure Table 7.4 Investigations in fulminant hepatitis. Baseline essential investigations Biochemistry Bilirubin, transaminases Alkaline phosphatase Albumin Urea and electrolytes Creatinine Calcium, phosphate Ammonia Acid–base, lactate Glucose Haematology Full blood count, platelets PT, PTT Factors V or VII Blood group cross-match Septic screen Omitting lumbar puncture Radiology Chest X-ray Abdominal ultrasound Head CT scan or MRI Neurophysiology EEG Diagnostic investigations Serum Paracetamol levels Cu, caeruloplasmin (> 3 years) Autoantibodies Immunoglobulins Amino acids Hepatitis A, B, C, E EBV, CMV, HSV Leptospira (if clinically relevant) Other viruses Urine Toxic metabolites Amino acids, succinylacetone Organic acids Reducing sugars

CMV, Cytomegalovirus; EBV, Epstein–Barr virus; HSV, herpes simplex virus; PT, prothrombin time; PTT, partial thromboplastin time.

Drugs and toxins Drug-induced liver disease is discussed in Chapter 8. The clinical features depend on the drug involved, but the biochemical and prognostic signs are similar to viral hepatitis. In paracetamol (acetaminophen) overdose, the development of FHF is related to the dose (> 15 g), the age of the child (infants are more resistant to paracetamol toxicity) and whether the toxic effect is exacerbated by alcohol or other drugs. Hepatic enlargement and tenderness develop between the 3rd and 5th day, which may be associated with renal failure. Lactic acidosis, early hypoglycaemia and renal failure are ominous signs. The

113

diagnosis is confirmed by establishing serum or urine levels of paracetamol or metabolites. In sodium valproate poisoning (Chapter 8) there should be a history of drug ingestion and a background of developmental delay and convulsions. Hepatomegaly is evident. Serum aminotransferase levels are usually elevated, but only to a mild–moderate degree (usually < 400 IU/l), and jaundice is minimal (serum bilirubin usually < 200 µmol/l). Amanita phalloides poisoning is responsible for most mushroom poisoning. It is particularly common in France and Poland (Broussard et al. 2001). Mild cases develop abdominal pain, vomiting and diarrhoea 8–12 h after ingestion. More severe cases develop renal and hepatic failure within 3–4 days. The amatoxins can be detected in serum and urine. Metabolic liver disease Infants with metabolic liver disease are more likely to present with hypoglycaemia, metabolic acidosis and convulsions (Chapter 5). Encephalopathy may be difficult to detect and coagulopathy may be overlooked, particularly if jaundice is a late feature. Rapid shrinking of the liver is not usually a feature. Screening tests include plasma and urine amino acids, urinary succinyl acetone and organic acids, plasma and cerebrospinal fluid (CSF) lactate and/or muscle biopsy for electron transport chain enzymes (Chapter 5). FHF is a recognized presentation of Wilson’s disease. Kayser–Fleischer rings in the cornea are present in 50% of older children. Haemolysis, mildly elevated transaminases and a comparatively low alkaline phosphatase may suggest the diagnosis (Chapter 13).

Management There is no specific therapy for FHF except hepatic replacement. Management therefore is directed towards early consideration for liver transplantation, hepatic support, and prevention and treatment of complications while awaiting recovery or a suitable donor for liver transplantation (Devictor et al. 1993; Kucharski 1993; Munoz 1993). The key elements are medical support in the setting of an intensive care unit and rapid referral to a transplant centre. It is essential to take a full history from the parents, which would include establishing appropriate risk factors such as information on intravenous injections, infusions of blood products, foreign travel or contact with jaundice. It is important to establish which medications family members are taking, and in adolescents to enquire about drug addiction and sexual contact. The initial physical examination should establish hepatic, cerebral, cardiovascular, respiratory, renal and

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Section: 4: Acute Liver Disease

acid–base status. The patient’s conscious state and degree of coma should be established and a complete central nervous system examination performed. Evidence of chronic liver disease or other signs which may indicate aetiology, such as Kayser–Fleischer rings, cataracts and needle marks, should be established. Liver size should be measured and marked on the abdomen. The presence of impaired central nervous system function with acute liver disease is an indication for immediate hospitalization independent of any other clinical or biochemical findings. General measures Management should be in an intensive care unit setting with routine intensive care monitoring. Until a diagnosis is made it is assumed that all children are infectious and that all blood, excretions and secretions are potentially capable of transmitting viral hepatitis. Enteric isolation procedures must be enforced (Table 7.5). A central venous catheter is useful for assessment of central venous pressure and volume status, but may reTable 7.5 Management of fulminant hepatitis. No sedation except for procedures Minimal handling Monitor: Heart and respiratory rate Arterial BP, CVP Core/toe temperature Neurological observations Gastric pH (> 5.0) Blood glucose (> 4 mmol/l) Acid–base Electrolytes PT, PTT Fluid balance 75% maintenance Dextrose 10–50% Sodium (0.5–1 mmol/l) Potassium (2–4 mmol/l) Maintain circulating volume with colloid/FFP Coagulation support only if required Drugs Vitamin K H2-antagonist Antacids Lactulose N-acetylcysteine Broad-spectrum antibiotics Antifungals Nutrition Enteral feeding (1–2 g protein/day) PN if ventilated

BP, Blood pressure; CVP, central venous pressure; FFP, fresh frozen plasma; PN, parenteral nutrition; PT, prothrombin time; PTT, partial thromboplastin time.

quire surgical placement with coagulation support. Use of a triple lumen catheter, which enables simultaneous administration of blood products, intravenous fluids and drugs, is helpful and may facilitate exchange blood transfusions or haemodialysis if required. An indwelling arterial line for continuous measurement of blood pressure and for biochemical and acid–base monitoring is essential. A nasogastric tube is passed and placed to gravity, with regular gentle saline lavage to detect upper GI haemorrhage. The urinary bladder is catheterized and strict output records maintained to help in the evaluation of fluid status and renal function. Ideally, the patient is placed on a bed that permits the body weight to be recorded frequently. Baseline biochemical and other investigations should be performed (Table 7.4) and management instigated as in Table 7.5 and Fig. 7.2. Frequency of monitoring will depend on the severity of illness, ranging from daily in mild cases to 4- to 6-hourly in patients in stage III and IV coma, and should include: • complete blood count • blood gases and electrolytes • aminotransferases • prothrombin time • daily monitoring of plasma creatinine, bilirubin and ammonia. It is useful to take a chest X-ray to diagnose left ventricular failure or aspiration. An abdominal ultrasound may indicate liver size and patency of hepatic and portal veins, particularly if liver transplantation is being considered. Fluid balance The aim of fluid balance is to maintain hydration and renal function while not provoking cerebral oedema. Maintenance fluids consist of 10% dextrose in 0.25 N saline, and intake should be 75% of normal maintenance requirements unless cerebral oedema develops. A total sodium intake of 0.5–1 mmol/kg/day is usually adequate. Potassium requirements may be large, 3–6 mmol/ kg/day, as guided by the serum concentration. As patients may become hypophosphataemic, intravenous phosphate may be given as potassium phosphate. Attempts should be made to maintain urinary output using loop diuretics in large doses (frusemide at 1– 3 mg/kg every 6 h), dopamine (2–5 µg/kg/min) and colloid/fresh frozen plasma (FFP) to maintain renal perfusion. Should profound oliguria occur, consideration should be given to haemofiltration or dialysis. Anaemia should be corrected, maintaining the haemoglobin concentration above 10 g/dl to provide maximum oxygen delivery to tissues. Coagulopathy should be managed conservatively; the massive requirements for FFP may result in fluid overload.

Chapter 7: Fulminant Hepatitis and Liver Failure Stage I

Stage II

Stage III

Stage IV

Hospital admission for observation

Transfer to ICU

Intubation for airway management

Head CT if not already obtained

Protein restriction 0.8–1.0 g/kg/day

Frequent neurologic assessment

Consider exchange transfusion or plasmapheresis

Mannitol if CT finds cerebral oedema

Oral lactulose and/or neomycin to lower serum ammonia

Consider flumazenil

Avoid Benzodiazepines

Monitor for signs of cerebral oedema

115

If significant cerebral oedema, neurologic outcome poor even with OLT

Head CT if seizure activity or signs of increased ICP

Arrange transfer to transplant centre

Fig. 7.2 An algorithm using hepatic encephalopathy as an indicator for changing patient management.

Other therapy It is usual to prescribe vitamin K (2–10 mg i.v.), although it is not usually effective. H2-antagonists and antacids (see below) should be administered prophylactically to prevent GI haemorrhage from stress erosions. The role of N-acetylcysteine (70 mg/kg 4-hourly) in the management of FHF other than paracetamol poisoning is unproven, but anecdotal results suggest that it may have a role. Amulticentre study, supported by the National Institutes of Health (USA), of its role in the management of acute liver failure is in progress. Antibiotic therapy The results of surveillance cultures can be used to guide antibiotic therapy in the event of suspected infection, but broad-spectrum antibiotics (amoxycillin, cefuroxime, metronidazole and prophylactic fluconazole) are only prescribed if sepsis is suspected or liver transplantation is anticipated (Larcher et al. 1982). Nutritional support The role of parenteral nutrition in the management of

patients with acute liver failure is controversial. The main aims of therapy are: • to maintain blood glucose (> 4 mmol/l) and ensure sufficient carbohydrates for energy metabolism • to reduce protein intake to 1–2 g/kg/day, either enterally or parenterally • to provide sufficient energy intake to reverse catabolism, either enterally or parenterally. Children who are mechanically ventilated should have parenteral nutrition, as it may be 7–10 days before full normal diet is resumed following transplantation. Central nervous system monitoring A baseline electroencephalogram (EEG) is helpful to stage coma and provide information on prognosis (see Plate 21, Atlas: p. 446). Computed tomography (CT) scans are probably not useful early in encephalopathy, but may provide information on cerebral oedema or irreversible brain damage later in the disease. Frequent evaluation of neurological function and blood ammonia is essential to follow the progress of hepatic encephalopathy. Continuous or frequent electroencephalography may demonstrate abnormal electrical activity predisposing to convulsions, particularly in infants, but is not generally necessary. The role of intracranial pressure monitoring remains controversial. There are many systems in use: extradural monitors (e.g. Ladd transducers), which are easy to insert but inaccurate; subdural systems (e.g.

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Section: 4: Acute Liver Disease

Gaeltec transducers), which may also be inaccurate; and Camino catheters, which are inserted into the brain or dura. All forms of intracranial monitoring are potentially hazardous in patients with severe coagulopathy, but they may provide helpful information on changes in intracranial pressure and improve selection for liver transplantation. Prevention and management of complications The clinical course is dominated by the complications of hepatic failure, and therapy should be focused on their prevention and management. Hypoglycaemia Hypoglycaemia (blood glucose < 400 mg/l) develops in the majority of children. It may contribute to central nervous system impairment and other organ dysfunction. Factors contributing to hypoglycaemia include: (i) failure of hepatic glucose synthesis and release; (ii) hyperinsulinaemia (due to failure of hepatic degradation); (iii) increased glucose utilization (due to anaerobic metabolism); and (iv) secondary bacterial infection (Vilstrup 1986; Walsh et al. 2000; Clark et al. 2001; Harry et al. 2002). Frequent bedside monitoring of blood glucose concentrations (every 2–4 h) and the intravenous administration of glucose (10–50% dextrose) are required to prevent this complication. Increased insulin production, secondary to excess glucose infusion, leads to increased glucose need, and can be avoided by permitting blood glucose to remain between 400 and 600 mg/l. Profound refractory hypoglycaemia carries a grave prognostic implication and often heralds the imminent death of the patient. Coagulopathy and haemorrhage The management of coagulopathy and haemorrhage is a major part of the overall care of the child with FHF. Profound disturbances in haemostasis develop secondary to failure of hepatic synthesis of clotting factors and fibrinolytic factors, reduction in platelet numbers and function, or intravascular coagulation (O’Grady et al. 1986). The coagulation factors synthesized by hepatocytes include factors I (fibrinogen), II (prothrombin), V, VII, IX and X, and a reduction in synthesis leads to the prolongation of prothrombin and partial thromboplastin time. The prothrombin time is the most clinically useful measure of hepatic synthesis of clotting factors. Prolongation of the prothrombin time often precedes other clinical evidence of hepatic failure, such as encephalopathy, and may alert the clinician to the severity of acute hepatitis; it is a guide to the urgency of liver transplantation. Administering vitamin K parenterally assures the sufficiency of

this essential cofactor, but rarely improves coagulation in FHF. The prothrombin time depends upon the availability of factor VII, which has a shorter half-life than other factors and decreases more rapidly than other liver-derived clotting factors. As a result, measurement of factor VII may be a more sensitive indicator than the prothrombin time. Fibrinogen concentrations are usually normal unless there is also disseminated intravascular coagulation (DIC). The level of factor VIII may help differentiate between DIC and FHF as it is synthesized by vascular endothelium and therefore in FHF is normal or increased, possibly as an acute-phase response or due to decreased utilization. Decreased levels of factor XIII may contribute to poor clot stabilization. A reduction in platelet numbers (80 ¥ 109/l) occurs in up to half of adult patients, although thrombocytopenia is less of a problem in paediatric experience. Severe thrombocytopenia, requiring platelet transfusion, suggests hypersplenism, intravascular coagulation or aplastic anaemia. The use of extracorporeal support devices may also contribute. Intravascular coagulation as detected by abnormal concentrations of fibrin degradation products are present in almost all patients, indicating ongoing clot deposition and dissolution, most probably as a consequence of tissue necrosis in the liver. DIC is rarely significant, but can contribute to organ damage. The administration of commercial concentrates containing activated clotting factors may precipitate DIC. Bleeding from needle puncture sites and line insertion is common, while pulmonary or intracranial haemorrhage may be terminal events. Petechiae reflect decreased platelet function, disturbed vascular integrity, or DIC. Although in the early stages of assessment prolongation of prothrombin time is a sensitive guide to prognosis and the need for liver transplantation, life-threatening coagulopathy should be corrected with FFP, cryoprecipitate and platelets as needed. It is not necessary to maintain coagulation parameters (prothrombin time) in the normal range. In general, mild to moderate coagulopathy (prothrombin time < 25 s) requires no therapy except support for procedures. Marked coagulopathy (prothrombin time > 40 s) should be corrected (10 ml/kg of FFP every 6 h) to prevent the risk of bleeding, particularly intracranial haemorrhage. If major bleeding occurs, additional attempts should be made to correct coagulation using 15– 20 ml/kg FFP every 6 h, or continuous infusions at a rate of 3–5 ml/kg/h. Administration of recombinant factor VII (80 µg/kg) reliably corrects the coagulation defect in patients with FHF for a period of 6–12 h and may be useful in preparation for invasive procedures. Double-volume exchange transfusion may temporarily improve coagulation and DIC and control haemorrhage. Haemofiltration may be necessary to control fluid balance if much coagu-

Chapter 7: Fulminant Hepatitis and Liver Failure lation support is required. Platelet counts should be maintained above 50 ¥ 109/l by infusion of platelets. DIC is rarely severe enough to require heparin infusion. Prevention of gastrointestinal haemorrhage GI tract haemorrhage may be life-threatening due to gastritis or stress ulceration. High-dose H2-antagonists (ranitidine 1–3 mg/kg 8-hourly) or H-pump inhibitors (omeprazole 10–20 mg/kg/day) should be administered intravenously and sucralfate (1–2 g 4-hourly) may be given by nasogastric tube to reduce upper GI tract bleeding. Encephalopathy Clinically, acute hepatic encephalopathy is defined as any brain dysfunction that occurs as a result of acute hepatic dysfunction (Ferenci et al. 2002) and may be exacerbated by sepsis, GI bleeding, electrolyte disturbances or sedation, particularly benzodiazepine administration. Clinical manifestations and progression are highly variable, but acute hepatic encephalopathy usually evolves over days through definable stages. It may progress rapidly, with coma developing within hours of the earliest detectable signs. A scale for grading clinical encephalopathy is presented in Table 7.6 (Trey & Davidson 1970; Teasdale & Jennett 1974). This scale is useful for assessing encephalopathy in older patients, but has less value in assessing neonates and infants, particularly in the early stages of encephalopathy. Although alterations in the EEG are not specific, the EEG is useful for monitoring progression in hepatic encephalopathy (Table 7.6). The earliest abnormalities may not be detectable by clinical assessment, but are apparent to family members. These include: • Personality changes, reflective of forebrain dysfunction, include regression, irritability, apathy and occasionally euphoria. Younger children are more likely to be irritable and apathetic.

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• Sleep disturbances, such as insomnia or sleep inversion, are often observed. Intellectual deterioration, observed in stage I of chronic hepatic encephalopathy, is usually not evident in acute encephalopathy. • Constructional apraxia related to disturbed spatial recognition may be present. Simple age-related tasks may be clinically useful tools for the day-to-day assessment of inattentiveness and apraxia. Subtraction of serial 7s, recall of events (such as recently viewed videos), handwriting and figure drawing are appropriate tasks that older children can be asked to repeat daily in order to assess early encephalopathy. Younger children when asked to colour a figure in a simple colouring book may not complete the task (inattentiveness), or scribble far outside the lines (constructional apraxia). • Drowsiness and lethargy are readily apparent as the patient progresses into stage II hepatic encephalopathy. • Asterixis develops and is a useful sign, but it cannot be elicited with regularity in children less than 8–10 years of age. • Motor impairment becomes evident, including ataxia, dysarthria and apraxia. Other neuromotor disturbances that can be detected at stage II encephalopathy include hyperreflexia, sustained clonus, rigidity, extensor posturing and bizarre facial expressions. EEG abnormalities are detectable at this stage. Mental deterioration is clearly evident — the personality changes and behaviour becomes inappropriate, with outbursts of anger or crying. Infants exhibit increasing irritability and often produce high-pitched, ear-piercing screams. They may refuse to suckle or eat. • Stage III hepatic encephalopathy is characterized by deepening somnolence and stupor. The patient is arousable by vigorous physical stimuli, but does not respond to commands. Patients are disoriented and often do not recognize family members. School-aged children and teenagers in deepening stage II and stage III coma often exhibit extreme agitation and rage. Biting may be a problem, and individuals caring for such children must be

Table 7.6 Clinical stages of hepatic encephalopathy Stage

Asterixis

EEG changes

Clinical manifestations

I (prodrome)

Slight

Minimal

II (impending)

Easily elicited

III (stupor)

Present if patient co-operative

Usually generalized slowing of rhythm Grossly abnormal slowing

IV (coma)

Usually absent

Mild intellectual impairment, disturbed sleep–awake cycle Drowsiness, confusion, coma, inappropriate behaviour, disorientation, mood swings Drowsy, unresponsive to verbal commands, markedly confused, delirious, hyperreflexia, (+) Babinski sign Unconscious, decerebrate or decorticate response to pain present (IVA) or absent (IVB)

Appearance of delta waves, decreased amplitudes

Adapted from Trey & Davidson (1970) and Sussman (1996).

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Section: 4: Acute Liver Disease

aware of the potential health risks involved. Seizures may develop. Neurological findings are more profound (see Table 7.6). • Progression into stage IV hepatic encephalopathy is heralded by the onset of coma. The patient responds only to painful stimuli. At first, the patient is flaccid but in deeper stage IV the patient will assume decerebrate posturing, and brainstem reflexes are lost. Acute hepatic encephalopathy is completely reversible after resolution of the hepatic dysfunction. Management Although the role played by ammonia in the development of encephalopathy is controversial, therapy to reduce ammonia production or accumulation is indicated. The essential components of therapy are: (i) restriction of dietary protein; (ii) enteral antibiotics; (iii) enteral lactulose; and (iv) controlling the complications of fulminant hepatic failure that contribute to ammonia accumulation. In the early stages of hepatic encephalopathy conventional measures are taken to minimize the formation of nitrogenous substances by the intestine. Some units give enemas with a high magnesium sulphate content to evacuate colonic contents, and cleanse the large bowel periodically with a solution such as 1% dextrose. Acathartic, such as sodium-free magnesium sulphate and/or a nonabsorbable disaccharide (lactulose 1–2 ml/kg every 4–6 h) may be administered orally or via the nasogastric tube. Neomycin (50–100 mg/kg/day) may also be used to prevent ammonia production if diarrhoea secondary to lactulose is a problem. Protein intake should be limited to 0.5–1 g/kg/day and may be administered enterally or parenterally to limit the production of ammonia. Caloric intake is maintained in the early stages with glucose polymers and supplemented by infusion of 10% dextrose solution, while frequently monitoring blood glucose. The older patient with aggressive delirium is a particular risk to care providers. Sedation is not usually needed, except in violent patients to prevent self-injury. Elective ventilation should be considered if the encephalopathy progresses. If sedation is required, either for restraint or during procedures, short-acting barbiturates or opiates can be safely utilized, but benzodiazepines should be avoided. There are potential therapeutic implications related to the GABA receptor, which has been implicated in encephalopathy. Flumazenil (a benzodiazepine antagonist) may produce temporary reversal of hepatic encephalopathy (Bansky et al. 1989). Administration is followed in minutes by a clinical response, which may last for several hours, and it has been suggested that a lack of response to flumazenil may indicate a poor prognosis. Flumazenil holds significant potential for improving the diagnosis and establishing the prognosis in children with hepatic encephalopathy. It may also facilitate the management of FHF by rendering patients more responsive

and, thereby, extending the time before protective airway management and other invasive interventions are required. Many of the complications of FHF, such as GI haemorrhage, increase the potential for ammonia accumulation and its consequent neurotoxicity. Measures should be taken to prevent and control haemorrhage. Dehydration, electrolyte and acid–base disturbances should be corrected, and blood glucose concentration should be maintained by administering 10–25% glucose solution. Cerebral oedema Brain death associated with cerebral oedema is the most frequent cause of death in fulminant hepatic failure and contributes to reduced survival after liver transplantation (O’Brien et al. 1987; Blei 2000). Every effort should be made to prevent this complication since the prognosis is poor once it is evident (see Plate 22, Atlas: p. 446). Cerebral oedema may develop between stage III and stage IV encephalopathy and present within hours of the onset of coma. It is heralded by changes in the neurological examination — abnormally reacting or unequal pupils, muscular rigidity and decerebrate posturing, mild clonus and/or focal seizures, and loss of brainstem reflexes. There may be alteration of respiratory pattern, bradycardia and an increase in blood pressure. It is associated with a rise in intracranial pressure (ICP) > 30 mmHg (Lidofsky et al. 1992). CT or magnetic resonance imaging (MRI) scans of the brain will show flattening of the gyri and reduction of the size of the ventricles, but they are not helpful for early diagnosis. Loss of the definition of grey/ white matter is an ominous sign. Fixed, dilated pupils indicate brainstem coning and irreversible brain damage, but care in interpretation is required if sedative drugs have been used. The aetiology of cerebral oedema is not known, but iatrogenic factors may contribute. These include: fluid overload from therapeutic efforts to improve coagulopathy and hypotension; failure to maintain blood glucose concentrations leading to anaerobic brain metabolism, which can result in cerebral fluid shifts; while failure to maintain systemic blood pressure can lead to cerebral ischaemia and secondary oedema (Keays et al. 1991). Management Current treatment of cerebral oedema in FHF is inadequate, so every effort must be made to prevent it. The key strategy is fluid restriction (< 75% of maintenance), maintaining circulating volume with colloid. The intravenous infusion of mannitol (0.5 g/kg every 4– 6 h) helps to control acute increases in intracranial pressure and may reverse acute neurological changes. Serum osmolarity should be monitored during mannitol therapy and should not exceed 320 mosmol/l. Elective ventilation should be performed if cerebral

Chapter 7: Fulminant Hepatitis and Liver Failure oedema is suspected. Intubation may be carried out using a short-acting agent (atracurium 300–600 µg/kg i.v. and then 100–200 µg/kg as required) to prevent the rise in ICP associated with the gag reflex. Further sedation may be required with physiotherapy and suction. Hyperventilation (PCO2 < 3.5 kPa) may have a temporary effect in reducing ICP but metabolic compensation limits this to 24 h. Diligent efforts should be made to maintain cerebral perfusion pressure (mean arterial pressure minus intracranial pressure) by the administration of blood products, albumin and inotropic agents (adrenaline or noradrenaline). Corticosteroids are of no value in preventing or reducing cerebral oedema. Barbiturate coma (thiopentone 0.5–1 mg/kg i.v. followed by an infusion of 0.5–3 mg/ kg/h) may maintain cerebral perfusion while a donor liver is awaited, but has no proven value in FHF. Convulsions should be treated promptly with phenytoin (10 mg/kg i.v.) or phenobarbitone (10–15 mg/kg i.v.). Persistent convulsions may respond to thiopentone infusion (0.5–3 mg/kg/h) but are a grave prognostic sign. Monitoring intracranial pressure is controversial (Keays et al. 1993) as it has no therapeutic role and does not improve overall outcome; however, it may improve selection for liver transplantation. Electrolyte and acid–base disturbances Disturbances in sodium homeostasis, either hyponatraemia and/or hypernatraemia, are observed in virtually all children (Record et al. 1975). Hyponatraemia is more common, despite sodium retention by the kidney. It may result from decreased water excretion, increased antidiuretic hormone, disturbances in the sodium/potassium pump, or the excess administration of hypotonic saline. Hypernatraemia is less common, but is related to the administration of sodium-rich intravenous fluids and the vigorous use of lactulose or mannitol. Hypokalaemia occurs secondary to increased retention of sodium by the kidney from secondary hyperaldosteronism, the vigorous use of diuretics, excessive vomiting or nasogastric suction. Occasionally hyperkalaemia is observed in patients with massive hepatic necrosis and/or haemolysis. Hypocalcaemia and hypomagnesaemia frequently occur and should be corrected. Acid–base disturbances are common and may be secondary to liver failure, sepsis or the underlying disease. Respiratory alkalosis is observed in the early stages of encephalopathy, due to central hyperventilation. Metabolic alkalosis is seen with hypokalaemia and vigorous use of diuretics, particularly frusemide. Metabolic acidosis may be multifactorial and develop secondary to metabolic liver disease with accumulation of organic acids, including lactate and free fatty acids, although ketosis is usually minimal. Other factors include: administration of blood

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preserved with citrate, tissue hypoxia and anaerobic metabolism, renal failure; or paracetamol poisoning (Bernal & Donaldson 2002). Severe metabolic acidosis requires intravenous sodium bicarbonate (8.4%), elective ventilation or bicarbonate dialysis. Respiratory failure and respiratory acidosis develop as coma deepens, requiring mechanical ventilation. Renal dysfunction Renal insufficiency complicates the course in 75% of children (Wilkinson et al. 1975; Bihari et al. 1986) and may be due to: prerenal uraemia, acute tubular necrosis and functional renal failure. Prerenal uraemia may be due to dehydration or GI bleeding because of absorption of nitrogenous substances from the gut. A marked increase in blood creatinine concentration may develop from decreased glomerular filtration and/or increased muscle breakdown. Acute tubular necrosis is seen in the minority of patients and may occur due to hypovolaemia or dehydration related to mannitol infusion or diuretic therapy. Features include: abnormal urinary sediment; urinary sodium concentration > 20 mmol/l, reduction in creatinine clearance (urine/plasma creatinine ratio < 10); and oliguria (urine output < 0.5 ml/kg/h). Functional renal failure (hepatorenal syndrome) is the commonest cause of renal insufficiency. Features include sodium retention (urinary sodium concentration < 20 mmol/l), normal urinary sediment, and reduced urinary output (< 1 ml/kg/h). The aetiology is multifactorial, and electrolyte imbalance, sepsis and hypovolaemia all play a part. Endotoxaemia may contribute to renal injury. The aim of management is to maintain circulating volume to prevent prerenal hypovolaemia and ensure that urine output is > 0.5 ml/kg/h. A fluid challenge (10 ml/kg) may be successful unless central venous pressure indicates fluid overload (> 8–10 cmH2O), when the use of frusemide (1–2 mg/kg i.v. or 0.25 mg/kg/h by infusion) may be effective. Established renal failure requires haemodialysis or filtration for fluid overload. While functional renal failure recovers quickly after liver transplantation, acute tubular necrosis may severely complicate the postoperative management (Brown et al. 1996). Although 50% of patients require haemodialysis or haemofiltration support, renal function returns to normal after successful liver transplantation. Ascites The use of ultrasound in the pretransplant assessment has demonstrated excessive peritoneal fluid in most patients, probably due to acute portal hypertension, from lobular collapse, vasodilatation, poor vascular integrity and re-

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duced oncotic pressure. Clinically evident ascites occurs in less than half the patients but may be a site for secondary bacterial or fungal infection, indicating the necessity for paracentesis in septic patients without an obvious focus of infection. Therapy is not indicated, other than the correction of oncotic pressure with albumin infusion and general fluid management. Cardiovascular and pulmonary complications Cardiac output is increased secondary to reduced vascular resistance and arteriovenous shunting (Bihari 1986). Reduced vascular resistance may be due to gut-derived endotoxin or to substances released from the necrotic liver, as removal of the liver improved haemodynamic stability in a few cases. Patients frequently exhibit clinical evidence of warm extremities, facial flush and erythema of palms and soles, despite profound hypotension (‘warm shock’). Hypotension due to haemorrhage, bacteraemia or increased capillary permeability is a frequent event and may be refractory to volume replacement and to administration of pressor agents. Sinus tachycardia is present in 75% of patients (Psacharopoulos et al. 1980), while inappropriate bradycardia is a late sign that may be associated with a rise in intracranial pressure, suggesting a failure of central regulatory mechanisms, which may occur in the absence of clinically evident cerebral oedema. The combination of hypotension, evidence of peripheral vasodilatation, and metabolic acidosis (or elevated blood lactate) is an indication of imminent death. Cardiac dysrhythmias have been reported in adults. Although there are no detailed studies in paediatric patients, abnormal electrocardiographic patterns including T-wave and ST-segment changes occur with electrolyte imbalance. Cardiac arrest in children with multiorgan failure or undergoing plasmapheresis has been described (Psacharopoulos et al. 1980). Necropsy findings demonstrate a dilated heart with pale myocardium and occasional petechial haemorrhage of the endocardium. Small pericardial effusions are commonplace. Respiratory problems Defective ventilation and ventilatory response to chemical stimuli is commonly observed. Hyperventilation often accompanies stage II–III encephalopathy and results in respiratory alkalosis. Patients in stage IV coma develop hypoventilation, hypoxia and hypercapnia. Arterial blood gas analysis usually reveals a mixed respiratory–metabolic acidosis. Although these patients may increase ventilation in response to transient hypoxia, ventilation is not maintained if hypoxia is prolonged. Elective

mechanical ventilation guided by arterial blood gas analysis should be initiated at the first sign of respiratory failure. Unfortunately, positive pressure ventilation, with positive end expiratory pressure, may reduce hepatic perfusion and exacerbate metabolic acidosis. Poor oxygenation despite adequate (mechanical) ventilation can be the result of intrapulmonary shunting of blood — a secondary ventilation–perfusion mismatch due to microvascular dilatation. Necropsy findings include diffuse dilation of the pulmonary vascular bed and occasional spider naevi. Intrapulmonary shunting resolves promptly after liver transplantation or spontaneous recovery. About a third of adult patients with fulminant hepatic failure demonstrate clinical and/or radiographic evidence of pulmonary oedema (Warren et al. 1978), which is higher than has been observed in children with FHF. It may be due to vasodilatation and loss of vascular integrity and can respond to diuretics and correction of plasma oncotic pressure. Pulmonary infection from Staphylococcus aureus, Gramnegative bacteria, Pseudomonas and Candida often complicates the course. Risk factors include pulmonary oedema, intubation, mechanical ventilation and immunodeficiency. Prophylactic antibiotics should not be used, and positive endotracheal tube cultures should not be treated unless accompanied by clinical or radiographic evidence of pulmonary infection. Other complications include aspiration pneumonia and pleural effusions. Pulmonary haemorrhage is a terminal event. Secondary bacterial and fungal infections The majority of adults and 50% of children will develop significant infection (Rolando et al. 1990), which may be related to impairment of cellular and humoral immune systems. The organisms most often implicated are Grampositive (S. aureus, S. epidermidis and streptococci), presumably of skin origin. Occasionally Gram-negative bacteria or fungal infection are observed. Urinary tract infections, from indwelling catheters, and pulmonary infection, particularly in ventilated children, are common. Management includes surveillance cultures from indwelling catheters, urine cultures and surface swabs. Broad-spectrum antibiotics should be started prior to the suspicion of sepsis, as the signs may be subtle. For example, a rise in heart rate, the difference in the core/toe temperature gradient, a fall in blood pressure or urine output, the rapid development of hypoglycaemia, hypothermia or a deterioration in the mental state. Amoxycillin (25 mg/kg/dose t.d.s.), cefuroxime (20 mg/kg/dose t.d.s.), and/or metronidazole (8 mg/kg/dose t.d.s.), if there is a suspicion of anaerobic infection, are reasonable first-line medications. Prophylactic antifungals such as amphotericin (1.5 mg/kg/day) or fluconazole (3–6 mg/

Chapter 7: Fulminant Hepatitis and Liver Failure kg/day) may be effective, although potentially nephrotoxic. They should be started as soon as a patient is listed for liver transplantation. Positive cultures in the absence of clinical infection should result in removal or replacement of the infected catheter and administration of the appropriate antimicrobials, with close attention to the possibility of additional, perhaps opportunistic infection. Aminoglycoside antibiotics should be avoided, if possible, because they can contribute to renal failure. Pancreatitis Pancreatic lesions consistent with acute pancreatitis have been found at autopsy in a significant proportion of adults with FHF, but this is rarely clinically evident. Children with valproic acid toxicity may have significant pancreatic lesions, with pain, hypotension and disturbed calcium homeostasis. Aplastic anaemia Bone marrow failure is a potentially fatal complication of sporadic non-A-G hepatitis (Tzakis et al. 1988; Whitington & Alonso 2001), parvovirus B19 and HSV-VI fulminant hepatic failure. It may not be evident before transplantation, and carries a high mortality. Bone marrow transplantation, administration of granulocyte colony stimulating factor or granulocyte/macrophage stimulating factor may be therapeutic options. Specific therapies Paracetamol ingestion The standard emergency management for ingested poison (gastric lavage, forced diuresis, etc.) should be instituted. Early detection of paracetamol toxicity should be established. Treatment with N-acetylcysteine (140 mg/kg initially with 70 mg/kg 4-hourly) should start within 24 h of ingestion and then continue until liver failure has resolved. Amanita phalloides poisoning Benzylpenicillin (10 000 000 U/kg/day) may reduce hepatic uptake of amatoxin, whilst thioctic acid (300 mg/ kg/day i.v. infusion) may reduce hepatic damage. Haemodialysis or haemofiltration may also remove the amatoxin. Hepatic support Many different measures have been used to support the liver while awaiting regeneration or transplantation, including a variety of experimental drugs such as

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prostaglandin E, insulin or glucagon, which have not been shown to be effective. Methods to remove potential neuroactive toxins include double-volume exchange transfusion, plasmapheresis, charcoal haemoperfusion, liver assist devices containing chemical scrubbers (Mitzner et al. 2001) or cultured hepatocytes (Sussman et al. 1992), extracorporeal perfusion through human or animal livers (Horslen et al. 2000), and cross-circulation with animals. Although these therapeutic manoeuvres may provide support during liver regeneration or while awaiting a donor, none has been shown to have any benefit with regard to survival. Double-volume exchange transfusion (in children < 15 kg) and plasmapheresis in older children may produce a transient improvement in coagulopathy and neurological state but may contribute to haemodynamic instability (Singer et al. 2001). Artificial liver support, using either porcine hepatocytes or a hepatoma cell line, has shown some benefit in improving coagulopathy and reducing encephalopathy in adults, acting as ‘a bridge to transplantation’, although long-term outcome and survival was not affected (Hughes & Williams 1996). There is a limited anecdotal experience in children (LePage et al. 1994; Okamoto et al. 1996). Molecular Absorbent Recirculating System (MARS) MARS is an alternative form of haemodialysis which uses a specific filter to remove toxic products, but not albumin. It has a role in the management of both acute liver failure and acute on chronic liver failure in adults (Ben Abraham et al. 2001; Schmidt et al. 2001). Its use in the management of children is anecdotal, but it may have a role to play in creating a ‘bridge to transplantation’. Hepatocyte transplantation Hepatocyte transplantation as therapy for acute liver failure using cell suspensions or synthetic constructs is at an early stage of research (Bilir et al. 2000; Kobayashi et al. 2000). Liver transplantation Liver transplantation should be considered in all children who develop a stage III or IV hepatic coma, as mortality in this group exceeds 70% (O’Grady et al. 1989). Transplantation is indicated for all forms of FHF, namely viral hepatitis (including hepatitis B), paracetamol overdose, halothane hepatitis and mushroom poisoning (see Plate 23, Atlas: p. 446). It is also appropriate for certain forms of inborn errors of metabolism, for example Wilson’s disease and tyrosinaemia type 1, although contraindicated

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for children with multisystem disease or mitochondrial deletions (Thomson 1998) (Chapter 5). As a successful outcome following liver transplantation is less likely than with other forms of liver disease (Brems et al. 1987; Superina et al. 1989) selection is critical (Emond et al. 1989) and is based on previous experience of mortality in the pretransplant era (O’Grady et al. 1989). Transplantation using a living donor can accelerate the process and is associated with better outcome in the setting of FHF (Emre et al. 1999; Miwa et al. 1999; Mack et al. 2001). The aetiology of FHF is an important factor in determining whether transplantation is appropriate. The highest mortality is seen in children with non-A-G hepatitis, particularly those with a delayed onset of coma and rapid progression to stage III or IV hepatic coma, a shrinking liver, falling transaminases associated with an increase in bilirubin, and coagulopathy (Rivera-Penera et al. 1997; Lee et al. 2001). These children should be immediately considered for transplantation. Children with fulminant Wilson’s disease are unlikely to recover with medical treatment and require transplantation. In contrast, children with hepatitis A and children with drug-induced liver disease, particularly paracetamol poisoning, may make a complete recovery with intensive medical therapy. Thus careful monitoring for poor prognostic factors is required before selection. In practical terms, it is appropriate to list for emergency liver transplantation all children who have reached stage III hepatic coma, as the shortage of donor organs may mean a considerable wait for transplantation, or death on the waiting list. As the development of irreversible brain damage is a major contraindication to transplantation, it is essential to be certain that brain damage has not occurred prior to the operation. Current techniques are inadequate, but include monitoring ICP, the identification of cerebral infarction or intracranial haemorrhage by cerebral CT or MRI scans, and looking for evidence of mid-brain coning, such as fixed, dilated pupils. Auxiliary transplantation, in which the recipient liver is left in situ to regenerate, is a controversial treatment for FHF, but may have the benefit that the graft may be removed if the original liver regenerates (Otte 1999; Azoulay et al. 2001). It is not suitable for transplantation for acute liver failure secondary to metabolic liver disease, as there is no potential for these livers to recover and there may be a risk of hepatoma in the cirrhotic liver. Family support Families of children with FHF are naturally devastated by the development of potentially fatal acute liver failure in their child. These families require a considerable amount of psychological support and counseling, particularly as

many families will not be able to grasp the seriousness of their child’s condition and the complications of liver transplantation. Psychological problems in both the family and recipient of the liver transplant are common and will need addressing following the operation. The particular problems of self-poisoning in adolescents may need additional psychiatric help.

Prognosis There are few reliable criteria that determine prognosis in a child with FHF despite attempts to correlate clinical variables and laboratory data with outcome (Trey et al. 1970; Tygstrup & Ranek 1986; Shakil et al. 2000). Children under 10 years and adults over 40 years of age have the worst overall prognosis (O’Grady et al. 1988; O’Grady et al. 1989), which varies according to aetiology. Patients with fulminant hepatitis A have the best overall survival at 68%, while survival rates for other aetiologies in descending order are: paracetamol overdose 53%, hepatitis B 39%, non-A-G hepatitis 20%, with halothane and other drug toxicities having the worst at 12% (O’Grady et al. 1988). The absence of an obvious aetiology in a child with severe hepatitis with encephalopathy (a presumed diagnosis of sporadic non-A-G hepatitis) is an indicator of poor outcome, since the recovery rate in such cases is less than 10%. A recent paediatric study has confirmed that children with hepatitis A, autoimmune hepatitis or paracetamol poisoning are more likely to recover spontaneously (Ee et al. 2003). Infants under the age of 1 year with severe coagulopathy secondary to metabolic liver disease or familial erythrophagocytosis have a particularly poor prognosis (Bhaduri & Mieli-Vergani 1996) as they often present as neonates and the diagnosis may not be established soon enough. Although liver transplantation is a viable option in children of any age, the difficulty in obtaining suitable donor organs in time means many infants die without transplantation (Chapter 20). In paracetamol poisoning, acid–base status and renal function on presentation correlate with prognosis (O’Grady et al. 1989; Bernal & Donaldson 2002), while other studies have indicated that factor V levels of < 20% are associated with a high mortality and requirement for rapid transplantation (Bernuau et al. 1986; Pereira et al. 1996). As in adults, the duration of illness before the onset of encephalopathy at the time of presentation may have prognostic significance in children (Rivera-Penera et al. 1997; Lee et al. 2001). There does not appear to be any significant difference in survival rate between patients who present with late-onset hepatic failure compared with those with acute fulminant hepatitis. Survival does correlate with degree of severity of encephalopathy, as survival was 18% for patients with stage

Chapter 7: Fulminant Hepatitis and Liver Failure IV hepatic coma, 48% for those with grade III coma and 66% for grade II coma. The development of cerebral oedema and renal failure, particularly in association with shrinking liver (collapsing liver mass), is associated with a grave prognosis. Clinical experience indicates that patients showing signs of stabilization and improved coagulation parameters have a better outlook for spontaneous recovery (Emond et al. 1989). A prothrombin time (> 50 s), which correlates with the degree of necrosis, is a bad prognostic sign, but does not necessarily indicate a fatal outcome. Increased concentrations of a-fetoprotein as an index of regeneration do not necessarily predict survival, and some patients recover without developing detectable a-fetoprotein levels. Although mortality tends to be greater with more extensive histological necrosis and complete absence of regenerative activity, attempts to correlate potential survival with assessment of histological damage have not been helpful and do not justify performing a liver biopsy (Gazzard et al. 1975). Spontaneous recovery from FHF is associated with complete histological recovery, even when extensive necrosis is present.

Outcome The mortality without treatment for FHF is in excess of 70%. Major causes of death in children prior to viable liver transplantation were: sepsis, 15%; haemorrhage, 50%; renal failure, 30%; and cerebral oedema, 56% (Psacharopoulos et al. 1980); these remain the main causes of death (Emond et al. 1989). Therapeutic intervention such as corticosteroid therapy for cerebral oedema may increase the risk of haemorrhage from gastritis, duodenal ulceration or perforation. Insertion of intracranial pressure sensors for monitoring may cause intracerebral haemorrhage. Only liver transplantation has an appreciable effect on mortality, although long-term survival is 56–66%, which is lower than with transplantation for other forms of liver disease. Cerebral dysfunction or brain death following transplantation was the cause of death in all of the above series, indicating the importance of not transplanting to patients with irreversible brain damage. Survivors of liver transplantation face psychological sequelae of such a procedure and the long-term complications of this operation (Chapter 20). Patients with hepatitis B who recover from fulminant hepatitis have less chance of recurrence following liver transplantation than do patients with chronic hepatitis B and do not become chronic carriers. In patients with spontaneous regeneration of the liver, the long-term outlook is excellent. Complete clinical and biochemical resolution occurs and the liver recovers completely (Karvountzis et al. 1974), although a post-necrotic cirrhosis may develop in some survivors.

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Warren, R., Trewby, J.W., Laws, J.W. & Williams, R. (1978) Pulmonary complications in fulminant hepatic failure: analysis of serial radiographs from 100 consecutive patients. Clinical Radiology 29, 363–369. Whitington, P.F. (1996) Metabolic liver disease in childhood. In: Liver and Biliary Diseases (ed. N. Kaplowitz), pp. 511–534. Williams & Wilkins, Baltimore. Whitington, P.F. & Alonso, E.M. (2001) Fulminant hepatitis in children: evidence for an unidentified hepatitis virus. Journal of Pediatric Gastroenterology and Nutrition 33, 529–536. Whitington, P.F., Soriano H.E. & Alonso, E.M. (2001) Fulminant hepatic failure in children. In: Liver Disease in Children (eds F. J. Suchy, R. J. Sokol & W. F. Balistreri), pp. 63–88. Lippincott, Williams & Wilkins, Philadelphia.

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Chapter 8: Chronic Hepatitis SUZANNE DAVISON

General features, 127 Definition and pathogenesis, 127 Clinical features, 127 Principles of investigation, 128 Differential diagnosis, 128 Laboratory investigations, 128 Histology, 129 Management of chronic hepatitis, 129 Chronic viral hepatitis, 130 Chronic hepatitis B infection, 130

Hepatitis D infection, 136 Hepatitis C infection, 136 Autoimmune liver disease, 142 Autoimmune hepatitis, 142 Treatment, 144 Sclerosing cholangitis, 146 Overlap syndrome/autoimmune sclerosing cholangitis, 148 Drug-induced liver disease, 148 Role of the liver in drug metabolism, 148

General features A diagnosis of chronic hepatitis encompasses a wide range of diseases, with distinct aetiologies, which typically lead to slowly progressive inflammatory damage and fibrosis. Despite the chronicity of the underlying disease process, the duration of signs and symptoms at diagnosis may be short, and the clinical presentation may resemble an acute hepatitic illness. In addition, hepatitis due to viral infection may evolve from an acute inflammatory process to chronicity. Diseases that may manifest histologically as chronic hepatitis may also present with other clinical and histological features. This chapter will include those diseases that present with chronic hepatitis, and will also include consideration of other hepatic manifestations: • hepatitis B and C virus infections • autoimmune liver disease • drug-induced liver disease.

Mechanisms of drug-induced liver disease, 148 Pathogenesis, 148 Host factors, 149 Other risk factors, 149 Clinicopathological spectrum, 149 Natural history, 150 Diagnosis of suspected DILD, 150 Drugs implicated in DILD, 151

tic and therapeutic implications. However, in up to 10% of patients with chronic hepatitis, the precise cause remains obscure and is termed cryptogenic. The process of chronic hepatitis is one of continuing inflammation centred on the hepatocyte, which leads to hepatocellular damage. It requires a trigger, a target and a mechanism of persistence. The trigger may be a viral antigen, autoantigen or drug-induced cell damage. The target may be a component of the cell structure, ultrastructure, or an enzymatic pathway. Persistence may be due to viral mechanisms for immune escape, an ineffective host immune response or the continued administration of a drug. Clinical features The clinical presentation of chronic hepatitis may be varied, even for a specific aetiology. Asymptomatic presentation

Definition and pathogenesis The term chronic hepatitis has been applied to a clinically diverse spectrum of diseases that fulfil defined histological criteria. There is considerable heterogeneity in their pathogenesis, course, prognosis and response to treatment. The ability to make a precise diagnosis has been improved by serological techniques for detection of autoantibodies and antiviral antibodies, by molecular and immunohistochemical techniques for detection of viruses and hepatocellular autoantigens. This has led to a revised classification of chronic hepatitis (Desmet et al. 1994; Table 8.1), which encompasses the histological activity of the disease process, the aetiology, with prognos-

Diagnosis may be made following: • incidental detection of abnormal liver enzymes • screening those at risk: family members of a hepatitis B/C virus carrier transfusion recipient following diagnosis of donor infection patient with an associated disorder, e.g. inflammatory bowel disease recipient of a known toxic agent, e.g. methotrexate. Insidious onset This is characterized by a gradual onset of:

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Table 8.1 Classification of chronic hepatitis. Aetiology

Chronic hepatitis B/C/D Autoimmune hepatitis Chronic drug-induced hepatitis

Grade (histology)

Mild/moderate/severe inflammatory activity

Stage (histology)

Without fibrosis Mild/moderate/severe fibrosis Cirrhosis

• fatigue, anorexia and weight loss, which may be intermittent • abdominal discomfort • variable or fluctuating jaundice. Symptoms may have been present for many years, and histological progression to cirrhosis may already be apparent at diagnosis. Complications of cirrhosis, such as portal hypertension or bleeding varices, may be the presenting symptom. Acute onset An apparent acute illness mimicking acute viral hepatitis is a common presenting feature of autoimmune hepatitis. Although hepatitis B or C virus infection may occasionally present during the acute infection, presentation in this way may also be precipitated by superimposed infection by a different infective agent, for example delta virus in hepatitis B infection. Chronic disease may also present with a picture indistinguishable from fulminant hepatic failure. Principles of investigation The principles of investigation should be to: • establish the diagnosis and exclude differential diagnoses • stage disease and detect complications (Chapter 14) • detect associated conditions. Early diagnosis is of prognostic value in both drug-induced liver disease and autoimmune hepatitis. Furthermore hepatitis C virus (HCV) and hepatitis B virus (HBV) infection respond less well to interferon therapy once cirrhosis is established. Differential diagnosis The aetiological classification given in Table 8.1 does not include those diseases caused by genetic defects, such as Wilson’s disease, a1-antitrypsin deficiency and cystic fibrosis, or disorders in which bile ducts are the focus of the disease. These disorders are important to consider in the differential diagnosis of chronic hepatitis.

Table 8.2 History: relevant points in differential diagnosis of hepatitis. Ethnic origin: risk of HBV in family members Risk factors of patient /other family members for parenteral virus acquisition: Transfusion of blood-derived products/haemodialysis Intravenous drug abuse Ear piercing/tattooing/previous surgery Prolonged neonatal jaundice Vaccination status Previous symptoms of acute hepatitis (maybe 10–15 years earlier) Features of allergy Family history: including autoimmune disorders Drug history/availability of drugs in household Risk from occupational exposure/sexual exposure/foreign travel Symptoms of extrahepatic disease/autoimmune disease Developmental history, deterioration in performance (Wilson’s disease)

HBV, Hepatitis B virus.

Depending on the mode of clinical presentation, the differential diagnosis may include: • autoimmune hepatitis • sclerosing cholangitis • chronic viral hepatitis • acute infective hepatitis • drug-induced liver disease • metabolic liver disease • cystic fibrosis • a1-antitrypsin deficiency • Wilson’s disease. A careful history is invaluable in considering this wide range of disorders (Table 8.2). Laboratory investigations Biochemical abnormalities Biochemical abnormalities in chronic hepatitis are nonspecific: • serum aminotransferase — alanine aminotransferase (ALT) and aspartate aminotransferase (AST) — are usually raised, may fluctuate spontaneously to normal levels, and do not always correlate with histological severity • serum alkaline phosphatase and g-glutamyl transpeptidase (GGT) are usually normal or mildly elevated except in the presence of cirrhosis • serum bilirubin is variable, and may be normal, especially in chronic hepatitis. Diagnostic investigations These should include the following: • autoimmune markers: autoantibodies immunoglobulins

and

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Table 8.3 Serological and biochemical markers of HBV infection. Host HBV status

ALT

HBV DNA

cAb

sAg

sAb

eAg*

eAb

Acute infection

Raised

Detectable (> 105 genome copies/ml)

IgM then IgG

+

–

+

–

Chronic infection: Immune tolerance Immune clearance Non-replicative

Normal Raised/fluctuating Normal

High Detectable but variable Undetectable

IgG IgG IgG

+ + +

– – –

+ + –

– – +

Resolved infection

Normal

Undetectable

IgG

–

+

–

+

cAb, Antibody to core antigen of virus; sAg, surface antigen of virus; sAb, antibody to sAg; eAg, nonstructural e antigen of virus; eAb, antibody to eAg. *Where the precore mutant HBV is present, eAg is not produced.

Table 8.4 Current recommendations for immunization against HBV in newborn (Immunization against Infectious Disease, HMSO 1996). Maternal status sAg + + +

eAg

eAb

Anti-HBV immunoglobulin 200 IU within 12 h

+ -

+ -

Yes No Yes

HBV vaccine: three doses within 12 h, at 1 and 6 months Yes Yes Yes

• viral serology (Tables 8.3 and 8.4; see also Chapter 6) • a1-antitrypsin level and phenotype • serum copper and caeruloplasmin and 24-h urinary copper excretion • drug levels where appropriate. Histology (see Plate 24, Atlas: p. 447) Hepatitis, both acute and chronic, is characterized histologically by: • inflammatory cell infiltrate of predominantly lymphocytes and plasma cells • hepatocellular damage manifest by swelling (balloon degeneration) or shrinkage • hepatocellular necrosis, which may be: spotty (focal) bridging (confluent): either portal–portal or portal– central piecemeal (at interface of parenchyma and connective tissue): periportal or periseptal. In chronic hepatitis, staging depends on the degree of fibrosis, which may be: • expansion of portal tracts; • moderate: porto–portal or periportal septa • severe: porto–central septa with architectural distortion

• cirrhosis: fibrous septa surrounding parenchymal nodules. The role of a liver biopsy is to assess the histological severity of disease, as there may be no pathognomonic features for the underlying cause. Although considerable overlap exists, certain features are of value in distinguishing between HCV infection and autoimmune hepatitis (Bach et al. 1992): • chronic HCV infection: biliary lesions: small bile duct damage or loss steatosis: micro- and macrovesicular lymphoid aggregates or follicles in portal tracts • autoimmune hepatitis: severe lobular or piecemeal necrosis broad areas of parenchymal collapse multinucleated hepatocytes cirrhosis. Features suggestive of drug-induced hepatitis are: • hepatocellular necrosis disproportionately severe compared with clinical manifestations • prominence of eosinophils in the inflammatory infiltrate • presence of microvesicular fat • presence of granulomata • coexistence of cholestasis and biliary lesions. With immunohistochemical methods, a definitive diagnosis may be obtained in: • chronic HBV infection — by HBsAg detectable in hepatocyte by immunostaining and cAg by orcein staining • HDV infection — by HDV antigen in hepatocyte detectable by immunofluorescence or immunoperoxidase stains. Management of chronic hepatitis The principles of management of chronic hepatitis are to remove the causative agent, ameliorate the inflammatory process, limit histological progression and minimize the

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complications of both the disease and the treatment. Identification of the precise aetiology and prognostic factors, together with knowledge of the natural history of the disease process, are crucial for implementing the appropriate therapy. Specific treatment strategies are described in the following sections, according to aetiology.

Chronic viral hepatitis Viral infections account for at least 90% of chronic hepatitis, with HBV and HCV the leading causative agents. Chronic viral hepatitis is the principal cause of chronic liver disease in the world (Scheuer 1991). Although different viruses may lead to similar clinical symptoms, signs, biochemical abnormalities and histological characteristics, the natural history following infection and rate of progression may be variable. This is exemplified by HCV infection, which may lead to rapid progression to cirrhosis within 2 years, but more typically slowly progresses over decades. There are also considerable differences in response to therapy, influenced not only by the infecting virus, but also by host factors including route of acquisition, ethnic origin and coexisting disease. A diagnosis of chronic viral hepatitis must be supplemented by characterization of not only the viral agent, but also specific viral and host factors which will influence the prognosis. Chronic hepatitis B infection Chronic HBV infection and its prevention pose a major health challenge worldwide: chronic HBV carriers comprise 5% of the world population (Kane et al. 1993). The likelihood of remaining a chronic carrier after HBV infection is highest in infancy (McMahon et al. 1985). The risk of developing cirrhosis and primary hepatocellular carcinoma is related to the duration of chronic infection, and acquisition in infancy is associated with an estimated 25% lifetime risk of cirrhosis or primary hepatocellular carcinoma. The particular challenges that HBV poses in childhood therefore are the prevention of HBV acquisition and the prevention of progressive liver disease in those who become infected. HBV transmission Perinatal transmission Exposure to maternal blood efficiently transmits HBV. Mothers who are e antigen (eAg)positive have the highest infectivity and a 70–90% risk of transmitting infection to their offspring. Transmission may occur through placental tears, trauma during delivery, and contact of the infant mucous membranes with infected maternal fluids. Intrauterine transmission may occur but this does not appear to be a major route. Women

who are e antibody (eAb)-positive have a lower risk of transmitting infection. However if their offspring are infected, they are at risk of developing fulminant liver failure (Beath et al. 1992). Horizontal transmission HBV is present in infected individuals in high concentrations in blood, serum and serous exudates, semen, vaginal fluid and saliva. Parenteral and sexual exposure therefore provide effective routes of transmission. Although HBV is also found in low concentrations in faeces and breast milk, these are not associated with a significant risk of transmission. Children at high risk include those requiring frequent transfusions (e.g. with haemolytic anaemia, thalassaemia, haemophilia), those with high-risk sexual behaviour, and intravenous drug users. Environmental transmission in childhood may occur by exposure to infected body fluids through a broken skin surface, either directly by biting or by accidental contamination. Household transmission of HBV from infected family members may occur: up to 40% of children who are born to carrier mothers but not infected at birth acquire infection in the first 5 years of life (Beasley & Hwang, 1987). An increased risk of environmental transmission also occurs in residential institutions and haemodialysis centres. Virology HBV is a DNA virus of the hepadnavirus family. HBV can be classified into seven genotypes, A–G according to nucleotide sequence (Chu & Lok 2002). The virus particle is made up of partially double-stranded circular DNA, which together with the nonstructural eAg and the core antigen (cAg), comprises the virus core. The outer shell is composed of the surface antigen (sAg). After infecting hepatocytes, the viral genome reaches the host cell nucleus where it is converted to covalently closed circular DNA (cccDNA). Replication occurs by first production of a messenger RNA intermediate, followed by reverse transcription by viral DNA polymerase to HBV DNA. This sequence is unusual: most DNA viruses do not incorporate a reverse transcription step during replication. DNA synthesis by reverse transcription is not ‘proofread’ in the same way as it is during DNA polymerization, and thus errors may occur giving rise to viral mutations. The ability of HBV to generate mutant species confers several advantages, including evasion of the host immune response and acquiring resistance to antiviral agents. A well-characterized and important mutation occurs in the precore region of the genome, resulting in the failure of eAg expression. This mutation has been implicated in severe exacerbations of chronic hepatitis and in fulminant hepatitis. Following replication, the new genomic DNA becomes

Chapter 8: Chronic Hepatitis associated with viral proteins (cAg, sAg and eAg) to form mature HBV particles which are then released from the hepatocyte. In infected individuals, although whole virions are present in the circulation, the viral components that predominate are spheres or tubules consisting only of sAg. In addition, eAg is detectable in the serum of those who have ongoing viral replication. Serological markers Examination of the serological markers of HBV infection — both viral particles and the host pattern of antibody response — and their change with time allows the distinction to be made between acute hepatitis, chronic infection and resolved past infection (Table 8.3). The first serum marker to appear during acute infection is sAg, occurring several weeks to months after initial exposure. It eventually disappears with clinical recovery. The eAg is also normally present during the acute phase (although absent in infection with a precore mutant) and is indicative of a highly infectious state, with HBV DNA also detectable in blood. The host response is first apparent with the appearance of IgM and IgG antibody to cAg (cAb), followed by the appearance of anti-eAb. The IgM component eventually declines and becomes undetectable, whereas IgG persists. In patients infected with the precore mutant virus, the lack of eAg expression is associated with an absence of eAb production, though viral replication and high infectivity persist with the presence of HBV DNA in blood. Natural history of hepatitis B infection Following acquisition of HBV, the following may occur: • acute hepatitis • chronic infection. Symptomatic acute hepatitis is uncommon in children, especially in young children and infants. There is usually complete resolution with lifelong immunity. Occasionally fulminant hepatitis may occur (see Chapter 7). Asymptomatic chronic infection is the most likely outcome following acquisition in infancy and early childhood, occurring in more than 95% of infants infected and 85–95% of those aged 1–5 years. It is defined by the persistence of sAg in peripheral blood for at least 6 months, irrespective of eAg/eAb status. Chronic HBV infection is characterized by three stages (Chu et al. 1985; Chu & Liaw, 1997): immune tolerance, immune clearance and residual non-replicative infection. Immune tolerance In the initial stage of chronic infection, infected hepatocytes express viral proteins (cAg, eAg, sAg) and there is a high level of replicating virus, with high levels of HBV DNA detectable in the circulating blood. The host T-cell response is actively suppressed. As

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there is no immune-mediated destruction of infected hepatocytes, there is no elevation of hepatic aminotransferase enzymes and no significant hepatic inflammation. The affected individual is usually asymptomatic. This state may persist for several decades, particularly after perinatal acquisition, before the immune response becomes active and immune clearance is attempted. Immune clearance During this stage a T-cell-mediated inflammatory response is directed against infected hepatocytes, leading to cell necrosis and hepatic fibrosis. This is characterized by elevation in aminotransferase enzymes. Continued viral replication and immune destruction during this stage lead to progressive liver damage and ultimately cirrhosis. Progression to cirrhosis is accompanied by risk of liver failure and hepatocellular carcinoma. Although the evolution of liver damage is typically slow, both these sequelae have been reported in childhood. With immune clearance of infected cells, levels of circulating DNA fall, eventually becoming undetectable. Together with clearance of eAg and emergence of eAb, this signifies the end of viral replication. However, this seroconversion may be accompanied by a flare in liver inflammation, manifest by a transient deterioration in liver function. If successful seroconversion is achieved, either spontaneously or by successful treatment, aminotransferase enzymes return to normal and disease progression is halted. The risk of end-stage liver disease is reduced, and even if cirrhosis is already present there may be clinical improvement. Residual non-replicative infection Following resolution of both viral replication and immune-mediated damage, HBV DNA remains integrated in the hepatocyte genome and surface antigen expression may continue. Another gene product, termed the X protein, is also produced and may have a role in malignant transformation. There is a continued risk of hepatocellular carcinoma, even after replicative infection has been eliminated. This risk is reduced further if sAg is cleared and seroconversion to surface antibody (sAb) occurs. Clinical presentation and diagnosis Acute infection Symptomatic acute HBV infection is unusual in childhood. It may present with malaise, anorexia and abdominal discomfort, which usually precedes the onset of jaundice, and occurs weeks to months after exposure. Raised aminotransferase enzymes are detected in serum, and the typical serological markers of acute infection are present (Table 8.3). Acute infection is rarely a severe illness, although in up to 1% of infected cases fulminant hepatic failure may occur. Patients with severe symptoms during acute infection are least likely to develop persistent infection, and

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those requiring liver transplantation for fulminant infection are less likely to have recurrence in the transplanted liver. Mild or asymptomatic acute infection is more likely to progress to chronicity. Chronic infection Chronic carriers of HBV are often asymptomatic, but fatigue and anorexia may occur. The only biochemical abnormality may be mild transaminitis. Presentation may be delayed until the onset of complications of cirrhosis and portal hypertension or with hepatocellular carcinoma. Because of the typical lack of symptoms, diagnosis is usually made by screening those known to be at risk. An acute exacerbation of hepatitis or more rapid progression of chronic disease may occur with hepatitis delta infection, co-infection with hepatitis C or emergence of the pre-core mutation. Extrahepatic manifestations Manifestations of HBV infection outside the liver, often due to deposition of circulating immune complex, may occur in both acute and chronic hepatitis and include: • polyarteritis nodosa (rare) • essential mixed cryoglobulinaemia (uncommon, more frequently associated with HCV) • glomerulonephritis • arthralgia/arthritis • rashes. Polyarteritis nodosa, a medium vessel vasculitis, is the only type of vasculitis reported to be associated with HBV infection. It most frequently involves the kidneys, peripheral nervous system and gastrointestinal tract leading to hypertension, mononeuritis multiplex and abdominal pain. Cutaneous involvement may occur. It is rare in childhood: a case has been reported of a 2-year-old who presented with hypertensive encephalopathy (Balkaran et al. 2000). Glomerulonephritis (GN) complicates HBV infection most frequently in children, and predominantly in areas of the world where HBV is endemic. Membranous and membranoproliferative GN are the most common pathological types seen in association with HBV, with nephrotic syndrome the usual clinical presentation. The natural history is generally benign, with up to 85% of affected children in spontaneous remission within 2 years, and only a small risk of chronic renal insufficiency (Wilson 1997). Histology of infection Chronic HBV infection may lead to a wide spectrum of histological severity, ranging from minimal inflammatory infiltrate to piecemeal necrosis, and mild fibrosis to established cirrhosis. Pathognomonic features of HBV are the detection by immunohistochemistry of cAg, demonstrable in hepatocyte nuclei and cytoplasm, and

sAg, most abundant in ‘ground-glass hepatocytes’. The characteristic ground-glass appearance is due to the granular appearance of hepatocytes whose cytoplasm is rich in endoplasmic reticulum and HBV surface material (see Plates 24 and 25a, Atlas: p. 447). Prevention of HBV infection Strategies to prevent HBV transmission include: • Strategies aimed to minimize spread from carriers: health education of high-risk populations specific advice to identified carriers screening of blood/organ donors screening personnel in occupations at high risk of transmission. • Strategies aimed at conferring immunity in those at risk, including vaccination of: healthcare workers family members and sexual partners of identified carriers infants born to carrier mothers all infants adolescents i.v. drug abusers active homosexuals. Prevention of perinatal transmission HBV transmission to the newborn may be successfully prevented by immunization, with an effective response to vaccine in up to 97% of newborn infants. Strategies to prevent perinatal transmission include either: (i) immunization of at-risk infants, identified either by selective screening of at-risk women or by universal screening of all women during pregnancy; or (ii) universal immunization of all infants. Immunization of at-risk infants. Comparison of selective vs. universal screening of women in Britain revealed that selective screening fails to identify about half of the women with babies at risk (Banatvala et al. 1990). There was previously considerable regional variation in antenatal screening policy in England and Wales, and in 1995 less than one-third of pregnancies occurred in districts with a universal screening policy (Boxall 1995). Since April 2000, however, it has become the policy in England and Wales for all women to be screened during pregnancy. Current immunization recommendations, according to maternal serological status, are shown in Table 8.4. Universal immunization. In 1992 an Assembly of the World Health Organization recommended that all countries should integrate hepatitis B vaccination into their national immunization programmes by 1997. Economic and epidemiological evaluation suggested this to be cost effective even in countries of low HBV endemicity (i.e. < 2% of the population being carriers). Furthermore, in 1994 a target of reducing the incidence of new carrier chil-

Chapter 8: Chronic Hepatitis dren by 80% by the year 2001 was set. There is already evidence of the success of universal HBV vaccination: since its introduction in Taiwan, the incidence of hepatocellular carcinoma in children has declined from an average annual incidence of 0.7 to 0.36 per 100 000 (Chang et al. 1997). In low endemicity populations, acute HBV is related to high-risk sexual behaviour or i.v. drug abuse. Pilot studies indicate that vaccination of adolescents at school may be an effective strategy (van Damme & Vorsters, 2002). Effective immunization is defined as the development of a protective antibody level above 100 IU/l. Poor responders (10–100 IU/l) should receive a booster dose, and non-responders (< 10 IU/l) should be re-vaccinated. The duration of protective levels is dependent on the sAb titre achieved by immunization. The rate of disappearance of protective antibody has been studied in a large cohort of children vaccinated in infancy following the implementation of universal HBV vaccination in Taiwan (Wang et al. 2003). Protective levels waned at a rate of approximately 10% per year, with a rise in sAb titre occurring following a booster dose. Prevention of horizontal transmission Children with chronic HBV infection are at risk of social isolation and stigmatization if inappropriate guidance is given to their families, carers, health workers and other professionals. There is no obligation for parents to inform schools and nurseries of their child’s HBV status: the same precautions should apply in dealing with blood/body fluid spillage of all children. Staff of schools and other institutions as well as healthcare workers should adhere to the Universal Infection Control Precautions (UK Health Departments 1998), which recommend to: • treat all blood and body fluids as potential sources of infection • wear protective clothing when dealing with body fluids • use good hand hygiene • cover any broken skin • use and dispose of sharps appropriately • disinfect body fluid spillages correctly • dispose of waste and excreta carefully. During hospital admission children with hepatitis B do not need to be nursed in isolation. At home and in school, social and sporting activities of children should not be restricted on account of their hepatitis B status. Immunization should be offered to all non-immune family members. Management of chronic HBV infection Despite their apparent well-being, chronic HBV carriers should remain under medical supervision, the purpose of which should be:

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• identification of natural resolution of chronic carriage • early identification of progressive liver disease • consideration for antiviral therapy • detection of hepatocellular carcinoma • support and education of the whole family regarding minimizing transmission but avoiding social isolation or stigmatization • screening and immunizing family members. This may be achieved by annual outpatient review to include: • HBV serology and viral markers (HBV DNA, eAg, sAg, eAb, sAb) • serum aminotransferase enzymes and bilirubin: exacerbation of liver dysfunction should prompt consideration of intercurrent infection with other viruses • serum albumin and a-fetoprotein • coagulation studies • liver ultrasonography. Liver biopsy in children with chronic HBV infection is of value in assessing the degree of inflammation and fibrosis, particularly when treatment is being considered. Treatment The aim of treatment is to reduce the risk of morbidity and mortality from cirrhosis and hepatocellular carcinoma. The first step is the eradication of replicative infection: clearance of eAg is associated with improved survival (Niederau et al. 1996; Lau et al. 1997) and a reduction in transmission risk. Natural seroconversion occurs at a variable rate, depending on age at acquisition and ethnic origin and is in the order of 10–20%. The impact of any treatment strategy must be compared with this background rate. In a recent study, with a mean follow up period of 4.9 ± 2.9 years, clearance of eAg occurred in 58% of 90 in treated children (who received interferon, lamivudine or interferon then lamivudine) compared with 37% of 68 untreated. Loss of sAg occurred in 10 treated and one untreated patient. The cumulative probability of eAg clearance and sAg clearance 10 years after the initial visit were both significantly higher in the treated patients (Vo Thi Diem et al. 2002). The decision to treat and the type of treatment require consideration of: • disease activity • histological stage • likelihood of response • treatment associated side-effects • previous treatment • co-existing disease • HBV genotype (Chu & Lok 2002; Gerner et al. 2002). Disease activity before and during treatment may be assessed by markers of viral activity:

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• HBV DNA levels (by hybridization assays, bDNA signal amplification or polymerase chain reaction (PCR)) • presence of eAg and markers of immune mediated inflammation: • aminotransferase enzymes • histology. Successful eradication of hepatitis B infection requires effective immune-mediated clearance of infected hepatocytes and cessation of viral replication before end-stage disease, i.e. cirrhosis, has occurred. To date, treatment is rarely completely successful because of side-effects, poor efficacy and viral resistance. There are two main strategies to treat chronic HBV infection: • immune modulatory therapy, e.g. interferon • antiviral agents, e.g. lamivudine. Immune modulatory therapy Interferon (IFN)-a is the treatment for which there has been the most experience. The mode of action is to augment the pre-existing host immune response and it is most likely to be successful in those with immune activation against infected cells, characterized by: • persistently elevated serum aminotransferases • the presence of HBsAg, eAg and detectable HBV DNA in serum • features of chronic hepatitis on liver biopsy. Interferon. Interferons are naturally occurring proteins, which are produced in response to viral infection. They enhance the immune response by: • stimulating lymphocyte proliferation • increasing major histocompatibility complex (MHC) antigen expression and thus T-cell recognition • increasing natural killer cell activity. Interferon has an antiviral effect by degrading viral mRNA and inhibiting viral protein synthesis, and also protects non-infected cells from viral invasion. The recommended treatment regime of IFN-a is 5– 10 MU/m2 thrice weekly by subcutaneous injection for 4 – 6 months. Meta-analysis of studies of IFN-a in adults reports 33% eAg clearance compared with 12% in controls (Wong et al. 1993). In children, the response rates to IFNa therapy are very variable, but not dissimilar to those reported in adult studies. Differences in response rates are achieved depending on route of acquisition, ethnic origin, disease activity and treatment regime. Sustained clearance varies between 0 and 50% of those treated, and is usually around twice that of untreated controls (Merican 2000). Predictors of IFN responsiveness include: • active histology • low HBV DNA levels (< 1000 pg/ml) • high serum aminotransferase enzymes (more than twice upper limit of normal) • short duration of disease

• non-Oriental ethnic origin • horizontal transmission. Interferon therapy is unlikely to be of benefit therefore in children with perinatally acquired infection who have normal or minimally elevated aminotransferase enzymes. Limitations of interferon therapy. In addition to its limited efficacy, interferon is limited by its adverse sideeffect profile, although children tolerate treatment better than adults. Fever and flu-like symptoms are invariable during initiation of treatment, and bone marrow suppression is common. Autoimmune thyroid disease and alopecia are frequent, and mental disturbance including severe depression may occur. Furthermore, interferon treatment is potentially hazardous in patients with cirrhosis, as a flare of immune activity with increased immune damage occurs prior to seroconversion, which may lead to decompensation of liver function. Steroid priming prior to interferon treatment. The transient rise in transaminases that occurs during treatment is associated with increased likelihood of eAg clearance. Pretreatment with corticosteroids (‘priming’) and their withdrawal prior to commencing IFN-a may exacerbate the host immune response, facilitating seroconversion. In a study of the long-term effects of IFN treatment with a 5-year follow-up, those who had received steroid priming had a significantly higher chance of seroconversion, with almost 50% becoming eAg and HBV DNA-negative (Sira et al. 1997). The benefit however remains unproven (Gregorio et al. 1996a; Yokosuka 2000), and is associated with the risk of precipitating fulminant liver failure. Interferon therapy: recommendations. Based on European experience, consensus recommendations, based on short-term efficacy, are as follows (Jara & Bortolotti 1999): • The rationale for treatment is to accelerate HBeAg clearance in a subgroup of patients. • Candidates for treatment are children with HBeAg and HBV DNA positivity, with low–intermediate HBV DNA levels and abnormal aminotransferase enzymes, aged 2 years or more. • IFN is contraindicated in children with decompensated liver disease, cytopenia, severe renal or cardiac disorder and autoimmune disease. • The standard treatment regimen is 5 mU/m2 thrice weekly for 6 months. Retreatment in non-responders is not indicated. Antiviral agents Antiviral agents directed predominantly against viral replication include nucleoside or nucleotide analogues. These are usually phosphorylated within infected cells to their active form, and are effective by incorporation into viral DNA leading to inhibition of viral replication. The drug must be selective for viral DNAto minimize toxicity: the safety of early agents being evaluated was limited by their effects on mitochondrial

Chapter 8: Chronic Hepatitis DNA. Most reported clinical experience is with lamivudine, which is now licensed for chronic hepatitis B in adults. Lamivudine. Lamivudine is a pyrimidine nucleoside analogue. It prevents replication of HBV in infected hepatocytes: it is incorporated into viral DNA leading to chain termination, and competitively inhibits viral reverse transcriptase. It leads to a rapid reduction in plasma HBV DNA load, 97% reduction within 2 weeks of commencing treatment (Malik & Lee 2000), and undetectable levels within 4 weeks, which is sustained during treatment (Farrell 2000). The concomitant decrease in circulating viral protein may also have a beneficial effect by promoting a more vigorous immune response (Boni et al. 1998). Significant histological improvement following lamivudine therapy, with resolution or reduced progression of fibrosis, has been demonstrated (Leung 2000). In three large placebo-controlled trials in adults (Lai et al. 1998; Schiff et al. 1998; Deinstag et al. 1999), histological improvement occurred in 52–56% of treated patients compared with 23–25% in controls. Loss of eAg after 1 year of treatment occurred in 17–33% receiving lamivudine compared with 11–13% receiving placebo. As with IFN, response rates are related to low pretreatment serum HBV DNA levels and raised aminotransferase enzymes: Chien et al. report 65% seroconversion after 52 weeks’ treatment if with ALT > 5 ¥ ULN, compared with 38% if only > 2 ¥ ULN (ULN, upper limit of normal) (Chien et al. 1999). However, there does not appear to be any variation in response according to ethnic origin or duration of infection, and it is safe to use lamivudine in patients with cirrhosis as an immune-mediated flare does not occur. Prolongation of treatment for up to 3 years may improve seroconversion rate, but increases resistance. Limitations of lamivudine. • Relapse — Unfortunately, rebound to pretreatment levels is almost invariable after cessation of therapy: the ccc intermediate of HBV DNA is stable and persists during treatment: the formation of cccDNA may be dependent on cellular rather than viral polymerase, and thus not inhibited by lamivudine (Moraleda et al. 1997; Kock & Schlicht 1993). Furthermore, elimination of the infected cells remains dependent on T-cell-mediated lysis: in the absence of effective clearance, due to the long half-life of infected cells, infection may persist for many years (de Jong et al. 1998). • Resistance — HBV may acquire resistance to lamivudine due to a specific HBV mutation (tyrosinemethionine-aspartate-aspartate or YMDD mutation) in the polymerase gene (Ling et al. 1996). The mutant virus has an altered tertiary structure that reduces the ability of lamivudine rather than viral nucleoside to be incorporated. The YMDD variant emerges in 15–20% after 1 year of treatment and increases with time. Due to survival advantage of the wild type by more effective replication, the

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mutant virus may revert to wild type after lamivudine therapy is withdrawn. Experience with lamivudine in children. A preliminary dose ranging study of lamivudine in children demonstrated it to be well tolerated, with a dose of 3 mg/kg/day (maximum 100 mg) providing levels of exposure and trough concentrations similar to that in adults receiving 100 mg (Sokal et al. 2000). A subsequent international, randomized double-blind placebo-controlled trial of 286 children with chronic HBV showed a complete response (eAg clearance and undetectable HBV DNA after 52 weeks’ treatment) in 23% compared with 13% placebo (Jonas et al. 2002). In those with ALT > 2, response rates were 34% and 16%, respectively. YMDD variant emerged in 18%. This study confirmed the safety of lamivudine and its superiority when compared with placebo, but also highlighted its limited efficacy and the problem of resistance. Future treatment strategies It is likely that the antiviral effect of a nucleoside/nucleotide analogue in combination with IFN may lead to an improved response. Evidence is emerging in support of lamivudine/interferon combination therapy, with improved eAg clearance when compared with monotherapy (Mutimer et al. 2000; Schalm et al. 2000). Improved tolerability of interferon maybe achieved by pegylated interferon: the conjugation of the polyethylene glycol molecule (PEG) with IFN-a2b leads to reduced clearance, thereby reducing injection frequency from thrice to once weekly. Future trials evaluating monotherapy or combination therapy may incorporate this form of interferon. A number of other nucleoside/nucleotide analogues are under evaluation (Wolters et al. 2001), and include famciclovir and adefovir. Famciclovir (a guanine analogue) is the prodrug of penciclovir. Headaches and nausea are the most common side-effects (Zerr & Frenkel 1999), and phase II studies are in progress. Mutations in the viral reverse transcriptase gene, however, may occur, and although situated at a different site to lamivudine, may lead to cross-resistance. Adefovir is a purine analogue. In addition to inhibition of viral replication, it may also augment natural killer cell activity and endogenous interferon activity (Calio et al. 1994). Furthermore, HBV strains resistant to lamivudine and famciclovir appear to be susceptible to adefovir (Perillo et al. 1999). Phase II trials support its efficacy, and it appears to be well tolerated. It is currently undergoing clinical evaluation. Treatment of hepatitis B infection: recommendations In all children with HBV infection, the role of treatment should be considered. At present, clear guidelines are only available for interferon treatment, which is the only licensed treat-

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ment for children with HBV infection. However, the availability of pegylated interferon, together with preliminary trials of other antiviral agents, will lead to further therapeutic trials of both monotherapy and combination therapy in children.

• be asymptomatic with complete resolution of infection • develop acute hepatitis or fulminant hepatic failure • develop rapid progression of chronic hepatitis.

Hepatitis B in the immunosuppressed patient Patients coinfected with HBV and HIV, organ transplant recipients and chronic carriers requiring chemotherapy, for example for haematological malignancies, present a problem. Immunodeficiency potentiates HBV replication with increased serum levels of HBV DNA and eAg. Although there may be no clinical manifestations other than a rise in ALT, it may lead to acute hepatitis and fulminant hepatic failure. Furthermore, if immunosuppressive therapy is withdrawn, the return in immune function may lead to rapid destruction of infected hepatocytes, acute hepatitis, and liver failure. Lamivudine has been shown to be effective in ameliorating these effects (Merican 2000), both with pre-emptive treatment (Al-Taie et al. 1999; Xunrong et al. 2001) and in the treatment of acute or fulminant hepatitis in this setting (Kawai et al. 2001; Saif et al. 2001).

The prevention of HBV infection and eradication of chronic HBV carriage will prevent the disease associated with HDV infection. Successful treatment of HDV hepatitis with interferon requires high doses (5 million units daily or 9–10 million units three times weekly), with lower doses having no lasting benefit (Hoofnagle & Di Bisceglie 1997).

Liver transplantation Indications for liver transplantation are considered in Chapter 20. Chronic HBV-related disease is an infrequent indication for transplantation in children. Although transplantation transiently reduces the viral titre in the circulation, persistence of HBV in extrahepatic sites leads to re-infection of the graft (Demetris et al. 1986). In fulminant HBV infection, HBV replication appears to be interrupted and recurrence after transplantation is infrequent (Brechot et al. 1984). Hepatitis D infection Hepatitis D, or delta virus (HDV), is a defective RNA virus. The virion is a hybrid consisting of a nucleocapsid core, comprising HDV RNA genome and HDV antigen, and a lipid envelope containing HBsAg. HDV can only replicate in the presence of HBsAg, and thus HDV infection only occurs in chronic HBV carriers. The route of transmission is mainly parenteral: infection may occur at the same time or subsequent to HBV acquisition. Diagnosis A diagnosis of HDV infection is made by detecting HDV antibodies and HBsAg in serum. HDV antigen may also be detected in liver tissue by immunohistochemical techniques, and HDV RNA may be detected in serum. Clinical presentation HDV infection in HBV carriers may:

Treatment

Hepatitis C infection Introduction HCV infection emerged as the major cause of transfusionacquired non-A non-B hepatitis when it was first characterized in the 1980s. It is a major cause of chronic liver disease and a frequent indication for liver transplantation in adult programmes. In children, HCV infection was identified through the ‘look back’ process in recipients of infected blood transfusions, and was particularly prevalent in those with haemophilia, leukaemia and thalassaemia. It is clear that although infected children are asymptomatic, HCV infection is often persistent and a possible cause of morbidity in later life. Currently most new cases of HCV infection in childhood are in those born to infected mothers. Epidemiology and transmission Worldwide prevalence of chronic HCV infection is estimated at 3%, with 150 million people being chronic HCV carriers (European Association for Study of the Liver (EASL): Consensus statement 1999). The prevalence varies considerably between different populations, and is higher in Eastern and Southern Europe than in the North and West (Reesink et al. 1990; EASL 1999). The estimated prevalence in England and Wales is 2–400 000, with rates varying from 0.04% in blood donors to 50% in intravenous drug users (National Institute for Clinical Excellence (NICE) Publications 2000). Prior to the introduction of anti-HCV antibody (Ab) screening of blood products and organ donors in 1990, HCV accounted for up to 90% of transfusion-associated hepatitis. Parenteral transmission is so effective that almost every individual receiving a blood transfusion or solid organ from an anti-HCV Ab-positive donor was likely to become infected (Wreghitt et al. 1994; Tillmann & Manns 1996). The risk of parenteral acquisition of HCV infection was increased in children exposed to multiple donors, either by receiving multiple blood transfusions or

Chapter 8: Chronic Hepatitis by repeated infusion of pooled products. In children with haemophilia, anti-HCV Ab seroprevalence ranged from 50 to 82% (Tedder et al. 1991). Although this route of acquisition has largely been eliminated, HCV continues to be acquired parenterally in i.v. drug users, through sexual transmission, by vertical transmission and by nosocomial spread. Furthermore, sporadic transmission is frequent: at least 50% of the infected population has no identifiable risk factor. Two large European studies have examined the route of acquisition in children with HCV infection (see Table 8.5) (Gibb et al 2000a; Bortolotti et al. 2001). The large number of children with transfusion-acquired HCV infection reflects those infected prior to donor screening: in the Italian series, 90% of children infected since 1991 were as a result of vertical transmission from an infected mother. This is likely to remain the major route of transmission to children. Unlike hepatitis B virus infection, vertical transmission of HCV from an infected mother is infrequent, occurring in only 5–10% of deliveries. The seroprevalence of HCV infection in pregnant women in the UK is estimated to be 0.2%, with an estimated 1150 pregnancies occurring each year in women infected with HCV and 70 infants acquiring infection (Ades et al. 2000). The risk of transmission is increased by coexistent maternal HIV infection (Tillmann & Manns 1996) and high maternal HCV RNA titres (Ohto et al. 1994). The route of acquisition of HCV infection in the mother may also be significant: those with transfusion-acquired infection and those who use intravenous drugs have higher transmission rates to offspring than those with no known risk factor (Resti et al. 1998). In a study of infants born in the UK and Ireland, the vertical transmission rate was 6.7% overall, and 3.8 times higher in HIV co-infected than HIV-negative women (Gibb et al. 2000b). Infection may occur in utero (Resti et al. 1998) or at the time of delivery (Gibb et al. 2000b). There is conflicting

Table 8.5 Route of HCV acquisition in children.

Route of transmission

UK/Ireland n = 182 (1997–1998) Gibb et al. 2000a

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evidence regarding the benefit of delivery by Caesarean section in reducing transmission risk in both HIVinfected and non-infected mothers (Maccabruni et al. 1995; Paccagnini et al. 1995; Tovo et al. 1997; Resti et al. 1998; Gibb et al. 2000b). There is also currently insufficient evidence to discourage breast feeding: there is little evidence of an increased risk of transmission, despite HCV RNA being frequently detectable in colostrum (RuizExtremera et al. 2000). Pathogenesis HCV is a single-stranded RNA flavivirus. The viral genome encodes a polyprotein, comprising viral structural proteins (core and envelope) and non-structural proteins (including RNA polymerase). Following infection with HCV, the host generates a B-cell response with the appearance of anti-HCV antibody. This response may be absent in the presence of immunodeficiency. The production of anti-HCV antibody does not constitute an effective response: it is not a neutralizing antibody, and does not lead to immune protection. An HCV-specific T-cell response, mediated by CD4-positive and CD8positive lymphocytes, may also be detected (Lau et al. 2002). In the majority of infected patients, despite evidence of both humoral and cell-mediated immune response, there is viral persistence: infected cells are able to evade T-cellmediated lysis, and antigenic variation in viral encoded envelope proteins allows evasion from neutralizing antienvelope antibody (Booth & Thomas 1996). The propensity of HCV to mutate and generate ‘quasi species’ is likely to contribute to these mechanisms. The persistent infection and continued ineffective inflammatory response lead to progressive necroinflammatory damage and fibrosis. It appears likely that HCV is not itself cytopathic to hepatocytes, and that the inflammatory damage is therefore predominantly immune mediated (Cerny & Chisari 1999). Clinical manifestations

Italy n = 606 (1990–1999) Bortolotti et al. 2001

Blood transfusion

134 (74%)

206 (34%)

Surgery/ percutaneous exposure

6: 2 renal transplant 2 needlestick 2 intravenous drug use

Maternal infection

40 (22%)

279 (46%)

Other/ unknown

2 (both unknown)

67

54

The incubation period ranges from 6 to 12 weeks. Signs and symptoms are usually absent: few patients experience symptoms during the acute stage, with fever, malaise, nausea, abdominal discomfort and jaundice. Chronic infection is either asymptomatic or may be accompanied by fatigue. Of 606 children with chronic HCV infection, only 8% had symptoms or signs, which included anorexia, weight loss, abdominal pain, hepatomegaly and splenomegaly (Bortolotti et al. 2001). Furthermore, the majority of children have no or only minimal disturbance of liver enzymes, even in the presence of inflammation. In those with persistently elevated liver enzymes, the existence of other diseases, particular-

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ly hepatitis B and autoimmune liver disease, must be considered. The mean time to presentation with symptomatic disease, usually due to the complications of cirrhosis, is 10 –15 years. Aggressive disease with progression to cirrhosis and end-stage liver disease has been described in childhood (Birnbaum et al. 2000), but is uncommon. Adiagnosis of chronic HCV infection should be considered in infants and children: • with unexplained elevation of aminotransferase enzymes • with an acute hepatitic illness • with unexplained chronic liver disease • born to infected mothers. The diagnosis should be accompanied by careful consideration of the factors that may influence natural history, prognosis, decision to treat and likely therapeutic response: • mode of acquisition • duration of infection • co-infection with HIV/HBV • underlying disease (thalassaemia, leukaemia, etc.) • associated extrahepatic manifestations • complications of chronic liver disease. Laboratory investigations The approach to diagnosis in older children is outlined in Fig. 8.1. Diagnosis in infants at risk of perinatal infection is shown in Fig. 8.2.

Serology The diagnosis of HCV infection is suggested by the serological detection of anti-HCV antibody (Ab) by enzyme-linked immunoassay (EIA). There are important factors to consider when interpreting the results: • Anti-HCV Ab is detectable at a very variable interval after initial exposure, and thus may initially be absent. • Anti-HCV Ab may persist for up to 10 years after clearance of viraemia and resolution of infection (Farci et al. 1991). • Anti-HCV Ab may be absent in patients with HCV infection who are immunocompromised. • Maternal anti-HCV Ab may persist in the newborn for up to 18 months (see below). Detection of anti-HCV Ab should therefore be supplemented by detection of HCV RNA by PCR in order to clarify HCV status. Furthermore, in the absence of antiHCV antibody but continuing clinical suspicion, HCV RNA should be assayed. The special case of screening for HCV infection in infants born to infected mothers is considered below. HCV RNA detection and quantification HCV may be detected in peripheral blood by amplification of HCV RNA by reverse transcription-polymerase chain reaction (RTPCR) or by a bDNA assay. HCV RNA detection establishes the presence of viraemia and suggests both infection and infectivity. A transient absence of detectable HCV RNA may occur despite viral replication, due to fluctuations in the level of viraemia below the detection thresh-

Anti HCV positive

HCV RNA qualitative PCR

Positive*

Negative

Repeat 6 months:

Positive

Positive

Chronic infection

Fluctuating viraemia

Liver biopsy**

Negative

Resolved infection likely

Fig. 8.1 Diagnosis of HCV infection in older children. *Supplementary assays if HCV RNA positive to determine likely response to therapy, should include genotype and quantitative polymerase chain reaction (PCR). **Liver biopsy is of value in staging histological disease, determining likelihood of response to therapy (cirrhosis is less likely to respond to interferon) and in assessment of treatment response.

Chapter 8: Chronic Hepatitis

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Test 1* HCV RNA by PCR Age 4–8 weeks

Likely infection

Neg

Pos

Infection unlikely

Test 2** HCV RNA by PCR Age 8–12 months

Pos

Chronic infection refer

Neg

Pos

Indeterminate: Infection (–/+) Resolved infection (+/–) Infection with fluctuating viraemia

Neg

Not infected Confirm with anti HCV Ab at 18 mths

Test 3 Anti HCV antibody HCV RNA by PCR Age18 months

Anti HCV Ab positive RNA All pos

Chronic infection Refer

RNA Pos/neg

Indeterminate Check LFT Needs follow up Refer

Anti HCV Ab negative RNA Neg/pos

Unlikely scenario ? immunodeficiency Refer

RNA All neg

Transient viraemia Reassure Discharge

Fig. 8.2 RNA, Hepatitis C virus (HCV) RNA. Anti-HCV antibody testing is not recommended in test 1 or test 2 due to passive maternal antibody persistence in the majority of infants. It may be helpful in the following situations: *If maternal anti-HCV status is not known, a negative anti-HCV antibody result with negative HCV RNA excludes infection.

However, a positive anti-HCV antibody result is not helpful in any situation due to possible maternal antibody transfer. **A negative anti-HCV antibody result with two negative HCV RNA results excludes infection, and the infant could be discharged. However, passive maternal antibody may still be present, and thus a positive HCV antibody result is not helpful.

old, or false-positive results may occasionally occur. Serial monitoring is thus required. HCV infection is confirmed by the presence of HCV RNA in two consecutive samples, and chronic infection defined by HCV RNA persistence for at least 6 months. In resolved hepatitis, HCV RNA disappears from the serum before anti-HCV Ab. Following perinatal transmission, HCV RNA may be undetectable for the first few weeks or months (Dunn et al. 2001; Ceci et al. 2001).

antibody has led to the development of an ELISA assay for the detection and quantification of HCV core antigen in peripheral blood (Peterson et al. 2000). This has been demonstrated to be an accurate, precise and specific indirect marker of HCV replication that correlates with viral load. However, its value is limited at low levels of viraemia, e.g. during evaluation of antiviral therapy, as the current detection threshold is equivalent to 20 000 HCV RNA IU/ml (Bouvier-Alias et al. 2002).

HCV antigen The need for a simple, accurate diagnostic test for diagnosis of HCV infection prior to appearance of

Genotype HCV isolates may have genomic variations, and have been grouped according to genetic similarity into

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types 1–6 and subtypes a, b and c. Identifying the genotype in an individual patient is not crucial to the diagnosis, but is of epidemiological interest and may have therapeutic implications. In western Europe and the USA, genotypes 1a, 1b, 2a, 2b and 3a are represented, with 3a more prevalent in patients with a history of i.v. drug abuse. Type 4 occurs predominantly in Egypt, the Middle East and Africa. Screening the newborn infant Determination of HCV status in the newborn infant is difficult. However, a clear protocol of investigation is needed to facilitate diagnosis or reassurance and avoid prolonged uncertainty and anxiety. Anti-HCV Ab detection in infancy may reflect maternal rather than endogenous antibody. As most infected mothers will be anti-HCV Ab-positive, a positive result in the newborn infant is expected. Loss of maternal antiHCV Ab occurs at a variable rate: in one study, an estimated 50% of uninfected children had become seronegative by 8 months, and 95% by 13 months (Gibb et al. 2000b). The estimated proportion of uninfected children who continue to have detectable maternal antibody at 18 months is < 0.1% (Dunn et al. 2001). Detection of anti-HCV Ab at 18 months is therefore highly suggestive of infection. HCV RNA detection is more useful than antibody testing in infancy: the specificity of HCV RNA detection by PCR in one study was 97% irrespective of age (Dunn et al. 2001). The sensitivity of HCV RNA testing was however only 22% for infants under 1 month, but 97% after 1 month. Allowing for false-positive results, it was estimated in the above study that if HCV RNA is performed at 1 month of age, a positive result gives a 73% probability of infection if the mother is HIV-negative and 90% if HIV-positive. A negative result almost certainly excludes infection. However, a recent study suggests that in babies with a subsequent diagnosis of chronic infection, HCV RNA may remain undetectable until 8 months of age (Ceci et al. 2001). A suggested approach to the diagnosis of HCV infection in infants is given in Fig. 8.2. Histology The most characteristic features are mild portal tract inflammation with lymphoid aggregates, some inflammatory bile duct damage and mild steatosis. Histological features of chronic HCV infection are suggestive but not pathognomonic, and may resemble autoimmune hepatitis (see Plates 24 and 25b, Atlas: p. 447). Episodes of increased inflammatory activity are associated with piecemeal necrosis and fibrosis is variable. Viral proteins may be detected by immunohistochemical stains (Fischer et al. 1996). A giant-cell hepatitis in association with

HCV infection has been described (Thaler et al. 1992). Histological severity is considered under natural history (see below). Natural history The majority of adults with HCV infection do not have effective immune clearance and become chronically infected (EASL 1999). Severity of disease and/or rate of progression are adversely affected by: • age at acquisition • duration of infection • genotype 1b • excessive alcohol ingestion • co-infection with HBV and/or HIV • immunodeficiency • iron overload. The severity and progression of disease may be considered in terms of persistent infection (i.e. persistence of HCV RNA), liver function abnormality, histological severity and morbidity/mortality. These parameters are not always correlated: in the absence of cirrhosis, chronic HCV infection in adults may cause significant reduction in the quality of life (Foster et al. 1998). Furthermore, the presence of severe histological disease may not be accompanied by clinical symptoms or signs, even after 10–20 years of infection (Seeff et al. 1992), and 20% of patients with normal alanine aminotransferase enzyme (ALT) have significant histological disease (EASL 1999). In the UK, the construction of a National Register of Transfusion-acquired HCV has provided a resource for further study of the natural history (Harris et al. 2000). After a mean duration of infection of 11 years (range 8–20) in 924 people, including children, 37% had abnormal liver enzymes, but only 14% signs or symptoms. Of the 363 who underwent biopsy, 10% had cirrhosis (Harris et al. 2002). The mortality from all causes did not differ in those with HCV infection compared with controls, and excessive alcohol ingestion was a significant co-factor in 40% of the liver-related deaths. Natural history in childhood The population of children with HCV infection is changing from those with transfusion acquired and often coexisting disease to otherwise healthy children infected perinatally. Studies of outcome following HCV infection acquired in childhood are emerging, but are limited by heterogeneity of the population included, the route of acquisition, the presence of coexisting disease, and also by the limited number of children with histological assessment. There is conflicting opinion as to whether this is a benign and more slowly progressive disease than in adults, or one where significant progression frequently occurs early but insidiously. HCV RNA persistence. Resolution of infection is sug-

Chapter 8: Chronic Hepatitis gested by viral clearance, which is defined as undetectable HCV RNA by PCR in at least two consecutive samples. The frequency of spontaneous viral clearance in paediatric studies is very variable. Although it has been suggested that transfusion-acquired disease has the higher likelihood of resolution, there may be higher frequency of clearance following vertical transmission than previously reported. Of 182 children with chronic infection (the majority having transfusion-acquired disease) spontaneous clearance occurred in only 16% (Gibb et al. 2000a). Other studies, restricted to transfusion-acquired HCV infection, have suggested better clearance rates with persistence occurring in 45–57% after 3–20 years (Matsuoka et al. 1994; Chang et al. 1994; Vogt et al. 1999). Following vertical acquisition, reported clearance rates are again extremely variable. In a multicentre European study of 104 children, 90% had evidence of persistent infection (Tovo et al. 2000), and an earlier study also suggested a high propensity to chronicity (Bortolotti et al. 1997). In contrast, recent studies report viral clearance occurring in 75% of vertically infected infants (Ceci et al, 2001; Ruiz-Extremera et al. 2000). The study of Ceci incorporated frequent HCV RNA monitoring: at birth, 4, 8 and 12 months. It was therefore more likely to detect infants with infection that subsequently resolved than those studies incorporating less frequent HCV RNA testing. Histology. It is likely that the small proportion of children who have undergone a liver biopsy are those with clinical evidence of active inflammation or more severe disease. The reported high prevalence of histological disease may therefore over-emphasize the actual spectrum of severity. Most studies suggest that children with chronic HCV infection undergoing liver biopsy have mild to moderate inflammation (Bortolotti et al. 1994; Badizadegan et al. 1998; Gibb et al. 2000a). However, in another study, after 20 years of chronic transfusion-acquired HCV infection, most had only minimal inflammation, and three with either periportal fibrosis or cirrhosis had a coexisting disease (Vogt et al. 1999). The prevalence of significant fibrosis is variable, ranging from 24% to 78% and correlating with age and duration of infection (Badizadegan et al. 1998; Gibb et al. 2000b). In a study of infants with perinatal HCV infection, all 20 who underwent biopsy had only minimal or moderate inflammation (Tovo et al. 2000). In a study examining histological progression in nine children who underwent two sequential biopsies, progression of fibrosis occurred in five over a median period of 2.8 years. The predicted median time to cirrhosis was estimated as 17.14 years (Bunn et al. 2000). Clinical progression. Chronic HCV infection in infancy and childhood is usually asymptomatic, and unlike in adulthood it rarely progresses to end-stage disease re-

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quiring transplantation. However, aggressive disease with decompensated cirrhosis has been reported in three children with vertically acquired infection (Birubaum et al. 2000), all of whom required liver transplantation. Future studies. A 20-year follow-up study of HCV infection acquired by transfusion in the neonatal period is being conducted (Aach et al. 2000). The National Register of HCV cases in England, Scotland and Wales UK will provide a valuable resource for further studies (Gibb et al, 2000a). Extrahepatic disorders HCV infection appears to be strongly associated with autoimmune disorders, including essential mixed cryoglobulinaemia, membranoproliferative glomerulonephritis (with HCV probably having a direct pathogenic role) and also porphyria cutanea tarda. There is also a suggested association with autoimmune thyroiditis. Signs and symptoms of these disorders should be sought in patients with chronic HCV infection (Gumber & Chopra 1995). Although HCV infection may precipitate anti-LKM-1-positive chronic hepatitis (type 2b), this appears to be uncommon in children (see p. 143, Virus-induced autoantibodies). Management of children with chronic HCV infection The most effective method of monitoring disease progression and the optimal timing of therapeutic intervention are yet to be determined. The aims of management are to: • monitor viraemia and detect resolution of infection • assess liver dysfunction and its progression • consider prognostic factors • consider optimal timing of antiviral therapy. Children with HCV infection should be seen at 6 to 12monthly intervals in centres with expertise in assessing children with liver disease. Treatment The aims of treatment are to: • eradicate HCV infection (loss of HCV RNA in peripheral blood) • reduce necroinflammatory damage and progression of fibrosis • reduce the risk of complications of cirrhosis including hepatocellular carcinoma • normalize liver function • improve quality of life As the natural history is variable, and there is no wholly effective therapy, there is no consensus on whether treatment should be deferred until more effective therapy is available, or whether early treatment is

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more likely to be successful, and may prevent progression in childhood. Current treatment options are: • interferon monotherapy • interferon/ribavirin combination therapy. Interferon monotherapy in children The mechanism of action of IFN-a is discussed above. The predictors of a favourable IFN-a response from adult studies are similar in children, namely short duration of disease and the absence of cirrhosis. An analysis of 19 trials of IFN-a for children with HCV infection examined the effect of treatment in 366 children compared with 105 untreated controls (Jacobson et al. 2002). Response to treatment occurred in a mean of 54% (range 0–91%), with a sustained response in 36% (0–73%). Genotype 1 adversely affected the likelihood of response, with a sustained response in 27% of children, compared with 70% in those with other genotypes. The spontaneous clearance rate in untreated children was 5%. Treatment regimes varied, with duration of therapy ranging from 6 to 18 months. Most studies used 3 MU/m2 by subcutaneous injection three times weekly, although higher and lower doses were also used. Combination therapy: interferon/ribavirin Ribavirin is a guanosine nucleoside analogue, which although ineffective as monotherapy (Kjaergard et al. 2002), appears to have synergy with IFN-a. Its mode of action is uncertain, but may include enhancement of T-cell-mediated immunity, and direct inhibition of viral polymerase (Lau et al. 2002). Haemolytic anaemia is the most frequent sideeffect of ribavirin treatment due to accumulation of phosphorylated ribavirin in erythrocytes which shortens their life span (Lau et al. 2002). In adults combination therapy has superseded monotherapy as sustained response rates are improved (Kjaergard et al. 2002) and is recommended for those with moderate to severe chronic hepatitis C. Six months’ treatment is recommended, with a further 24 weeks in patients with genotype 1 if a response (clearance of HCV RNA) has occurred in the initial 24 weeks. Factors which increase the likelihood of response include: • genotype other than 1 • baseline viral load < 3.5 million copies/ml • minimal histological disease • female gender • age < 40 years. Small studies of combination therapy in children support its efficacy in achieving sustained HCV RNA clearance and improved likelihood of response compared with IFN-a alone (Lackner et al. 2000; Christensson et al. 2000; Woynarowski et al. 2001; Kelly et al. 2001; Suoglu et al. 2002; Wirth et al. 2002).

Future treatment strategies PEG interferon. The covalent attachment of a polyethylene glycol (PEG) moiety to IFN-a enhances its half-life and removes its immunogenicity (Nieforth et al. 1996), leading to once-weekly rather than thrice-weekly injections. Pegylated interferon is more effective than IFN monotherapy (Glue et al. 2000) and is more likely to reduce the rate of progression of fibrosis and improve necroinflammatory damage (Poynard et al. 2002). Emerging new therapies include viral enzyme inhibitors, cytokines, antisense oligonucleotides targeted against ribosomal binding site, and a ribozyme-specific approach (Boyer & Marcellin 2000). The successful development of an effective vaccine is hampered by the genetic heterogeneity of the virus, the mutability of viral envelope proteins and the lack of a suitable animal model (EASL 1999).

Autoimmune liver disease Autoimmune liver disease encompasses disorders of the liver associated with circulating autoantibodies, in which an inflammatory response targets either components of the hepatocyte, giving rise to parenchymal inflammation (autoimmune hepatitis), or the biliary tree (sclerosing cholangitis), or both (overlap syndrome). Autoimmune hepatitis Autoimmune hepatitis (AIH) is a chronic inflammatory disorder affecting the liver, which is characteristically responsive to immunosuppression. A genetic predisposition is suggested by the increased frequency of HLA haplotypes HLA B8/DR3 and allotypes DR3 and DR4 and the coexistence of other autoimmune disorders. Proposed triggers that may initiate the inflammatory process include viruses (see p. 143, Virus-induced autoantibodies). The circulating autoantibodies that characterize AIH are subdivided into types according to which organelle gives rise to the autoantigen (Obermayer-Straub & Manns 1996). This leads to the classification of AIH shown in Table 8.6. Up to 20% of patients, however, do not have any of these antibodies detectable (Johnson & Mc-

Table 8.6 Classification of autoimmune hepatitis (AIH). AIH type

Characteristic autoantibody

Type 1

Anti-nuclear (ANA) Anti-smooth muscle (SMA) Anti-liver-kidney microsomal (LKM-1) Anti-soluble liver antigen (SLA)

Type 2 Type 3

Chapter 8: Chronic Hepatitis Farlane 1993; Alvarez et al. 1999a). Other autoantibodies, which may occur in types 1 and 2 AIH, include antineutrophil cytoplasmic (ANCA), anti-liver-pancreas protein, anti-liver cytosol and anti-actin antibodies. Autoantigens which act as targets for autoantibodies include components of two multigene enzyme families involved in drug metabolism: cytochrome P450 enzymes (Zanger et al. 1988; Guenguen et al. 1989; Manns et al. 1989) and UDP-glucuronosyl transferases (Philipp et al. 1994). The precise role of autoantibodies in hepatic inflammation is not established. However, titres of autoantibodies, which react against hepatocyte membrane components, including those directed against two components of the liver-specific lipoprotein — alcohol dehydrogenase (Ma et al. 1993) and human asialoglycoprotein receptor — correlate with disease activity (McFarlane et al. 1986). Following activation of the inflammatory response in AIH, the resulting cytokine production leads to perpetuation of the response by macrophage activation, enhanced HLA expression and B-cell autoantibody production, leading to continued hepatocellular lysis (Mieli-Vergani & Vergani 1996). Drug-induced autoantibodies Drug-induced chronic hepatitis may be associated with the same autoantibodies as those that typify AIH. Antinuclear autoantibodies (ANA) and anti-smooth muscle antibodies (SMA) have been seen in association with a-methyldopa and nitrofurantoin, an anti-liver-kidney microsomal antibody (LKM-2) in association with the diuretic tienilic acid (Homberg et al. 1984), and anti-liver microsomal antibodies with dihydralazine (Nataf et al. 1986). Although the mechanism of drug-induced hepatitis is not fully characterized, hydroxylation of the drugs by cytochrome P450 may lead to an unstable metabolite, which if bound to cellular components may form a neoantigen against which an immune response is mounted. Resolution of the hepatitis usually occurs after prompt withdrawal of the drug, with continuing drug ingestion incurring a worse prognosis (see p. 148, Druginduced liver disease). Virus-induced autoantibodies A wide range of viruses have been associated with the onset of AIH. These include measles, Epstein–Barr, human herpesvirus 6, and hepatitis A and C, of which the most clearly associated is HCV. The molecular structure of the HCV polyprotein in part resembles that of a component of cytochrome P450, a phenomenon termed molecular mimicry. HCV may therefore trigger the production of LKM antibodies. Patients with LKM-1positive AIH are now further subdivided into those with

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type 2a (anti-HCV-negative) or type 2b (anti-HCVpositive) AIH. Patients with type 2b AIH differ from 2a in that they: • tend to be older (rarely children) • have an equal sex distribution • have less inflammatory activity apparent histologically. The disease process resembles a viral infection rather than an autoimmune disease, and thus treatment should be with antiviral agents rather than immunosuppression. An epitope of cytochrome P450 also displays homology with a herpes simplex virus type 1 (HSV-1) protein. A high prevalence of HSV infection is described in adults with type 2a AIH (Manns 1993). In childhood, however, no increased prevalence of antibodies to either HCV or HSV-1 was found in patients with type 2 AIH (Gregorio et al. 1996b). Clinical features AIH is a heterogeneous disease with a broad spectrum of severity at presentation. A short history may belie the chronicity of the underlying disease process, which may have been present for several years. Aseries of 52 children with AIH (32 with type 1 AIH; 20 with type 2 AIH) reported from King’s College Hospital, London, has characterized the mode of presentation and clinical features in childhood (Gregorio et al. 1997). In both types there was: • a 75% female preponderance • a variable age at onset (median of 10 years in type 1 and 7.4 years in type 2), with occasional presentation in infancy • other autoimmune disorders affecting patients in 20% and a first-degree relative in 40% of cases • similar severity and outcome. The mode of presentation was variable, with the following predominant types emerging: • acute presentation resembling viral hepatitis (in more than 50%) with anorexia, malaise and abdominal discomfort preceding the onset of jaundice • fulminant hepatic failure (in 11%, more common in type 2) • insidious onset with no or non-specific symptoms and intermittent jaundice, with a delay to presentation of many years • complications of cirrhosis and portal hypertension • incidental finding of raised hepatic aminotransferases. Associated disorders The following may occur with AIH, either preceding its onset or evolving subsequently: • autoimmune thyroiditis • Graves’ disease

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• • • • • • •

coeliac disease inflammatory bowel disease diabetes mellitus Sjögren’s syndrome haemolytic anaemia glomerulonephritis idiopathic thrombocytopenia. AIH may also occur in 10–20% of patients with autoimmune polyglandular syndrome type 1 (or APECED), which is characterized by hypoparathyroidism, Addison’s disease, chronic mucocutaneous candidiasis and ectodermal dystrophy. Diagnostic criteria Descriptive criteria for the diagnosis of AIH were initially proposed by the International Autoimmune Hepatitis Group (IAHG) in 1993 (Johnson & McFarlane 1993). Prospective evaluation has led to subsequent revision (Alvarez et al. 1999a). Current guidelines for a definite diagnosis are given in Table 8.7. The recommendations also include criteria for a probable diagnosis, which in childhood are modified as follows (Johnson & McFarlane 1993): • abnormal copper and caeruloplasmin concentrations in serum but in whom Wilson’s disease has been excluded • any elevation of serum globulin or gammaglobulin or Table 8.7 Descriptive criteria for diagnosis of autoimmune hepatitis (International Autoimmune Hepatitis Group Report: Alvarez et al. 1999a). Features

Definite

Histology

Moderate or severe interface hepatitis +/– lobular hepatitis or central portal bridging necrosis without biliary lesions or well defined granulomas without prominent changes suggesting different aetiology

Serum biochemistry

Any abnormality in aminotransferase enzymes especially if alkaline phosphatase not markedly elevated Normal a1-antitrypsin, copper and caeruloplasmin

Serum immunoglobulins

Total serum globulin or gammaglobulin or IgG concentrations > 1.5 times upper limit of normal

Serum autoantibodies

Seropositivity for ANA/SMA or anti-LKM-1 antibodies at titres > 1 : 80 Seronegativity for AMA

Viral markers

Seronegativity for markers of current infection with hepatitis A, B or C virus

Other aetiological factors

Average alcohol consumption < 25g/day No history of recent use of known hepatotoxic drugs

IgG concentration, ANA or LKM-1 titre ≥ 1 : 10, and/or SMA ≥ 1 : 20 • no circulating ANA, SMAand LKM-1 antibodies but in whom there is any other defined liver autoantibody. A scoring system has also been devised by the IAHG, primarily for research purposes, but which may be of clinical value in difficult cases (Alvarez et al. 1999a). Severity of liver dysfunction In addition to the diagnostic tests listed above, the following investigations should be performed to provide a basis for prognosis, for planning appropriate therapy and monitoring response: • hepatic synthetic function: prothrombin time and serum albumin • histological assessment of severity of inflammatory activity and extent of fibrosis (except where coagulopathy precludes the safety of percutaneous liver biopsy and a transjugular approach is not feasible) • assessment of complications of cirrhosis: ascites and oesophageal varices. At presentation, more than 50% of children in the London series (Gregorio et al. 1997) had moderate to severe portal inflammation, periportal or periseptal necrosis, and lobular or nodular activity. Cirrhosis was present in 70% of children with type 1 and 40% of children with type 2 AIH. Multiacinar or panacinar collapse was seen in 17% and was associated with a clinical presentation of acute liver failure. Young age at presentation, type 2 AIH, coagulopathy, high bilirubin and initial histological activity were all associated with a worse outcome, the endpoint being either death or liver transplantation. Independent predictors of poor prognosis were the bilirubin level and coagulopathy at diagnosis, however, and not the type of AIH. Treatment AIH, although variable in presentation, is typically responsive to anti-inflammatory and immunosuppressive therapy, which should be commenced even in those with fulminant presentation or cirrhosis. Acomplete response to therapy has been defined by the IAHG (Alvarez et al. 1999a) as: 1 Either or both of: • marked improvement of symptoms and return of serum AST or ALT, bilirubin and immunoglobulin values completely to normal within 1 year and sustained for at least a further 6 months on maintenance therapy, or • a liver biopsy specimen at some time during this period showing at most minimal activity, or 2 Either or both of:

Chapter 8: Chronic Hepatitis • marked improvement of symptoms together with at least 50% improvement of all liver test results during the first month of treatment, with AST or ALT levels continuing to fall to less than twice the upper limit of normal within 6 months during any reductions toward maintenance therapy, or a liver biopsy within 1 year showing only minimal activity, or • a liver biopsy within 1 year showing only minimal activity. Corticosteroid therapy In children, an initial prednisolone dose of 2 mg/kg/day (maximum of 60 mg) should be commenced. A gradual tapering of steroid dose, after normalization of aminotransferase levels, is aimed to minimize the treatment side-effects but maintain progression towards remission. Remission, characterized by improved hepatic aminotransferase levels, is achieved in 80% within 3 months, and may be accompanied by decreased serum globulin levels, although titres of the characteristic autoantibody do not always parallel disease activity. Symptomatic improvement usually precedes complete biochemical recovery, with histological resolution lagging by a further 3–6 months (Manns & Strassburg 2001). In the London series (Gregorio et al. 1997), 45/47 children demonstrated a biochemical response to steroids, and the majority became clear of jaundice after median treatment duration of 3 months. Maintenance of remission is usually achieved with low-dose prednisolone. However, if the dose required to maintain remission leads to significant side-effects, the addition of other immunosuppressive agents may allow prednisolone to be reduced or withdrawn completely. Most experience in treatment of adults and children has been with azathioprine, but other agents are increasingly described as having a potential role. Azathioprine Azathioprine acts by inhibiting maturation of lymphocyte precursors, and thus is only effective after at least 3 months of treatment. Azathioprine, gradually increased to 2 mg/kg/day, should be introduced if prolonged steroid administration is necessary or if unacceptable side-effects occur. It may also be commenced at initiation of treatment when relapse is considered likely. Remission may be maintained with azathioprine alone or in combination with low-dose steroids. Other immunosuppressive agents Cyclosporine Cyclosporine has been shown to be effective in patients with AIH types 1 and 2 resistant to pred-

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nisolone/azathioprine and is well tolerated (Fernandes et al. 1999; Debray et al. 1999). Cyclosporine has also been evaluated as initial therapy for AIH. In a study of 32 children prescribed cyclosporine as monotherapy for 6 months, low-dose prednisolone and azathioprine were added to maintain remission, and cyclosporine was withdrawn 1 month later (Alvarez et al. 1999b). Thirty patients successfully completed treatment and all had normal liver enzymes by 12 months. Mild adverse effects were reported and resolved after discontinuation of treatment. However, as the side-effects of cyclosporine, including renal impairment, gingival hyperplasia and hirsuitism may cause more significant morbidity than those of prednisolone, it has not become established as first-line treatment. Tacrolimus Tacrolimus is a more potent immunosuppressive agent than cyclosporine, but also has significant toxicity. There is limited evidence supporting its role in treatment of AIH in adults, with biochemical improvement after 3 months, but a rise in serum creatinine after 1 year of treatment (Van Thiel et al. 1995). In another study, the combination of tacrolimus and reduced dose prednisolone as initial therapy led to significant improvement in liver function in six of seven patients with severe AIH (Heneghan et al. 1999). Mycophenolate mofetil Mycophenolate mofetil (MMF) is the prodrug of mycophenoloic acid. Its effect on purine synthesis leads to decreased T and B-lymphocyte proliferation (Heneghan & McFarlane 2002). Bone marrow suppression and gastrointestinal disturbance are the most common side-effects. Initial experience with MMF in the treatment of AIH is emerging. In a study of seven adults who were either resistant to or intolerant of azathioprine, MMF was shown to be effective with prednisolone at inducing remission, and as monotherapy in maintaining remission (Richardson et al. 2000). Of 12 children with autoimmune liver disease (AILD) either refractory to or intolerant of azathioprine (and cyclosporine in six), normalization or significant improvement in hepatic aminotransferase enzymes occurred in 10. One child did not respond, and in one MMF was discontinued due to severe nausea (Aw et al. 2002). Duration of treatment There is no established optimal duration of treatment. Cessation of therapy may be considered if there is no biochemical evidence of liver dysfunction for at least 1–2 years, and if the liver biopsy shows no inflammatory activity (Heneghan & McFarlane 2002). Remission is more likely to be maintained in type 1 than in type 2 AIH. In the London series all four children with

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type 2 AIH who had treatment discontinued according to the above criteria relapsed at a median of 2 months, whereas remission was maintained for up to 13 years of follow-up in 6/9 with type 1 (Gregorio et al. 1997). In one study, sustained remission rates were related to total duration of treatment, with 67% probability after 4 years of therapy, but only 10% after 1–2 years of treatment (Kanzler et al. 2001). Indications for liver transplantation AIH may lead to consideration for liver transplantation because of: • fulminant hepatic failure • complications of cirrhosis • intolerable side-effects • failure of medical therapy Despite an apparent initial response to immunosuppression, gradual histological progression over years may occur. Failure of medical treatment is more likely when established cirrhosis is present at diagnosis, when there is a long history prior to commencing treatment, and in early-onset AIH. Recurrence after transplantation, despite immunosuppression, occurs in 25%. Sclerosing cholangitis Sclerosing cholangitis is a chronic inflammatory disorder that may affect both the intra- and extrahepatic bile ducts and lead to fibrosis. It is a rare cause of progressive liver disease in childhood, and may have its onset in infancy or even in the neonatal period. The diagnosis rests on typical bile-duct lesions being visualized by cholangiography. The increasing recognition of this disease in children, from five cases prior to 1987 to almost 200 reported since, reflects the introduction of percutaneous and endoscopic cholangiography into paediatric practice, rather than an actual increase in prevalence. The nomenclature is confusing. Sclerosing cholangitis may be termed primary if it is not secondary to bile duct abnormalities (e.g. cysts, carcinoma, cholelithiasis or previous surgery). However, others only use the term ‘primary’ to describe sclerosing cholangitis occurring in the absence of any recognized associated disorder or circulating autoantibody. In this chapter, sclerosing cholangitis (SC) will not be prefixed. Those conditions in which it is secondary to biliary abnormalities, such as Caroli’s disease, are referred to elsewhere and will not be considered here. Aetiology and associated disorders SC is a progressive disorder that affects both intrahepatic and extrahepatic ducts. Although the pathological

Table 8.8 Frequency (%) of associated disease in sclerosing cholangitis (SC). Sisto (n = 78)

Debray (n = 56)

Total (n = 134)

Associated disorder: IBD (UC) Histiocytosis X Immunodeficiency Other

76 48 (38) 15 10 3

55 13 (7) 25 14 3

67 33 (25) 19 12 3

No associated disorder

24

45

22

IBD, Inflammatory bowel disease; UC, ulcerative colitis. Series reported by Sisto et al. (1987) and Debray et al. (1994).

changes may represent a common response to a variety of causes, including infection, in children SC is most commonly associated with markers suggestive of an autoimmune pathogenesis. The non-organ-specific antinuclear and/or anti-smooth muscle antibodies are present in two-thirds, and IgG is frequently raised. These findings may also occur in association with histological features typical of AIH, and may suggest an ‘overlap syndrome’ (see Plate 26, Atlas: p. 448, and see below: Overlap syndrome). Inflammatory bowel disease, in particular ulcerative colitis (UC), is the most frequent associated extrahepatic disease (Table 8.8). Its onset may be preceded by symptoms of SC, and thus routine monitoring of liver function in children with UC may facilitate early diagnosis. A genetic predisposition to SC is likely: in the series reported by Debray et al. (1994) the overall rate of parental consanguinity in children with SC was 23%, while in those children with neonatal onset this rose to 40%. Clinical features Clinical presentation of SC may be subdivided according to age of onset into neonatal or post-neonatal. • Neonatal onset SC typically presents with cholestatic jaundice and clinically resembles extrahepatic biliary atresia. However, cholangiography confirms extrahepatic bile duct patency and jaundice usually resolves within the first year of life, though progression to biliary cirrhosis is usual. • Post-neonatal onset SC may be accompanied by a recognized associated disorder (Table 8.8) or occur in isolation, when it presents at a mean age of 3.5 years (Debray et al. 1994). The insidious nature of the disease may lead to a delay in diagnosis of several years from the initial onset of symptoms or signs. This gives rise to the complications of portal hypertension being manifest at presentation in almost 50% of cases. Modes of presentation, leading to a wide differential diagnosis, include:

Chapter 8: Chronic Hepatitis • abdominal pain, weight loss, and intermittent jaundice, resembling AIH • complications of cholestasis, including cholangitis and pruritis • complications of cirrhosis, e.g. ascites or variceal haemorrhage • asymptomatic: incidental finding of abnormal liver function or hepatomegaly, or detected due to presence of associated disease, e.g. liver function monitoring in patient with inflammatory bowel disease (IBD). The median survival from clinical onset of SC in Debray’s series was 10 years, mortality being due to liver failure and complications of portal hypertension. Those with jaundice at presentation (except neonates) in whom the bilirubin level persists above 5 times normal appear to have a worse prognosis, whereas in those with IBD or chronic active hepatitis (CAH) the disease may evolve more slowly. Laboratory investigation Elevated alkaline phosphatase and GGT are the most consistent biochemical abnormalities in both neonatal and post-neonatal onset SC. Alkaline phosphatase. This may range from just above to more than 16 times the upper limit of normal, and in neonatal onset SC it remains elevated despite resolution of jaundice. Though occasionally normal at presentation, it subsequently becomes elevated during the course of the disease. Gamma-glutamyl transpeptidase. This is almost always elevated at diagnosis, ranging from just above to 50–100 times the upper limit of normal. Bilirubin. The bilirubin level in serum may be normal at presentation in at least 50% of cases, contributing to the diagnostic delay. It may be intermittently elevated during the course of disease, with persistent elevation (see above) being associated with a worse prognosis. Hepatic transaminases. These are moderately elevated in the majority of cases, and may be raised to 50 times the upper limit of normal. Prothrombin time and albumin. Hepatic synthetic function is usually preserved unless decompensation following progression to cirrhosis has occurred. Elevated prothrombin time may occur due to fat-soluble vitamin deficiency, and thus be responsive to vitamin K. Diagnostic imaging Ultrasound Ultrasonography may reveal intra- and extrahepatic bile duct dilatation, a heterogeneous or nodular echotexture characteristic of cirrhosis, or the manifestations of portal hypertension, including splenomegaly, ascites and varices. However, the appearances may be normal in up to 50% of cases.

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Cholangiography The diagnosis of SC is confirmed by cholangiography (Plate 26, Atlas: p. 448) that reveals typical lesions of: • irregular intrahepatic ducts • focal saccular dilatation • intervening short annular strictures (giving a beaded appearance) • an abnormally large gall bladder • increased common bile duct diameter • extrahepatic ductal irregularity. Cholangiography may be performed either by a direct intraoperative approach, by a percutaneous transhepatic route or by endoscopic retrograde cholangiopancreatography (ERCP). ERCP in children, though technically feasible, is associated with a risk of pancreatitis. In one series mild pancreatitis occurred in 7% of children (Gregorio et al. 2001). More recently the development of magnetic resonance cholangiopancreatography (MRCP) has provided a non-invasive mode of diagnosis. In adults, MRCP has been shown to be accurate in the detection and localization of primary sclerosing cholangitis (Fulcher et al. 2000), and experience in children is increasing (Plate 26, Atlas: p. 448). Histology The pathognomonic feature is fibrous obliterative cholangitis (Sisto et al. 1987) with periductular fibrosis or inflammatory infiltrate, but is only seen early in the disease process. Another diagnostic feature seen in hepatectomy tissue is the presence of intrahepatic cholangiectasis with ductal obliteration. The following are almost invariable but not diagnostic features of SC (El-Shabrawi et al. 1987): • acute or chronic cholangitis • periportal copper-associated protein (orcein stain) • portal fibrosis • neoductular proliferation. Occasional features include cholestasis and piecemeal necrosis that may resemble AIH. Treatment The aims of treatment are to ameliorate symptoms and minimize disease progression due to obstruction or infection. Medical treatment As with other cholestatic disorders, fat-soluble vitamin supplementation and nutritional support must be provided, together with prompt antimicrobial therapy for episodes of cholangitis. Treatment of pruritis with ursodeoxycholic acid (UDCA) at 15 mg/ kg/day may be of benefit if given early in the disease process and may also lead to a significant improvement in hepatic aminotransferase enzymes (Stiehl et al. 1994).

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Immunosuppression does not confer the same benefit in SC as in AIH even in the presence of autoimmune markers, unless as part of the overlap syndrome. Treatment of the associated diseases, including IBD, does not reduce progression of disease in SC. Indications for surgery Isolated biliary strictures, if causing obstruction, may require intervention, which may be achieved by percutaneous dilatation and stenting. Other surgical drainage procedures (portoenterostomy, choledochoenterostomy) may palliate symptoms but do not improve outcome. In addition, there is an increased risk of ascending cholangitis following surgery, and subsequent liver transplantation may become technically more difficult. Biliary tract surgery in SC should therefore be avoided where possible. Orthotopic liver transplantation (OLT) has proved successful in treating children with SC: in one series, 11/15 (73%) children are alive without recurrence 6 months to 6 years after transplantation (Debray et al. 1994). Ulcerative or indeterminate colitis may develop for the first time after liver transplantation. Overlap syndrome/autoimmune sclerosing cholangitis An overlap syndrome of SC and AIH is described in adults (Gohlke et al. 1996) and may be more common in children (El-Shabrawi et al. 1987; Debray et al. 1994; Wilchanski et al. 1995). Although there are as yet no agreed diagnostic criteria, it is characterized by the elevation of the autoantibodies ANA ± SMA at presentation and raised levels of IgG, in the presence of the typical biliary lesions of SC at cholangiography. This may be an under-recognized disorder: of 55 children with a clinical presentation of autoimmune hepatitis, 27 (49%) had a diagnosis of sclerosing cholangitis on cholangiography (Gregorio et al. 2001). These children did not have pruritis or any distinguishing clinical features suggestive of biliary disease, and in particular bilirubin, alkaline phosphatase and GGT levels were similar to those with AIH without evidence of cholangitis. The coexistence of both features of AIH and SC at diagnosis, together with the observation of SC evolving in a patient with AIH, suggests that this may be a single disease process. Biochemical and histological response to immunosuppression is similar to AIH, but the addition of UDCA may be beneficial.

ingly large number of therapeutic agents contribute to a rising incidence. Direct evidence for causation and increased awareness of toxicity of some agents has led to a reduction in their use (e.g. halothane, nitrofurantoin). As these classical examples decrease, commonly used drugs are most likely to be implicated, including nonsteroidal anti-inflammatory drugs (NSAID) and antimicrobials. In addition, anticonvulsant, anticancer and immunosuppressive therapy are widely used in paediatric practice and have well-characterized hepatotoxic effects. Role of the liver in drug metabolism The liver plays a crucial role in the metabolism of virtually all drugs. Most drugs are lipophilic, and thus to be detoxified and excreted in bile or filtered by the renal glomerulus they must be rendered hydrophilic. This is achieved in the liver by two predominant mechanisms: first, oxidation or demethylation by the cytochrome P450 enzyme system (see below), and second, conjugation by glucuronidation or sulphation by specific transferases. In addition, other enzymes, for example alcohol dehydrogenase, are required for the metabolism of certain drugs. Electrophilic intermediate metabolites generated during these reactions are potentially harmful: binding of glutathione, catalysed by glutathione-S-transferase, provides a mechanism for detoxification of these reactive species. Mechanisms of drug-induced liver disease The term ‘drug-induced liver disease’ (DILD) encompasses liver dysfunction caused by two distinct mechanisms: direct hepatotoxicity and adverse drug reaction. The distinction lies in the predictability of the toxic effect: • Direct hepatotoxicity arises from the administration of a drug with intrinsic toxicity to the liver and is usually dose dependent (e.g. paracetamol, aspirin). • Adverse drug reactions comprise the majority of DILD. An adverse drug reaction is unpredictable and idiosyncratic, and may occur despite recommended treatment regimes being prescribed. This type of reaction occurs with a low frequency in the population exposed to the drug, is variable in presentation, is dose independent, and may result in diverse pathology. Host factors may be of particular importance (see below).

Drug-induced liver disease

Pathogenesis

Drug induced liver disease (DILD) should be considered in the differential diagnosis of all forms of acute and chronic liver disease. Although the incidence of DILD is rare, its importance lies in the diversity, severity and potential reversibility of its manifestations. An increas-

Drug-induced injury most commonly arises in the hepatocyte, due to its central role in drug metabolism, although biliary cells, Ito cells, and sinusoidal endothelium may also be targets. A drug itself or an intermediate metabolite may:

Chapter 8: Chronic Hepatitis • impair cell structure • inhibit enzyme activity • overwhelm glutathione cytoprotection • provide an antigenic determinant on the cell surface, provoking an inflammatory response • evoke a type IV systemic hypersensitivity reaction. These mechanisms may occur in combination, and for many drugs the precise mechanism remains unknown. The outcome for a given agent may be largely determined by host factors. Host factors DILD may be considered the end result of an interaction between a pharmacologically active compound after host metabolism in the presence of environmental influences (Farrell 1994). Consideration of factors that may affect drug metabolism is crucial if inappropriate prescribing and the risk of DILD are to be minimized. Factors affecting enzyme activity Genetic factors. The cytochrome P450 system is composed of a family of almost 300 genes that code for P450 enzymes. These genes are distributed among several chromosomes and thus the encoded enzymes are susceptible to considerable polymorphism. Genetic variation in these enzymes influences drug metabolism and may contribute to DILD either by excess toxic metabolite production or deficient precursor metabolism. Other hepatic enzymes are also polymorphic: genetic variation in N-acetyl transferase-2 activity is expressed phenotypically as a slow or fast acetylator and is relevant to isoniazid toxicity (see p. 154). Age. Full activity of an enzyme system may not be present in the first few years of life as it may be subject to developmental regulation (Kearns 1995). These developmental deficiencies may be of clinical significance. The rate of cytochrome P450 activity may also be influenced by age. A relative decrease in metabolism by glucuronidation compared with sulphation in children may be responsible for their decreased susceptibility to paracetamol hepatotoxicity. Concomitant drug therapy. Enzyme activity, especially of cytochrome P450, may be enhanced or inhibited by other drugs. Induction (e.g. by ethanol, phenobarbitone, phenytoin, carbamazepine, rifampicin, isoniazid, omeprazole) may increase the rate of generation of toxic metabolites, increasing the susceptibility to DILD. Factors affecting glutathione cytoprotection Alcohol and starvation may lead to glutathione depletion, and thus diminished cytoprotection, especially relevant in paracetamol toxicity. Replenishing with N-

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acetylcysteine re-establishes protection. Drugs that induce enzyme activity may also lead to glutathione depletion because of the increased generation of metabolites requiring conjugation. Other risk factors There is an increased risk of adverse drug reactions with age, which may reflect polypharmacy or an increased likelihood of concurrent disease. There is, however, an increased risk of valproate hepatotoxicity in children less than 3 years of age (see p. 155). For unknown reasons, many forms of DILD are more common in women, especially acute and chronic hepatitis. Individuals with a past history of adverse drug reaction are also more likely to experience a reaction to another agent. Clinicopathological spectrum DILD may have a wide spectrum of severity of liver injury and may resemble all other forms of liver disease. There is considerable overlap in the type of disease produced, and many drugs may produce more than one syndrome. Early symptoms are nonspecific, although in hypersensitivity reactions fever, rash and eosinophilia may be present. A particular feature of DILD is significant biochemical and histological abnormality occurring with few symptoms. The predominant clinicopathological manifestations of DILD are outlined below. Enzyme induction without disease Induction of hepatic enzymes may be of no clinical significance and not associated with hepatic disease or dysfunction, for example GGT induction by phenytoin/ phenobarbitone. Acute hepatitis/ hepatocellular necrosis This is the most common manifestation of DILD. The clinical presentation may be similar to: • acute viral hepatitis, with fever, anorexia, nausea or vomiting, followed by right upper quadrant tenderness with variable jaundice • allergic hepatitis, presenting with fever, rash, eosinophilia and lymphadenopathy, which may resemble infectious mononucleosis • fulminant hepatic failure. Histological changes in acute hepatitis reflect hepatocellular damage with degeneration and necrosis, accompanied by an inflammatory cell infiltrate. Specific features suggestive of a drug-induced rather than a viral hepatitis are referred to on p. 150 (Plate 27, 28, 29, Atlas: p. 449).

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Cholestasis Acute cholestasis manifests with the rapid onset of jaundice and pruritis. Causes include cotrimoxazole and erythromycin estolate. Without hepatitis recovery is usually rapid and complete, but with hepatitis there may be a more prolonged course. Histological features include inspissated bile within the canaliculi and bile pigment in hepatocytes and Kupffer cells. Significant bile duct injury may occur (e.g. flucloxacillin) and lead to more severe and chronic symptoms and resemble sclerosing cholangitis. Cholestasis may be accompanied by mild or moderate hepatocellular necrosis. Granulomatous hepatitis A wide variety of drugs may be responsible, though the most frequent cause is carbamazepine (see Plate 27, Atlas: p. 449). Clinical features include fever and malaise. The associated degree of hepatitis and cholestasis is variable. Drug-induced chronic hepatitis This is one of the least common forms of DILD but it is important, as prevention is possible. Examples of responsible agents include methyldopa, nitrofurantoin and chronic paracetamol ingestion. Clinical features Drug-induced chronic hepatitis may resemble AIH, with either an acute hepatitic onset or more insidious onset of tiredness, lethargy, anorexia, weight loss and hepatic discomfort. Jaundice and pruritis are unusual at presentation. A prolonged course is usually due to continued ingestion, as there is rarely perpetuation of the hepatic injury after withdrawal of the drug. Signs of liver disease are more likely than in acute hepatitis. Histological features These are often nonspecific and resemble those of autoimmune hepatitis. Features suggestive of DILD are referred to on p. 129 (see also Plate 24, Atlas: p. 447). The severity of the histological changes is the most important factor predicting outcome. Fatty liver Microvesicular fat within hepatocytes is associated with cellular dysfunction, and is typical of Reye’s syndrome, and valproic acid and tetracycline hepatotoxicity. Macrovesicular fat may be seen with amiodarone and may lead to rapid progression to cirrhosis. Fibrosis Progressive fibrosis without clinical manifestations may

occur, for example due to methotrexate, vitamin A or actinomycin D (see plate 28, Atlas: p. ••). Vascular disorders These range from sinusoidal dilatation (oestrogens) to veno-occlusive disease (cytotoxic chemotherapy). Anabolic steroids and cytotoxic chemotherapy have been implicated in peliosis hepatitis, in which hepatic sinusoids are destroyed forming blood-filled lakes or lacunae within the liver, which may rupture spontaneously. Hepatic tumours These are the least common form of DILD, accounting for < 1%, with oral contraceptive steroids the most commonly implicated agent. Natural history Resolution of histological and biochemical changes is the usual outcome following withdrawal of the agent causing DILD. The time for recovery is variable, depending on the type of hepatic injury. However, there is evidence to suggest that full recovery is not invariable. Of 33 adults re-evaluated 1–19 years after a definite diagnosis of DILD, 13 (39%) had abnormal liver enzymes, abnormal imaging (ultrasound or isotope scan) or both, and in 3/5 repeat liver biopsy showed significant abnormality. Factors predicting persistence or development of chronic liver disease were fibrosis on original biopsy and continued exposure to the drug. The drugs most commonly implicated in this series were antibiotics, NSAIDs and psychotropic drugs (Aithal & Day 1999). Diagnosis of suspected DILD History The diagnosis of DILD rests predominantly on an accurate history, which should cover the following aspects: • all drugs ingested in at least the 3 months prior to symptoms, including those bought over the counter and those accidentally ingested • total dosage given and previous courses (e.g. methotrexate) • timing of symptoms in relation to drug administration • symptomatology: presence of fever, rash, etc. • risk factors: previous drug reaction, family history, alcohol intake, concomitant drug therapy, underlying disease • exclusion of other causes of the symptomatology and biochemical/histological pattern: consider risk factors for other diseases (e.g. hepatitis A/B, autoimmune disease, etc.)

Chapter 8: Chronic Hepatitis • resolution after drug withdrawal (recurrence after a challenge may be confirmatory but is usually contraindicated).

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reports exist for many drugs, and a more detailed compendium is included in other texts. Paracetamol

Laboratory investigation The diagnosis of DILD is usually based on circumstantial evidence and exclusion of other causes. In instances of dose-dependent direct hepatotoxicity, a specific diagnosis or likely diagnosis may be achieved by: • drug levels (aspirin, paracetamol) • specific antibodies (halothane) • eosinophilia. If no biochemical or clinical improvement is seen after withdrawal, the diagnosis of DILD should be reconsidered. Histology Liver biopsy is of value unless rapid resolution of liver function occurs following drug withdrawal. Histological assessment permits the severity to be established as well as supporting causation and excluding differential diagnoses (see p. 129). Prevention The risk of DILD may be minimized by careful prescribing: the specific risk factors in an individual patient (see p. 149, Host factors) must be considered as well as the indications for a drug with known hepatotoxic effects (e.g. flucloxacillin). Continued prescribing of drugs with a dose-dependent effect or toxic threshold (e.g. methotrexate) requires careful monitoring of levels and of liver function. Treatment Withdrawal of the causative drug is the most effective important step in minimizing hepatic disease and allowing prompt recovery. Specific treatment is rarely available or necessary. Two exceptions are paracetamol toxicity, where provision of N-acetylcysteine is of benefit (see below), and sodium valproate toxicity where carnitine may be of benefit (see p. 155). Supportive treatment for acute liver failure is detailed in Chapter 7. Drugs implicated in DILD Almost any drug in the appropriate setting may give rise to DILD. The following examples are included, either because their role in DILD is firmly established and the hepatic manifestations are well characterized and reproducible, or the agents are in common paediatric use although the drug reaction itself may be rare. Anecdotal

Paracetamol toxicity is the most common cause of drug-induced fulminant liver failure. It leads to a direct, dose-dependent hepatotoxic effect: excess ingestion of paracetamol overwhelms the predominant mode of metabolism — conjugation to sulphate and glucuronide (Fig. 8.3). Metabolism is therefore directed to the alternative pathway via cytochrome P450, generating a reactive metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), which is detoxified by conjugation with glutathione. Excess metabolism by this pathway depletes glutathione, leading to NAPQI accumulation. This reactive species binds covalently to cell macromolecules, impairing mitochondrial and probably nuclear function and leading to cell death. In addition to acute liver failure due to deliberate overdose of paracetamol, prolonged administration may lead to paracetamol accumulation (Nahata et al. 1984) and thus toxicity. Repeated doses of paracetamol at supratherapeutic doses may be unintentionally administered by carers to children leading to hepatotoxicity in a younger age group (Rivera-Penera et al. 1997). As metabolism of paracetamol leads to a progressive reduction in measured paracetamol level following ingestion, the diagnosis may not be confirmed if a prolonged interval has elapsed prior to assay. The estimation in the serum of the adduct formed by NAPQI binding to cellular proteins, 3-(cystein-S-yl)-acetaminophen, may be of value in confirming the suspected diagnosis

Paracetamol

5%

95%

Conjugated to sulphate/glucuronide

cyt P450

NAPQI highly reactive

Rapidly bound to intracellular glutathione

Urine excretion as mercapturic acid

Fig. 8.3 Paracetamol metabolism diagram.

Excretion in urine

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(Webster et al. 1996). However, the clinical application of paracetamol–protein adduct measurement in children with paracetamol overdose is currently limited by poor sensitivity of current methodology (James et al. 2001). Since legislation restricting pack size of paracetamol and salicylates in the UK was introduced in 1998, the annual number of deaths from paracetamol poisoning has decreased by 21% with a 15% reduction in non-fatal self-poisoning (Hawton et al. 2001). Risk factors for paracetamol-induced hepatotoxicity The risk of hepatotoxicity with paracetamol ingestion is related to several factors. These include: • age of child • dose ingested • delay prior to commencing treatment • concomitant ingestion of enzyme inducers (e.g. antituberculous or anticonvulsant therapy) • glutathione depletion (alcohol, starvation). Therapeutic doses of paracetamol in the presence of inducers, however, are not likely to produce toxicity (Rumack 2002). Clinical manifestations The symptoms predictably progress after ingestion of paracetamol as follows: • First 24 h: anorexia, nausea and vomiting. • 24–48 h: minimal symptoms; right upper quadrant tenderness may develop. • Days 2–4: overt hepatic injury: marked elevation of hepatic transaminases, jaundice, coagulopathy and encephalopathy depending on severity. Renal dysfunction due to acute tubular necrosis with oliguria or anuria with metabolic acidosis. In 25–30%, acute renal failure may supervene. • Days 4–5: recovery may occur. Management Although exogenously administered glutathione cannot gain entry into the hepatocyte, Nacetylcysteine is able to substitute for glutathione in conjugation with NAPQI. Oral or intravenous Nacetylcysteine may confer protection against paracetamol-induced liver damage. Acute ingestion of 150 mg/kg of paracetamol is associated with a likelihood of significant hepatotoxicity, although the presence of other risk factors (see above) may lead to significant damage with smaller amounts. Paracetamol levels in plasma, measured at least 4 h after ingestion, are of value in determining the need for treatment. Treatment with N-acetylcysteine should not be delayed to await paracetamol levels. Treatment within 15 h of ingestion is beneficial in preventing massive hepatic necrosis, but later administration, even up to 36 h post ingestion, may also have a beneficial effect on survival (Harrison et al. 1990). Careful monitoring of coagulation, glucose, acid–base

and renal function is essential (Chapter 7). Fluid intake should be restricted to at most 60% of maintenance requirements, to protect against cerebral oedema, and vitamin K administered (5–10 mg, by slow intravenous infusion, daily for 3 days) to support coagulation factor synthesis. The likelihood of spontaneous recovery or the need for transplantation is dependent on the severity of hepatic failure: prognostic factors and further management are detailed in Chapter 7. Nonsteroidal anti-inflammatory drugs Although a structurally heterogeneous group, most NSAIDs not only share similar therapeutic antiinflammatory and antipyretic effects, but also adverse effects. Although toxicity of individual agents is rare, together they cause a significant proportion of DILD, reflecting their widespread use. Most NSAID-associated liver disease occurs within the first 2 months of commencing treatment and is due to hepatocellular injury, although cholestasis may also occur. For some agents, features of hypersensitivity are characteristic. Clinically insignificant elevation of hepatic aminotransferases is common, occurring in up to 15%. Severe and fulminant hepatitis has been reported. In patients with elevated baseline aminotransferase activity, the more frequently hepatotoxic NSAIDs should be avoided. Serum aminotransferase activity should be monitored monthly for the first 6 months, and more frequently if they become elevated. In the presence of systemic signs of hypersensitivity (fever, rash, eosinophilia), the NSAID should be discontinued and one of a different chemical group instituted (Fry & Seeff 1995). Aspirin In the majority of cases, aspirin hepatotoxicity is mild, asymptomatic and reversible. Aspirin gives rise to dose-dependent hepatotoxicity when its metabolic pathway becomes saturated. The precise hepatotoxic mechanism of the salicylic metabolite is not known. Salicylate levels are useful in establishing a likely diagnosis. Adverse effects are associated with levels exceeding 15 mg/dl in 90% of those affected (levels that are regularly achieved in children treated for juvenile chronic arthritis), and exceeding 25 mg/dl in 70%, and relate to both dose and duration of treatment. An asymptomatic elevation in transaminases (usually 250 mmol/l, and a prolonged prothrombin time are associated with a poor prognosis. Management. As elevation of aminotransferase enzymes is common, serial measurement neither improves early detection of acute hepatitis, nor predicts significant liver injury. Patients receiving isoniazid should be warned to report any clinical symptoms, particularly jaundice, to enable prompt withdrawal. Treatment is supportive, with withdrawal of isoniazid and use of alternative antituberculous regimens. A rapid biochemical resolution occurs in most patients, although more severe toxicity occurs on re-administration. A minority of patients may develop fulminant liver failure despite stopping isoniazid and may require liver transplantation. Rifampicin Rifampicin is rapidly eliminated in bile, undergoes enterohepatic circulation and progressively undergoes deacetylation in the liver. It impairs bilirubin

Chapter 8: Chronic Hepatitis uptake and may elevate serum bilirubin. It also induces cytochrome P450 and thus enhances its own metabolism. Liver disease and concomitant isoniazid therapy increase the half-life, and thus most toxicity occurs in patients receiving both isoniazid and rifampicin than with rifampicin alone. Rifampicin-associated hepatitis, however, occurring 1–6 weeks after commencing treatment, is reported. Pyrazinamide Pyrazinamide may lead to a dose-related hepatotoxicity. Previous high-dose regimens were associated with liver injury in 15%, whereas current lower dose regimens carry a lower risk. Isoniazid and pyrazinamide in combination may have a synergistic effect on hepatotoxicity. Anticonvulsant therapy DILD is a well-known complication of anticonvulsant therapy. An underlying metabolic abnormality may be present, and be the cause of the underlying neurological disease as well as the hepatotoxicity. Prolonged convulsions may lead to hypoxic/ischaemic liver damage and must be considered in the differential diagnosis of liver dysfunction. Phenytoin Phenytoin may give rise to a benign elevation of GGT and ALP as a result of hepatic enzyme induction. Of more clinical significance is a dose-independent acute hepatitis, the onset of which is variable, with features of allergy including fever, rash and eosinophilia and also a high frequency of lymphadenopathy and splenomegaly. Histology may reveal the presence of granulomata. Full recovery after withdrawal is usual. Carbamazepine Carbamazepine toxicity resembles that of phenytoin, with both hepatocellular and cholestatic features with evidence of hypersensitivity. Typically, the onset of symptoms occurs after 4 weeks, with high fever, rigors, weakness, jaundice and hepatic discomfort, resembling cholangitis. There may be a skin rash and peripheral oedema. Serum immunoglobulins, especially IgE, may be raised, while complement levels may be decreased. Eosinophilia is usually present. Clinical deterioration may continue despite stopping medication. Histological changes reflect both hepatocellular damage and cholestasis, and granulomata may be seen (see Plate 27, Atlas: p. 449). In children, fatal hepatocellular necrosis is also described (Hadzic et al. 1990). Valproic acid In paediatric practice, the syrup form of valproic acid, sodium valproate, is usually prescribed. In the first few weeks after commencing treatment, raised aminotransferases may occur but are rarely associated with symptoms. The greatest risk of hepatotoxicity is in

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children in the first 3 years of life. The onset is typically within 5 months of starting treatment, and manifests as acute liver failure due to hepatocellular necrosis, usually with macro- and sometimes extensive microvesicular fatty change in the liver. The most common presenting symptoms in a series of 29 patients with fatal valproic acid hepatotoxicity (Bryant & Dreifuss 1996) were: • diminished conscious level • jaundice • vomiting • bleeding • increased frequency of convulsions • anorexia • oedema. There may be associated mild pancreatitis. Apart from age, other risk factors include concomitant anticonvulsant therapy, especially with P450 inducers (valproic acid undergoes extensive hepatic metabolism by cytochrome P450), fatty acid oxidation defects and urea cycle disorders. Routine monitoring of liver function may not distinguish those with impending liver failure from those with minor enzyme elevation: fulminant failure may occur without any preceding biochemical abnormality and may progress despite discontinuation of valproic acid (see Plate 29, Atlas: p. 449). The early administration of intravenous l-carnitine was associated with improved hepatic survival in a retrospective study of 92 patients with severe, valproate-induced hepatotoxicity (Bohan et al. 2001). Treatment is otherwise supportive, as for fulminant hepatic failure. The role of transplantation is controversial: the presence of an underlying metabolic disorder with likely progressive multisystem manifestations, not reversible by liver transplantation, should be sought. Arole for carnitine supplementation to prevent hepatotoxicity in children receiving valproic acid has also been proposed (Raskind & El-Chaar 2000). Lamotrigine In a large study of 1096 children and adolescents taking lamotrigine, abnormal liver function was not described (Messenheimer et al. 2000). However, lamotrigine-associated hepatotoxicity has been reported in four children (Arnon et al. 1998; Fayad et al. 2000), although all were receiving concurrently other anticonvulsant medication. Onset of liver dysfunction was 1–6 weeks after commencement of treatment with lamivudine, and symptoms (including jaundice, vomiting, hepatomegaly ± ascites) or abnormal liver function tests (LFT) resolved within 1 week. Fatal hepatic failure, following an initial presentation with rash and fever, has been described in a 35-year-old woman (Overstreet et al. 2002).

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Drugs used in gastrointestinal disorders H2-antagonists and proton pump inhibitors Both cimetidine and ranitidine are associated with raised aminotransferase activity, which is common, transient and may reverse while therapy is continued. Significant hepatocellular or cholestatic injury is rare in children. Hypersensitivity reactions are unusual. Cimetidine is a reversible inhibitor of cytochrome P450, depending on host variation and other drugs, which has a theoretical but unproven beneficial effect in paracetamol toxicity. Other drug effects may be potentiated (e.g. warfarin) and the dose should be reduced accordingly. Ranitidine has a lower affinity for cytochrome P450 and interaction with other drugs is less marked or significant. Omeprazole has similar adverse effects to H2-blockers in type and frequency, with reversible elevation in aminotransferase levels reported (Bashir & Lewis 1995; Koury et al. 1998). Other proton pump inhibitors, including lansoprazole and pantoprazole, are structurally very similar and considered likely to have similar pharmacokinetics, metabolism and interactions (Andersson 1996). Sulphasalazine and related compounds Liver injury associated with sulphasalazine is uncommon, and relates to a hypersensitivity reaction to the sulphapyridine moiety. Fever, rash, lymphadenopathy and eosinophilia may occur within 2–3 weeks of treatment, but massive hepatic necrosis, though documented, is rare. Olsalazine and mesalazine lack the sulphapyridine moiety, and were initially considered to be less hepatotoxic. However, mesalazine-associated hepatotoxicity, including cholestasis, chronic hepatitis and granulomatous hepatitis, is becoming more apparent (Braun et al. 1999; Deltenre et al. 1999). Immunosuppressive drugs Azathioprine Azathioprine can give rise to a broad spectrum of liver dysfunction: • asymptomatic liver enzyme elevation • hepatitis and/or cholestasis and bile duct injury • vascular injury (especially following renal transplantation) • sinusoidal dilatation, perisinusoidal fibrosis • peliosis (blood-filled cavities without endothelial lining) • veno-occlusive disease. As indications for azathioprine include organ transplantation, chronic inflammatory disorders and autoimmune disease, liver damage may occur in a complex setting, and azathioprine may not be considered as the potential cause. The onset may be months to years after starting treatment, although the hepatitic and cholestatic features may manifest earlier. Disease progression occurs

with continued treatment. A therapeutic trial of azathioprine withdrawal may be necessary to establish or exclude its role. Cyclosporine Cyclosporine may rarely be associated with hyperbilirubinaemia, cholestasis and cholelithiasis. Methotrexate Methotrexate is a folic acid antagonist and has an expanding therapeutic role, including leukaemia, solid tumours, psoriasis and rheumatoid arthritis. It is a dose-dependent hepatotoxin, which has a fibrogenic effect, possibly by activation of hepatic Ito cells. The total dose administered is the most important predictor of fibrosis, although the dose schedule used may be relevant: low-dose, weekly pulsed therapy appears to carry a lower risk of significant fibrosis. Other risk factors for methotrexate toxicity include alcohol ingestion and pre-existing liver disease. In addition, as methotrexate is renally excreted, impairment of renal function (including decreased renal blood flow due to NSAID administration) will contribute to the risk of toxicity. Hepatic fibrosis is usually asymptomatic, unless accompanied by manifestations of portal hypertension. Extensive fibrosis may be present with normal liver function, but serial monitoring is recommended. Minor enzyme abnormalities are common, especially with high doses, and do not correlate with significant hepatic damage. Liver biopsy should be performed to assess hepatic fibrosis if liver enzymes are persistently abnormal, or after 4 g or 2 years of treatment. In the presence of fibrosis, the risks and benefits of continued treatment must be considered, as there may be some reversal of fibrosis after stopping treatment. Cytotoxic therapy Cytotoxic chemotherapy and veno-occlusive disease are discussed in Chapter 15: The liver in systemic disease.

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Chapter 9: Congenital and Structural Abnormalities of the Liver DING-YOU LI AND KATHLEEN B. SCHWARZ

Fibropolycystic disease, 162 Embryology of the IHBDs, ductal plate and ductal plate malformation (DPM), 162 Classification, 163 Differential diagnosis of fibropolycystic

disease of the liver, 171 Management issues, 172 Future research, 173 Hepatic vascular anomalies, 173 Classification, 173

This chapter will provide a comprehensive overview and problem-orientated approach to the diagnosis and management of intrahepatic congenital and structural abnormalities, with particular emphasis on two major categories, fibropolycystic disease and vascular anomalies. The hereditary fibropolycystic diseases are a heterogeneous group of conditions in which there is increased hepatic fibrosis in association with cysts lined by biliary epithelium. These conditions include solitary cysts, autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), congenital hepatic fibrosis (CHF), Caroli’s disease and Caroli’s syndrome (see Plate 30, Atlas: p. 450). Clinical presentation varies from asymptomatic hepatomegaly, as in the case of solitary cysts, to portal hypertension, renal failure and rarely liver failure. The majority of vascular anomalies of the liver are haemangiomas, which, like solitary cysts, may present as incidental findings or as asymptomatic hepatomegaly; giant cavernous haemangiomas may be complicated by symptoms related to the massive hepatomegaly and compression of abdominal viscera and/or by the consequences of arteriovenous shunting such as congestive heart failure and pulmonary oedema. Innovations in paediatric radiology such as computed tomography (CT), magnetic resonance imaging (MRI), MR cholangiopancreatography (MRCP), and colour Doppler ultrasound have enhanced the non-invasive diagnosis of these abnormalities.

Fibropolycystic disease Polycystic disease was first described by Bristowe (1856). The term ‘fibropolycystic disease’ is a general term used to describe several conditions with a variable degree of

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Clinical features, 174 Diagnosis, 174 Pathology, 176 Management and outcome, 176 Promising lines of research, 177

intrahepatic bile duct (IHBD) dilatation and associated periportal fibrosis. Polycystic disease is usually not confined to the liver, and other organs may be affected. In particular, as the cystic lesions most severely affect the kidneys, the severity of the renal lesions determines the clinical presentation and the long-term prognosis of polycystic disease. Embryology of the IHBDs, ductal plate and ductal plate malformation (DPM) The pathogenesis of the congenital fibrocystic diseases of the liver is linked with the embryonic development of the IHBDs. It is thought that the IHBDs develop from the hepatocyte precursor cells, which lie in contact with the mesenchyme surrounding the portal vein. This process starts during the 3rd month of gestation with the formation of the larger IHBDs at the level of the hilum and proceeds distally to the smaller terminal portal branches, which are completed in the first month of the postnatal period (Desmet 1992a). The basic lesion in all variants of fibropolycystic disease is the ductal plate malformation (DPM), which affects all levels of the intrahepatic biliary tree such as the segmental, septal and interlobular ducts and the ducts of the terminal portal tracts (Desmet 1992a) (Fig. 9.1). The ductal plate is a structure corresponding to the most immature state of the bile duct and is characterized by an interrupted cylindrical layer of cells around the future portal tract which is later doubled by a second layer of keratin-rich bile duct epithelium over several segments of its circumference. Around the 12th week of gestation, the ductal plate is remodelled in response to unknown signals induced by epithelial–mesenchyme interactions, which result in the incorporation of dilated parts of the double epithelial layer into the portal mesenchyme. The unincorporated epithelial layer then

Chapter 9: Abnormalities of the Liver DPM + ectasia

Fig. 9.1 Schematic representation of the biliary tree and the diseases discussed in this chapter. The placement of diseases at different levels of the tree indicates the approximate size of the bile ducts affected by ductal plate malformation (DPM) in a particular disorder. The disorders mentioned on the left are characterized by mild or marked dilatation of the bile duct structures, whereas the entities listed on the right develop with a variable degree of involution (‘destructive cholangitis’) of the ductal plate remnants associated with fibrosis. (With permission from Desmet 1992a).

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DPM + involution

A.D.P.K.D.

von MEYENBURG complexes

A.R.P.K.D.

C.H.F.

CAROLI disease

disappears. The normal development of IHBDs requires progressive remodelling of ductal plate involving precisely tuned interactions between the mesenchyme and the ductal plate epithelia. Any interruption in the remodelling of the ductal plate may result in the persistence of the excess embryonic epithelial duct structures termed DPM (Jorgensen 1977). The exact biochemical defect that leads to the formation of cysts remains unknown. DPM is often associated with abnormalities in the ramification pattern of the portal vein giving rise to smaller, closer spaced branches termed ‘pollard willow formation’ (Desmet 1985; Desmet & Callea 1990). DPM involving all segments of the IHBDs results in a combination of anatomical clinical entities including CHF-ARPKD, ARPKD-Caroli’s, CHF-Caroli’s and CHF-von Meyerburg complex (Desmet 1992a, 1992b; Sung et al. 1991). Classification Cystic diseases of the liver may be parasitic or nonparasitic. Typically, non-parasitic cystic lesions are solitary or multiple (sporadic) or polycystic (hereditary).

CAROLI syndrome

Older literature is confusing and many changes in the classification of the fibropolycystic diseases of the liver and kidneys have been proposed, primarily due to the changes in the classification of the cystic renal lesions (Welling & Grantham 1989). The basis of modern classification is shown in Table 9.1. The intrahepatic bile duct cysts may be connected to the biliary tree (communicating or non-communicating). Communicating ductal cysts have more clinical significance as they tend to present with medical complications such as cholangitis and biliary calculi. Desmet (1992a) divided the congenital diseases of the IHBDs, as illustrated in Fig. 9.1, into two main groups: (i) diseases characterized by necroinflammatory destruction of the IHBDs, and (ii) diseases characterized by a degree of dilatation of IHBDs, also associated with a variable degree of fibrosis. Disorders associated with dilatation of the bile ducts include ADPKD, ARPKD and Caroli’s disease, whereas disorders that develop with involution or destructive cholangitis include von Meyerburg complexes (or microhamartomas), CHF and Caroli’s syndrome. The cause of involution of the bile ducts and renal epithelia remains unknown.

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Table 9.1 Classification of fibropolycystic lesions of the liver Parasitic Nonparasitic Solitary/multiple — sporadic Polycystic — hereditary Noncommunicating with the biliary system Autosomal dominant polycystic kidney disease (ADPKD) Communicating with the biliary system Autosomal dominant polycystic kidney disease (ARPKD) Congenital hepatic fibrosis (CHF) CHF — ARPKD or ADPKD CHF — Caroli’s disease (Caroli’s syndrome) CHF — nephronophthisis CHF — tuberous sclerosis CHF — vaginal atresia CHF — malformations Meckel–Gruber syndrome, Jeune syndrome Ivemark syndrome, Laurence–Moon–Biedl Caroli’s disease Polycystic liver disease — isolated Miscellaneous Traumatic, infarction, neoplasic

Solitary cysts Solitary simple cysts occur at all ages without symptoms. They may be discovered incidentally by antenatal ultrasound or other radiological studies or at autopsy. They most frequently involve the right lobe of the liver. The cysts usually contain serous fluid and are lined by atrophic biliary epithelium. Multiple cysts develop with potassium deficiency, toxic renal injury, metabolic disease and congenital disorders. Management is usually conservative. Observation alone is recommended unless there are symptoms such as abdominal pain from bleeding into the cyst or rapid enlargement. Radiological or surgical aspiration is rarely required. If they become infected, antibiotic therapy is recommended with lipid-soluble antibiotics such as trimethoprim-sulfamethoxazole or ciprofloxacin (Gabow & Bennett 1991; Piccoli & Witzleben 1991) (see Plate 31, Atlas: p. 450). Autosomal dominant polycystic kidney disease This was the first fibropolycystic liver disease to be described as a heritable trait (Steiner 1899). Although previously referred to as adult polycystic kidney disease (APKD), the nomenclature has changed since the disease may present in early infancy and childhood and is now more correctly termed ADPKD. This disease results in cyst formation in the kidneys, liver, pancreas, spleen, thyroid, endometrium, ovaries, seminal vesicles and epididymis (Fick & Gabow 1992; Martinez & Grantham 1995). The disease is inherited as an autosomal dominant

trait and each offspring of an affected person runs a 50% risk of acquiring the disease. Both sexes are affected equally. Molecular genetics and pathogenesis ADPKD is one of the most common genetic disorders world-wide, with an estimated prevalence of 1 in 400–1000 people (Dalgaard 1957; Gabow 1993) and accounts for 12% of patients with end-stage renal disease (ESRD) in the USA (Vollmer et al. 1983). At least two causal genes are thought to be responsible for ADPKD: PKD1 and PKD2. PKD1 is located on chromosome 16p13.3 and is responsible for 85% of families with ADPKD, whereas PKD2 is mapped on chromosome 4q21-23 and causes approximately 15% of familiar ADPKD (Reeders et al. 1985; Kimberling et al. 1993; Mochizuki et al. 1996; Arnaout 2001; Wu 2001). The existence of a third genetic locus, PKD3, has recently been questioned (Paterson & Pei 1998, 1999). The human PKD1 gene consists of 46 exons. It is 52 kb in size and transcribed into a 14-kb mRNA (Reeders et al. 1985; European Polycystic Kidney Disease Consortium 1994). PKD1 gene lies immediately adjacent to the TSC2, a gene responsible for approximately 50% of tuberous sclerosis, in a tail-to-tail orientation (European Polycystic Kidney Disease Consortium 1994). Polycystin-1, the protein product of PKD1, is a 4303 amino acid integral membrane protein with 11 transmembrane domains and a predicted molecular mass of approximately 460 kDa (Geng et al. 1996). It has a large extracellular region with potential protein–protein and protein– carbohydrate interaction domains and may function in cell-to-cell, or cell-to-matrix interactions. Polycystin-1 is expressed in cell membranes of the ureteric bud and collecting ducts of fetal kidneys in mouse and human tissues and is highly expressed in the mesenchyme of the developing kidney and liver (Van Adelsberg & Frank 1995; Geng et al. 1996). The exact function of the protein remains unknown. The human PKD2 gene contains 15 exons, spans 68 kb of genomic DNA and is transcribed into a 5.4-kb mRNA. Polycystin-2, the PKD2 gene product, has 968 amino acids with predicted molecular weight of 110 kDa. It is an integral membrane protein with six transmembrane spans and intracellular amino- and carboxyl-termini (Mochizuki et al. 1996). Polycystin-2 shows sequence homology to a subunits of voltage-activated calcium channels (Mochizuki et al. 1996), and associates with the transient receptor potential channel proteins (TRPC)-1, which is activated by G-protein-coupled receptor activation and/or depletion of internal Ca2+ stores (Tsiokas et al. 1999). A recent study has demonstrated that polycystin-2 is a calcium-activated intracellular calcium release channel and suggests that ADPKD may result from the loss of a regulated intracellular calcium release signalling mechanism (Koulen et al. 2002). Polycystin-2 is highly ex-

Chapter 9: Abnormalities of the Liver pressed in the endoplasmic reticulum of kidney epithelial cells (Koulen et·al. 2002). At least three additional genes related to PKD1 and PKD2 has also been identified recently: (i) PKDL maps to chromosome 10q25, has 16 exons and encodes a polycystin-2-like protein of 805 amino acids, polycystin-L. No role for PKDL in ADPKD has been shown; (ii) PKDREJ maps to chromosome 22q13.3 and encodes polycystinREJ, which is 2253 amino acids long and is homologous to polycystin-1 region extending from the beginning of the REJ domain to the C-terminus. Its expression is limited to testis in humans, excluding its role in ADPKD; (iii) PKD2L2 is located on chromosome 5q31 and encodes a protein of 613 amino acids, polycystin-2L. Its expression has only been documented in testis. Knockout mouse models have helped to better understand the functional roles of polycystin-1 and polycystin2. Both PKD1 and PKD2 knockout mice are embryonic lethal, and exhibit multiple renal and pancreatic cysts (Lu et al. 1997; Wu et al. 1998), suggesting a loss of function of polycystin-1 or -2 as a mechanism for cystogenesis in ADPKD. Interestingly, the PKD2-deficient mice exhibit a cardiac structural defect from ventricular and atrial septum defects to complete absence of their septa, whereas no cardiac septum defect was observed in PKD1-deficient mice (Kim et al. 2000a; Wu et al. 2000). Those findings demonstrated that PKD1 and PKD2 may have independent functional roles during development. Numerous mutations in PKD1 and PKD2 have been identified (Wu & Somlo 2000). The majority of the mutations are either point mutations or deletion/insertion mutations that introduce stop codons or frame shifts, which results in premature termination of protein synthesis. Localization of mutations within either PKD1 or

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PKD2 may contribute to the different clinical phenotypes of ADPKD (Hateboer et al. 1999, 2000). Apopular hypothesis for cyst formation is the so-called somatic second-hit or two-hit model (Fig. 9.2), which proposes that cystogenesis in ADPKD is caused by compound trans-heterozygote cells with an inherited germline mutation in PKD1 and a second somatic mutation in PKD2, or vice versa (Qian & Watnick 1999; Arnaout 2001; Wu 2001). Increasing genetic evidence did support this hypothesis for a trans-heterozygous model for cystogenesis and for a co-operative interaction between the two PKD gene products, polycystin-1 and -2 (Tsiokas et al. 1997; Qian et al. 1997; Ong et al. 1999; Koptides et al. 2000; Watnick et al. 2000). In cystic DNA from a kidney of an ADPKD1 patient, Koptides et al. (2000) showed somatic mutations not only in the PKD1 gene of certain cysts, but also in the PKD2 gene of others, generating a transheterozygous state with mutations in both genes. One mutation in PKD1 is of germinal nature and the mutation in the PKD2 gene is of somatic nature. Watnick et al. (2000) found somatic mutations of PKD2 in 71% of cysts analysed in two families with different germline PKD2 mutations. Therefore, a somatic acquired mutation in PKD1 may act as a modifier for disease severity of PKD2, or vice versa. Pathology Macroscopically, large asymmetric hepatic cysts are visualized throughout the liver and tend to increase with age. The cysts are lined by biliary epithelium, which secretes a serous fluid that fills the cavity (Grunfeld et al. 1985). They are surrounded by a fibrous capsule and are non-communicating with the biliary tree. They are frequently associated with von Meyerburg complexes or microhamartomas, which are rounded nodules, 1 cm in

PKD1

PKD2 Inherited mutation (dashed line) in either PKD1 or PKD2 gene

A second somatic mutation on the healthy allele of the same gene or the other PKD gene gene, leading to trans-heterozygosity

Fig. 9.2 The somatic second-hit model of cyst formation. In autosomal dominant polycystic kidney disease (ADPKD), all cells have an inherited germline mutation in one PKD allele (e.g. PKD1) and a second random somatic mutation (second hit) occurs in the normal allele of either the PKD1 or PKD2 gene.

Increased proliferation and cyst formation

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diameter, closely related to the portal tracts and which are scattered through the entire liver parenchyma (Grunfeld et al. 1985). The microhamartomas are usually discovered at autopsy as they are asymptomatic. In contrast, the renal cysts are irregular in size and have an uneven distribution affecting the collecting system, tubules and glomeruli, and progressively replace the parenchyma leading to renal failure (Blyth & Ockenden 1971). Asymptomatic pancreatic cysts occur in 5–10% of patients (Fick & Gabow 1994). Clinical features ADPKD presents with abdominal distension due to bilaterally enlarged kidneys and hepatomegaly, abdominal pain, haematuria, hypertension, renal infection, nephrolithiasis and renal insufficiency (Blyth & Ockenden 1971). Loss of renal concentrating ability and hypertension are early signs of the disease. Sixteen percent of children less than 18 years have systolic blood pressures in the 95th percentile for their age (Fick & Gabow 1994). Flank pain, renal cyst haemorrhage, infection or nephrolithiasis most commonly occur after the fourth decade of life (Gabow & Bennett 1991). Hepatic cysts are the most common extrarenal manifestation of ADPKD and appear more frequently with increasing age and declining renal function. Although liver cysts are uncommon in paediatric patients with ADPKD, they are found in 30% of adult patients with ADPKD under 40 years, and in 77% of patients over 60 years of age (Milutinovic et al. 1980; Gabow et al. 1990; Torres 1999). Approximately 25% of ADPKD-affected individuals do not develop liver cysts (Torres 1999). Hepatic cysts have been diagnosed by biopsy as early as 8 months of age (Milutinovic et al. 1989). Both sexes are affected equally, although women tend to have more extensive liver cysts correlating directly to the number of pregnancies (Everson et al. 1988). Patients with PKD2 mutations have a typically milder course than those with PKD1 mutations (Hateboer et al. 1999). Median age of death or onset of ESRD is 53 years in individuals with PKD1 and 69 years in those with PKD2. PKD1 patients are four times more likely to have hypertension than PKD2 patients. Overall survival is significantly higher in women than men with PKD2, but this difference is not observed with PKD1. Other associations with ADPKD include: 1 Intracranial aneurysms, which occur in 10% of patients and constitute a major life-threatening complication. They are more frequent in patients with a family history of cerebral aneurysms and in those with severe polycystic liver disease. Life-threatening rupture of intracranial aneurysms occurs in 5% of patients and the mean age at rupture is earlier for ADPKD patients than the average population (Chapman et al. 1992; Chauveau et al. 1992). Intracranial arachnoid cysts occur in 8% of patients. Contrary to cerebral aneurysms, arachnoid cysts remain

asymptomatic and patients generally do not develop complications such as intracranial bleeding or subdural haematomas (Schievink et al. 1995). 2 Cardiac disease, such as mitral valve prolapse, aortic root dilatation, aortic dissection, and aneurysms of the coronary arteries and the aorta, have been reported in adults (Hossack et al. 1988). 3 Inguinal and abdominal hernias have also been described. Colonic diverticula occur in 80% of adult patients requiring renal dialysis, but have not been reported in children (Scheff et al. 1980). Hepatic cysts tend to have fewer complications, such as bleeding and infection, than renal cysts but may result in massive hepatomegaly and chronic abdominal pain. Complications noted in adults include: • Ascites and oesophageal varices secondary to non-cirrhotic portal hypertension (Vauthey et al. 1992). • Obstructive jaundice secondary to biliary obstruction, cholangitis or gall-bladder involvement. Biliary colic has been associated with an intraluminal cyst in the cystic duct resulting in hydrops of the gall bladder (Hollingsworth 1982). Gall-bladder disease is more common with symptomatic liver disease (Harris et al. 1996). • Compression of the pancreas, displacement of other organs and elevation of the diaphragm resulting in dyspnoea (Wallach et al. 1991). • Rare complications include Budd–Chiari syndrome secondary to anatomical obstruction of the inferior vena cava from enlarged liver cysts, which has been reported in adults particularly after nephrectomy (Clive et al. 1993). Despite the presence of multiple cysts, the liver parenchyma remains intact. The serum aminotransferases, albumin and prothrombin time are normal, although g-glutamyl transpeptidase (GGT) may be mildly elevated in symptomatic liver disease. Diagnosis Diagnosis is primarily by abdominal ultrasonography of liver and kidneys. ADPKD should be considered in any child with a renal cyst, whereas the presence of more than three cysts in both kidneys in a patient with a positive family history strongly suggests ADPKD (Parfrey et al. 1990). False-negative ultrasound examinations under the age of 30 may be more common in families with the PKD2 gene mutations, as renal cysts develop later in life (Bear et al. 1992). CT with contrast enhancement is slightly more sensitive than ultrasound for detecting cysts and is particularly useful in identifying cyst haemorrhage. The combination of MRI and ultrasound may demonstrate the internal morphology of a cyst and distinguish a simple hepatic cyst from other hepatic cystic lesions. MRI is particularly helpful in displaying the relationship of the cyst to the hepatic vascular structures (Wilcox et al. 1985). The diagnosis may be confirmed by hepatic and renal histology. Prenatal diagnosis of ADPKD is possible using a linked

Chapter 9: Abnormalities of the Liver DNA probe derived from the a-globin region (Reeders et al. 1986). Management and outcome Management is directed towards treatment of both renal and liver disease. Treatment for renal disease is supportive and includes standard therapy with nutritional support, a low-sodium and low-protein diet, antihypertensive medication and dialysis and/or renal transplantation for ESRD. Treatment for liver disease is directed towards the prevention and management of complications. Families should be reassured that despite abdominal distension, hepatic function remains normal for many years. Recurrent cholangitis should be managed with lipid-soluble antibiotics such as trimethoprim-sulfamethoxazole, chloramphenicol or ciprofloxacin, which penetrate cyst walls, and with prophylactic antibiotics (Gabow & Bennet 1991). Pain from cyst haemorrhage is usually self-limited and may be treated with mild analgesics and bed rest (Fick & Gabow 1992). Percutaneous or surgical decompression of the cysts should be reserved for severe, unmanageable pain. Somatostatin has been used in reducing ascites by inhibiting bile secretion after surgical fenestration of cysts (Vauthey et al. 1992). Cholecystectomy should be considered in patients with severe hepatic involvement (Harris et al. 1996). Initial treatment of portal hypertension should be conservative in the first instance, although occasionally portal-systemic shunting may be appropriate. Successful liver-kidney transplantation has been performed for severe complications from liver disease, with up to 60 months survival and normal hepatic function (Starzl et al. 1990; Rogers et al. 2001). Prophylactic screening of all patients with ADPKD for intracranial aneurysms is mandatory, with surgery as indicated by a neurosurgeon. As intracranial arachnoid cysts are asymptomatic and do not enlarge with age, surgery is not required (Raffel & McComb 1994). Autosomal recessive polycystic kidney disease (ARPKD) The term ARPKD has replaced the older ‘infantile polycystic disease’ since the disease also presents in adults. ARPKD is characterized by the association of renal cysts arising from dilated collecting ducts, and biliary dysgenesis known as congenital hepatic fibrosis. It has an incidence of 1 in 6000 and 1 in 40 000 births (Cole 1990). A gene mutation on both arms of chromosome 6 is responsible for the disease. Intrafamilial variation of the disease has been reported, which implies different expression of the same gene complex (Martinez & Grantham 1995). Molecular genetics The responsible gene for ARPKD, PKHD1, has mapped to 6p21.1-p12 (Zerres et al. 1994;

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Guay-Woodford et al. 1995; Lens et al. 1997; Mücher et al. 1998; Park et al. 1999). ARPKD is genetically homogeneous, with both severe and mild cases of the disease mapped to the same locus (Zerres et al. 1994). Amazingly, two groups recently simultaneously reported that PKHD1 is a large gene, encoding a 4074-amino-acid protein, called fibrocystin by one group (Ward et al. 2002) or polyductin by another group (Onuchic et al. 2002), which is predicted to have a large extracellular region, a single transmembrane domain near its carboxyl terminus, and a short cytoplasmic tail. It amino terminus contains immunoglobulin-like plexin-transcription-factor domains and parallel b-helix 1 repeats (Onuchic et al. 2002). The function of fibrocystin is not yet known, but it may act as a receptor with critical roles in collecting-duct and biliary development (Ward et al. 2002). Interestingly, polyductin shares the general structural features with hepatocyte growth-factor receptor and plexin, which belong to a superfamily of proteins involved in regulation of cell proliferation and of cellular adhesion and repulsion (Onuchic et al. 2002). Pathology In ARPKD there is both renal and hepatic enlargement. The kidneys are symmetrically affected. The renal cysts develop at the terminal collecting tubules in association with interstitial fibrosis, which leads to the appearance of medullary sponge kidney or even ADPKD. Hepatic lesions are uniform and are not seen macroscopically, although macroscopic cysts may be present in more severe forms. The portal tracts are filled with connective tissue and abnormal bile ducts, which are dilated and communicate with the rest of the biliary system (Witzleben 1990). With increasing age, a decrease in the number of ductular structures and an increase in the portal fibrosis are noted. If the immature bile ducts undergo necroinflammatory changes resulting in fibrosis, ARPKD is associated with CHF. If incomplete remodelling of the ductal plate occurs earlier in the development, when the larger segmental ducts begin to form, ARPKD is associated with Caroli’s disease (Desmet 1992a). Clinical features The main clinical features are renal. Blyth and Ockenden (1971) assigned patients with ARPKD to four groups according to the age of presentation: the perinatal, neonatal, infantile and juvenile groups. In the perinatal group, infants present at birth with large renal masses resulting in abdominal distension, uraemia, hypertension and metabolic acidosis and die shortly after birth secondary to renal failure and respiratory distress. The respiratory failure is caused by compression of the thoracic viscera, atelectasis, congestive heart failure or even pneumomediastinum. Mechanical ventilation and management of hypertension may prolong life beyond the first month of life. The majority of

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renal tubules are dilated at autopsy whereas there is only minimal periportal hepatic fibrosis. In the neonatal group, children present in the first few months of life with bilaterally enlarged kidneys, and progressively develop renal failure. Death occurs within weeks to a few months after presentation. All have dilated IHBDs with minimal periportal fibrosis. In the infantile group, children present with enlarged kidneys and hepatosplenomegaly at between 3 and 6 months of age. Chronic renal failure with hypertension and portal hypertension ensues. Without medical intervention, death may occur before 10 years of age. All have dilated IHBDs with moderate periportal fibrosis. In the juvenile form, children present between 6 weeks and 1–5 years, mainly with hepatomegaly, which later may progress to portal hypertension, often necessitating a portocaval shunt. They have the mildest renal disease compared with the other groups as they have less renal cysts. However, all have dilated IHBDs with gross periportal fibrosis. Diagnosis Diagnosis is established by ultrasonography, CT, MRI, MRCP, intravenous pyelography and percutaneous liver and kidney biopsies. Liver function may be normal. Haplotype-based prenatal diagnosis is feasible and reliable in pregnancies at risk for ARPKD (Zerres et al. 1998) provided an accurate diagnosis of ARPKD has been made in a previously affected sib. Management Currently, treatment consists of symptomatic management of the sequela of the disease. This includes: control of hypertension, which is the major cause of morbidity in the neonatal period, and treatment of renal failure with dialysis and renal transplantation. Treatment of the hepatobiliary disease consists of control of variceal bleeding either with sclerotherapy (Roy et al. 1997; Jamil et al. 1999) or banding. Occasionally, portosystemic shunts are necessary to reduce bleeding if hepatic function remains normal. Transjugular intrahepatic portosystemic stent shunt (TIPSS) has been successful in one patient with ARPKD and portal hypertension (Benador et al. 2001). Long-term outcome depends on the severity of the renal disease. Congenital hepatic fibrosis CHF was first reported by Kerr et al. (1978) and is an autosomal recessive disorder that is characterized by hepatomegaly and portal hypertension with intact lobular architecture but with superimposed periportal fibrosis and dilated IHBDs. Renal cystic disease is present in the medulla and cortex in most patients and most closely corresponds to ARPKD. Because CHF is most commonly associated with ARPKD, many authorities suggest that the

juvenile form of the ARPKD is synonymous with CHF, based on the similar clinical presentation and pathology findings (Piccoli & Witzleben 1991). The exact incidence of the disease is not known. Pathology CHF results from ductal plate malformation of the intrahepatic bile ducts (Desmet 1992b). Macroscopically, the hepatic cysts may or may not be visible or confined to one lobe (Alvarez et al. 1981). As discussed above, a process of destructive cholangitis and involution occurs, resulting in periportal fibrosis. The rate of bile duct destruction and fibrosis differs from patient to patient, and may remain unchanged in some (Bernstein et al. 1988). The liver contains broad bands of fibrous tissue, which are separate from the hepatic parenchyma and contain irregular cysts lined by biliary epithelial cells. The portal tracts are enlarged and are linked by the bands of fibrous tissue. The biliary cysts are numerous and may communicate with the rest of the biliary system. The portal vein branches are often hypoplastic and the hepatic artery branches are supernumerous (Fauvert & Benhamou 1974). There is little inflammatory infiltrate unless there is coexistent cholangitis. The hepatic parenchyma is normal (see Plate 31, Atlas: p. 450). In the kidneys, the cystic dilatation affects the collecting ducts and distal tubules, and is less frequent than in ARPKD. The renal cysts develop from involution of the abnormal tubules. Progressive involution leads to nephronophthisis (Witzleben & Sharp 1982). Other associations CHF has been associated with the following conditions: 1 Medullary cystic kidney disease (MCKD) and juvenile nephronophthisis (NPHP): they have different modes of inheritance and different age of onset, but otherwise resemble one another. MCKD1 affects mainly adults, has an autosomal dominant inheritance pattern and maps to chromosome 1q21 (Christodoulou et al. 1998), whereas juvenile nephronophthisis is recessive and the NPHP1 gene maps to chromosome 2q13 (Hildebrandt et al. 1997). A second MCKD locus, MCKD2, has recently been mapped to chromosome 16p12 (Scolari et al. 1999). Nephrocystin, the NPHP1 gene product, appears have a role in mediating cell adhesion (Hildebrandt & Omram 2001). The onset of NPHP is in childhood, and patients progress to end-stage disease within 5–10 years. Other renal lesions seen in conjunction with CHF include renal dysplasia (Proesmans et al. 1986) and ADPKD (Tazelaar et al. 1984). 2 Meckel–Gruber syndrome of encephalocoele, polydactyly and hepatosplenomegaly is an autosomal recessive disorder which presents at birth with massive renal lesions and severe hepatic cystic disease (Landing et al. 1980). 3 Jeune syndrome is an autosomal recessive disorder

Chapter 9: Abnormalities of the Liver with typical radiological features of pulmonary hypoplasia due to underdevelopment of the thoracic cage. Other common features include renal, hepatic and pancreatic abnormalities. It is characterized by less severe hepatic cystic disease than CHF or Meckel–Gruber syndrome, and later-onset renal cystic disease (Landing et al. 1980). 4 Ivemark’s familial dysplasia includes CHF with localized renal dysplasia, with severe interstitial fibrosis leading to renal failure in infancy (Landing et al. 1980). 5 CHF is also seen in combination with von Meyerburg complexes, Caroli’s disease and choledochal cysts (Buts et al. 1980). 6 Other associated malformations include the Lawrence–Moon–Biedl syndrome (Nakamura et al. 1990), hypoplasia of the musculus depressor anguli oris (Thapa et al. 1989), arteriovenous pulmonary fistula (Maggiore et al. 1983), pulmonary fibrosis and emphysema (Williams et al. 1964), vaginal atresia and tuberous sclerosis (Landing et al. 1980). 7 CHF has been associated with increased copper deposition, which exceeded 500 µg/g of dry liver (Evans et al. 1984). 8 Intestinal lymphangiectasia and gluten-sensitive enteropathy have been reported in two children (Abdullah et al. 1991). Pelletier et al. (1986) described a new syndrome with intestinal lymphangiectasia, secretory diarrhoea, enterocolitis cystica superficialis and CHF. 9 Cavernous transformation of the portal vein is significantly increased in CHF (Bayraktar et al. 1997). Clinical features Clinical symptomatology varies, and different forms of CHF have been described, such as the portal hypertensive CHF, the cholangitic CHF and latent forms of CHF (Murray-Lyon et al. 1978). Symptoms may manifest early in life, in childhood or in adult life and include: • Upper gastrointestinal haemorrhage from ruptured oesophageal varices (Kerr et al. 1978) secondary to portal hypertension, which is caused by presinusoidal block. Gastrointestinal bleeding has been reported as early as 19 months of age (Fiorillo et al. 1982). The course of the disease is dominated by recurrent gastrointestinal bleeding, which is well tolerated and not associated with encephalopathy Alvarez et al. 1981; Abdullah et al. 1991). • Recurrent episodes of cholangitis from associated anomalies of the IHBDs, Caroli’s disease, choledochal cyst and gallstones may lead to septicaemia. • Arterial hypertension, proteinuria and microscopic haematuria. • Failure to thrive in patients with significant renal involvement. • Renal failure may occur due to associated polycystic kidneys. On physical examination, abdominal distension is

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present due to hepatosplenomegaly. The liver is firm with a prominent left lobe. Diagnosis Ultrasonography of the liver and kidneys will provide information about the extent of renal cystic involvement and associated choledochal cysts or Caroli’s disease (described below). The liver appears hyperechoic secondary to fibrosis and ductular proliferation. Concomitant liver Doppler flow studies may detect portal hypertension. Liver function tests, including serum aminotransferases, bilirubin, cholesterol, albumin, ammonia and prothrombin time, are all normal. Serum alkaline phosphatase and GGT levels may be normal or mildly elevated, especially if there is recurrent cholangitis (Kerr et al. 1978). Thrombocytopenia, either isolated or associated with neutropenia, is seen in patients with hypersplenism. The diagnosis is made by percutaneous liver biopsy, but since a large number of portal tracts is needed, a surgical biopsy may be more helpful. Renal function abnormalities are less frequent than in ARPKD and include decreased glomerular filtration rate, reduced ability to concentrate the urine, and decreased acidification. Plasma urea and creatinine may be elevated. Upper gastrointestinal endoscopy will identify oesophageal or gastric varices and is indicated when gastrointestinal bleeding occurs. Splenoportography may demonstrate elevated portal and splenic pressures, portal thrombosis, splenic occlusion, duplication of the intrahepatic branches of the portal vein or even natural splenorenal or gastrorenal shunts (Alvarez et al. 1981). MRI and hepatic angiography are helpful for visualization of vascular anatomy. Management Management is aimed at preventing the sequelae of portal hypertension. Prompt intervention and management of acute variceal bleeding with sclerotherapy or banding via upper endoscopy is required. H2-receptor blocker therapy may be started to avoid bleeding episodes from coexisting peptic ulcer disease. Early surgical intervention with portocaval, splenorenal or meso-rex shunting should be considered, particularly in patients with recurrent bleeding despite optimal medical management and trials of variceal ablation. Careful selection of the shunt operation is required in order not to impair the feasibility of liver or renal transplantation if required in the future (Alvarez et al. 1981). Splenectomy at the time of the shunt operation may facilitate renal transplantation but is associated with an increased risk of bacterial infection and requires preoperative pneumococcal vaccination and lifelong prophylactic penicillin (McGonigle et al. 1981). Ascending cholangitis should be treated aggressively with antibiotics after the responsible organism is identified by blood culture or liver tissue culture, in order to avoid worsening liver function.

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Prognosis and outcome The prognosis depends on the extent of hepatic and renal disease. Liver disease usually does not progress in childhood, but in the past, prior to the advent of liver-kidney transplantation, some patients died of complications of portal hypertension, hypersplenism and renal failure. If required, portosystemic shunting reduces portal hypertension and is well tolerated (Kerr et al. 1978; Alvarez et al. 1981), but may now be replaced with a meso-rex shunt, if this is technically possible (deVille de Goyet et al. 1999). Unless kidney failure is present, patients can have a normal diet and lead a normal life. Recurrent uncontrolled cholangitis is an indication for liver transplantation (De Vos et al. 1988). Cholangiocarcinoma and amyloidosis may develop in adulthood. Caroli’s disease and Caroli’s syndrome Caroli’s disease was first described by Caroli (1958) as an entity characterized by segmental or saccular dilatation of the IHBDs associated with renal tubular ectasia or medullary sponge kidney and pancreatic cysts. Subsequently, a second entity was described that was seen in children and was characterized by dilatation of the larger IHBDs, periportal fibrosis, cirrhosis and portal hypertension corresponding to CHF. This second entity has been termed Caroli’s syndrome, and is more frequently encountered than Caroli’s disease. The two varieties may be autosomal recessive and are associated with renal lesions closely related to ARPKD (Welling & Grantham 1989). Pathology Caroli’s disease represents ductal plate malformation of the larger IHBDs (Desmet 1992a). In the simple variety, there is saccular dilatation of the right and left hepatic ducts with predominant involvement of the segmental ducts. Intraluminar polypoid projections and crossbridges have been seen within the saccular dilatations of the IHBDs. The ectatic ducts communicate with the rest of the biliary system and contain bile. Stagnant bile sludge contained within the dilated ducts is prone to infection and stone formation (Desmet 1992a). Percutaneous liver biopsy reveals centrilobular cholestasis and bile ductule proliferation with polymorphonuclear cell infiltration of the portal tracts. Caroli’s syndrome involves ductal plate malformation of the large intrahepatic and interlobular bile ducts, which undergo involution resulting in the formation of the typical CHF lesion (Desmet 1992a). There is associated periportal fibrosis as seen in CHF (Desmet 1992a). Macroscopically, the liver contains multiple cysts up to 1 cm in diameter, dilated IHBDs with inspissated bile and calculi, and the parenchyma is nodular. The common bile duct and right and left hepatic ducts may be dilated. Many authorities now believe that Caroli’s disease is an

unfortunate term because it describes a large spectrum of clinically different cystic diseases such as any radiographically evident communication of the biliary tree, isolated dilatation without ductal plate malformation, intrahepatic dilatation with associated choledochal cyst (types IV and V), Caroli’s disease associated with CHF and others. Additionally, a variety of renal lesions (ADPKD, ARPKD) have been associated with the two entities, which differ from the original lesion first described by Caroli (Mall et al. 1974; Jordan et al. 1989; Piccoli & Witzleben 1991). Clinical features The clinical symptoms of Caroli’s disease are repeated episodes of cholangitis, biliary cholelithiasis and hepatic abscesses leading to septicaemia (Caroli 1958). The disease presents at any age but usually manifests in young adults with fever with or without jaundice. Patients with Caroli’s syndrome display symptoms of Caroli’s disease and CHF, i.e. cholangitis and the sequelae of portal hypertension. In both entities, patients are anicteric and have firm hepatomegaly. Diagnosis Ultrasound findings include anechoic, ovoid structures with irregular margins suggesting communication between the lesions (Bass et al. 1977). Occasionally, the intrahepatic cystic dilatations may be confused with multiple hepatic abscesses but concurrent gallium-67 citrate scintigraphy may be helpful in distinguishing between the two entities. CT scanning demonstrates lowdensity branching, tubular structures which may help distinguish it from polycystic disease. CT scanning with contrast showing retention of contrast in the dilated bile ducts may further increase the sensitivity of the study. Hepatic scintigraphy utilizing derivatives of 99mTc iminodiacetic acid cannot distinguish biliary dilatation due to Caroli’s disease from dilatation due to obstruction. More invasive procedures, such as endoscopic retrograde cholangiography or percutaneous transhepatic cholangiography, may differentiate intrahepatic or extrahepatic dilatations and identify biliary stones (see Plate 32, Atlas: p. 450). The diagnosis may be confirmed by histology (Hermansen et al. 1979; Moreno et al. 1984). Serum aminotransferases, alkaline phosphatase and serum bilirubin levels are usually normal, unless the patient has active cholangitis. Management and prognosis Management includes antibiotics either for prophylaxis or treatment of cholangitis. The role of surgery is limited unless there is mechanical obstruction due to biliary calculi, and may cause worsening of cholangitis. The long-term prognosis of the disease depends on the severity of the renal lesions and the degree of periportal fibrosis and hepatic dysfunction. Cholangiocarcinoma and amyloidosis are long-term sequelae of the disease.

Chapter 9: Abnormalities of the Liver Polycystic liver disease Polycystic liver disease (PCLD) has recently been described as a separate entity genetically distinct from ADPKD and Caroli’s disease (Berrebi et al. 1982; Simon et al. 1993; Pirson et al. 1996). It includes the development of multiple cysts in the liver and kidney and rarely in other organs. Recent reports suggest that the disease may be inherited in an autosomal dominant pattern without renal cysts. In a medicolegal autopsy series the incidence of isolated hepatic disease was 0.05%, and the von Meyerburg’s complex was microscopically present in all cases of PCLD (Karhunen & Tenhu 1986). More family studies are needed to confirm whether this disease is truly a separate entity or a variation in the expression of ADPKD. Recently, a genetic locus for isolated PCLD without renal cysts was mapped to chromosome 19p13.2-13.1 (Reynolds et al. 2000). Clinical features and diagnosis The main clinical symptoms are related to renal disease. Hepatic involvement is associated with abdominal discomfort secondary to hepatomegaly. Portal hypertension is a rare complication. The diagnosis is suggested by ultrasound or CT scanning and may be confirmed by histology or family history. Management Management includes renal support and/or transplantation or control of portal hypertension. Occasionally large cysts require aspiration or drainage into the peritoneal cavity. Traumatic cysts Traumatic cysts are thought to occur after intrahepatic haemorrhage from abdominal trauma. The blood is resorbed and bile fills the space, creating a cyst. They are asymptomatic but may occasionally present with anorexia or abdominal pain from distension or rupture of the cyst. Rarely, they may become infected (Piccoli & Witzleben 1991). Treatment includes antibiotics, and aspiration or drainage of the cysts if symptoms are severe. Cysts secondary to infarction These cysts occur after focal vascular insufficiency of the liver and have been observed in liver transplant recipients following occlusion of the hepatic artery. They are lined by endothelium and contain bile. They are asymptomatic but may occasionally become infected. They are usually discovered incidentally on CT (Piccoli & Witzleben 1991), or ultrasound, as shown in Plate 31, Atlas: p. 451.

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Differential diagnosis of fibropolycystic disease of the liver An algorithm for the evaluation of a child with fibropolycystic disease detected by ultrasound of the liver is shown in Fig. 9.3. In order to distinguish between the different forms of fibropolycystic disease in a child with hepatomegaly, a thorough medical history must be taken. Patients with a positive family history of cystic diseases, especially among first-degree relatives, are particularly at risk for having polycystic disease. History of previous fever, chills, jaundice, haematemesis, melaena, haematuria and abdominal pain or trauma should be sought. On physical examination, the liver and kidneys should be carefully palpated. Typically, hepatomegaly is obvious. When present, splenomegaly and prominent superficial abdominal veins suggest portal hypertension, which is the presenting sign of CHF in childhood. Bilateral abdominal masses represent markedly enlarged kidneys, which are easier to palpate in neonates and infants with ARPKD. Flank tenderness secondary to pyelonephritis may be present in patients with significant renal involvement. If there is significant renal involvement, then either ADPKD or ARPKD are likely. The blood pressure may be at or above the 95th percentile for age. More subtle signs of renal tubular disease, particularly loss of concentrating ability, microscopic haematuria and proteinuria, may be detected by urinalysis. If portal hypertension is prominent, then CHF is likely. Laboratory tests including serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, GGT, prothrombin time, albumin, conjugated and unconjugated bilirubin are normal as the liver parenchyma is intact. Thrombocytopenia or leukopenia suggests hypersplenism. Elevated liver enzymes suggest cholangitis or another liver disease. Occasionally, there is cholestasis with mild elevations in GGT if there is sludge formation from stagnant bile in Caroli’s disease and choledochal cyst. The erythrocyte sedimentation rate (ESR) is elevated in cholangitis, which may occur with the cholangitic type of CHF, Caroli’s disease and Caroli’s syndrome. Ultrasound of the abdomen is helpful in differentiating between the different forms of polycystic disease (see above). • A single hepatic cyst may be solitary, traumatic, neoplastic or secondary to infarction. • Multiple cysts affecting liver, kidneys, pancreas, ovaries and other organs suggest ADPKD. • Cysts confined to the liver may represent PCLD or perhaps variable expression of ADPKD, and these patients should be followed up over time. • Patients with combined hepatic and renal cysts may have either ARPKD or CHF. If renal failure is prominent

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Section 5: Liver Disease in Older Children Liver ultrasound

Vascular anomalies (see Fig. 9.4)

Fibropolycystic disease

Solitary lesion Multiple cysts

History of trauma Liver and renal cysts Cysts in other organs Yes

Liver cysts only

No

ADPKD Traumatic cyst

Liver and renal cysts Renal disease

Infarct

Neoplasma

Renal failure

Simple cyst Delayed or absent

Portal hypertension

Yes

CHF

CT/MRI

Caroli's syndrome

Caroli's disease

within the first days or months of life, ARPKD is likely, although CHF is also associated with a variety of renal disorders, which may mimic ARPKD. The presence of portal hypertension suggests CHF. Percutaneous renal biopsy will help distinguish between ADPKD, ARPKD or other lesions associated with the polycystic diseases. Management issues Transjugular intrahepatic portosystemic stent shunts TIPSS is a percutaneously created shunt through the liver parenchyma connecting an intrahepatic branch of the portal vein to a main hepatic vein (Richter et al. 1990; Zemel et al. 1991). TIPSS was designed to decompress the

Early

Immediate

Neonatal or infantile ARPKD

Perinatal ARPKD

No

Liver biopsy

Fig. 9.3 Algorithm for diagnosis of fibrocystic diseases of the liver.

Isolated PLD

portal circulation in patients with portal hypertension and is similar to a surgical side-to-side portalcaval shunt but avoids the need for general anaesthesia and laparostomy. It has been used increasingly to treat complications of portal hypertension such as variceal bleeding, refractory ascites, hepatic hydrothorax, and hepatorenal syndrome (Jalan et al. 2000; Ong et al. 2000). TIPSS is also an effective method for shunting in Budd–Chiari syndrome (Blum et al. 1995; Perello et al. 2002) and veno-occlusive disease (Fried et al. 1996; Smith et al. 1996). This procedure has been successfully used in the paediatric population (Johnson et al. 1996; Heyman et al. 1997; Hackworth et al. 1998; Kimura et al. 2000; Benador et al. 2001). TIPSS have been successfully placed in the setting of polycystic liver disease (Spillane et al. 1997; Bahramipour et al. 2000; Shin & Darcy 2001) and ARPKD prior to renal transplantation (Benador et al. 2001). Although multiple prospective randomized clinical trials show that TIPSS is significantly more effective in re-

Chapter 9: Abnormalities of the Liver ducing variceal rebleeding from portal hypertension of diverse aetiology in adults compared with endoscopic sclerotherapy or band ligation (Ong et al. 2000), survival rates are comparable. Since TIPSS may be complicated by shunt stenosis or occlusion rates up to 87% in the first year (Ong et al. 2000), it is unlikely that this procedure will be useful in the long-term management of a child with portal hypertension secondary to ARPKD and/or CHF, but may act as a bridge to transplantation. Indications for liver transplantation In most patients with fibropolycystic disease of the liver, hepatic function remains normal but portal hypertension is a major problem. The indications for liver transplantation are related to the development of hepatic dysfunction, which may develop secondary to recurrent cholangitis, extensive biliary disease, increasing hepatic fibrosis, or gross abdominal distension with respiratory embarrassment. Combined liver and kidney transplantation may be required for both renal and hepatic dysfunction. Future research 1 The function of polycystin-1 and -2 and their interaction with various signalling molecules are still unclear. Studies toward the effects of various cytokines and growth factors on cyst proliferation would significantly advance our understanding of ADPKD. 2 Transforming growth factor (TGF)-a was overexpressed in transgenic mice with ADPKD (Lowden et al. 1994). An increased activity of the epidermal growth factor receptor (EGFR) in the affected kidneys has been consistently observed. Interestingly, a mutant EGFR with decreased tyrosine kinase activity in a murine model of ARPKD is correlated with an improvement in kidney function and a substantial decrease in cyst formation in the collecting ducts (Richards et al. 1998). Therefore, approaches to target TGF-a, tyrosine kinase (Sweeney et al. 1999) and EGFR would have the potential to decrease cyst formation. Other promising signal transduction modulators include ErbB TK inhibitors, Ras inhibitors and PKA type 1 inhibitors (Qian et al. 2001). 3 Since somatic mutations are important for cyst development, it is conceivable that any treatment capable of reducing the rate of somatic mutations would slow down the progression of ADPKD. Those may include antimutagents (inhibitors of phase 1 enzymes or inducers of phase 2 enzymes) and antioxidants. 4 Long-term goal would be gene therapy to express the respective wildtype polycystin protein or replace the mutated gene with the normal PKD gene.

Hepatic vascular anomalies The great majority of vascular anomalies of the liver in in-

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fancy and childhood are haemangiomas (Ehren 1983; Boon et al. 1996; Burrows et al. 2001; Kassarjian et al. 2002). The utility of histology will be reviewed in detail. Classification Vascular anomalies may be classified clinically by symptoms (Table 9.2). Although cystic mesenchymal hamartomas are usually avascular at angiography (Stocker & Ishak 1990), they are included in the list of vascular anomalies because they may contain areas of vascular connective tissue. Focal nodular hyperplasia is a disorder in which a benign single or multifocal lesion of the liver occurs which is characterized by a firm, irregular mass with a central scar supplied by single or multiple large ‘feeder arteries’ (Stocker & Ishak 1981). Symptomatic haemangiomas of the liver in childhood fall into two types: infantile haemangioendotheliomas, seen principally in the first year of life (Dehner 1978) and which tend to be solid; and cavernous haemangiomas, which tend to be cystic. Both forms may be found in the same lesion. By convention, cystic haemangiomas greater than 4 cm in diameter have been referred to as ‘giant cavernous haemangiomas’. Very little is known about the pathogenesis of hepatic haemangiomas, although one family in which several members developed giant cavernous hepatic haemangiomas exhibited selective inhibition of natural killer cell activity (Tomiyama et al. 1989).

Table 9.2 Classification of vascular malformations of the liver Asymptomatic Incidental Solitary haemangioma Multiple haemangiomas Hepatomegaly Cystic mesenchymal hamartoma Extramedullary haematopoiesis Focal nodular hyperplasia Symptomatic Congestive heart failure/hepatomegaly Infantile haemangioendothelioma Giant cavernous haemangioma Arteriovenous malformation Arterioportal fistula Portovenous fistula Other extrahepatic conditions Syndromes Klippel–Trenaunay–Weber Rendu–Osler–Weber Miscellaneous Systemic cystic angiomatosis Angiosarcoma Bacillary angiomatosis Peliosis hepatis

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Section 5: Liver Disease in Older Children

Kassarjian et al. (2002) proposed a classification system for hepatic haemangioma based on angiographic findings and classified lesions into five types. Type 1 lesions were the classic haemangiomas with early filling of abnormal vascular channels and with stagnation and pooling of contrast material. They did not have any early filling of hepatic veins or an arteriovenous or portovenous shunt. Type 2 lesions contained focal high-flow nodules with early filling of veins and with no visible direct shunts. Type 3 lesions contained angiographically visible direct arteriovenous (including arterioportal) shunts, whereas type 4 lesions contained direct portovenous shunts. Type 5 lesions contained both direct arteriovenous and portovenous shunts. Clinical features The most common vascular anomalies in childhood are haemangiomas or haemangioendotheliomas (see Plate 34, Atlas: p. 451). In a series of 43 children with hepatic vascular anomalies in infancy, 90% were haemangiomas and 10% were arteriovenous malformations (Boon et al. 1996). 1 Haemangioma: Almost all patients with hepatic haemangioma present before 6 months of age and most present within the first 2 months (Iyer et al. 1996; Keslar et al. 1993; Boon et al. 1996). Solitary or multiple haemangiomas are asymptomatic and may be an incidental finding. Alternatively, these benign tumours may present with asymptomatic hepatomegaly, which may be associated with a systolic bruit. Cutaneous haemangiomas are common, and pulmonary and cerebral haemangiomas occur in 10%. From 20% to 40% of patients present with symptoms due to the mass effect (abdominal distension, vomiting), or with congestive heart failure, which is sometimes complicated by consumption coagulopathy (Kasabach–Merritt syndrome; Kasabach & Merritt 1940), microangiopathic haemolytic anaemia, and obstructive jaundice. Rarely, hepatic haemangiomas can present as hydrops fetalis. Hepatic haemangioma can be focal or multifocal and about 80% of infants with multiple hepatic haemangiomas have the classic triad of hepatomegaly, congestive heart failure and anaemia (Boon et al. 1996). 2 The Klippel–Trenaunay–Weber syndrome is a nonhereditary congenital condition characterized by hemihypertrophy, capillary malformations, and venous stasis with or without arteriovenous malformations (Alpay et al. 1996). Hepatic haemangiomas and focal nodular hyperplasia presumably secondary to an abnormal hepatic vascular supply have been associated with this syndrome (Haber et al. 1995). 3 Osler–Weber–Rendu disease, or hereditary haemorrhagic telangiectasia, is an autosomal dominant condition in which the vascular lesions can involve the liver in addition to the gut and the skin (Vase & Grove 1986).

4 Systemic cystic angiomatosis is a congenital vascular malformation involving multiple organ systems, particularly the liver, spleen, kidney and colon (Bardequez et al. 1990). The clinical presentation is determined by the organ(s) involved. 5 Hepatic angiosarcomas are rare, highly vascular malignant tumours in children (Alt et al. 1985) sometimes associated with cutaneous haemangiomas, exposure to arsenicals or neurofibromatosis (Lederman et al. 1987). 6 Bacillary angiomatosis (BA) is caused by a rickettsial organism, Rochalimaea henselae. The patient may present with chills, headaches, fever and malaise, and typical cutaneous lesions appear as bright-red round papules or nodules. The lesion affects spleen, lymph nodes and bone as well as liver (Ramirez et al. 1995). Given the dramatic clinical presentation, differentiation of the hepatic BA lesion from other vascular malformations is not difficult. 7 Peliosis hepatis is a rare lesion characterized by bloodfilled cavities, which are scattered throughout the liver. Medications such as androgen-anabolic steroids, oestrogens, oral contraceptives and azathioprine have been implicated (Herrera 1981). 8 Arteriovenous malformations (AVMs) are much less common than haemangiomas. In the neonatal period, AVMs usually present as congestive heart failure. Later in childhood, most hepatic AVMs are seen in patients with hereditary haemorrhagic telangiectasia and result in congestive heart failure, hepatic ischaemia and portal hypertension (Burrows et al. 2001). 9 Arterioportal fistula usually occurs as an isolated congenital anomaly and can be seen in patients with hereditary haemorrhagic telangiectasia, Ehlers–Danlos syndrome, trauma, and iatrogenic procedures such as liver biopsy (Vauthey et al. 1997). The main symptoms at presentation are symptoms of portal hypertension with associated ascites, malabsorption, gastrointestinal bleeding, and abdominal pain. A small percentage of patients presents with high-output congestive heart failure (Vauthey et al. 1997; Burrows et al. 2001). 10 Intrahepatic portovenous fistulae (PVF) are very rare and usually seen in infants with hepatic haemangioma, though isolated cases are reported (Paley et al. 1997; Kim et al. 2000b). We encountered a 1-week-old baby with intrahepatic PVF presented with cholestasis, coagulopathy, thrombocytopenia and initial a-fetoprotein (AFP) level of 66 471 ng/ml, which increased to 267 447 ng/ml at 2 weeks of age. Interestingly, the PVF spontaneously disappeared on the follow-up imaging study at 2 months of age. AFP decreased significantly but remained high at 42 250 ng/ml at 3 months of age. Diagnosis Adiagnostic algorithm for vascular anomalies of the liver is shown in Fig. 9.4. Vascular abnormalities of the liver are

Chapter 9: Abnormalities of the Liver

175

Liver ultrasound

Vascular anomalies

Fibropolycystic disease (see Fig. 9.3)

Cutaneous haemangiomas Yes No Family history Doppler ultrasound

More hyperechoic areas

No

Yes

MRI Heterogeneous lesion with mix of hypo- and iso-echioc and hyperreflective areas; high-flow vessels

Suspicion of malignancy

Yes MRI

Haemangioma

AVM

AVF

No

Liver biopsy Fine needle aspiration

PVF

Fever

Yes Focal nodular hyperplasia

Malignant vascular neoplasm

Benign vascular neoplasm

Fig. 9.4 Diagnostic algorithm for vascular anomalies of the liver. AVM, Arteriovenous malformation; APF, arterioportal fistula; PVF, portovenous fistula.

usually discovered in an infant or child when hepatomegaly and/or right upper quadrant pain lead to the performance of an ultrasound scan. Ultrasound of a haemangioma typically detects a heterogeneous septated space-occupying lesion with a mixture of hypoechoic, isoechoic, and hyper-reflective areas (Samad et al. 1995). The diagnosis of fetal hepatic haemangioma may be made by prenatal sonography (Sepulveda et al. 1993). It is important to differentiate neuroblastomas, which tend to be more hyperechoic, from haemangiomas in the neonatal period. Cavernous haemangiomas may be differentiated from malignant neoplasms ultrasonographically because the haemangiomas usually exhibit signs of increased blood flow, such as enlarged upper abdominal aorta, coeliac, and hepatic arteries and veins, combined with a smaller aorta inferiorly (Plate 34, Atlas: p. 450). Differentiation of a cavernous haemangioma from a malignant neoplasm can be difficult, and referral to a specialized unit is recommended.

Osler–Weber –Rendu

Hemihypertrophy

Bacillary angiomatosis

Yes

Klippel–Trenaunay –Weber

No

Systemic cystic angiomatosis

Colour Doppler techniques demonstrate a variety of flow patterns, which may overlap with patterns described for malignant tumours (Paltiel et al. 1992), but only haemangiomas or arteriovenous malformations exhibit blood velocities faster than the aorta (Paltiel et al. 1992). This technique may also demonstrate lowresistance flow in the hepatic artery, or reverse flow in the distal aorta characteristic of a ‘steal’ to the low-resistance bed of the haemangioma during the diastolic phase. The combination of colour Doppler ultrasound and the contrast agent Levovist may be useful in difficult cases as there is no signal enhancement in the centre of the haemangioma (Ernst et al. 1996). Further confirmation may be obtained with contrast CT, in which the characteristic finding is initial peripheral and septal enhancement of contrast with delayed partial centripetal filling. However, this appearance has also been seen with cystic mesenchymal hamartoma (Kaufman 1992). MRI is the most useful single modality in the diagnosis of hepatic haemangiomas (Brown et al. 1987; Burrows et al. 2001). MRI can show the extent of hepatic haemangioma as well as its characteristics and structure. It has a sensitivity of 90% and specificity of 92% for the diagnosis of haemangiomas, and the technique has been useful in evaluation of premature newborns (Rodriguez-Balderrama et al.

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Section 5: Liver Disease in Older Children

1993). Intravenous gadolinium and gradient-recalled echo sequence are extremely helpful, especially in the focal lesions, to distinguish haemangioma from malignant tumours or AVMs (Boon et al. 1996; Burrows et al. 2001). Hepatic angiography is generally reserved for patients with congestive heart failure, for whom therapeutic embolization is considered (Mahboubi et al. 1987; Keslar et al. 1993; Burrows et al. 2001) (Chapter 3). It helps to classify the lesion based on the variable angioarchitecture of the hepatic haemangioma and can demonstrate any direct arteriovenous, arterioportal and portovenous shunts within the haemangioma (Kassarjian et al. 2002). Laboratory findings in children with haemangioma include anaemia, increased aminotransferase levels, and hyperbilirubinaemia (Keslar et al. 1993; Boon et al. 1996). Although high serum AFP levels up to 35 000 ng/ml have been reported (Mhanni et al. 2000; Zenge et al. 2002), AFP level is not usually elevated and may differentiate malignant vascular lesions from benign lesions. Many angiogenesis-related markers, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in body fluids (particularly blood and urine) are of prognostic significance (Takahashi et al. 1994; Qin & Tang 2002). Hypothyroidism may be associated with infantile hepatic haemangiomas, perhaps because bFGF or other growth factors induce type 3 iodothyronine deiodinase expression in haemangiomas. It requires very high doses of levothyroxine treatment to reduce serum thyrotropine concentrations to normal (Huang et al. 2000). Therefore, thyroid function should be assessed in children with large haemangiomas. If diagnosis is not possible by non-invasive techniques, CT or ultrasound-guided percutaneous liver biopsy can be used to establish the diagnosis, although there is a high risk of haemorrhage (Pereyra et al. 1982; Tung & Cronan 1993). Reports in adults suggest that fine needle aspiration under ultrasound guidance can be performed with minimal risk to the patient (Kaw & Esparza 1991), with bleeding in only one patient out of 36 undergoing the procedure (Taavitsainen et al. 1990). No large series of infants or children undergoing percutaneous liver biopsy or fine needle aspiration to establish the diagnosis of cavernous haemangioma of the liver has been reported to date. If this type of technique is contemplated, it should be performed only in a clinical setting of optimum safety, including backup by paediatric surgeons and a paediatric intensive care unit and with appropriate blood products (fresh frozen plasma, platelets, and packed red blood cells) available in case of haemorrhage. Pathology Angiomas may be differentiated from other liver neoplasms by immunohistochemistry using stains for factor

VIII and basement membrane protein, which are negative in tumours such as fibrosarcomas (Saeger 1990). Cytokeratin 7 is typical of the mature biliary tract, and cytokeratin 19 is typical of embryonic and fetal hepatocytes. Haemangiomas typically are positive for cytokeratin 7 whereas hepatoblastomas exhibit cytokeratin 19 (Pontisso et al. 1993). Ultrastructural analysis of haemangiomas reveals capillaries and stromal cells, including typical smooth muscle cells, modified smooth muscle cells, and fibroblast-like cells. This finding suggests that the cavernous haemangioma of the liver may be of a hamartomatous nature (Kojimahara 1986). Management and outcome Therapy is determined by the severity of symptoms and the size of the tumour. Most lesions continue to grow over the first year of life, and then spontaneously regress (Zenge et al. 2002). Complications such as congestive heart failure, arteriovenous shunting and coagulopathy often dictate earlier therapeutic intervention. Asymptomatic haemangiomas and giant cavernous haemangiomas require no treatment except careful observation for the known complications. Indications for treatment include: rapid enlargement of the tumour with respiratory embarrassment, cardiac failure or abdominal pain; large solitary tumours which may rupture — particularly giant cavernous haemangioma, which may lead to spontaneous haemoperitoneum (Scribano et al. 1996) — and progressive portal hypertension from arterioportal venous shunting (Shimada et al. 1994). Systemic or intralesional corticosteroids may encourage resolution in symptomatic haemangiomas (Lemarchand-Venencie 1992), particularly prior to surgery. In the past, interferon (IFN)-a was tried with some success (Ezekowitz et al. 1992). However, spastic diplegia has been reported as a severe complication of IFN-a treatment of haemangiomas in infancy (Barlow et al. 1998; Worle et al. 1999). Vincristine was also reported as an effective treatment of corticoid-resistant life-threatening infantile haemangiomas (Perez et al. 2002). Radiotherapy is controversial and probably ineffective. Hepatic artery embolization may be effective (Pereyra et al. 1982), particularly to stabilize patients prior to elective hepatic resection or as an alternative to hepatic artery ligation (Yamamoto et al. 1991). Surgical ligation of the hepatic artery may not provide sufficient control of cardiac failure as portohepatic shunts (between the portal and hepatic veins) as well as arteriovenous shunts (between the hepatic artery and hepatic veins) can occur (Burrows et al. 2001; Kassarjian et al. 2002) and embolization may be needed (Chapter 3). Solitary symptomatic haemangiomata should be removed surgically, while surgical management of cavernous haemangiomas should be reserved for pro-

Chapter 9: Abnormalities of the Liver gressive tumour enlargement and subcapsular bleeding. Congestive heart failure should be managed in the conventional way. In a series of 16 infants and children with hepatic haemangiomas, high-output cardiac failure was present in 58% of newborns, and seven haemangiomas were resected; the outcome was excellent (Luks et al. 1991). Successful liver transplantation for giant cavernous haemangioma complicated by consumption coagulopathy (Kasabach–Merritt syndrome) has been reported (Mora et al. 1995). Although Subramanyan et al. recently (2001) reported a successful transcatheter coil occlusion of hepatic arteriovenous malformation in a neonate, embolization is not usually a good option for AVMs because of their diffuse nature and the risk of causing further hepatic ischaemia and necrosis (Burrows et al. 2001) and liver transplantation may be required. Intrahepatic PVF may involute spontaneously before 1 year of age (Ono et al. 1998) or be cured by embolization (Vauthey et al. 1997). Promising lines of research 1 The natural history and effectiveness of treatment options for vascular anomalies are unclear. Due to the rarity of these lesions, multicentre co-operative studies are needed to clarify the role of corticosteroids and IFN-a for haemangiomas, cyclophosphamide, endovascular embolization, and surgical resection. 2 Accurate diagnosis of vascular anomalies is essential for any new treatment protocol. The angiographic classification by Kassarjian et al. 2002) provides the best angioarchitecture description for haemangioma, but is invasive and not practical for all patients. Non-invasive vascular imaging techniques such as MRI with intravenous gadolinium should be applied to the classification system.

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Chapter 10: Non-Alcoholic Steatosis EVE A. ROBERTS

Introduction, 183 NAFLD in adults, 183 Pathogenesis of NAFLD, 184 Hyperinsulinaemia, 184 Leptin, 185

Genetic factors, 185 Childhood obesity, 185 Epidemiology of NASH/NAFLD in children, 186 Clinical features, 187

Introduction Steatosis, the accumulation of fat in hepatocytes, is a feature of many liver diseases. Steatosis is categorized as ‘large-droplet’ (macrovesicular) when one or a few fat droplets nearly fill the hepatocyte or a ‘small-droplet’ (microvesicular) when numerous tiny droplets are found, giving the hepatocyte a somewhat foamy appearance. Inflammation may also be present. In adults, alcoholic liver disease is a common cause of steatosis, but although alcoholic liver disease may occur in adolescents it is rare in younger children. In children the causes of steatosis include certain drugs, such as methotrexate, inherited metabolic disorders, and liver disease associated with obesity and/or disordered action of insulin, known as non-alcoholic fatty liver disease (NAFLD), which is the major focus of this chapter. Microvesicular steatosis, associated with mitochondrial dysfunction, is discussed in detail in Chapters 5 and 12.

NAFLD in adults Childhood NAFLD needs to be considered in the context of the disease in adults. In the late 1970s chronic liver disease associated with obesity (with or without hyperlipidaemia and with or without non-insulin-dependent diabetes mellitus) was described as a new and separate disease entity (Adler & Schaffner 1979; Ludwig et al. 1980). This condition was originally called ‘non-alcoholic steatohepatitis’ (NASH) because it resembled alcoholic hepatitis histologically but was not due to ethanol abuse. Recently, the more inclusive term ‘non-alcoholic fatty liver disease’ (NAFLD) has been favoured because it includes the entire spectrum: simple hepatic steatosis without inflammation, NASH, and the resulting cirrhosis in which steatosis may no longer be prominent. NAFLD is highly prevalent in adult populations (Lee 1989; Wanless & Lentz 1990). NAFLD occurs in both men and women,

Diagnostic approach, 188 Treatment, 189 Outcome, 191 Conclusion, 191

and although most adult patients with NAFLD are obese (body mass index > 30), and many have type 2 diabetes mellitus, not all affected patients are obese (Bacon et al. 1994). They may be asymptomatic or have only nonspecific constitutional symptoms. The serum aminotransferases are modestly elevated, but serum bilirubin is normal or near-normal and biochemical features of cholestasis are not present. Findings suggestive of an autoimmune process may be present, such as increased serum IgG and detectable nonspecific tissue autoantibodies. Hyperlipidaemia is usually due to hypertriglyceridaemia. Hepatic histology is required for defining the NAFLD lesion rigorously (Brunt 2001). In adults there is a broad spectrum of findings: macrovesicular or rarely microvesicular steatosis without or with active inflammation; mild to moderate fibrosis or cirrhosis. If there is no inflammation, then this is considered to be simple steatosis, as by definition NASH involves inflammation and/or fibrosis (see Plate 35, Atlas: p. 452). Signs of inflammation include ballooning degeneration of hepatocytes or focal hepatocyte drop-out. With mild NASH, macrophages may be the only inflammatory cell present, but in more active lesions neutrophils are usually found, typically adjacent to degenerating hepatocytes. Mallory’s hyaline may be found in hepatocytes. If it is not present, histological staining for ubiquitin may reveal this feature (Banner et al. 2000). Inflammation and fibrosis are typically most severe in the perivenular zone. In adults, these histological findings can be associated with other disease processes, notably chronic hepatitis C, Wilson’s disease and medications/herbs causing a ‘pseudo-alcoholic hepatitis’ lesion. Only a shaky consensus currently exists as to how much alcohol can be consumed by an individual before the hepatic steatosis should be attributed to alcohol excess rather than to NAFLD. Until recently NAFLD in adults has been regarded as a trivial disorder. Its increasing prevalence and the accu-

183

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mulating evidence for severe outcomes have reversed this assessment. Most adults with pure steatosis do not have progressive liver disease (Teli et al. 1995) and weight reduction generally leads to improvement in serum aminotransferases (Palmer & Schaffner 1990). However, at least 8–17% of adults with steatosis with inflammation and fibrosis ultimately develop cirrhosis (Lee 1989; Powell et al. 1990; Wanless & Lentz 1990; Willner et al. 2001). In one study of adults with an average follow-up of 6.5 years, Kaplan–Meier analysis showed that the 5-year probability of survival in NAFLD was 67% and the 10-year survival was 59% (Propst et al. 1995). Some adult patients with NAFLD eventually require liver transplantation, and fatty liver disease may reoccur after liver transplant (Molloy et al. 1997; Charlton et al. 2001; Contos et al. 2001; Ong et al. 2001). It appears that hepatocellular carcinoma can complicate NAFLD in adults (Zen et al. 2001; Ratziu et al. 2002; Shimada et al. 2002).

Pathogenesis of NAFLD Hyperinsulinaemia The pathogenesis of NAFLD remains unknown (Fig. 10.1). Hyperinsulinaemia, in association with insulin resistance, is accepted as an essential component of the disease mechanism (Marchesini et al. 1999; Tankurt et al. 1999; Paradis et al. 2001; Sanyal et al. 2001; Willner et al. 2001; Chitturi et al. 2002; Pagano et al. 2002). In many patients, NAFLD appears to be a part of the metabolic syndrome currently known as ‘syndrome X’ (Cortez-Pinto et al. 1999; Luyckx et al. 2000). Differences between insulin resistance in the liver and peripheral tissues may account for some of the features of NAFLD. The greater insulin resistance in muscles and adipose tissue compared with liver leads to mobilization of free fatty acids, and hepatocellular deposition of free fatty acids. Increased plasma free fatty acids and/or increased free fatty acid concentrations in hepatocytes probably also play an important role in the development of steatosis and inflammation (Wanless & Lentz 1990; de Almeida et al. 2002). Free fatty acids are highly destructive in tissues and cause damage to intracellular membranes through lipid peroxidation and injury to mitochondria resulting in decreased b-oxidation of hepatic free fatty acids. Insulin inhibits oxidation of free fatty acids, and thus hyperinsulinaemia may enhance free fatty acid hepatotoxicity. Recent findings implicate SREBP-1c (sterol response element binding protein-1c), which regulates hepatocellular glucose, triglyceride synthesis and fat metabolism, as a key player in the intracellular mechanisms leading to hepatocyte damage (Foufelle & Ferre 2002; Horton et al. 2002). Upregulation of SREBP-1c due to hyperinsulinaemia probably accounts for increased hepatocellular production of triglycerides and very low-density lipoproteins, and thus

HYPERINSULINAEMIA Disorders of hepatocellular insulin signalling pathway Role of SREBP-1c Hepatocellular processes Direct toxicity of free fatty acids Mitochondrial dysfunction (Toxifying) cytochromes P450 Peroxisomal processes Exposure to cytokines Inadequate cytoprotective mechanisms

Uncoupling protein-2 PPAR-g TNF-a

Genetic factors MTP, PPAR-a, MnSOD polymorphisms PI MZ, other a1-antitrypsin variants Abnormal Fe handling (~HFE) Genes abnormal in lipodystrophies, Alstrom and similar syndromes

Fig. 10.1 Elements in the pathogenesis. Non-alcoholic fatty liver disease (NAFLD) is typical of a polygenic disorder with a complex interaction between environment (increased carbohydrate and fat intake, increased sedentary activity) and host, including genetic factors. Contributors to the pathogenesis of NAFLD may differ from patient to patient. Details of this disease mechanism remain obscure at the current time.

the hypertriglyceridaemia, which is characteristic of NAFLD. Current concepts about the pathogenesis of NASH suggest that a second factor is needed to account for the inflammation and fibrosis (Day & James 1998; Chitturi & Farrell 2001). Candidate factors include mitochondrial dysfunction, functional changes due to cytokines such as tumour necrosis factor (TNF)-a, increased toxification (for example, through hepatocellular cytochromes P450) or decreased cytoprotection in hepatocytes. Ongoing low-grade inflammation has been documented in obese adults, mainly with C-reactive protein and serum fibrinogen as sensitive markers for systemic inflammation (Visser et al. 1999; Festa et al. 2001; Pannacciulli et al. 2001); similar findings have been reported in obese children (Visser et al. 2001). Mitochondrial dysfunction may be important in the more severe forms of NAFLD since mitochondria play an important role in fat metabolism and are also an important source of reactive oxygen species in hepatocytes (Pessayre et al. 2001, 2002). Low serum levels of antioxidants such as vitamin E have been found in obese children (Decsi et al. 1997; Strauss 1999). It is likely that similar mechanisms operate in children with NAFLD, but there are few studies documenting this. As in adults, hyperinsulinaemia has an important role in the aetiology (Cruz & Hud 1992; Brockow et al. 1995; Stuart et al. 1998; Hermanns-Le et al. 2002). Acanthosis nigricans (darkening of the skin) has been reported in several clinical series of childhood NAFLD (Rashid &

Chapter 10: Non-Alcoholic Steatosis

185

Roberts 2000). The darkening of the skin is usually at the nape of the neck, in the axillae, groin and sometimes in other flexural areas. Often subtle, it is generally easier to identify in children with increased skin pigmentation. It is due to hyperplasia of pigmented skin cells bearing receptors for insulin and insulin-like growth factors (Torley & Munro 2002). In an unselected cohort of adolescents aged 12–15 years 128 (19%) had acanthosis nigricans; of these 39% had hyperinsulinaemia and 49% were obese. Multiple linear regression revealed that only acanthosis nigricans, obesity and physical activity were statistically significant predictors of hyperinsulinaemia. Children with acanthosis nigricans and obesity early in life may have the earliest clinical features of the metabolic syndrome X (Kerem et al. 2001). Acanthosis nigricans is also a feature of several of the paediatric metabolic/genetic diseases in which there is a quantitative or functional abnormality of insulin receptors (Kahn et al. 1976; Yanovski & Arioglu 2001). Many of these disorders such as Alström syndrome, Bardet–Biedl syndrome, and polycystic ovary syndrome are associated with NAFLD (Boor et al. 1993), while acanthosis nigricans was present in 92% of children with type 2 diabetes mellitus (Zuhri-Yafi et al. 2002).

hydroxysteroid dehydrogenase 1, which converts cortisone to cortisol, may be important in metabolic syndrome X (Masuzaki et al. 2001), while the genes responsible for the lipodystrophy syndromes and other metabolic diseases with insulin receptor abnormalities may also be involved. Apolipoprotein E, which is polymorphic and functions as a modifier protein for other hepatic disorders, may function as a modifier gene in NAFLD (Mensenkamp et al. 2000). Preliminary data implicate a low-activity promoter polymorphism in the MTP gene (Bernard et al. 2000), PPARA*3 encoding PPAR-a, and the mitochondrial manganese superoxide dismutase (MnSOD). Genetic variability in the immune response may also be important: a polymorphism in the promoter region of the TNF-a gene has been identified associated with NAFLD, but its mechanistic role requires further clarification (Grove et al. 1997; Valenti et al. 2002). Underlying metabolic abnormalities may act as disease modifiers. For instance, heterozygosity for HFE, the gene abnormal in hereditary haemochromatosis, is associated with more extensive hepatic fibrosis (George et al. 1998). Partial deficiency of a1-antitrypsin is prevalent among patients with NAFLD but its pathogenic role is unclear (Czaja 1998).

Leptin

Childhood obesity

Leptin, which is a satiety factor synthesized in white adipose tissue, binds to hypothalamic receptors to reduce appetite and increase energy expenditure. It has recently been implicated in the pathogenesis of NASH (Chitturi & Farrell 2001). Genetically obese, diabetic mice (ob/ob mice) have a mutation that prevents the synthesis of leptin and thus they overeat, becoming obese. They also have insulin resistance, hyperlipidaemia and fatty livers (Pelleymounter et al. 1995). Leptin levels are also low in lipoatrophic diabetic mice, which have insulin resistance and fatty livers due to over-expression of SREBP-1 (Shimano et al. 1996). Treatment with leptin reduces both insulin resistance and the fatty livers in these mice (Shimomura et al. 1998). Although leptin levels are low in humans with lipodystrophy syndromes, they are high in obese humans, suggesting resistance or dysfunctional receptors (Chitturi & Farrell 2001). Leptin resistance has also been identified as a feature of syndrome X (Kennedy et al. 1997). Thus treatment of childhood NASH with leptin is unlikely to be of benefit in most individuals.

Childhood obesity has become a major public health problem (Strauss & Pollack 2001). Current estimates of the prevalence of overweight and obesity in children depend on the definitions used. Definitions may use absolute weight, percent of ideal weight-for-height or ageand gender-normative data for body mass index (BMI), in which it is accepted that a BMI of > 25 is considered overweight and a BMI of > 30 is considered obese (Power et al. 1997; Kiess et al. 2001). These definitions hold only for adolescents over 16 years old and have to be redefined on an age-related basis for younger children. Approximately 12–25% of children are considered obese. A recent study indicates that nearly 40% of Canadian children aged 2–13 years are either overweight or obese. In the USA, the prevalence of obesity has increased since 1986, especially in certain ethnic groups: to 21.5% for Afro-American children, 21.8% for Hispanic children, and 12.3% for non-Hispanic Caucasian children. Similar data are available from Europe (Livingstone 2000, 2001). Current dietary patterns, including high carbohydrate snacks and beverages, less physical activity with more time spent watching television or working at a computer, are important factors for this epidemic of childhood obesity. Although the exact relationship between childhood obesity and type 2 diabetes mellitus is uncertain, the incidence of both primary hypertension and type 2 diabetes mellitus, both of which are within the spectrum of the metabolic syndrome and NASH in adults, has risen dramatically in

Genetic factors Attempts to identify a genetic basis include examining the genes involved in formation of adipose tissue, the development of insulin resistance, of alcoholic liver disease or related metabolic diseases. The gene encoding 11b-

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children in the past few years (Power et al. 1997; FagotCampagna et al. 2000). Whether obesity in childhood and adolescence inevitably leads to obesity in adulthood is a complex question (Power et al. 1997; Dietz 1998), which has not been fully proven. Recent studies indicate that childhood obesity is associated with greater morbidity in adulthood due to a variety of diseases, whether or not the individual remains obese (Kiess et al. 2001). Epidemiology of NASH/NAFLD in children Several large series of childhood NAFLD have been reported, most of which involve some selection, either referral bias or previous liver histology making it difficult to determine the prevalence of NAFLD in children. The first reports of childhood NASH appeared in the 1980s. Moran and colleagues reported three obese American children with fatty liver and steatohepatitis (Moran et al. 1983). These children, two boys and a girl, were 10–13 years old and had BMIs ranging from 28.5 to 33.2 at presentation. Serum aminotransferases were elevated (ALT higher than AST), and liver biopsy revealed macrovesicular steatosis with variable degrees of inflammation and fibrosis. Extensive clinical assessment revealed no other liver disease and the patients had biochemical improvement of hepatic indices when they lost weight. Since then a number of small studies have documented the relationship between obesity, elevated aminotransferases, hypertriglyceridaemia, hyperlipidaemia (Vajro et al. 1994; Kocak et al. 2000) and ultrasonographic evidence of fatty liver (Tazaura et al. 1997) while others confirmed the presence of steatohepatitis (Baldridge et al. 1995), fibrosis and even cirrhosis in one child who had long-standing obesity, maturity-onset diabetes mellitus and hyperlipidaemia (Kinugasa et al. 1984). The largest paediatric NAFLD series published to date is of 36 patients from a variety of ethnic backgrounds collected prospectively between 1985 and 1995 at the Hospital for Sick Children in Toronto (Rashid & Roberts 2000). The male : female ratio was 3 : 2, and patients were 4–16 years old at time of diagnosis, 20% of whom were less than 10 years old at diagnosis. Most patients were obese (weight > 20% above ideal weight for height): the range was 114–192% of ideal weight for height. Approximately 30% of the cohort had acanthosis nigricans; two brothers had Bardet–Biedl syndrome; one adolescent female had polycystic ovary syndrome; one child had severe hypothyroidism, and another was heterozygous for a1antitrypsin (PI MZ). Non-specific autoantibodies, most often low-titre antismooth muscle antibodies (a feature now being reported in adults with NAFLD), were present in a few patients. Four children developed diabetes mellitus after the diagnosis of NAFLD was established. Liver biopsy was performed in 24 patients, 71% of whom had

some fibrosis. One child had cirrhosis at 9 years old. Weight loss was associated with improvement in serum aminotransferases. Series of 17 patients reported from Adelaide (Manton et al. 2000) and 27 from Montreal (Sathya et al. 2002) had similar findings. Most of the children were obese and asymptomatic, although 30% had either abdominal pain or fatigue. Hypertriglyceridaemia was found in 56% of the patients and hyperuricaemia in 18% (Sathya et al. 2002). Liver biopsies showed fibrosis in nine of 17 biopsies, with ‘bridging’ or ‘early bridging’ in three of these and ‘evolving cirrhosis’ in another from an 11-year-old male (Manton et al. 2000). Weight loss was the most effective treatment, defined as normalization of serum aminotransferases. Thirty-nine children, predominantly male, with NAFLD have been described from Texas (Squires RH, Jr. and Lopez MJ, personal communication) which confirmed the pattern already described, but highlighted the importance of ethnicity: 20 were Hispanic, 14 Caucasian, four Asian, and one Afro-American. Five children had recovered from childhood cancer. Acanthosis nigricans was present in more than 40%, fasting serum insulin was three times the upper limit of normal in 17 patients. Thirty-one children underwent liver biopsy, which revealed steatohepatitis in all 31, fibrosis in 21 and cirrhosis in two children. In another report two boys, aged 10 and 14 years, were described with NAFLD, which progressed rapidly to cirrhosis; the older patient had had a craniopharyngioma resected (Molleston et al. 2002). Familial clustering of NAFLD was prominent in a large American study (Willner et al. 2001), which highlighted a 14-year-old male with cirrhosis whose mother also had NAFLD with less severe fibrosis. Unselected studies of schoolchildren give a better picture of the prevalence of NASH and obesity. An ultrasonographic study of 810 school children from northern Japan demonstrated an overall prevalence of fatty liver in 2.6%, which had a strong correlation to indices of obesity such as BMI (Tominaga et al. 1995). In the National Health and Examination Survey, cycle III (NHANES III) in the USA serum ALT and gamma-glutamyl transpeptidase were measured in 2450 children, aged 12–18 years, who were classified as ‘obese’ if the BMI was > 95th percentile for age and gender or ‘overweight’ if it was between the 85th and 95th percentiles. In this relatively unselected study, 6% of overweight, and 10% of obese, adolescents had an elevated ALT, but alcohol use could not be excluded (Strauss et al. 2000). Elevated ALT and fatty liver on sonography was more common in older children with more severe obesity, but no statistically significant differences were found in different age groups or with longer duration of obesity. In studies in which obese children were screened for abnormal serum aminotransferases the prevalence was

Chapter 10: Non-Alcoholic Steatosis 10–25% (Bergomi et al. 1998), but sonographic features of fatty liver were also found in five of 27 (19%) children who had normal ALT (Tazawa et al. 1997). Clinical features The most common clinical presentation is the incidental finding of isolated hepatomegaly or slightly elevated hepatic aminotransferases in a child who may have: • Obesity (BMI > 25). It is essential to use an age- and gender-adjusted guide to BMI for children since the adult thresholds of ‘overweight’ and ‘obesity’ only apply to individuals over 16 years old. Thus the degree of adiposity may be greatly underestimated in young children. The utility of waist circumference or waist–hip ratio for tracking adiposity has not been established throughout the paediatric age bracket and may not be relevant prior to puberty. • Type 1 or 2 diabetes mellitus. The association of fatty liver and insulin resistance in adults with type 2 diabetes has been well defined and occurs in 10–75%. It is now thought to be a significant factor for mortality (de Marco et al. 1999). The prevalence in children has not been as well established. Fatty liver has also been described in children with type 1 diabetes mellitus, particularly if it is not well controlled (Mauriac’s syndrome). • Previous chemotherapy. Obesity with or without the metabolic syndrome of obesity, hyperinsulinaemia, and hyperlipidaemia (Talvensaari et al. 1996a,b) in survivors of childhood neoplasia is a well-recognized problem, particularly following acute lymphoblastic leukaemia (Odame et al. 1994; Mayer et al. 2000; Reilly et al. 2000). This may explain a higher incidence of NAFLD, although other factors, such as the drug treatment for childhood neoplasia, may play a role. Hypothalamic surgery Fatty liver has been reported following neurosurgery for various suprasellar tumours (Evans et al. 2002). Neurosurgical excision of these rare tumours is followed by pituitary dysfunction, hyperphagia and rapid weight gain. In all the four children studied, fatty liver developed rapidly and persisted long term, with the development of cirrhosis and portal hypertension in one. Metabolic disease Fatty liver is associated with a number of metabolic or genetic diseases, which include the following. Alström syndrome Alström syndrome is a rare autosomal recessive disorder which is similar to Bardet–Biedl syndrome. The genetic basis of Alström syndrome is being determined (Collin et al. 2002; Hearn et al. 2002), but it is

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thought that modifier genes may play a role. It is characterized by pigmentary retinopathy with infantile conerod dystrophy, obesity, sensorineural deafness, dilated cardiomyopathy, diabetes mellitus with insulin resistance, and normal intelligence (Michaud et al. 1996; Russell-Eggitt et al. 1998). There are numerous reports of associated hepatic dysfunction with Alström syndrome (Marshall et al. 1997; Chang et al. 2000; Chen et al. 2000; Chou et al. 2000; Hung et al. 2001). The liver disease has been attributed to alcoholic liver disease (Sebag et al. 1984), with mild steatosis, portal inflammation and moderate fibrosis (Connolly et al. 1991), or hepatic steatosis with cirrhosis (Awazu et al. 1995, 1997). An 8-year-old girl with Alström syndrome who was obese with hyperinsulinaemia with non-insulin dependent (type 2) diabetes mellitus developed progressive liver disease. She had periportal and sinusoidal fibrosis, with ballooned hepatocytes on liver biopsy at 5 years old and decompensated cirrhosis at 8 years old (Quiros-Tejeira et al. 2001). Development of type 2 diabetes mellitus and hepatic dysfunction with steatosis has also been observed in adults with Alström syndrome (Satman et al. 2002). Bardet–Biedl syndrome Bardet–Biedl syndrome is characterized by progressive loss of visual acuity due to retinal dystrophy, central obesity, renal dysgenesis leading to progressive renal insufficiency, and male hypogonadism. Polydactyly or other abnormalities of the extremities are variable features, and mental retardation appears to occur in only a few patients (Green et al. 1989). Noninsulin dependent (type 2) diabetes mellitus may develop in these patients because of defective insulin receptor function (Escallon et al. 1989; Green et al. 1989; Iannello et al. 2002). Bardet–Biedl syndrome is genetically heterogeneous with at least six different loci associated with the phenotype (Katsanis et al. 2001a,b); candidate gene products may be responsible for the functional disorder or act as gene modifiers (Hamacher et al. 2001; Mykytyn et al. 2001). Cirrhosis has been reported in one patient previously (Pagon et al. 1982). Alström/Bardet-Biedl like Occasional patients cannot be categorized as either syndrome. A brother and sister both had a multisystemic disease with some features of each syndrome as well as polycystic ovaries in the girl: one had hepatic steatosis and both had decreased insulin receptor binding (Boor et al. 1993). Polycystic ovary syndrome (PCOS) PCOS is a multisystem endocrine disorder of adolescent (Lewy et al. 2001) and young adult women characterized mainly by disorders of ovulation with menstrual disorders, features of androgen excess including hirsutism and acne, and structurally abnormal ovaries. Central obesity occurs in half the patients. Acanthosis nigricans is frequently present

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(Conway & Jacobs 1990). Insulin resistance appears to be due to insulin receptor dysfunction or to postreceptor mechanisms (Dunaif 1997; Parsanezhad et al. 2001). Hyperinsulinaemia intensifies the adverse effects of androgen excess. Hypertriglyceridaemia is often present. To date few paediatric cases of PCOS with NAFLD have yet been reported but this may be because PCOS is a disease of adolescence. Modest weight loss (5–10% overall) or metformin improves ovarian function and diminishes other features of androgen excess (Batukan & Baysal 2001; De Conciliis et al. 2001; Nardo & Rai 2001). Turner syndrome Girls with Turner syndrome (XO) are often obese. Abnormal liver biochemistry has been attributed to hormonal treatment, including administration of growth hormone and oestrogen, as in two girls, 13 and 14 years old, who had steatosis and fibrosis on liver biopsy (Salerno et al. 1999). Another 4-year-old with Turner syndrome and severe obesity (body weight 159% of ideal weight) had elevated ALT years prior to hormone treatment (Sato et al. 2001). Lipodystrophy Lipodystrophy/lipoatrophy syndromes are primary disorders of insulin action, and hyperinsulinaemia is associated with relative insulin resistance. They are genetically heterogeneous. AGPAT2 is mutated in congenital generalized lipodystrophy (Agarwal et al. 2002). The gene product, 1-acylglycerol-3-phosphate Oacyltransferase, is involved in the synthesis of triacylglycerol and glycerophospholipids. In a different form of congenital generalized lipodystrophy, mutations are found in BSCL2, whose gene product is a novel human protein called seipin, a protein of unknown function, although homologous to G-protein (Magre et al. 2001). Some autosomal familial partial lipodystrophies are associated with mutations in LMNA, which encodes lamin A/C, a nuclear envelope protein (Shackleton et al. 2000; De Sandre-Giovannoli et al. 2002). Lamin A has been shown to interact with SREBP 1 and 2, which is at least a candidate mechanism for fatty liver (Lloyd et al. 2002). Other autosomal familial partial lipodystrophies are associated with mutations in PPARG, which encodes the peroxisome proliferator-activated receptor-g (Agarwal & Garg 2002). These observations in the lipodystrophy syndromes not only support the contention that hyperinsulinaemia associated with insulin resistance is critical in the pathogenesis of NAFLD, but also indicate some genes and gene products which may be important in the disease mechanism of NAFLD. Patients with lipodystrophy/lipoatrophy syndromes have complete or partial lack of adipose tissue, elevated insulin and low leptin levels. The most severely affected patients develop diabetes mellitus (Reitman et al. 2000). NAFLD has been detected in patients with congenital forms of lipodystrophy, including one patient who later

underwent liver transplantation (Powell et al. 1989; Cauble et al. 2001). The severity of the hepatic steatosis is proportional to the extent of extrahepatic fat loss. Diagnostic approach It is important to consider and exclude alternative aetiologies for hepatic steatosis in any child who appears to have NAFLD (Table 10.1). The main differential diagnoses include: Table 10.1 Differential diagnosis of fatty liver in children with macrovesicular steatosis. Nutritional Dehydration, severe infection Acute starvation Protein-calorie malnutrition (kwashiorkor) Total parenteral nutrition Jejuno-ileal bypass; gastric reduction operations Obesity Non-alcoholic fatty liver disease Systemic disease Chronic hepatitis C Schwachman syndrome (pancreatic insufficiency) Coeliac disease Inflammatory bowel disease Diabetes mellitus Nephrotic syndrome Drugs Amiodarone Methotrexate Prednisone/glucocorticoids L-asparaginase Vitamin A Ethanol Inherited metabolic disorders Cystic fibrosis Wilson’s disease a1-antitrypsin deficiency Hereditary tyrosinaemia, type I Homocystinuria Galactosaemia Hereditary fructose intolerance Glycogen storage diseases (mainly types I, VI) Sialidosis, mannosidosis, fucosidosis Refsum disease Abeta- or hypobetalipoproteinaemia Neutral lipid storage disease Wolman disease Cholesterol ester storage disease Tangier disease Familial hyperlipoproteinaemias Citrullinaemia, argininaemia, arginosuccinic aciduria (ornithine transcarbamylase deficiency: mainly microvesicular fat) Systemic carnitine deficiency (usually microvesicular fat) Weber–Christian disease Chronic granulomatous disease Porphyria cutanea tarda

Chapter 10: Non-Alcoholic Steatosis Table 10.2 Diagnostic approach to the investigation of nonalcoholic fatty liver disease/non-alcoholic steatohepatitis. Groups to be investigated All children with • type 2 diabetes mellitus • simple obesity • acanthosis nigricans • history of certain interventions, e.g. cranial surgery and bone marrow transplantation in whom ALT and/or AST have been raised at least twice in a 6-month period Routine blood tests Full blood count and coagulation Urea and electrolytes, uric acid Liver function tests: Bilirubin, AST, ALT, ALP, GGT, albumin ALT/AST ratio should be documented Tests to exclude other causes of liver disease Autoantibodies, immunoglobulins and complement Copper and caeruloplasmin a1-antitrypsin level and phenotype Amino and organic acids Iron, ferritin Thyroid function tests Serology for CMV, EBV, HAV, HBV and HCV Fasting lipids Cholesterol Triglycerides HDL-cholesterol Low-density lipoprotein Fasting metabolic tests Glucose Insulin C-peptide Leptin Lactate Free fatty acids 3-hydroxybutyrate Ultrasound scan of abdomen (and ovaries if female) Liver biopsy for histopathology and frozen specimen DEXA scan for body fat composition and distribution

• Chronic hepatitis C which should be excluded by virological testing. • Drug hepatotoxicity, especially methotrexate. • Inherited metabolic disease, especially Wilson’s disease which may present with prominent hepatic steatosis (Chapter 13). • Cystic fibrosis (CF). Hepatic steatosis is a very common liver abnormality, which affects 30–40% of CF patients (Colombo et al. 1999; Lindblad et al. 1999) (Chapter 11). It should be excluded by sweat testing and mutation analysis. The main investigations are in Table 10.2 but should include: • Routine haematology and liver function tests. Labora-

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tory studies show that serum ALT is more elevated than serum AST. • Urea and electrolytes. Hyperuricaemia is common. • Fasting lipids. Hypertriglyceridaemia is the typical blood lipid abnormality. • Autoantibodies, immunoglobulins and relevant metabolic investigations. • Viral serology. • Abdominal ultrasound. Studies in adults show that imaging can identify patients with hepatic steatosis quite accurately, especially if the steatosis is moderately severe, but does not distinguish simple steatosis from NASH (Saadeh et al. 2002). Microvesicular steatosis due to inherited mitochondrial disorders, urea cycle disorders, and valproic acid hepatotoxicity may occasionally be severe enough to be identified by liver ultrasound and should be excluded. • Liver biopsy is important for the diagnosis of NAFLD and may distinguish between NASH and other possible diagnoses. The optimal timing of liver biopsy has not been determined. Some advocate deferring liver biopsy in children with possible NASH until after a trial of weight loss for 3–6 months: if weight loss is not achieved and serum aminotransferases remain elevated, a liver biopsy is performed. Early biopsy for younger children or those with acanthosis nigricans is reasonable, but insufficient data are available to evaluate these criteria. Histological findings in childhood NASH may be slightly different from those in adults with NASH (Matteoni et al. 1999; Brunt 2001), but the essential findings of macrovesicular steatosis, inflammation or its residua, and fibrosis are present in the majority of cases (Rashid & Roberts 2000). Both the histological scoring and the histological features of NAFLD in children require further precision. • Measurement of insulin resistance. These include fasting glucose, insulin and C-peptide. Formulae for estimating insulin resistance, such as HOMA-IR, the homeostasis model assessment insulin resistance index (Matthews et al. 1985; Radziuk 2000), have been validated for use in children, but their use is still restricted to the research setting. It is important to have a consistent approach to evaluating children with hepatic steatosis, which expedites the diagnostic process and facilitates treatment. A model based on current practice is shown (Fig. 10.2). Treatment The approach to treatment is best within a multidisciplinary management team to deal with the diverse aspects of this disorder (medical, endocrinological, dietary, psychosocial). Treatment is directed towards management of obesity, insulin resistance or reducing lipid peroxidation or oxidative stress. The usual reported endpoints for

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Section 5: Liver Disease in Older Children Elevated AST/ALT

Check height/weight/BP/Acanthosis nigricans Exclude other liver disease

Ultrasound consistent with fat in liver

Liver biopsy

NAFLD

NASH

Potentially benign

Potentially progressive

Treat obesity

Repeat liver enzymes in 6 months

Normal

Clinical monitoring

Abnormal

Consider protocol treatment

judging efficacy are normalization of serum aminotransferases, loss of steatosis on ultrasound, or histological improvement on liver biopsy. Obesity The only treatment thus far shown to be convincingly effective in childhood NAFLD is the treatment of obesity by

Fig. 10.2 Approach to diagnosis and treatment. Most patients are asymptomatic and are referred because of elevated serum aminotransferases or abnormal findings on liver sonography. Timing of liver biopsy remains somewhat controversial, but it is required to confirm the diagnosis of nonalcoholic steatohepatitis (NASH). Treatment modalities are not yet defined for children: only ursodiol has been tested in a clinical trial. NAFLD; non-alcoholic fatty liver disease (simple steatosis).

weight loss. Reduction in body weight has led to normalization of serum aminotransferases in several clinical series (Vajro et al. 1994; Manton et al. 2000; Rashid & Roberts 2000; Vajro et al. 2000), while substantial improvement in liver histology was reported in one paediatric patient (Vajro et al. 1994). Although it has not been established how much weight must be lost to achieve improvement, the usual strategy is to reduce caloric intake and increase

Chapter 10: Non-Alcoholic Steatosis moderately intense aerobic exercise. Achieving and maintaining weight loss in children is difficult, especially as nutrition must be maintained for general growth. Well-designed studies examining treatment of childhood obesity have shown that a specific diet designed to minimize hyperinsulinaemia may be more effective than the conventional low-calorie diet (Ludwig et al. 1999; Spieth et al. 2000). This low glycaemic index diet may be easier to maintain long-term than a calorie-restricted diet and consists of comparatively straightforward food inclusions/restrictions: inclusion of fruits, vegetables, legumes, whole-grain or high fibre or traditionally processed grains and pasta, and exclusion or limited consumption of white potatoes, sugar (sucrose), and highly refined white flour (Ludwig 2002). Complementing the child’s weight reduction regimen with family-based behavioural intervention may also enhance success (Goldfield et al. 2001). Instituting a regimen of regular physical exercise is important because exercise also reduces hyperinsulinaemia. Drug treatment of insulin resistance/oxidative stress Few pharmacological treatments have been investigated in either children or adults. Treatment directed towards reducing insulin resistance includes weight loss but some drugs have been used: • Metformin which appears to act directly on SREBP-1c (Lin et al. 2000; Zhou et al. 2001) has been used for treatment of NASH in adults (Marchesini et al. 2001), but it has not been used in children with NAFLD as there are concerns about hepatotoxicity. Nevertheless, there is some experience with metformin in relevant childhood diseases. It has been used in children with acanthosis nigricans with improvement (Hermanns-Le et al. 2002) and in obese adolescents to induce weight loss (Kay et al. 2001). In these adolescents the combination of metformin plus low-calorie diet was more effective than the low-calorie diet alone. It has also been used effectively for treatment of children with type 2 diabetes mellitus (Jones et al. 2002; Zuhri-Yafi et al. 2002), polycystic ovary syndrome (Nardo & Rai 2001; Arslanian et al. 2002), and Prader–Willi syndrome (Chan et al. 1998). • Thiazolidinediones such as troglitazone have improved both liver function tests and histology in adults (Caldwell et al. 2001). Troglitazone has been withdrawn because of hepatotoxicity, but trials with rosiglitazone are in progress (Angulo & Lindor 2001; Neuschwander-Tetri 2002). Drugs used to reduce or prevent lipid peroxidation or oxidative stress include N-acetyl cysteine (used in the treatment of paracetamol toxicity and acute liver failure) for which there are no specific data in NASH. Others include: • Ursodeoxycholic acid. A small randomized controlled

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trial of ursodeoxycholic acid (10–12.5 mg/kg/day was conducted with 31 children with NAFLD diagnosed by sonography. There was no additional benefit over weight reduction and diet, and ursodeoxycholic acid alone was ineffective in improving liver biochemistries and the sonographic appearance (Vajro et al. 2000). • Vitamin E (400–1200 IU/day orally) in an open-label pilot study in 11 children with NASH was associated with improvements in serum aminotransferases, but there was no major change in BMI or in sonographic appearance of the liver. Biochemical relapse occurred in two children who discontinued vitamin E (Lavine 2000). • Betaine is commonly used for various disorders of homocysteine metabolism in children (Ogier de Baulny et al. 1998). It has been used in adults with NASH, but it has not been examined in childhood NASH. Components of the complex system regulating nutrient intake and utilization may provide opportunities for treatment of NASH. These include leptin (Uygun et al. 2000; Wang et al. 2001), adiponectin (Maeda et al. 2001; Haque et al. 2002; Maeda et al. 2002), resistin (Steppan & Lazar 2002) and the intracellular nutrient-sensing pathway, the hexoseamine biosythesis pathway (Obici et al. 2002). Since hyperleptinaemia and leptin resistance occur in NAFLD, simple supplementation along this regulatory pathway is unlikely to be effective. By contrast, in generalized lipodystrophy syndromes characterized by defective expression of leptin, leptin supplementation has improved hepatic steatosis (Oral et al. 2002). Outcome The majority of children with non-alcoholic steatosis have childhood NAFLD. Simple hepatic steatosis appears to be benign; but there are no long-term studies as yet to determine the outcome in children and there are no data about long-term extrahepatic disease. NASH may be more severe in certain ethnic groups, including Hispanics and Asians, or in association with metabolic disorders characterized by abnormalities in insulin receptor/signalling, such as lipodystrophy syndromes. Progression to cirrhosis is reported but is rare in children. Hepatocellular carcinoma may develop. Adult studies demonstrate that the more severe forms of NAFLD may progress to chronic liver failure necessitating liver transplantation. NASH recurs post-liver transplantation, but the prognosis is similar to other indications (Contos et al. 2001). The role of therapy is undetermined, as only weight loss has had a significant effect on histology.

Conclusion NAFLD/NASH is due to disordered insulin action, with hyperinsulinaemia and relative insulin resistance. Like

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type 2 diabetes in children, it is likely to become an important liver disease among children as the prevalence of childhood obesity continues to increase. It occurs in young children and there is no female predominance in the paediatric age bracket. Most children are either asymptomatic, or present with vague abdominal pain. Weight loss through dietary redesign with a low glycaemic index diet and a regimen of regular exercise is the mainstay for treatment. The efficacy of vitamin E supplementation or ursodeoxycholic acid in children is unclear, although other drug treatments, such as metformin, may be shown to be effective in the near future.

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Strauss, R.S. (1999) Comparison of serum concentrations of alpha-tocopherol and beta-carotene in a cross-sectional sample of obese and nonobese children (NHANES III). Journal of Pediatrics 134, 160–165. Strauss, R.S., Barlow, S.E. & Dietz, W.H. (2000) Prevalence of abnormal serum aminotransferase values in overweight and obese adolescents. Journal of Pediatrics 136, 727–733. Strauss, R.S. & Pollack, H.A. (2001) Epidemic increase in childhood overweight, 1986–1998. Journal of the American Medical Association 286, 2845–2848. Stuart, C.A., Gilkison, C.R., Smith, M.M., Bosma, A.M., Keenan, B.S. & Nagamani, M. (1998) Acanthosis nigricans as a risk factor for non-insulin dependent diabetes mellitus. Clinical Pediatrics (Phila) 37, 73–79. Talvensaari, K.K., Knip, M., Lanning, P. & Lanning, M. (1996a) Clinical characteristics and factors affecting growth in longterm survivors of cancer. Medical and Pediatric Oncology 26, 166–172. Talvensaari, K.K., Lanning, M., Tapanainen, P. & Knip, M. (1996b) Long-term survivors of childhood cancer have an increased risk of manifesting the metabolic syndrome. Journal of Clinical Endocrinology and Metabolism 81, 3051–3055. Tankurt, E., Biberoglu, S., Ellidokuz, E. et·al. (1999) Hyperinsulinemia and insulin resistance in non-alcoholic steatohepatitis. Journal of Hepatology 31, 963. Tazawa, Y., Noguchi, H., Nishiomiya, F. & Takada, G. (1997) Serum alanine aminotransferase activity in obese children. Acta Paediatrica 86, 238–241. Teli, M.R., James, O.F., Burt, A.D., Bennett, M.K. & Day, C.P. (1995) The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 22, 1714–1719. Tominaga, K., Kurata, J.H., Chen, Y.K. et·al. (1995) Prevalence of fatty liver in Japanese children and relationship to obesity. An epidemiological ultrasonographic survey. Digestive Diseases and Sciences 40, 2002–2009. Torley, D. & Munro, C.S. (2002) Genes, growth factors and acanthosis nigricans. British Journal of Dermatology 147, 1096–1101. Uygun, A., Kadayifci, A., Yesilova, Z. et·al. (2000) Serum leptin levels in patients with nonalcoholic steatohepatitis. American Journal of Gastroenterology 95, 3584–3589. Vajro, P., Fontanella, A., Perna, C., Orso, G., Tedesco, M. &

De Vincenzo, A. (1994) Persistent hypertransaminasemia resolving after weight reduction in obese children. Journal of Pediatrics 125, 239–241. Vajro, P., Franzese, A., Valerio, G., Iannucci, M.P. & Aragione, N. (2000) Lack of efficacy of ursodeoxycholic acid for the treatment of liver abnormalities in obese children. Journal of Pediatrics 136, 739–743. Valenti, L., Fracanzani, A.L., Dongiovanni, P. et·al. (2002) Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease. Gastroenterology 122, 274–280. Visser, M., Bouter, L.M., McQuillan, G.M., Wener, M.H. & Harris, T.B. (1999) Elevated C-reactive protein levels in overweight and obese adults. Journal of the American Medical Association 282, 2131–2135. Visser, M., Bouter, L.M., McQuillan, G.M., Wener, M.H. & Harris, T.B. (2001) Low-grade systemic inflammation in overweight children. Pediatrics 107, E13. Wang, J., Obici, S., Morgan, K., Barzilai, N., Feng, Z. & Rossetti, L. (2001) Overfeeding rapidly induces leptin and insulin resistance. Diabetes 50, 2786–2791. Wanless, I.R. & Lentz, J.S. (1990) Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 12, 1106–1110. Willner, I.R., Waters, B., Patil, S.R., Reuben, A., Morelli, J. & Riely, C.A. (2001) Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. American Journal of Gastroenterology 96, 2957–2961. Yanovski, J.A. & Arioglu, E. (2001) When a child can’t clean her neck. Journal of Pediatrics 138, 608. Zen, Y., Katayanagi, K., Tsuneyama, K., Harada, K., Araki, I. & Nakanuma, Y. (2001) Hepatocellular carcinoma arising in non-alcoholic steatohepatitis. Pathology International 51, 127–131. Zhou, G., Myers, R., Li, Y. et·al. (2001) Role of AMP-activated protein kinase in mechanism of metformin action. Journal of Clinical Investigation 108, 1167–1174. Zuhri-Yafi, M.I., Brosnan, P.G. & Hardin, D.S. (2002) Treatment of type 2 diabetes mellitus in children and adolescents. Journal of Pediatric Endocrinology and Metabolism 15 (Suppl. 1), 541–546.

Chapter 11: Hepatobiliary Disease in Cystic Fibrosis BIRGITTA STRANDVIK

Introduction, 197 Genetics, 197 Epidemiology, 197 Definition of liver disease, 198 Pathogenesis, 198 Clinical features, 201 Diagnosis, 202 Liver function tests, 202 Ultrasonography, 202 Hepatobiliary scintigraphy, 202

Magnetic resonance imaging, 202 Endoscopy, 202 Liver biopsy, 203 Anthropometry, 203 Pathology, 203 Focal biliary fibrosis, 203 Management, 203 Prevention of hepatic and biliary disease, 203

Introduction Cystic fibrosis (CF) is an autosomal recessive disease, first recognized in the late 1930s as a pancreatic disease, different from coeliac disease (Andersen 1938). It has a worldwide distribution and was initially considered one of the most common causes of biliary cirrhosis in children (Di Sant’Agnese & Blanc 1956). Most of the patients, who died early from pulmonary disease, were found to have liver disease at autopsy (Bodian 1952; Di Sant’ Agnese & Blanc 1956; Craig et al. 1957; Oppenheimer & Esterly 1975a). The survival rate in CF has dramatically improved as a result of centralized care, the development of efficient antimicrobial therapy and better nutrition. Although the main cause of death is still pulmonary deterioration due to chronic bacterial colonization and abnormal mucus production in the lower airways, successful lung transplantation has further increased life expectancy (Yacoub et al. 1997; Egan et al. 2002). Significant liver disease is more likely to affect long-term outcome in the future (FitzSimmons 1993).

Genetics The disease is found in all ethnic populations but is most common in the white population with an estimated incidence relative to live births of 1 : 3400 (Kosorok et al. 1996). The gene was identified in 1989 (Kerem et al. 1989; Riordan et al. 1989; Rommens et al. 1989) and is located on chromosome 7q31. It codes for a large protein of 1480 amino acids, named cystic fibrosis transmembrane conductance regulator (CFTR), which belongs to the ABCcasett family, which are ATP-dependent channels and transporters (Ames & Lecar 1992). CFTR functions as a

N-acetyl-cysteine, 204 Nutritional support, 204 Management of hepatic and biliary complications, 204 Liver transplantation, 205 Gene therapy, 205 Prognosis and outcome, 205 Future prospects for research, 206

chloride channel and is involved in ATP transport (Reisin et al. 1994), in the regulation of other ion channels (Greger et al. 1996), and in endosome fusion (Biwersi et al. 1996). It is very probable that the complete function of CFTR is not yet fully understood. The most common mutation found in Caucasians, dF508, has been calculated to be more than 50 000 years old (Morral et al. 1994). More than 1000 mutations have been identified. The relationship between genotype and phenotype is confined to pancreatic insufficiency (Kerem & Kerem 1996) and possibly to essential fatty acid deficiency (Strandvik et al. 2001). As it is likely that there are both genetic and environmental triggers for the development of disease, the role of genetic risk factors and modifier genes is being investigated (Salvatore et al. 2002).

Epidemiology Since liver disease in CF is often subclinical, epidemiological data of prevalence are uncertain and there are only five prospective studies available (Psacharopoulos et al. 1981; Feigelson et al. 1993; Lindblad et al. 1999; Ling et al. 1999; Colombo et al. 2002). In these studies, as well as in some others (Scott-Jupp et al. 1991; Di Sant’Agnese & Davis 1979), clinical liver disease was seen in 4–6% of the patients, but biochemical liver disease without clinical symptoms occurs in 20–50%. The liver disease usually becomes apparent before or at onset of puberty (Scott-Jupp et al. 1991; Potter et al. 1997; Lindblad et al. 1999) and is less commonly present in adult patients. Steatosis and fibrosis are common findings at biopsy or autopsy, about 50% and 25–50% of cases, respectively (Table 11.1). The biliary tract is almost always involved and the prevalence increases with age, probably partly due to

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Table 11.1 Prevalence of liver disease in cystic fibrosis: survey of literature. Prevalence percentage

Age group

Diagnostic tool

Diagnosis

References

New-borns

Autopsy Autopsy Autopsy

Steatosis Steatosis/fibrosis MLC/cirrhosis Fibrosis

60 60/23 1/9 10

Oppenheimer & Esterly (1975)

Infants

Autopsy Autopsy Autopsy Clinics, LFT

Fibrosis MLC Fibrosis BLD/MLC

25 22 15 5 mmol/l • hyperlipidaemia (cholesterol > 6 mmol/l and triglycerides > 3 mmol/l) • hyperuricaemia (> 350 mmol/l, age dependent) • mildly elevated plasma aminotransferases • normal plasma bilirubin, albumin, coagulation. Liver histology demonstrates uniform distension of hepatocytes with glycogen and prominent lipid vacuoles. Glycogen content of the liver is raised (normal < 6%). Normal liver architecture may be obscured by the distended hepatocytes, but there is no fibrosis or cirrhosis (see Plate 40, Atlas: p. 454). The stored material stains strongly positive with periodic acid–Schiff (PAS) and is digestible by diastase. Histochemical stains for glucose-6-phosphatase are negative. Diagnosis is confirmed by demonstrating the enzyme deficiency on liver biopsy and/or by mutation analysis. Antenatal diagnosis by chorion villus sampling is possible if the mutation has been identified, otherwise enzyme analysis on fetal liver biopsy is the only option (Golbus et al. 1988). Management and outcome. The main aim of therapy is to prevent hypoglycaemia and suppress the secondary metabolic derangements. This is achieved by providing a continuous supply of exogenous glucose, which maintains normal blood glucose concentrations and inhibits counterregulatory responses. Glucose requirement in GSD I has been estimated to be 8–10 mg/kg/min in infants and 5–7 mg/kg/min in older children (Chen 2001). In infants this is best achieved by frequent daytime feeding. Continuous nocturnal enteral glucose feeds are usually required initially. In older children and adults, use of oral uncooked cornstarch, which is hydrolysed in the gut to release glucose slowly over hours, may reduce the need for continuous or nocturnal feeding (Chen et al. 1993). The dosage of cornstarch required to ensure metabolic stabili-

ty varies greatly, but usually 1–2 g/kg/dose of cornstarch is given 4–12-hourly depending on individual fasting tolerance. Tests to estimate fasting tolerance and monitoring of pre- and postprandial glucose and lactate concentrations are useful in making decisions about dietary adjustments. With increasing age, tendency towards hypoglycaemia becomes less, perhaps as a result of the natural decrease in metabolic rate (Smit 1993). Adequate dietary treatment can result in correction of many of the metabolic abnormalities and result in greatly reduced morbidity. Some long-term complications such as hypoglycaemic brain damage and poor growth respond well to dietary management, although patients tend to be shorter than their peers (Wolfsdorf et al. 1999). Onset of puberty is often delayed. Most females have ultrasound evidence of polycystic ovaries, though other features of polycystic ovarian disease are rare (Lee et al. 1995a) and the effects on fertility are unknown. Chronic hyperuricaemia can lead to gout, renal stones and oestopenia, resulting in pathological fractures (Talente et al. 1994; Lee et al. 1995b) and may require treatment with allopurinol. Early glomerular hyperfiltration slowly progresses to microalbuminuria, proteinuria and eventually reduced glomerular filtration rate secondary to focal glomerulosclerosis and interstitial fibrosis (Chen et al. 1988). Declining renal function and hypertension eventually occur, and renal dialysis and transplantation may be necessary. Other renal abnormalities that have been described include a Fanconi-like syndrome, distal tubular dysfunction, kidney stones and amyloidosis (Kikuchi et al. 1990; Restaino et al. 1993). It is unclear whether dietary management can prevent long-term renal dysfunction and osteopenia (Wolfsdorf & Crigler 1999), but a recent study suggests that poor metabolic control results in reduced muscle strength and low bone mass (Schwahn et al. 2002). Atherosclerosis is rare despite the atherogenic profile of plasma lipids (Aluapovic & Fernandes 1985). There is an increased risk of pancreatitis secondary to the lipid abnormalities. Hypertriglyceridaemia sometimes requires treatment; fish oil supplements have been effective in lowering plasma triglycerides and cholesterol (Levy et al. 1993). Epistaxis and easy bruising following minor trauma are commonly observed; bleeding times are prolonged and associated with abnormal platelet adhesion and aggregation (Marti et al. 1986). Surgical procedures should not be undertaken without first evaluating bleeding time and establishing good metabolic control. Intensive intravenous glucose therapy for 24–48 h prior to surgery can normalize abnormal bleeding times; Desmopressin has also been reported to reduce bleeding complications (Marti et al. 1986). Pulmonary hypertension is a rare fatal complication (Pizzo 1980; Hamaoka et al. 1990). The exact cause is unknown, but vasoconstrictive stimuli such as

Chapter 12: Metabolic Liver Disease severe metabolic acidosis, hypoxia and abnormal hepatic clearance of circulating vasoactive agents have been proposed as possible mechanisms (Kishnani et al. 1996). Successful pregnancies have been reported (Ryan et al. 1994). Liver adenomas are commonly present by the second or third decades of life, especially in suboptimally treated individuals (Howell et al. 1976). The adenomas may be single or multiple, and have the potential for malignant transformation. Regular ultrasound examinations and serum a-fetoprotein determinations are therefore essential. Though hepatic adenomas have been shown to regress following intensive dietary treatment (Parker et al. 1981), more recent long-term studies indicate that they may occur despite early continuous glucose therapy (Wolfsdorf & Crigler 1999). Liver transplantation is rarely undertaken, as the disease should be adequately controlled with dietary management. However, liver transplantation may be indicated for symptomatic multiple hepatic adenomata, to prevent the development of hepatocellular carcinoma and/or poor metabolic control (Faivre et al. 1997; Matern et al. 1999). Successful liver transplantation restores normal metabolic balance, allows catch-up growth and improves quality of life (Kirschner et al. 1991; Matern et al. 1999). However, it may not prevent the development of renal dysfunction with focal segmental glomerulosclerosis (Faivre et al. 1997) and this needs to be considered when treating with nephrotoxic immunosuppressive drugs. Glycogen storage disease type I non-a (previously known as GSD Ib, Ic and Id) Patients with GSD I non-a produce glucose-6-phosphatase but cannot transport its substrate (glucose-6-phosphate) to its site of action at the inner wall of the endoplasmic reticulum (ER). As the rest of the glycogenolytic enzymes are located in the cytoplasm, glucose-6-phosphate must be transported into the ER and the products of this reaction, glucose and phosphate, have to be transported out of the ER. It was originally believed that different proteins carried out these transport reactions, and the putative deficiencies of these transport proteins were labelled as GSD types Ib, Id and Ic, respectively. Recent evidence suggests that GSD types Ic and Id do not differ from GSD Ib clinically, enzymatically or genetically (Veiga-da-Cunha et al. 2000). Therefore, these conditions are now all categorized as GSD I non-a. The relative prevalence of GSD Ia : GSD I non-a is estimated to be around 5–10 : 1 (Fernandes & Smit 2000). The glucose-6-phosphatase transporter gene has been localized to chromosome 11q23. Several mutations have been reported; G339C and 1211delCT appear to be common in Caucasian patients, while W118R appears to be common amongst Japanese patients (Veiga-da-Cunha et al. 1998; Kure et al. 1998). Presentation. The clinical presentation, metabolic de-

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rangements and complications are the same as in GSD Ia, with the additional finding of neutropenia and impaired neutrophil function. Neutropenia becomes apparent in infancy or early childhood and is usually intermittent (Visser et al. 2000). Inflammatory bowel disease resembling Crohn’s disease may also occur, often preceded or accompanied by oral, perioral and perianal ulcers, infections, abscesses and fistulae. Diagnosis. Biochemical abnormalities and liver histology are indistinguishable from GSD Ia. Diagnosis requires demonstration of deficient glucose-6-phosphatase activity in fresh liver biopsy tissue in which hepatocytes and microsomes are intact. When the cell is disrupted by freezing, measured glucose-6-phosphatase activity is normal as the substrate has free access to the enzyme. Antenatal diagnosis is possible by mutation analysis in chorion villus tissue if the mutations are known, otherwise fetal liver biopsy is required. Management and outcome. Management of GSD I non-a patients is the same as in GSD Ia. Dietary metabolic control has no effect on neutropenia and neutrophil dysfunction, but treatment with granulocyte-colony stimulating factor (G-CSF) or granulocyte macrophage-colony stimulating factor (GM-CSF) successfully corrects neutropenia, decreasing the frequency of bacterial infections and improving chronic inflammatory bowel disease in these patients (Schroten et al. 1991; Hoover et al. 1996). Splenomegaly is an important short-term complication of G-CSF therapy in these patients, but usually does not result in clinically significant thrombocytopenia (Calderwood et al. 2001). Sweet syndrome (acute febrile neutrophilic dermatosis) has occurred in one patient after G-CSF treatment (Garty et al. 1996), but myelodysplasia and marrow exhaustion have not been reported. Prophylactic antibiotic therapy may be an option for patients with neutropenia who do not have inflammatory bowel disease. Glycogen storage disease type III GSD type III is caused by deficiency of the debrancher enzyme amylo-1,6-glucosidase resulting in accumulation of partially broken down glycogen molecules (limit dextrin). Patients with liver and muscle involvement (GSD IIIa) have a generalized debrancher deficiency that affects liver, muscle, fibroblasts, cardiac muscle and erythrocytes (Chen 2001), whereas patients with GSD IIIb have debrancher deficiency confined to the liver. Type IIIa is more common, occurring in about 80% of patients with GSD III. The inheritance of GSD III is autosomal recessive. The gene is located at chromosome 1p21 and several mutations have been reported. Muscle and liver isoforms of the enzyme are encoded by the same gene, although certain mutations (those associated with GSD IIIb) appear to be associated with retention of debrancher activity in muscle, but not in liver (Shen et al. 1996).

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Presentation. Presentation may be similar to GSD I . The main clinical features are hypoglycaemia, hepatomegaly, short stature, skeletal myopathy, hyperlipidaemia and cardiomyopathy. There is wide variability in clinical and biochemical phenotype, depending on the extent and localization of the enzyme defect. In contrast to GSD I, however, biochemical liver function abnormalities are common and renal enlargement is not present. Patients who have muscle involvement often develop slowly progressive skeletal myopathy and wasting, progressing from minimal signs in childhood to severe muscle weakness by the third or fourth decade of life (Di Mauro et al. 1979; Coleman et al. 1992b). Muscular involvement can be very variable and range from mild to severe and life threatening (Kiechl et al. 1999). Left ventricular hypertrophy is common in patients with muscular involvement, and may lead to significant cardiac dysfunction in the long term (Kiechl et al. 1999). Diagnosis. Patients characteristically have: • fasting hypoglycaemia with ketosis/ketonuria • hyperlipidaemia (cholesterol > 6 mmol/l with normal triglyceride < 3 mmol/l) • normal uric acid • normal or moderately increased lactate (2.5– 5.0 mmol/l) • elevated hepatic aminotransferases • increased creatine kinase (type IIIa); note that normal levels do not rule out muscle involvement. Liver histology is similar to GSD I. Two distinguishing features in GSD III are the presence of fibrosis and a relative paucity of steatosis. Diagnosis is confirmed by identifying the deficient enzyme in leucocytes or hepatic tissue. Antenatal diagnosis is possible by enzyme assay in chorion villus samples or cultured amniotic fluid cells as well as by mutation analysis in informative families. Management and outcome. General principles of treatment and prevention of hypoglycaemia are the same as for GSD I. Adequate dietary management is associated with catch-up growth, decreased liver size, and improved liver function. A high protein intake may help in improving glycaemic control, as protein can be used for gluconeogenesis, a pathway that is intact in GSD III (Slonim et al. 1983). With age, hepatomegaly, hepatic function and fasting tolerance improve and may completely resolve after puberty (Coleman et al. 1992a). However, progressive liver dysfunction and liver failure can occur. Hepatic adenomas have been reported in up to 25% of patients, but malignant transformation is rare. Hepatocellular carcinoma in association with advanced liver cirrhosis can occur (Matern et al. 1999; Haagsma et al. 1997). Liver transplantation may be indicated for cirrhosis, end-stage liver

failure and/or hepatocellular carcinoma (Matern et al. 1999). The long-term outlook is favourable for patients without muscle involvement (GSD IIIb). For those with GSD IIIa, the prognosis depends on the severity of neuromuscular and cardiac disease. At present, there appears to be no satisfactory way of preventing progressive myopathy (Chen 2001). Successful pregnancies have been reported (Mendoza et al. 1998; Lee 1999). GSD IV This rare disease is due to a defect in the enzyme required for normal branching of the glycogen molecule (a1,4glycan-6-glycosyltransferase). The glycogen that accumulates is abnormal and poorly soluble with fewer branch points than normal glycogen. Accumulation is generalized and occurs in liver, heart, muscle, skin, intestine, brain and peripheral nervous system. Inheritance is autosomal recessive. The hepatic and neuromuscular forms of GSD IV are caused by mutations on the same gene, which has been localized to chromosome 3p12 (Bao et al. 1996). Presentation The most common presentation is in infancy with liver dysfunction and failure to thrive. Initial hepatomegaly progresses to cirrhosis and portal hypertension with splenomegaly, ascites and variceal bleeding, leading to death by the age of 5 years (Chen 2001). Hypoglycaemia is rare except as a feature of liver failure. Some cases appear to have non-progressive liver disease (McConkie-Rossel et al. 1996), and hepatocellular carcinoma has been reported in one such individual (de Moor et al. 2000). Brancher enzyme deficiency may also present with neuromuscular symptoms without hepatic involvement. These individuals may present in the neonatal period with severe hypotonia and neurological involvement leading to death in infancy, in late childhood with myopathy and/or cardiomyopathy, or in adulthood with diffuse central and peripheral neurological symptoms associated with polyglucosan body storage in the nervous system (Chen 2001). In extreme cases, prenatal onset of symptoms may result in hydrops fetalis (Alegria et al. 1999). Diagnosis Clinical features of the hepatic form are indistinguishable from other causes of liver disease in infancy, and the diagnosis is usually suspected from liver histology. Pale, amphophilic hyaline deposits along with large lipid vacuoles are seen on light microscopy with fibrosis or cirrhosis. The abnormal glycogen can be demonstrated as large PAS-postive, diastase-resistant deposits in hepatocytes (see Plate 41, Atlas: p. 454) and with special stains such as Lugol’s iodine or colloidal iron phosphate. Simi-

Chapter 12: Metabolic Liver Disease lar histological findings may be demonstrable on cardiac and skeletal muscle biopsy. Confirmation of the diagnosis requires enzyme assay in liver, muscle, leucocytes or fibroblasts (Chen 2001). Antenatal diagnosis is possible by enzyme assay on cultured amniocytes or chorionic villus tissue, as well as by DNA analysis if the mutation(s) are known. Management and outcome Dietary management with continuous nasogastric feeding and/or cornstarch may help improve growth and muscle strength. Liver transplantation is an effective treatment for those patients who develop progressive liver failure. To date, 14 patients with GSD IV are reported to have undergone liver transplantation (Sokal et al. 1992; Rosenthal et al. 1995; Matern et al. 1999; Chen 2001). The nine survivors have not developed any neurological, muscular or cardiac complications up to 13.5 years post transplant, and some have had progressive reduction in myocardial amylopectin storage (Selby et al. 1991). Deficiencies of the liver phosphorylase system: glycogen storage diseases types VI and IX Defects of the phosphorylase system are due either to deficient phosphorylase enzymes or to defects of the phosphorylase activating system (phosphorylase kinase). These systems are enzymatically distinct in the liver and skeletal muscles. Muscle phosphorylase deficiency (GSD V) presents in adulthood with muscle cramps and exercise intolerance; it does not involve the liver and will not be discussed further. Of the liver phosphorylase system defects, phosphorylase kinase defects (GSD IX) are much more common than liver phosphorylase deficiency (GSD VI). The liver phosphorylase gene is located on chromososme 14q21-22. The genetics of the phosphorylase kinase system is very complex, as the enzyme consists of four subunits encoded on different genes (X chromosome as well as autosomes), which are differentially expressed in different tissues. The clinical expression of individual enzyme deficiencies and isoforms is variable and depends on both the severity and distribution of the enzyme defect. Presentation Patients with GSD VI usually present with hepatomegaly and growth failure in early childhood. Symptoms of hypoglycaemia, hyperlipidaemia and hyperketosis are mild if present. Plasma lactate and urate concentrations are usually normal. There is no cardiac or skeletal muscle involvement, and the condition has a benign course with reduction in hepatomegaly after puberty (Fernendes et al. 1974). Phosphorylase kinase deficiency (GSD IX) is clinically and genetically more heterogeneous. Seventy-five per-

217

cent of all cases have X-linked liver phosphorylase deficiency (type IXa), which manifests between the ages of 1 and 5 years with hepatomegaly, growth retardation, mild hypoglycaemia and mild elevation of hepatic transaminases, cholesterol and triglycerides (Willems et al. 1990). Hepatomegaly and growth retardation usually resolve after puberty. Autosomal recessive forms of phosphorylase kinase deficiency (GSD IXb, c) present with more severe liver disease, which may progress to cirrhosis with or without skeletal myopathy (van Beurden et al. 1997; Burwinkel et al. 1998). Rare variants with isolated muscle and cardiac involvement have also been described (Eishi et al. 1985; Servidei et al. 1988; Clemens et al. 1990). Diagnosis Liver histology reveals non-uniform distension of hepatocytes with fibrosis and small fat droplets. On electron microscopy, the cytoplasmic glycogen particles are seen in rosette formation, less compact than normal with a frayed pattern. Definitive diagnosis of phosphorylase and phosphorylase kinase deficiencies rely on specific enzyme assays in affected tissues, i.e. liver or muscle. Enzymes can be measured in leucocytes and erythrocytes, but the presence of different isoenzymes can make interpretation difficult. Management and outcome Treatment for these conditions is symptomatic. Frequent feeds and overnight feeding with or without cornstarch (Nakai et al. 1994) may be necessary for more severely affected patients, but many do not require any specific intervention. The tendency to hypoglycaemia diminishes with age, and catch-up growth usually occurs without any specific treatment. Fanconi–Bickel syndrome (glycogen storage disease type XI) This rare disorder is characterized metabolically by hepatorenal glycogen accumulation and fasting hypoglycaemia, postprandial hyperglycaemia and hypergalactosaemia. The disorder is due to defective function of the GLUT2 transporter which is the most important glucose transporter in hepatocytes, pancreatic b-cells, enterocytes, and renal tubular cells (Brown 2000). Deficiency results in impaired import and export of glucose and galactose in affected tissues. Hypoglycaemia occurs due to impaired glucose transport from the liver and defective renal reabsorption of glucose and galactose. Hepatic and renal glycogen accumulation results, leading to impaired tubular function, Fanconi nephropathy and rickets (Santer et al. 1998). Over 100 patients are currently known (Santer et al. 2002). The GLUT2 gene has been localized to chromosome 3q26.1-q26.3, and 34 different mutations have been reported (Santer et al. 2002). Parental consanguinity is commonly observed.

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Presentation The main clinical features are hepatomegaly secondary to glycogen storage, and renal tubular dysfunction. Presentation in infancy includes recurrent vomiting, fever, failure to thrive and hypophosphataemic rickets, while in early childhood, short stature, protuberant abdomen, hepatomegaly, moon-shaped facies, and fat deposition around the shoulders and abdomen are usual. Fasting hypoglycaemia is a frequent finding, though symptomatic hypoglycaemia is rare. Chronic diarrhoea due to sugar malabsorption may occur. Rickets and osteoporosis lead to pathological fractures. Mild abnormalities of liver function are common but hepatic adenomas and malignancies have not been reported. Diagnosis Characteristic findings on investigation include: • postprandial hyperglycaemia and hypergalactosaemia • fasting hypoglycaemia • mildly abnormal liver function tests • generalized renal tubular reabsorption defect: glycosuria, galactosuria, generalized aminoaciduria, phosphaturia, hypercalciuria, hyperuricosuria, mild proteinuria • mild metabolic acidosis related to renal bicarbonate loss • increased liver glycogen content on biopsy specimens. Antenatal diagnosis has not been reported. Management and outcome There is no definitive therapy available. Treatment is supportive, and includes replacement of water and electrolytes, alkalinization with bicarbonate solutions, vitamin D and phosphate supplementation, galactose restriction and frequent small meals (Santer et al. 1998). Uncooked cornstarch may be useful. Fructose may be used as an alternative carbohydrate source in patients with malabsorption, as its absorption is not mediated by GLUT2. The prognosis is good, and many patients reach adulthood in a stable condition, including the original patient described by Fanconi and Bickel (Santer et al. 1998); short stature appears to be the major subjective long-term problem. Galactosaemia Galactosaemia usually results in severe liver dysfunction in the neonatal period or early infancy, and is discussed in detail in Chapter 5. Hereditary fructose intolerance (HFI) Fructose is an important dietary source of carbohydrate (Cox 2002). It is metabolized in the liver, renal cortex and small intestine by three enzymes: fructokinase, aldolase B and triokinase. Hereditary fructose intolerance is caused

by deficiency of aldolase B resulting in an inability to convert fructose-1-phosphate into dihydroxyacetone phosphate and glyceraldehyde. Ingested fructose accumulates as fructose-1-phosphate, which has two major consequences: (i) hypoglycaemia resulting from inhibition of the glycogenolytic enzyme glycogen phosphorylase and impaired gluconeogenesis due to an inability to condense glyceraldehyde-3-phosphate and dihydroxyacetonephosphate; and (ii) depletion of the nucleotides ATP and GTP, as a consequence of their high utilization and sequestration in the formation of large amounts of fructose-1-phosphate. ATP depletion is believed to lead to impaired protein synthesis and ultimately, liver and renal dysfunction. The incidence may be as high as 1 : 23 000 live births in the UK (James et al. 1996). HFI is inherited as an autosomal recessive trait. The gene for aldolase B has been mapped to chromosome 9q22.3. About 20 mutations are known; three common mutations are found in most patients of European origin. In Britain the A149P mutation is common (James et al. 1996). In southern Europe, the A174D mutation is most prevalent (Brooks & Tolan 1993), while in eastern Europe, N334K is the common mutation (Cross et al. 1990). Presentation Infants and adults with HFI are asymptomatic until fructose, sucrose or sorbitol is ingested. The age of presentation depends on the timing of introduction of these sugars. Typically, first symptoms occur during weaning when fruits and vegetables are introduced into the diet and include gastrointestinal discomfort and hypoglycaemia following fructose-containing meals. Nausea, vomiting, pallor, sweating, lethargy, tremors and seizures may occur. If the condition remains unrecognized and fructose intake continues, failure to thrive, signs of liver disease (hepatomegaly, jaundice, coagulopathy) and proximal renal tubular dysfunction (renal tubular acidosis, hypophosphataemic rickets) develop. Younger infants and children may be at risk of death from liver and renal failure. HFI patients who survive beyond infancy develop an aversion to sweet foods and self-select a low-fructose diet. School age children may avoid social situations that require them to ingest sugar-containing foods, which can be misinterpreted as psychotic behaviour. Characteristically, patients with HFI have caries-free teeth and the diagnosis may be suspected by dentists (Newbrun et al. 1980). Some individuals are diagnosed only during family screening; for investigation for growth retardation or isolated hepatomegaly; others are recognized only after inadvertently receiving fructose or sorbitolcontaining infusions, sometimes with fatal results (Schulte & Lenz 1977).

Chapter 12: Metabolic Liver Disease Diagnosis Characteristic findings are: • increased conjugated bilirubin • hypoalbuminaemia • increased hepatic aminotransferases • hypoglycaemia • lactic acidosis • low plasma phosphate • plasma tyrosine and methionine may be elevated secondary to liver dysfunction • anaemia, acanthocytosis and thrombocytosis • positive urine reducing substances, fructosuria, proteinuria, generalized amino aciduria • abnormal renal tubular function tests. The diagnosis is confirmed by: • enzymatic deficiency (liver or intestinal mucosal biopsy) • mutation analysis. Hepatic pathology varies from hepatic necrosis in infants, who present with acute liver failure, to diffuse steatosis, periportal or lobular fibrosis, or cirrhosis (see Plate 42, Atlas: p. 454). Electron microscopy demonstrates the pathognomonic punched-out areas between cytoplasmic organelles known as ‘fructose holes’ (Phillips et al. 1987). Management and outcome Management consists of eliminating fructose, sucrose and sorbitol from the diet for life. Sucrose and sorbitol are frequently used as sweeteners in syrups and suspensions as well as in tablet coatings and toothpaste; the suitability of all medications must be checked before prescribing. Fructose elimination usually results in dramatic improvement in hepatic function with regression of fibrosis and prevention of cirrhosis, as well as improvement in renal function. Provided liver and renal disease are not advanced, full restoration of normal health, growth and development may be expected, although hepatomegaly may persist for years after adequate treatment (Odievre et al. 1978). Life-threatening fulminant hepatic failure may develop on the reintroduction of fructose, sucrose or sorbitol. The development of hepatoma has been reported (See et al. 1984). Fructose-1,6-bisphosphatase deficiency Fructose-1,6-bisphosphatase deficiency results in impaired gluconeogenesis from all precursors, including fructose. Maintenance of normal glucose concentrations therefore depends on dietary glucose and galactose and on hepatic glycogenolysis. Hypoglycaemia results when these sources of glucose are exhausted. Accumulation of the gluconeogenic precursors lactate, alanine and

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glycerol occurs. It is a rare disorder and incidence is unknown. The condition is inherited as an autosomal recessive trait. Liver and muscle express distinct enzymes, and the muscle enzyme is not involved in the disorder. The liver enzyme has been mapped to chromosome 9q22.2-22.3, and several mutations have been described (Kikawa et al. 1997). In some patients, no mutations have been identified, suggesting the existence of unidentified mutations in the promoter region of the gene or of mutations of other genes that regulate fructose-1,6-bisphosphatase activity (Hers & van Schaftingen 1982). Presentation Fructose-1,6-bisphosphatase deficiency is a life-threatening condition; about half of affected patients become symptomatic in the newborn period with lactic acidosis and hypoglycaemia. Presenting symptoms include hyperventilation secondary to profound lactic acidosis, irritability, hypotonia, somnolence, apnoeic spells, coma, convulsions and hepatomegaly. Other patients may present in infancy or early childhood with hypoglycaemia and acidosis triggered by a febrile illness. Subsequent attacks may be triggered by intercurrent illnesses, though patients remain very well between attacks. Ingestion of large quantities of fructose or sucrose are known to precipitate acute decompensation, though in contrast with hereditary fructose intolerance, children do not avoid sweet foods. Diagnosis Characteristic findings are: • hypoglycaemia • increased plasma lactate • metabolic acidosis • increased free fatty acids • hyperuricaemia • normal liver and renal function. Diagnosis is confirmed by demonstrating the enzyme deficiency in liver, renal cortex or jejunum. The enzyme is also expressed at low levels in leucocytes and diagnosis can be attempted in these cells; deficient leucocyte fructose-1,6-bisphosphatase activity is diagnostic, but normal activity does not rule out liver enzyme deficiency (Buhrdel et al. 1990; Besley et al. 1994). The enzyme is not expressed in skin fibroblasts and amniotic cells. Antenatal diagnosis is theoretically possible by mutation analysis, but has not yet been reported. Management and outcome Treatment of acute attacks consists of infusions of highconcentration glucose and bicarbonate to correct hypo-

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glycaemia and acidosis. The basic principle of long-term management is avoidance of fasting, particularly during intercurrent illnesses; overnight gastric drip-feeding may be required in very young infants. Dietary fructose and sucrose may have to be restricted, particularly during febrile illnesses. After diagnosis and institution of adequate management, the condition follows a relatively benign course. Fasting tolerance improves with age, and may be normal in adults (Moses et al. 1991).

Lysosomal storage disorders The lysosmes are intracellular organelles containing a large number of different enzymes at acid pH, their main function involving the degradation of macromolecules. The lysosomal storage disorders are each due to a specific enzyme deficiency resulting in abnormal storage of partially degraded macromolecules in the lysosomes (Table 12.3). The clinical spectrum of the storage disorders is wide, ranging from prenatal hydrops fetalis to mild disease in adulthood (Rapola 1994). Suggestive signs may include coarsening of facial features, neurological deterioration, and hepatosplenomegaly. Patients with storage disorders often have a characteristic skeletal dysplasia (dysostosis multiplex) with a large skull, spinal deformities and short, thick tubular bones. The liver and spleen are important sites for abnormal lysosomal storage, hence hepatosplenomegaly is a frequent finding, but the clinical picture is often dominated by neurodevelopmental regression. Gaucher disease, Niemann–Pick disease, Wolman disease and cholesterol ester storage disease have important hepatic manifestations. Gaucher disease Gaucher disease is the commonest lysosomal storage disorder, with a global frequency of 1 : 200 000 (Cox & Schofield 1997). It is caused by deficiency of b-glucosidase (glucocerebrosidase), resulting in accumulation of glucosylceramide, a normal intermediate in the synthesis and catabolism of complex glycosphingolipids. Gaucher disease is classified according to the presence and severity of neurological manifestations: • type 1 (non-neuronopathic) Gaucher disease includes patients without neurological manifestations • type 2 (acute neuronopathic) Gaucher disease includes patients with neurological involvement presenting in infancy • type 3 or (subacute neuronopathic) Gaucher disease presents in childhood and is associated with variable neurological manifestations. Type 1 is the most common subtype; the relative frequencies of types 1, 2 and 3 Gaucher disease are 94%, 5% and 1%, respectively (Charrow et al. 2000). The hallmark

of this condition is the accumulation of characteristic tissue macrophages (Gaucher cells), which have a ‘crumpled paper’ appearance histologically due to abnormal accumulation of phagocytosed glycosphingolipids. Gaucher cells are found in all tissues, and clinical manifestations reflect the sites and extent of abnormal glycosphingolipid storage (Cox 2001b). The main storage sites are the liver, spleen and bone marrow, although significant storage also occurs in the central nervous system, lymph nodes, lungs and glomerular mesangium. Some of the pathological consequences in these tissues may relate to vascular blockage by the Gaucher cells. The major accumulating lipids, glucosylceramide and glucosylsphingosine also induce tissue macrophages to secrete a large number of proinflammatory cytokines which are believed to mediate the acute inflammatory responses and tissue damage that underlie the clinical and biochemical manifestations. The gene has been localized to chromosome 1q21 and over 160 mutations have been described. Six common mutations (N370S, 84GG, IVS2(+1), V394L, R496H and L444P) account for > 90% of Jewish and 60–70% of nonJewish alleles (Gabrowski & Horowitz 1997). Broad phenotype–genotype correlations exist, with the N370S allele generally associated with milder and non-neuronopathic disease, and the L444P allele strongly associated with neuronopathic disease. Presentation Clinical expression is heterogeneous, ranging from ‘congenital’ Gaucher disease presenting with hydrops fetalis to asymptomatic glucocerebrosidase deficiency. Type 1 Gaucher disease The age at presentation of disease varies from childhood to late adulthood. Presenting features are related to (Zevin et al. 1993): • growth retardation • bone pain • hepatosplenomegaly • abdominal pain from hepatic or splenic infarction • hypersplenism (Zevin et al. 1993). Without treatment, progressive splenomegaly leads to transfusion dependency and the enlarged spleen may rupture with trauma. Liver fibrosis has been reported, but cirrhosis is rare (James et al. 1981). Clinically, hepatic complications include portal hypertension, abnormal liver function and liver infarction. The extent of bone involvement is a major determinant of long-term morbidity, and most adults with Gaucher disease develop complications including bone pain, osteoporosis, lytic lesions, pathological fractures and avascular necrosis (Elstein et al. 1997; Wenstrup et al. 2002). Other significant complications include bone marrow failure (Wenstrup et al. 2002), pulmonary hypertension (Elstein et al. 1998) and an increased

Chapter 12: Metabolic Liver Disease

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Table 12.3 Lysosomal storage disorders associated with hepatosplenomegaly.

Disorder

Enzyme defect

I. Sphingolipid and lipid storage disorders GM1 b-galactosidase Gangliosidosis

Clinical features

Hepatosplenomegaly (–, absent; +, mild; ++, moderate; +++, marked)

Outcome

Neurodegeneration, dysostosis multiplex, coarse features, hepatosplenomegaly, cherry red spot. Infantile, juvenile and adult forms recognized

Infantile form: ++ Juvenile forms: – or + Adult form: –

Infantile — death by 2 years Juvenile — death 3–10 years Adult — onset 2nd to 4th decade, slow neurodegeneration

Gaucher

b-glucosidase

Hepatosplenomegaly, bone and lung infiltration. Neurological (type II), non-neurological (type I) and intermediate (type III) forms

++ to +++

Type I (common) — prolonged survival, death due to pulmonary or haematological complications Type II — death in infancy Type III — variable survival into childhood

Niemann–Pick types A and B

Sphingomyelinase

Hepatosplenomegaly, lung infiltration, neurological (A) and non-neurological (B) types

++ to +++

Type A — death in infancy Type B — relatively normal life span

Niemann–Pick C

Cholesterol and sphingolipid trafficking defect

Neonatal hepatitis, hepatosplenomegaly, vertical ophthalmoplegia, ataxia, later neurodegeneration

++ to +++

Death 1–3 decades after onset of neurodegeneration

Wolman’s, and cholesterol ester storage disease

Acid esterase

Hepatosplenomegaly, steatorrhoea, failure to thrive, adrenal calcification, neurodegeneration. Cholesterol ester storage disease a mild variant, causing hepatic fibrosis in adults

++

Wolman’s — death in infancy Cholesterol ester storage disease — death from liver failure in adulthood

Farber’s

Ceramidase

Psychomotor deterioration, subcutaneous nodules, painful and deformed joints

+ to ++

Death in infancy; late onset variants known

– to ++

Severe cases — death in early childhood Milder cases — survival into adulthood, severely retarded

II. Mucolipidoses and glycoprotein storage disorders Mucolipidosis I a-neuraminidase Myotonic seizures, cherry red (sialidosis) spot, psychomotor retardation, hepatosplenomegaly and dysostosis multiplex Mucolipidosis II (I-cell disease)

N-acetylglucosamine-1phosphatase (defective enzyme transport into lysosomes)

Coarse facies, kyphoscoliosis, joint contractures, gingival hyperplasia, cardiomyopathy, dysostosis. Onset in infancy

++

Death by 4–6 years from cardiopulmonary disease

Mucolipidosis III

Same defct as mucolipidosis II

Stiff joints, kyphoscoliosis, short stature, low–normal intelligence. Presentation by 3–4 years

+ to ++

Usually survive into adulthood with severe orthopaedic problems and mild cardiac involvement

Galacto-sialidosis

Neuraminidase and b-galactosidase

Combined features of mucolipidosis I and GM1 gangliosidosis, onset usually in late childhood

++

Survival into adulthood usual with variable degree of mental retardation

Fucosidosis

a-fucosidase

Psychomotor retardation, mild dysostosis multiplex, angiokeratoma, visceromegaly. Onset in early childhood

++

Severe form (type I) — death by late childhood Mild form (type II) — survival into adulthood, variable degree of mental retardation

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Table 12.3 Continued. Hepatosplenomegaly (–, absent; +, mild; ++, moderate; +++, marked)

Disorder

Enzyme defect

Clinical features

a-Manno-sidosis

a-Mannosidase

Deafness, mild Hurler phenotype, mental retardation. Onset in infancy or early childhood

++ to +++

Slow intellectual deterioration, eventual developmental level at 5–7 years. Survival into adulthood usual

Sialic acid storage disorder

Defective sialic acid transport out of lysosomas

Infantile form (infantile sialic acid storage disorder): psychomotor retardation, coarse facies, hepatosplenomegaly, cardiomyopathy, onset in first few months of life.

Infantile form: ++ to +++

Infantile form: rapid deterioration, death by 1–5 years

Late-onset form (Salla disease): ataxia, nystagmus, developmental delay in childhood; severe mental retardation in adulthood

Late-onset form: –

Late-onset form: prolonged survival with slow neurodegeneration; average age at death 30–40 years

Hurler: psychomotor retardation, coarse facial features, growth retardation, dysostosis multiplex, corneal clouding, visceromegaly. Milder features in Scheie syndrome

Hurler: ++ Scheie: – to +

Hurler: death by 8–10 years Scheie: normal lifespan; orthopaedic problems common

Symptoms similar to Hurler syndrome, no corneal clouding. Rare milder variant with no mental retardation

Severe: ++

Death by mid-teens

Mild: – to +

Milder variant: normal life span

Commonest MPS disorder in UK, identical phenotype in all types. Marked mental retardation, severe behavioral and sleep disturbance. Mild somatic involvement, mild coarse features, no corneal clouding

All forms: – to +

Survival into late teens or adulthood with severe mental retardation

III. Mucopolysaccharidoses MPS I a-Iduronidase (Hurler or Scheie)

MPS II (Hunter)

MPS III (San Fillipo) Type A Type B

Iduronate sulphatase

Heparan-Nsulphatase a-acetylglucosaminidase

Outcome

Type D

Acetyl CoA: a-glucosaminide-N-acetyltransferase N-acetylglucosamine 6sulphatase

MPS IV (Morquio) Type A Type B

N-acetylglucosamine 6-sulphatase b-galactosidase

Both types phenotypically similar. No mental retardation, severe skeletal deformities and growth retardation, cervical myelopathy a potentially fatal hazard, mild corneal clouding

Both forms: +

Survival into adulthood common if death does not occur earlier due to cervical myelopathy. Cardiopulmonary compromise later due to thoracic deformity

MPS VI (Maroteaux– Lamy)

Arylsulphatase B

Skeletal deformities similar to Hurler syndrome, but no mental retardation. Variable cardiac involvement, mild corneal clouding

+

Severe forms — survive into late teens Mild form — normal life span

MPS VII (Sly)

b-glucuronidase

Variable phenotype ranging from hydrops fetalis to mild adult type similar to MPS I

++

Variable depending on severity

Type C

Chapter 12: Metabolic Liver Disease risk of lymphoproliferative malignancy (Cox & Schofield 1997). Type 2 Gaucher disease Type 2 differs from type 1 disease because presentation is in early infancy with: • marked hepatosplenomegaly • severe neurological involvement characterized by paralytic squint, dysphagia, persistent head hyperextension, trismus and generalized spasticity • death occurs by 2 years of age associated with progressive psychomotor regression and brain stem dysfunction (Erikson et al. 1997) • exceptional cases have a prenatal onset with hydrops fetalis or a later onset with similar but slower progression. Type 3 Gaucher disease Type 3 has intermediate severity between types 1 and 2. The main clinical features include: • severe visceromegaly which can lead to death from liver disease and portal hypertension in the 2nd to 4th decades • characteristic oculomotor apraxia (horizontal supranuclear gaze palsy) • dementia, ataxia, spasticity and epilepsy (myoclonic or complex partial seizures) develop over time and progress at variable rates (Erikson et al. 1997) • other patients have mild systemic manifestations but severe progressive neurological involvement leads to death in childhood from neurological complications. Diagnosis Specific diagnostic tests are: • glucocerebrosidase (leucocyes or cultured fibroblasts) • mutation analysis. Supportive tests include: • Demonstration of Gaucher cells in bone marrow aspirate or liver biopsy (see Plate 43, Atlas: p. 454). Gaucher cells are not specific for Gaucher disease and have been described in leukaemia, lymphoma, thalassaemia, multiple myeloma and AIDS complicated by tuberculosis. • Marked elevation of plasma angiotensin converting enzyme (ACE), tartarate-resistant acid phosphatase, and chitotriosidase. A number of non-specific haematological and biochemical abnormalities may be present: • anaemia, leucopaenia, thrombocytopaenia • abnormal hepatic transaminases • abnormal coagulation and fibrinolytic tests • increased ferritin and transcobalamin • polyclonal hypergammaglobulinaemia. Management and outcome Recombinant enzyme therapy is the main treatment for types 1 and 3 disease (Cox 2001a), allowing many individ-

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uals to live near-normal lives. No satisfactory treatment is available for type 2 disease. Enzyme replacement therapy (ERT) results in rapid improvement of liver, splenic and bone marrow pathology with corresponding clinical improvement, but skeletal disease is slow to respond and may be resistant to ERT. Advanced liver, splenic and bone marrow disease is not reversible by ERT. Neurological disease does not respond to ERT, as the enzyme does not cross the blood–brain barrier; but there may be some improvement when given intravenously in very high doses in type 3 disease (Vellodi et al. 2001). Substrate deprivation therapy is a recent development in the treatment of storage disorders. In lysososmal disorders there is an imbalance between the rate of production of a particular substrate and its catabolism, leading to accumulation within the lysosome. Substrate deprivation therapy restores this balance by reducing the rate of synthesis of the substrate. OGT 918 (N-butyldeoxynojirmycin) inhibits glucosyltransferase and impairs the synthesis of glycosphingolipids, which accumulates in a number of storage disorders. This product has been used in the treatment of non-neuronopathic Gaucher’s disease with favourable results and few side effects (Cox et al. 2000). Supportive and symptomatic treatment such as pain relief, bisphosphonates, calcium, vitamin D, steroids, bone marrow transplantation, splenectomy and liver transplantation are important in managing patients with Gaucher disease. Splenectomy is indicated only if severe hypersplenism is resistant to ERT or for splenic rupture, as acceleration of neurological, hepatic and pulmonary disease has been reported following splenectomy. Niemann–Pick disease (NPD) Niemann Pick disease refers to a group of storage disorders that are associated with a particular storage cell with a morphological appearance resembling ‘foamy’ histiocytes, as a result of sphingomyelin storage. Currently, 3 forms of Niemann Pick disease are recognised: types A, B and C. Types A and B (NPA and NPB) Types A and B disease are autosomal recessive disorders caused by deficiency of the lysosomal enzyme sphingomyelinase resulting in sphingomyelin storage. Type A NPD (NPA) is the infantile neurodegenerative phenotype, whereas type B NPD (NPB) is defined by the absence of neurological involvement, with relatively late-onset hepatosplenomegaly and survival into adulthood. The sphingomyelinase gene has been localized to chromosome 11p15.4, and about 20 mutations are known.

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With NPA disease, three mutations (R496L, L302P and fsP330) account for > 95% of mutant alleles in the Ashkenazi Jewish population (Schuchman & Miranda 1997); DR608 appears to be a relatively common type B mutation (Vanier et al. 1993). Several other ‘private’ mutations have been identified in Jewish and non-Jewish families with types A and B NPD (Schuchman & Desnick 2001). The spleen, lymph nodes, liver, bone marrow, kidneys and lungs are the main sites of sphingomyelin storage in both types Aand B, while type Apatients also accumulate sphingomyelin in the brain. Presentation Type A. The clinical presentation of type Ais uniform and includes: • a protuberant abdomen with massive liver and spleen enlargement becomes apparent in the first few months of life (rarely after 4–6 months) • lymphadenopathy • prolonged neonatal jaundice due to giant cell transformation in some cases • early neurological features include feeding difficulties, hypotonia and muscular weakness • recurrent vomiting and constipation • repeated chest infections and aspiration pneumonia, and a chest X-ray often reveals alveolar infiltration with a diffuse reticular or finely nodular pattern of the lung fields (Grunebaum 1976) • a cherry red macular spot is seen on ophthamological examination in about 50% of patients • psychomotor retardation becomes evident after 6 months with progressive loss of developmental milestones; eventually, all motor and intellectual abilities are lost • failure to thrive, spasticity and rigidity are prominent features in the later stages • cirrhosis, and multiple hepatocellular adenomata have been described (Tamaru et al. 1985) • death occurs by 2–3 years of age, usually from respiratory complications. Type B. The clinical presentation of type B is more variable. Some individuals may not be diagnosed until adulthood as there may be minimal clinical manifestations (Chan et al. 1977; Dawson & Dawson 1982). The features include: • Hepatospenomegaly, which may become less apparent as the child grows older. Progressive liver disease with biliary cirrhosis (Connolly & Kennedy 1984), portal hypertension and ascites (Tassoni et al. 1991) has been reported. Hypersplenism may lead to pancytopenia or splenic rupture (Dawson & Dawson 1982). • Pulmonary involvement in the form of diffuse reticular or finely nodular infiltration on chest X-ray. Lung disease may be progressive and lead to chronic hypoxia, dysp-

noea, recurrent bronchopneumonia, and in extreme cases, cor pulmonale (Lever & Ryder 1983). • Neurodevelopmental complications are rare, but neurological invovement such as cherry red maculae, ataxia, Parkinsonism and mental retardation has been recorded; these patients are thought to have an intermediate phenotype between types A and B (Elleder & Cihula 1983; Lipson et al. 1986; Takada et al. 1987). Diagnosis The diagnosis may be suspected when the characteristic Nieman–Pick ‘foam’ cells are found on bone marrow aspirate or on a liver biopsy (Plate 8, Atlas: p. 442). Niemann–Pick cells are not diagnostic of sphingomyelinase deficiency, as these cells may also be seen in other storage disorders including Niemann–Pick C disease, cholesterol ester storage disease, Wolman’s disease and GM1 gangliosidosis. Specific diagnostic tests are: • sphingomyelinase assay (leucocytes, lymphocytes or skin fibroblasts) • mutation analysis. Antenatal diagnosis is possible by assaying sphingomyelinase activity in chorionic villi or cultured amniocytes (Maziere et al. 1978; Vanier et al. 1985). Theoretically, prenatal diagnosis should also be possible using mutation analysis. Management and outcome Currently, no specific treatment is available for Niemann–Pick disease A and B, and management is essentially supportive. Liver transplantation in an infant in NPA and amniotic cell transplantation in NPB patients have been attempted with little success. One adult with NPB disease has had a liver transplant with subsequent reduction in hepatic cholesterol and sphingomyelin content, but long-term follow-up data are not available. Early bone marrow transplantation has failed to prevent progressive neurodegeneration in one infant; however, bone marrow transplant was successful in reducing the size of the liver and spleen as well as improving the radiological appearance of the lungs in one child with severe type B disease. Enzyme replacement therapy is potentially useful in type B disease, and clinical trials are planned; if these are successful, enzyme replacement therapy may become the treatment of choice for NPB disease in the near future. Developments with gene therapy are ongoing. Niemann–Pick C disease (NPC) Niemann–Pick disease type C originally referred to a group of patients who had the classical histopathological findings of ‘foamy’ histiocytes and increased tissue sphingomyelin along with a slowly progressive neurological illness (Crocker & Farber 1958). It is now known that NPC disease is clinically, biochemically and genetically dis-

Chapter 12: Metabolic Liver Disease tinct from NPA and NPB; it is caused by a defect of intracellular cholesterol and glycosphingolipid trafficking. The estimated incidence of NPC is approximately 1 : 150 000, making it more common than NPA and NPB combined (Patterson et al. 2001). It is inherited in an autosomal recessive manner. The defective gene (NPC 1) has been localized to chromososme 18q11-12 in > 95% of patients. It codes for an endosomal membrane protein which plays an important role in intracellular cholesterol and glycosphingolipid trafficking (Zhang et al. 2001); mutations result in impaired processing and accumulation. Over 100 mutations have been described, and three mutations (I1061T, P1007A and G992W/G992R) are sufficiently common to justify diagnostic testing, especially in late-onset variants (Millat et al. 2001b). Genotype–phenotype correlation may be possible on the basis of the nature and location of the mutation within the NPC1 protein (Millat et al. 2001b). Less than 5% of patients with NPC have a defect in another gene, HE1 (Human epididymis1, also known as NPC2 or HE1/NPC2), which has been localized to chromosome 14q24 (Millat et al. 2001a). The product of HE1/NPC is a small (132 amino acid), soluble, ubiquitously expressed lysosomal protein of unknown function Presentation The manifestations of NPC disease are extremely heterogeneous, and presentation can be at any time from intrauterine life to adulthood. The most common (‘classic’) phenotype presents in childhood with: • neonatal cholestasis that is self-limiting (Vanier et al. 1988) (Chapter 4) • hepatosplenomegaly is prominent in childhood, but becomes less apparent with advancing age, although portal hypertension has been reported (Kelly et al. 1993) • clumsiness and ataxia • early childhood development is usually normal, but behavioural problems may be noted as early as the pre-school period • supranuclear vertical gaze palsy which is the neurological hallmark of this disorder, and is found in virtually all cases by adolescence; it may manifest in early childhood as eye blinking and head thrusting on attempted vertical gaze (see Plate 8, Atlas: p. 442) • gelastic cataplexy (atonic seizures induced by emotional change). The neurological condition is slowly progressive, and over the years, dementia, dystonia, dysphasia and drooling become increasingly apparent. Progressive physical and intellectual disability leads to loss of self-care skills and mobility by adolescence. In the later stages of the illness, psychosis, severe dysphagia, spasticity and rigidity are common. Death usually occurs in the late teens or early adulthood due to respiratory complications. Very severe variants of NPC present with hydrops fetalis, liver and respiratory failure leading to death in

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early infancy. Severe pulmonary involvement leading to early death from respiratory failure may be associated with mutations in the HE1/NPC2 gene. Late-onset cases have a more insidious onset and slow progression. The age at presentation ranges from the 2nd to the 6th decades (Coleman et al. 1988). Psychiatric and cognitive disturbances are usually prominent, and a wide variety of neurological signs and symptoms may be found, including dysarthria, ataxia, dysphagia, spasticity, dystonia and vertical supranuclear gaze palsy. Hepatosplenomegaly may or may not be present and liver dysfunction is rare. Recently, a non-neuronopathic form of NPC has been described in adults with isolated organomegaly (Fensom et al. 1999). Diagnosis The diagnosis is suggested by the finding of liver dysfunction in the neonatal period associated with foam cells and sea-blue histiocytes in liver or bone marrow histology (see Plate 8, Atlas: p. 442). Diagnostic tests are: • accumulation of intracytoplasmic unesterified cholesterol in skin fibroblasts (by fillipin staining) • defective cholesterol esterification (skin fibroblasts) • mutation analysis. Antenatal diagnosis is possible by filipin staining, cholesterol esterification studies, and/or mutation analysis of cultured chorion villous cells or cultured amniocytes. Management and outcome Currently, there is no satisfactory treatment for NPC disease. Supportive and symptomatic management includes nutritional support for early liver disease, antiepileptic therapy and anticholinergics for dystonia and tremor. Multidisciplinary support is essential in the later stages when there is significant neurological and psychomotor disabilty. A number of different therapeutic approaches have failed to halt neurological progression. Liver transplantation in a 7-year-old girl with NPC disease and hepatocellular carcinoma (Gartner et al. 1986) led to initial stabilization, but abnormal storage recurred in the transplanted liver and neurological deterioration continued. Similarly, bone marrow transplantation in a 2.5-year-old resulted in regression of hepatosplenomegaly and decreased infiltration of foamy macrophages in the bone marrow and lung, but failed to prevent neurological deterioration (Hsu et al. 1999). Combinations of cholesterollowering agents have reduced hepatic cholesterol stores, but have not altered the long-term outcome (Patterson et al. 2001). As glycosphingolipid accumulation in the brain is thought to be the basis of the neuropathology of NPC disease, it is possible that inhibition of glycosphingolipid synthesis may be useful. OGT 918 (N-butyldeoxynojirmycin) inhibits glucosyltransferase and impairs the synthesis of glycosphingolipids. It has been used in the

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treatment of non-neuronopathic Gaucher disease with favourable results (Cox et al. 2000). In animal models of NPC, N-butyldeoxynojirmycin has been shown to delay the onset of neurological symptoms, reduce glycosphingolipid accumulation and increase the average life span (Zervas et al. 2001). Therapuetic trials of Nbutyldeoxynojirmycin in humans with NPC disease are under development. Wolman disease and cholesteryl ester storage disease (CESD) These two rare disorders are caused by a recessively inherited deficiency of lysosomal acid lipase resulting in accumulation of cholesterol esters and triglycerides in most body tissues. The disorders are allelic conditions that represent extreme variants of the same enzyme deficiency, with some residual enzyme activity in CESD. A number of secondary changes occur, including increased cholesterol synthesis, up-regulation of LDL-receptor gene expression and increased lipoprotein production. These changes are more pronounced in Wolman disease, which is associated with more severe acid lipase deficiency than in CESD. Wolman disease and CESD are recessively inherited. The gene has been localized to chromosome 10q22.2-22.3, and over 20 mutations described (Human Gene Mutation Database). There is some genotype–phenotype correlation for CESD, as many patients are homozygous or heterozygous for a splice junction mutation in exon 8 (called D254-2771) (Aslanidis et al. 1996; Anderson et al. 1999). No common mutation has been described in Wolman disease (Assman & Seedorf 2001).

adult life, though liver enlargement is frequently detectable from early childhood (Assman & Seedorf 2001). Liver dysfunction, splenomegaly, hyperlipidaemia and xanthelesma are often present. Malabsorption and malnutrition are not features and adrenal calcification is rare. Hepatomegaly increases with time with fibrosis, and liver failure has been described. Though premature atherosclerosis and atheromas have been detected in autopsied patients, clinically significant coronary or systemic vascular atherosclerosis is rare. Diagnosis Suggestive abnormalities include: • adrenal calcification on abdominal X-ray or ultrasound (decreased adrenal responsiveness may be found on provocative tests) • vacuolated lymphocytes on peripheral blood film • sea-blue histiocytes in bone marrow aspirate • liver dysfunction • hypercholesterolaemia and hypertriglyceridaemia. Specific diagnosis: • acid lipase assay (leucocytes or cultured fibroblasts) and/or DNA sequencing. Liver histology in both conditions usually reveals enlarged and vacuolated hepatocytes and Kupffer cells as well as large numbers of foamy histiocytes (Assman & Seedorf 2001). Periportal fibrosis may be prominent and cirrhosis may also be evident. Foam cells may also be seen in bone marrow aspirates, spleen and lymph nodes. In Wolman disease, small intestinal biopsy usually reveals extensive infiltration of the lamina propria with foamy histiocytes. Antenatal diagnosis is possible by direct enzyme assay in chorion villus cells or by mutation analysis.

Presentation Wolman disease Patients usually present in the first few weeks of life with vomiting and diarrhoea, malabsorption, failure to thrive and hepatosplenomegaly (Assman & Seedorf 2001). Jaundice, low-grade pyrexia, anaemia, abdominal distension and leukopenia may be present initially. The most striking feature is adrenal calcification that is demonstrable radiologically in most patients; other characteristic features are vacuolated lymphocytes in peripheral blood films and foam cells in bone marrow aspirates. Neurological signs and symptoms are not prominent, though lipid storage in neurons, microglia and astrocytes as well as delayed myelination may be found histologically. A rapid downhill course follows the initial presentation, and most patients die by 3–6 months of age. CESD The clinical manifestations are variable and less severe. The usual presenting feature is hepatomegaly in

Management and outcome Treatment of Wolman disease with intravenous alimentation, plasma infusion, corticosteroids and dietary supplements has been of limited benefit (Wolman 1995). Bone marrow transplantation has led to significant clinical and biochemical improvement for up to 4 years in one patient (Krivit et al. 2000). CESD responds to 3-Hydroxy 3Methyl glutaryl (HMG) CoA reductase inhibitors, cholestyramine, a low-cholesterol diet and fat-soluble vitamin supplements with significant improvement in plasma lipoprotein abnormalities and possible improvement in organomegaly and adrenal dysfunction (Leone et al. 1991; Tarantino et al. 1991; Glueck et al. 1992). Successful liver transplantation for chronic liver failure has been reported (Arterburn et al. 1991; Ferry et al. 1991; Leone et al. 1995). Promising results have been reported with enzyme replacement therapy in a mouse model (Du et al. 2001).

Chapter 12: Metabolic Liver Disease Congenital disorders of glycosylation (carbohydrate deficient glycoprotein (CDG) syndrome) CDG syndrome refers to a group of metabolic disorders that arise from defective glycosylation of proteins. Almost all plasma proteins, many proteins of cellular membranes and connective tissues, blood group substances, immunoglobulins and certain hormones are glycoproteins. Mechanisms of the synthesis and function of glycoproteins are complex (Keir et al. 1999; Jaeken & Matthijs 2001; Jaeken et al. 2001). They are essential for many structural, transport, immunological, hormonal, cell–cell signalling and enzymatic functions. There are numerous defects in the synthetic pathway with severe multisystem clinical manifestations. Two main groups of CDG are recognized: CDG I (types a–f) is caused by defects of synthesis and transfer of the carbohydrate chain to the nascent protein molecule, while CDG II (types a–c) results from defective processing of the carbohydrate chains. The gene for phosphomannomutase (CDG Ia) has been localized and many mutations have been reported. The most frequent Caucasian mutation, R141H, is believed to be fatal in the homozygous state. Other mutations have been reported, such as F119L from Scandinavia, D188G from Belgium and the Netherlands, and F144L, R238P and Y229S from Japan (Jaeken et al. 2001). The genes for the other CDG subtypes are known (Online Mendelian Inheritance in Man (OMIM)).

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• Multisystem disease. The main clinical features include: failure to thrive, diarrhoea, pericardial effusions, liver disease and proximal tubulopathy. Hepatic involvement includes hepatomegaly, abnormal transaminases, hypoalbuminaemia, coagulopathy, steatosis, fibrosis and cirrhosis. Mortality is high in this group, and many patients do not survive beyond 2 years. CDG Ib CDG Ib is caused by phosphomannose isomerase deficiency, and is phenotypically different from CDG Ia. Around 10 patients have been reported with protein losing enteropathy and congenital hepatic fibrosis but without neurological involvement. Infants present with diarrhoea, vomiting, failure to thrive, hepatomegaly, oedema due to severe hypoalbuminaemia, coagulopathy, a thrombotic tendency and hyperinsulinaemic hypoglycaemia (Jaeken et al. 2001; Babovic-Vuksanovic et al. 1999). Inverted nipples and abnormal fat pads have been reported, but not facial dysmorphism (Hendriksz et al. 2001). CDG Ic–f and CDG IIa–c CDG Ic–f and CDG IIa–c are rare. These patients have dysmorphism, epilepsy, psychomotor retardation and peripheral neuropathy (Leonard et al. 2001). Some have hepatomegaly and liver dysfunction. Not all patients with CDG match known subtypes (CDGX). The clinical features of these patients include fetal hydrops, cataracts, psychomotor retardation, hypotonia, seizures, thrombocytopenia, diarrhoea, vomiting, ascites and renal tubulopathy (Leonard et al. 2001).

Presentation

Diagnosis

The most common disorder is CDG Ia, due to phosphomannomutase deficiency. Though neurological symptoms dominate the clinical picture in most cases, liver and gastrointestinal function pathology is common and is the predominant feature in CDG Ib. CDG syndrome should be considered in any patient with unexplained liver dysfunction, especially if there is multisystem disease.

Supportive findings are: • increased transaminases • hypoalbuminaemia • coagulopathy. Histological examination of the liver usually reveals fibrosis, and jejunal biopsies may show villous atrophy and lymphangiectasis. Separation of plasma transferrin isoforms usually reveals characteristic patterns, although not all cases are abnormal. Confirmation of the diagnosis requires specific enzyme analysis in lymphoblasts or fibroblasts and mutation analysis. Antenatal diagnosis is possible by a combination of enzyme analysis and mutation analysis in CDG Ia. Prenatal diagnosis has not been reported for the other CDG subtypes.

CDG Ia There are two groups (de Lonlay et al. 2001): • Neurological involvement. The main neurological manifestations in both groups are neonatal hypotonia, ataxia, squint, cerebellar hypoplasia and psychomotor retardation. Younger patients may have facial dysmorphism (almond-shaped, upslanting palpebral fissures, high forehead and prominent maxilla), inverted nipples and abnormal gluteal, perineal, or suprapubic pads of fat. Older children often have stroke-like episodes, retinitis pigmentosa, areflexia, spinal deformties, fixed flexion deformities and in females, absent puberty (de Lonlay et al. 2001; Kjaergaard et al. 2001). They do not have progressive neurodegenerative disease, though the neurological signs become more prominent as children grow older (de Lonlay et al. 2001).

Management Oral mannose supplementation is useful in treating CDG Ib, with improvement in gastrointestinal symptoms, haematological abnormalities and growth (Hendriksz et al. 2001). It is unclear whether it will prevent progressive

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liver disease in CDG Ib. There is no therapy available for other forms of CDG, and treatment is supportive.

Mitochondrial respiratory chain disorders Disordered mitochondrial function leads to a wide variety of pathological and clinical manifestations. Hepatic and gastrointestinal dysfunction are often involved, and these disorders must be included in the differential diagnosis of liver disease in infancy and childhood. The clinical spectrum is very wide, and presentation may range from prenatal manifestation as hydrops fetalis, acute neonatal liver failure (Chapter 5) to mild myopathy in adulthood. Inheritance is maternal or autosomal depending on whether the defects are due to mitochondrial or nuclear DNA. Presentation Multisystem involvement is characteristic of respiratory chain disorders, and the liver and gastrointestinal tract are important target organs. Liver disease in the neonatal period (see Chapters 4 and 5) or early childhood is a common presentation. Extrahepatic features are common and may include lethargy, hypotonia, vomiting, poor neonatal reflexes, seizures, recurrent apnoea and cardiomyopathy (Cormier et al. 1991; Munnich et al. 1996b; Cormier-Daire et al. 1997). Intrauterine growth retardation, fetal hydrops, neonatal ascites, renal tubular disease, elevated a-fetoprotein and hypoalbuminaemia have also been described. Usually, progressive hepatic, neurological and/or other systemic deterioration lead to death in infancy or early childhood. Occasionally, liver disease may be static or even resolve with time (Morris 1999). A syndrome of severe anorexia, diarrhoea, vomiting, villous atrophy and liver dysfunction in infancy associated with mtDNA rearrangements has been reported (Cormier-Daire et al. 1994). The diarrhoea may improve or resolve by 5 years of age, but progressive neurological symptoms lead to rapid deterioration and death. Pearson syndrome is a multisystem disorder of infancy that is characterized by exocrine pancreatic insufficiency and sideroblastic anaemia (Morris 1999). Some patients develop progressive liver disease or renal Fanconi syndrome; those that survive may improve spontaneously but develop progressive external ophthalmoplegia (resembling Kaerns–Sayre syndrome) in later life. Pearson syndrome is usually associated with mtDNA rearrangements (Rotig et al. 1995). mtDNA depletion syndrome, a relatively recently recognized condition that presents as hepatic failure, hypotonia, renal dysfunction and lactic acidosis in the first few weeks of life, is discussed in Chapter 5.

Diagnosis Investigations for respiratory chain disease include: • Plasma lactate. Persistently elevated blood lactate concentrations are an important clue to respiratory chain disease, but are not specific and may be found in any sick neonate or infant, especially with significant liver disease. Glucose loading tests and lactate : pyruvate ratios seldom add to the information provided by repeated lactate measurements. • Increased CSF lactate concentrations are more specific and must be compared with plasma lactate. • Muscle biopsy for: histology for evidence of steatosis, ragged red fibres (see Plate 12, Atlas: p. 443) histochemistry staining for cytochrome oxidase and succinate dehydrogenase electron microscopy for the number and morphology of mitochondria respiratory chain enzyme analysis (complexes I–IV) usually confirms the diagnosis. Defects are often expressed in muscle, even in the absence of myopathy. Expression of results as ratios of activity improves discrimination (Munnich et al. 1996a). • Liver histology characteristically reveals a combination of steatosis, fibrosis, cholestasis and necrosis (Morris 1999), and on electron microscopy there may be increased numbers of structurally abnormal mitochondria (see Plate 12, Atlas: p. 443). Respiratory chain enzyme analysis is possible on liver biopsy specimens, but the results may be difficult to interpret in the presence of liver failure. • Mutation analysis for known mitochondrial and nuclear DNA defects, particularly if respiratory chain enzyme studies are normal • Urine organic acid analysis may reveal abnormal but nonspecific findings. • Evidence of multisystem involvement (echocardiography, neuroimaging and neurophysiology). As most cases of mitochondrial disease are due to nuclear DNA defects that are yet unknown, it is rarely possible to consider antenatal diagnosis. However, if respiratory chain defects are expressed in skin fibroblasts from the index case, reliable biochemical diagnosis may be possible on chorionic villous cells (Wanders et al. 1996). Management Treatment includes cofactor therapy with riboflavin, artificial electron acceptors such as menadione and vitamin C, and a variety of free radical scavengers such as coenzyme Q10, vitamin E, ibedenone, carnitine and methylene blue (Morris & Leonard 1996). Experience is anecdotal and the results variable. Only coenzyme Q10 has been evaluated in large studies, which have not indicated

Chapter 12: Metabolic Liver Disease reproducible clinical or biochemical improvement (Morris & Leonard 1996). Consideration of liver transplantation is a difficult management issue in an infant with liver failure due to suspected mitochondrial liver disease. In general, multisystem respiratory chain disease is a contraindication to liver transplantation. In the patients where clinical disease appears to be confined to the liver, liver transplantation may be a therapeutic option. A few patients with isolated mitochondrial liver disease have undergone successful liver transplantation with excellent long-term outcomes and no evidence of extrahepatic involvement (Dubern et al. 2001; Rake et al. 2000). However, other patients have developed progressive neurological disease after transplantation, even though they had no neurological involvement prior to transplantation (Thomson et al. 1998; Sokal et al. 1999). The use of liver transplantation in treating progressive mitochondrial liver disease remains controversial (see also Chapter 5).

Peroxisomal disorders Peroxisomes are small membrane-bound intracellular organelles that contain about 40 different anabolic and catabolic enzymes. Their functions include: • b-oxidation of very long-chain fatty acids (VLCFA) • b-oxidation of phytanic acid, a dietary branched-chain fatty acid • b-oxidation of di and trihydroxycholestanoic acids to chenodeoxycholic acid and cholic acid, which are bile acids precursors • conjugation of chenodeoxycholic acid and cholic acid with taurine and glycine to form the bile acids • the initial reactions of isoprenoid (cholesterol, dolichol and ubiquinone) biosynthesis and plasmalogen synthesis • lysine metabolism • glyoxylate metabolism • hydrogen peroxide metabolism • eicosanoid (prostaglandins, leukotrienes, thromboxane, prostacyclin) degradation. Peroxisomal disorders are classified into two main groups: (i) multiple enzyme deficiencies (such as the ‘Zellweger spectrum’ disorders and rhizomelic chondrodysplasia punctata), which arise from defective peroxisome synthesis, assembly and enzyme import, and (ii) genetic deficiency of a single peroxisomal enzyme (such as adrenoleukodystrophy, classical Refsum’s disease and hyperoxaluria type I). Over 20 different disorders have been described. The overall prevalence has been estimated to be 1 : 25 000 (Roth 1999). The disorders of peroxisome biogenesis are genetically heterogeneous and belong to 11 different complementation groups without correlation between complementation group and phenotype (Moser et al. 1995). Mutations in the genes responsible for peroxisomal assembly (PEX

229

genes) are known to be associated with ZS, NALD, IRD and RCDP (Gartner 2000; Suzuki et al. 2001). Presentation Disorders with multiple enzyme deficiencies Patients who have a disorder of peroxisomal biogenesis lack normal peroxisomes. Four conditions are recognized: Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum’s disease (IRD) and rhizomelic chondrodysplasia puctata (RCDP). They are all associated with severely deranged peroxisomal assembly, loss of multiple enzyme activites and multisystem involvement. Peroxisomes are absent or greatly reduced in number in skin fibroblasts and liver biopsy specimens. Zellweger syndrome is the most severe, IRD less so and neonatal ALD is between the two (Raymond & Moser 1997). Zellweger syndrome (ZS) (see also Chapter 4). Infants with ZS present in the neonatal period with characteristic dysmorphic features (prominent forehead, large anterior fontanelle, broad nasal bridge, epicanthal folds, high arched palate, micrognathia, redundant neck skin folds, clinodactyly and talipes equinovarus). Neurological abnormalities are prominent, including severe hypotonia, areflexia, poor suck reflex and seizures (Gould et al. 2001). Neuronal migration defects may be observed on neuroimaging. Other features such as corneal clouding, cataracts, pigmentary retinopathy, polycystic kidneys, cryptorchidism, dislocated hips and stippled epiphyses on radiographs (chondrodysplasia punctata) may be present. Liver disease is common and includes hepatomegaly, conjugated hyperbilirubinaemia, progression to cirrhosis and liver failure in the first few months of life, but the hepatic involvement is overshadowed by the neurological symptoms. Occasionally, the presentation resembles malabsorption with hepatomegaly, prolonged jaundice, liver failure, anorexia, vomiting and diarrhoea leading to failure to thrive (Poggi-Travert et al. 1995). Failure of psychomotor development is evident in early infancy, and survival beyond 1 year is rare. Patients with NALD and IRD have the same features as ZS but a milder phenotype. Infants have hepatomegaly and neonatal cholestasis; progressive liver disease is only significant in children who survive the first decade (Gould et al. 2001). There is no hepatic involvement in ‘classic’ RCDP, which presents with dysmorphism and psychomotor retardation. Disorders due to single peroxisomal enzyme deficiencies There are many isolated peroxisomal enzyme deficiencies; hepatic involvement is present (Table 12.4). Intact peroxisomes are found in liver biopsy and skin fibroblast specimens, and the biochemical and clinical abnormalities relate to the individual pathway.

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Table 12.4 Disorders due to single peroxisomal enzyme deficiencies associated with liver disease. Disorder/enzyme defect

Genetics

Clinical features

Biochemical features

Hepatic involvement

Outcome

Palmitoyl acylCoA oxidase deficiency

AR

Severe hypotonia, psychomotor retardation, seizures in infancy; no dysmorphism

Elevated plasma VLCFA

Hepatomegaly, fibrosis

Death by 2–4 years

Bifunctional protein deficiency (enoylCoA hydratase and hydroxyacylCoA dehydrogenase deficiency)

AR

Similar to Zellweger syndrome

Elevated plasma VLCFA, DHCA, THCA, pristanic acid

Hepatomegaly, hepatic dysfunction, coagulopathy

Death by 6 months to 2 years

Di- and trihydroxychole-stanoic acidaemia (unknown enzyme defects)

Unknown

Heterogeneous disorders with mild dysmorphism, ataxia, psychomotor retardation

Elevated THCA, DHCA; normal VLCFA

Progressive liver dysfunction, failure

Unknown

Mevalonic aciduria (mevalonate kinase deficiency

AR

Severe deficiency: developmental delay, dysmorphism, hepatosplenomegaly, lymphadenopathy. Mild deficiency: hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS)

Mevalonic aciduria on urine organic acid analysis

Liver dysfunction

Death in infancy or early childhood in severe deficiency

AR, Autosomal recessive; VLCFA, plasma very long chain fatty acids; DHCA, plasma dihydroxy cholestanoic acid; THCA, plasma trihydroxy cholestanoic acid.

Diagnosis Peroxisome biogenesis (multiple enzyme defects) Initial investigations on plasma include: • very long chain fatty acids (VLCFA) • dihydroxyacetone phosphate acyltransferase (DHPAT) (blood) • phytanate/pristanate (plasma) • plasmalogens (plasma). Morphological studies of liver/skin for fibroblasts may show complete absence/reduced or abnormal structure of peroxisomes. The diagnosis is confirmed by specific enzyme analysis in skin fibroblasts. Antenatal diagnosis is possible by measurement of VLCFA concentration and/or plasmalogen synthesis in cultured chorion villous samples or amniocytes. Management There is no treatment for multiple-enzyme dysfunction, but supportive care with anticonvulsants, dietary supplements for the liver disease and muscle relaxants is essential. Bile acid supplements have reduced cholestasis in a child with ZS (Setchell et al. 1992), while docosahexanoic acid (DHA) has led to some clinical improvement in the

‘Zellweger spectrum’ disorders (Raymond & Moser 1997). Therapeutic options are available for some of the single-enzyme disorders.

Alpers–Huttenlochler syndrome (progressive infantile poliodystrophy, progressive neuronal degeneration of childhood, PNDC) Alpers–Huttenlochler or Alper’s syndrome refers to a rapidly progressive early childhood encephalopathy with intractable seizures and neuronal degeneration. The aetiology of this disorder is unknown, and it may represent a heterogeneous group of disorders with common clinicopathological features (Morris 1999). In most cases, liver dysfunction is a prominent late feature. Respiratory chain abnormalities have been identified in a number of individuals who fulfil the diagnostic criteria (Harding 1990; Lyon et al. 1996), including complex I defects (Tulinius et al. 1991a,b), partial complex IV deficiency (Morris 1999), mitochondrial DNA depletion (Naviaux et al. 1999; Rahman et al. 2002), decreased cytochrome a+a3 (Prick et al. 1983), decreased NADH utilization (Gabreels et al. 1984; Fischer et al. 1986), pyruvate dehydrogenase deficiency (Prick et al. 1981) and citric acid cycle dysfunction

Chapter 12: Metabolic Liver Disease (Tulinius 1991a). The mode of transmission is unclear, but autosomal recessive inheritance has been suggested as the most likely inheritance pattern (Shoffner 2001). Presentation Typically, the neonatal period is normal. Presentation is between 2 months and 2 years with physical and developmental delay followed by the sudden onset of intractable epilepsy. Rapid neurological deterioration and blindness usually follow the onset of seizures. Overt hepatic disease presents later with jaundice, hepatomegaly, coagulopathy and rapidly progressive liver failure (Narkewicz et al. 1991), though biochemical evidence of liver dysfunction may predate the seizures. The hepatic symptoms may be exacerbated by treatment with valproic acid (Zimmerman & Ishak 1982). Most patients do not survive beyond 3 years, but some may follow a protracted course (Harding 1990). A few patients may have typical neurological features of Alper’s syndrome without liver disease; these infants follow an identical neurological course (Lyon et al. 1996) (see also Chapters 5 and 7). Diagnosis • Liver dysfunction may initially be mild with elevation of transaminases and bilirubin, but later, synthetic function is impaired. • Plasma carnitine concentrations may be low. • Urinary organic acids are nonspecific consistent with liver dysfunction. • Electroencephalography demonstrates high-amplitude polyspikes. • Visual evoked responses are reduced or absent and • Electroretinograms are normal. • Computed tomography (CT) or magnetic resonance imaging scans show progressive cerebral atrophy with low-density areas in the occipital and posterior temporal areas; the white matter is usually spared. • Liver histology reveals microvesicular fatty change, bile duct proliferation, and focal necrosis leading to bridging fibrosis and cirrhosis (see Plate 12a, Atlas: p. 443). Neuropathology reveals cortical involvement, with neuronal cell loss and gliosis (Harding et al. 1986). There is no definitive metabolic test. Antenatal diagnosis has not been reported. Management There is no effective treatment. The condition is fatal, with most children dying before 3 years or within a few months of developing overt liver disease. Liver transplantation is contraindicated as neurological progression continues post transplant (Delarue et al. 2000).

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Reye syndrome Reye syndrome (RS) is an acute childhood illness characterized by encephalopathy and fatty degeneration of the liver. The definition of this disorder is nonspecific, and it is now recognized that a number of different conditions, especially some inborn errors of metabolism, can present as Reye syndrome. There has been a substantial decline in the number of cases of ‘classical’ Reye syndrome (Hardie et al. 1996; Belay et al. 1999), attributed to: public health campaigns warning against the use of salicylates in children with influenza-like illnesses (Belay et al. 1999); the declining use of antiemetic medications in childhood illnesses (Casteels-Van Deale et al. 2000); and an increasing recognition that many cases previously diagnosed as RS have an underlying metabolic disorder (Hardie et al. 1996). Presentation and definition An internationally accepted epidemiological definition of Reye syndrome is (Hardie et al. 1996): a child under 16 years of age with: I Unexplained non-inflammatory encephalopathy and one or more of: II Serum hepatic transaminases elevated three or more times upper limit of normal OR Plasma ammonia levels elevated three or more times upper limit of normal OR Characteristic fatty infiltration of the liver. There are two major groups: 1 ‘Classic’ or ‘idiopathic’ R S typically occurs in children over 5 years of age, usually associated with an influenza or varicella-like prodrome with aspirin use in therapeutic dosage. There is a biphasic presentation — a viral prodrome (upper respiratory tract or gastrointestinal infection) followed several days later by the abrupt onset of encephalopathy heralded by profuse vomiting (Glasgow & Middleton 2001), personality changes and altered consciousness. Raised intracranial pressure may result in death or permanent neurological sequelae. The aetiology of this form of RS remains unclear, but epidemiological studies have suggested an association with aspirin exposure (Hall et al. 1988; Forsyth et al. 1989), or alternatively, the combination of a viral illness and the extrapyramidal reactions induced by anti-emetics may result in a clinical syndrome indistinguishable from RS (Casteels-Van Deale et al. 2000). 2 ‘Atypical’ RS or ‘Reye-like’ illnesses present in a similar manner to ‘classical’ RS, but in children less than 5 years of age. ‘Atypical’ RS is often associated with inherited metabolic disorders of fatty acid oxidation (such as medium

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chain acyl CoA dehydrogenase (MCAD) deficiency), disorders of organic acid and amino acid metabolism as well as urea cycle defects (Hardie et al. 1996). A number of patients previously diagnosed with RS have had the diagnosis revised when a metabolic, toxic or another cause has been identified on further investigation (Rowe et al. 1988; Porter et al. 1990). It is likely that the expansion of newborn screening programmes for metabolic disorders will result in a decline in the numbers of children presenting with ‘atypical’ RS. There is considerable overlap between these two groups, and all children with any form of RS must undergo thorough investigation to rule out potential underlying causes.

as a metabolic disorder or infection is identified, appropriate specific therapy is indicated. Liver transplantation is usually not necessary and may be contraindicated if there is severe multisystem involvement.

Disorders of intermediary metabolism Metabolic defects in intermediary metabolism involve catabolic pathways of amino acids, organic acids, fatty acid oxidation and the urea cycle. Some of these disorders present with liver dysfunction, a ‘Reye’-like encephalopathy (see p. 231), a mild ‘biochemical’ liver dysfunction or, more rarely, as acute liver failure. Tyrosinaemia type I

Investigation of Reye’s and Reye-like illness Typically, investigations demonstrate: • prolonged prothrombin time • hepatic dysfunction with raised aminotransferases • elevated ammonia • hypoglycaemia • CT scan may demonstrate cerebral oedema • EEG demonstrates marked slowing. Liver histology is not s pecific; usual findings are a microvesicular steatosis with glycogen depletion and cytoplasmic swelling. Electron microscopy confirms a loss of glycogen and demonstrates proliferation of smooth endoplasmic reticulum and an increase in peroxisomes. Mitochondria may be pleomorphic. Skeletal muscle demonstrates glycogen deposition and fat deposition. Aetiological investigations for treatable metabolic disorders include: • urine organic acids • urine amino acids • plasma amino acids • plasma and/or blood spot acylcarnitine profiles • screening for common MCAD and long chain hydroxyacyl CoA dehydrogenase (LCHAD) deficiency mutations. It is also important to rule out other causes of coma associated with abnormal biochemical liver function tests, including toxins, severe hypoxia and infections such as hepatitis and septicaemia. Management Management of ‘classic’ RS is directed towards supportive treatment of acute cerebral oedema, metabolic abnormalities, coagulopathy and hepatic encephalopathy (Chapter 7). It is important to treat cerebral oedema adequately in intensive care units with full facilities for monitoring and controlling raised intracranial pressure (Chapter 7), as the prognosis depends on the prevention of irreversible brain damage. If an underlying cause such

Amino acid disorders generally do not present with liver disease with the exception of tyrosinaemia type I (Tyr I), which is described in Chapter 5. Organic disorders Organic acids are carboxylic acids of low molecular weight, and are metabolites of amino acids, carbohydrates and fats. Organic acid disorders are due to defects in the catabolism of the branched chain amino acids, isoleucine, isoleucine and valine, and metabolism of propionate (Sweetman & Williams 2001; Fenton et al. 2001; Figs 12.1 and 12.2). The accumulated organic acids exist as carnitine conjugates, e.g. propionyl carnitine, isovaleryl carnitine. The commonest disorders are: methylmalonic acidaemia (MMA), propionic acidaemia (PA) (see Chapter 5) and isovaleric acidaemia (IVA); their combined incidence is in the order of 1 : 30 000–40 000. Presentation All these disorders have a neonatal presentation in the first few days of life (see Chapter 5); but a less acute presentation in infancy/early childhood with developmental delay, failure to thrive, with metabolic acidoses secondary to episodic illness is common. A ‘Reyelike’ encephalopathy may also occur. In these cases there may be elevation of hepatic transaminases (see Table 12.5). Diagnosis Characteristic features of these disorders include: • metabolic acidosis • hypoglycaemia • hypocalcaemia • ketonuria • neutropenia • hyperlactic acidaemia • hyperuricaemic • increased plasma and urine glycine. Diagnostic tests: • urine organic acids

Chapter 12: Metabolic Liver Disease VALINE

ISOLEUCINE

LEUCINE

2-oxo-3-methylvaleric acid

2-keto-isocaproic acid

233

Reduced 2-oxo-isovaleric acid CoA

NAD 1

1

1

2-methybutyryl CoA

isobutyryl CoA

isovaleryl CoA

+

NADH + H

CO2

FADH 2

tigyl CoA

methylacrylyl CoA

3-methylcrotonyl CoA FADH2 3 CO2

2-methy-3-hydroxy butyryl CoA

3-hydroxy sobutyryl CoA

3-methylgltaconyl CoA Biotin H2O

CoA

8

4

3-hydroxyisobutyrate

2-methylacetoacetyl CoA

3-hydroxy-3-methylglutaryl CoA

CoA

methylmalonic semialdehyde

Fig. 12.1 Disorders of branched amino acid catabolism. 1 Maple Syrup Urine Disease; 2 Isovaleric Acidaemia; 3 Methylcrotonylglycinuria; 4 Methylglutaconic Aciduria; 5 3-Hydroxy 3-Methylglutaric Aciduria; 6 Mevalonic Aciduria; 7 b-ketothidase deficiency; 8 3-Hydroxyisobutyric Aciduria; 9 Propionic & Methylmalonic Acidaemia.

7

5

Propionyl CoA

Acetyl CoA

Acetyl CoA

AcetoAcetate

Mevalonic Acid

CoA 9 Propionyl CoA

6

9 Succinyl CoA

Cholesterol

• acyl carnitine species (blood) • enzymes/substrate incorporation studies (fibroblasts). DNAanalysis is not usually required as metabolite profiles (organic acids and acyl carnitines) are usually diagnostic.

heparinized plasma) and urine (random) should be collected when the infant is acutely ill, i.e. before treatment with a low-protein diet is started (Chapter 5).

Management Whenever possible, specimens (blood, e.g.

There are six disorders of the urea cycle. Most present

Urea cycle disorders

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Table 12.5 Organic acid disorders. Conditions

Presentation/clinical features

Hepatic involvement

Propionic acidaemia Methylmalonic acidaemia Isovaleric acidaemia

Neonatal presentation: acute encephalopathy, hyperammonaemia, acidosis Acute intermittent late-onset form: Recurrent encephalopathy or Reye-like illness in infancy Chronic, progressive form: Anorexia, failure to thrive, gastrointestinal symptoms, psychomotor retardation

Hepatomegaly, hyperammonaemia, elevated transaminases, fatty infiltration on biopsy; pancreatitis has been described

3 methyl crotonyl glycinuria

Reye-like illness in infancy or early childhood; recurrent acidosis, hypoglycaemia, coma; chronic presentation with developmental delay has been described

Biochemical and histological features resembling Reye syndrome

3 methyl glutaconic aciduria

Variable presentation, including recurrent acidosis, hepatomegaly, Reye-like episodes, speech delay, hypotonia

Liver dysfunction and Reye-like features have been described

3 hydroxy 3 methyl glutaric aciduria

Neonatal, infantile or childhood presentation with vomiting, lethargy, coma, hyperammonaemia and hypoketotic hypoglycaemia; Reye-like illness beyond the neonatal period

Biochemical and histological features resembling Reye syndrome

Mevalonic aciduria

Variable presentation with dysmorphism, failure to thrive, psychomotor retardation, ataxia, recurrent fever with rash, diarrhoea and vomiting; milder variant with periodic fever and hyperimmuniglobulinaemia D

Hepatosplenomegaly and cholestatic liver disease have been described

Mitochondrial acetoacetylCoA thiolase deficiency (b-ketothiolase deficiency)

Infantile presentation with ketoacidosis during acute infections; hyperglycaemia and hyperammonaemia may occur; asymptomatic between attacks

Fatty infiltration of the liver has been described

3-hydroxyisobutyric aciduria

Infantile presentation with dysmorphism, brain malformations, ketosis, acidosis, failure to thrive

Not described

Malonic aciduria

Presentation in infancy or early childhood with acidosis, hypoglycaemia, developmental delay and cardiomyopathy

Not described

Table 12.6 Classification and genetics of porphyrias. Porphyria types

Condition

Deficient enzyme

Genetics

d-ALA dehydratase deficiency Acute intermittent porphyria Congenital erythropoietic porphyria Porphria cutanea tarda

ALA dehydratase PBG deaminase Uroporphyrinogen cosynthase Uro-porphyinogen decarboxylase Uro-porphyinogen decarboxylase Copro-porphyrinogen oxidase Protopophyrinogen oxidase Ferrochelatase

AR AD AR

Hepato-erythropoietoic porphyria Hereditary coproporphyria Variegate porphyria Erythropoietic protoporphyria

Acute neurovisceral

Cutaneous

+ +

Hepatic + +

+

Acquired (some cases familial) AD

+

+

+

+

+

AD

+

+

+

AD

+

+

+

Probably AR

ALA, d-Aminolevulinic acid; PBG, porpholinogen; AD, dominant; AR, autosomal recessive.

Erythropoietic

+

+

+

Chapter 12: Metabolic Liver Disease Gut Bacteria

235

Propionate

Cholesterol Thymine Uracil Isoleucine Valine Methionine Threonine Odd chain fatty acids

Propionyl CoA

HCO3 (1) D-Methylmalonyl CoA

(2a) L-Methylmalonyl CoA (2c) (2b)

Cobalamin II

Fig. 12.2 Disorders of propionate metabolism. (1) Propionic acidaemia; (2a, 2b) Methylmalonic acidaemia due to mutase deficiency; (2c) Methylmalonic acidaemia, due to defects in Cobalamin metabolism.

Hydroxy Cobalamin

with hyperammonaemia in the neonatal period. The later onset forms have variable presentation which includes an encephalopathic (‘Reye-like’) episode, anicteric hepatitis and/or mild hepatomegaly (see Chapter 5). Fatty acid oxidation defects Mitochondrial b-oxidation of fatty acids plays a major role in energy production, especially during periods of fasting. It is a complex process that involves uptake of fatty acids into the cell, activation to acyl CoA and then transport into the mitochondria, which requires the carnitine transport cycle. Within the mitochondria, the boxidation spiral requires a series of enzymes with carbon chain length specificity. These disorders can present as a ‘Reye-like’ illness (e.g. MCAD) or with acute illness usually in early infancy, with hepatomegaly/liver dysfunction. Fatty acid oxidation defects and urea cycle defects are covered in Chapter 5.

Cobalamin I

5 deoxy adenosyl obalamin

Succinyl CoA

which result in neurovisceral symptoms and/or cutaneous photosensitivity. They do not usually present as liver disease, but several forms can exhibit liver dysfunction. Most are caused by genetic deficiencies of the enzymes involved in haem biosynthesis, except for porphyria cutanea tarda, which is believed to be an acquired condition. Though porphyrias usually present in adulthood, symptoms can occasionally occur in childhood. Haem is synthesized in the bone marrow for haemoglobin synthesis and in the liver for cytochrome p450 enzymes. The liver and bone marrow pathways are differently regulated, and drugs, hormones and diet which may influence the pathway in the liver do not effect the bone marrow. The porphyrias are classified according to the primary tissue affected (hepatic or erythropoietic porphyrias), the specific enzyme deficiency, or the clinical presentation (acute neurovisceral or cutaneous) (Table 12.6). Presentation

The porphyrias The porphyrias are disorders of haem biosynthesis,

Symptoms may be non-specific. Liver disease is not usually a presenting feature, although secondary liver

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disease may occur in some of the defects. Neurovisceral features are common if there is an accumulation of porphyrin precursors, especially d-aminolevulinic acid. Acute intermittent porphyria is the commonest acute porphyria (Grandchamp 1998; Kaupinnen & Mustajoki 1992), with an estimated prevalence of 5 per 100 000 in northern European populations. Symptoms rarely occur in childhood and many adults with the genetic mutation remain asymptomatic. Acute attacks are precipitated by certain drugs, steroid hormones and poor nutrition. Typical manifestations during an acute attack include abdominal pain, nausea, vomiting, limb and chest pain, muscle weakness, peripheral neuropathy, tachycardia, hypertension, tremors and hypertension. Electrolyte imbalance, seizures, motor neuropathy and death may occur if the porphyria is not recognized and treated. Attacks may last several days, and complete recovery follows appropriate treatment. There is an increased risk of hepatocellular carcinoma in acute intermittent porphyria, as well as in porphyria cutanea tarda (see below). Similar neurovisceral symptoms occur in other acute porphyrias (Table 12.2). Porphyria cutanea tarda is the most common cutaneous porphyria (Elder 1998), which presents with chronic, blistering skin lesions on sun-exposed parts of the skin, such as the hands, neck, face, and back. Hypertrichosis, hyperpigmentation, thickening, scarring and calcification of affected skin may occur. Precipitating factors include alcohol intake, smoking, hepatitis C infection and oestrogen use. Patients with congenital erythropoietic porphyria may also have haemolytic anaemia and discolouration of the teeth. Erythropoietic protoporphyria may be complicated by liver disease, gall stones and rapidly progressive hepatic failure (Cox et al. 1998) which may be related to protoporphyrin accumulation in the liver. If liver dysfunction is associated with skin abnormalities or acute neurovisceral symptoms, then porphyria should be considered in the differential diagnosis. Diagnosis and genetics The clinical presentation determines relevant diagnostic tests. With acute neurovisceral symptoms, urinary daminolevulinic acid, porphobilinogen and total porphyrins are the most useful first-line tests, whereas with cutaneous symptoms, total plasma porphyrins should be measured initially (Egger et al. 2000). Faecal and erythrocyte porphyrins, specific enzyme assays and DNA analysis are necessary for confirmation of the specific diagnosis. Management Management is complex and varies for different disor-

ders and specific patients. Liver function should be monitored where appropriate. In eyrthropoetic porphyria, blood transfusions or haem therapy may be indicated in liver acute failure. Bone marrow transplantation and/or liver transplantation may be beneficial (Egger et al. 2000).

Abetalipoprotinaemia Lipids are transported in plasma as soluble lipoproteins, and classified according to their density and electrophoretic mobility. The typical lipoprotein consists of a lipid core (cholesterol and triglycerides) surrounded by a layer of phospholipid and cholesterol molecules and protein moieties called apoproteins. There are two major lipoprotein transport pathways: the exogenous pathway involves the transfer of dietary lipids from the intestines to the liver as chylomicrons, whereas the endogenous pathway transports lipids from the liver to peripheral tissues as very low density lipoproteins (VLDL). Apoprotein B is the major component apoprotein of chylomicrons and VLDL, and abnormalities of this protein result in significant disruption of the major lipid transport pathways, with potentially serious clinical consequences. Abetalipoproteinaemia is a rare, autosomal recessive disorder that is associated with absence of plasma b lipoprotein, undetectable plasma chylomicrons, LDL and VLDL levels, and results in severe fat malabsorption and secondary deficiency of fat-soluble vitamins. There is defective processing of B apoproteins or defective assembly and/or secretion of VLDL and chylomicrons. Microsomal triglyceride transfer protein (MTP) permits the transfer of lipid to apoprotein B, and several mutations in the gene controlling this protein have been reported in patients with abetalipoprotinaemia (BerriotVaroqueaux et al. 2000). Presentation The main clinical features include (Rodriguez-Oquendo & Kwiterovich 2000): • Presentation in early infancy with diarrhoea, vomiting and failure to thrive. The intestinal symptoms relate to the amount of fat in the diet; many patients develop a striking aversion to dietary fat. • Fat malabsorption with fat-soluble vitamin deficiency. • Acanthocytosis occurs as a result of altered lipid composition of erythrocyte membranes and results in shortened erythrocyte survival, hyperbilirubinaemia, erythroid hyperplasia and reticulocytosis. • Spinocerebellar degeneration begins in adolescence and consists of ataxia, dysmetria, dysarthria and peripheral neuropathy. • Pigmentary retinal degeneration develops in late childhood and may lead to progressive blindness.

Chapter 12: Metabolic Liver Disease • Anaemia secondary to nutritional deficiency and/or haemolysis may be present. • Fatty infiltration of the liver is common, and cirrhosis has been reported in a number of individuals, especially after medium chain triglyceride (MCT) supplementation. Diagnosis Diagnosis is suspected from: • acanthocytosis • low plasma vitamin concentration • absence of B lipoprotein on electrophoresis • undetectable apo B. Hypobetalipoprotinaemia refers to a distinct group of conditions associated with mutations of the apoprotein B gene. Over 30 mutations are currently known (human gene mutation database (HGMD)). The condition is dominantly inherited. Heterozygotes are asymptomatic. In the homozygous state, the clinical symptoms are indistinguishable from those of abetalipoprotinaemia, and these patients can only be differentiated by demonstrating hypolipidaemia in their parents. The approach to treating homozygotes is the same as for abetalipoprotinaemia. Management The gastrointestinal symptoms respond to a low-fat diet (total fat intake < 15 g/day), with clinical improvement and accelerated growth. Essential fatty acid supplementation is important. Medium chain triglycerides release fatty acids without the formation of chylomicrons for absorption, and could be used as a dietary energy source in abetalipoprotinaemia, but there is a risk of hepatic fibrosis (Rodriguez-Oquendo & Kwiterovich 2000). Nevertheless, short-term use of MCT feeds may be helpful for extremely malnourished individuals. Fat-soluble vitamin supplementation (oral), especially vitamin A and vitamin K, is necessary. Tocopherol (vitamin E) supplementation (150–200 mg/kg/day) inhibits the progression of neurological and retinal disease and may ameliorate these symptoms if started early (Bishara et al. 1982; Chowers et al. 2001).

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Chapter 13: Disorders of Copper Metabolism STUART TANNER

Copper metabolism, 243 The Wilson’s disease protein ATP7B, 243 The ATP7B gene, 245 Caeruloplasmin, 245 The prion protein, 246 Normal values, 246 Wilson’s disease (WD, McKusick277900), 246

Pathology, 249 Diagnosis, 249 Diagnosis in practice, 251 Treatment, 251 The future, 254 Non-Wilsonian copper-related cirrhosis in childhood, 254 ICC, 254 Tyrolean childhood cirrhosis, 255

Copper metabolism Copper is a component of cytochrome oxidase and other important cuproenzymes fundamental to free radical defence, neurotransmitter function, connective tissue synthesis, and iron metabolism (Table 13.1). Body copper status is largely regulated by biliary excretion whereas iron status is regulated by intestinal absorption. Copper is an essential nutrient. The recommended copper intake in the first 6 months of life is 80 mg/kg/day (Lönnerdal 1998). Estimated copper intakes in US children are 0.9–1.8 mg/day. The permitted copper concentration in drinking water is 2 mg/l. Clinical effects from either excess copper or copper deficiency are rare. Infantile copper toxicosis is considered below. Copper deficiency in infancy causes anaemia, neutropenia and bone changes and occurs if prematurity, malnutrition and chronic diarrhoea are associated with dietary deficiency. Copper is toxic, readily participating in reactions which promote the synthesis of damaging reactive oxygen species and is therefore transported in a protein-bound form. The transporter Ctr1 is responsible for high-affinity copper uptake into human cells, including enterocytes. Mice completely deficient for Ctr1 exhibit profound growth and developmental defects and die in utero in mid-gestation whilst heterozygotes exhibit tissuespecific defects in copper accumulation and copperdependent enzymes. The divalent metal transporter (DMT1) may also contribute to copper uptake in the enterocyte. Within the enterocyte, copper is bound to metallothionein, a 10 kDa cytosolic cysteine-rich protein. Metallothionein synthesis is induced by zinc, causing copper to be bound in the enterocyte and lost as it is desquamated at the villous tip, a ‘mucosal block’ to

Sporadic infantile copper toxicosis related to well water, 256 Childhood copper toxicosis without excess copper ingestion, 256 Conclusions and recommendations, 256

absorption. Copper is exported from the enterocyte to portal blood by the Menkes’ protein, ATP7A, absence of which causes accumulation of copper within intestinal cells, hence failure of absorption and apparent systemic copper deficiency. Copper is carried in portal blood loosely bound to albumin and to amino acids, particularly histidine. Hepatocyte copper handling is shown in Fig. 13.1. As in the gut, uptake at the plasma membrane is mediated by Ctr1. Copper is then chaperoned to its various intracellular destinations. Cox17p chaperones copper to the mitochondrion where it is essential for the assembly of functional cytochrome c oxidase. This is clearly an essential mechanism, as a mouse model using knockout Cox17p(–/–) mouse embryos do not survive gestation. The copper-chaperone for superoxide dismutase (CCS) carries copper to superoxide dismutase while Atox1 chaperones copper to the NH2-terminal domain of the Wilson’s disease protein ATP7B. Several Wilson’s disease (WD) mutations disrupt the protein–protein interactions between ATP7B and Atox1, suggesting that these interactions are important for normal copper homeostasis. Atox1 also regulates the copper occupancy of ATP7B. As yet, human disorders associated with Ctr1 or copperchaperone abnormalities have not been recognized. The Wilson’s disease protein ATP7B The Wilson’s disease gene ATP7B codes for a protein ATP7B whose structure is compatible with its proposed function as a transmembrane ATP-dependent copper transporter (Bull et al. 1993, Petrukhin et al. 1993, Tanzi et al. 1993). In the presence of increased copper concentration: 1 Copper binds to the six N-terminal domains.

243

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Table 13.1 Essential cuproenzymes. Enzyme

Action

Function

Cytochrome c oxidase

Transfers 4 electrons to O2 O2 + 4e- + 4H+Æ2H2O

Cellular respiration

Superoxide dismutase

2O2ÆH2O2 + O2

Free radical scavenging Antioxidant defence Dysfunction associated with amyotrophic lateral sclerosis

Lysyl oxidase

Oxidative deamination of lysine in newly formed collagen and tropoelastin

Connective tissue synthesis

Tyrosinase

Monophenol monooxygenase

Melanin synthesis

Dopamine b-monooxygenase

DopamineÆnoradrenaline

Catecholamine synthesis

Caeruloplasmin

Ferroxidase

Oxidizes ferrous iron released by storage sites to ferric iron which is transported by transferrin

Hepatocyte

nucleus SOD1 Transcription factors

CCS Cu1+

Cu1+ Ctr1

Holocaeruloplasmin

Atox 1

Albumin Histidine

ATP7B

Co

x1 7p

mitochondrion Cox

trans-Golgi

canaliculus

Fig. 13.1 Copper (Cu) is actively transported into the hepatocyte by Ctr1 at the basolateral membrane and handed to specific copper-chaperones. Atox1 carries Cu to the Wilson’s disease protein (WDP) in the trans-Golgi; CCS to cytoplasmic superoxide dismutase; and Cox 17p to mitochondria for cytochrome c oxidase (Cox). Any unbound cytoplasmic Cu is complexed to glutathione or metallothionein, and excess Cu is

sequestered in lysosomes. ATP7B transports Cu to the interior of the trans-Golgi where it is inserted into apo-caeruloplasmin. Holo-caeruloplasmin is exported into plasma. Cu induces ATP7B to traffic from trans-Golgi towards cytoplasmic vesicles adjacent to the bile canalicular membrane to achieve Cu excretion.

Chapter 13: Disorders of Copper Metabolism

245

Table 13.2 Wilson’s disease and Menkes’ disease. Feature Synonym Inheritance Gene locus Gene Tissue expression Cellular location of gene product membrane with Cu load Biochemistry

Pathology

Phenotypic variability Severe Mild Mutations reported 1997 Animal models

Wilson’s disease

Menkes’ disease

Hepatolenticular degeneration Autosomal recessive 13q14.3 ATP7B 21 exons, 7.5 kb Liver, kidney, placenta, brain Probably trans-Golgi, mainly bile canalicular membrane Cu trapped in hepatocytes Impaired caeruloplasmin synthesis Secondary basal ganglia Cu deposition Secondary Cu deposition in eye Hepatic damage Basal ganglia dysfunction Kayser–Fleischer rings Hepatic failure Late-onset neurological disease 95 (Cardiff database) Long Evans Cinnamon rat; Toxic milk mouse

2 There is phosphorylation of the invariant aspartyl residue, which leads to: 3 trafficking of the copper-laden ATP7B from trans-Golgi to a vesicular compartment adjacent to the canalicular membrane. Mutations that block formation of the phosphorylated catalytic intermediate prevent copper-induced relocalization from the TGN whilst mutations in the phosphatase domain result in hyperphosphorylation and constitutive trafficking from the TGN to the plasma membrane. There is little information about two important steps distal to ATP7B, namely the transfer of copper to apocaeruloplasmin, and passage of copper into the biliary canaliculus, both of which are impaired in Wilson’s disease. Cholestasis from any cause impairs biliary copper excretion. The nature of the high-molecular-weight copper complexes within bile remains controversial. Biliary copper is not reabsorbed in the gut. ATP7B shares a similar structure and presumed function with ATP7A, the Menkes’ protein, but differs in tissue localization. The Menkes’ gene is expressed in all tissues except liver; the Wilson’s gene is expressed only in liver, kidney, placenta and brain (Table 13.2). Within the kidney, ATP7B in the loops of Henle may have a role in copper reabsorption. Raised urinary copper levels in WD are probably a result of tubular ATP7B deficiency rather than simple copper ‘overflow’.

Kinky hair, steely hair X-linked Xq13.3 ATP7A All tissues except liver Trans-Golgi, trafficking to plasma Cu trapped in enterocytes Systemic Cu deficiency Impaired cuproenzyme synthesis

Abnormal connective tissue, cerebral vasculature

Menkes’ unresponsive to Cu-his Occipital horn syndrome 47 Mouse mutants (mottled, brindled, etc.)

The ATP7B gene The ATP7B gene is at 13q14.3 adjacent to the retinoblastoma locus. It is 7.5 kb in length and contains 21 exons. Many mutations have been described, scattered throughout the gene, with exons 8 and 14 being ‘hot-spots’. Described mutations include deletions, insertions, missense, nonsense, and splice site. An approximately 1.3-kb promoter of the WD gene contains four metal response elements. There is some evidence of a genotype/phenotype relationship. In patients homozygous for the H1069Q mutation, presentation is later and more likely to be neurological than in compound heterozygotes or patients with two other mutations. However, within a group of H1069Q homozygotes, many different clinical presentations have been reported. Indeed, different phenotypes are found in siblings with the same WD genotype. It is likely that the effect of genotype on clinical manifestation is modified by as yet unknown genetic or environmental factors. Caeruloplasmin Caeruloplasmin is a ferroxidase, the function of which is best demonstrated by the effects of its deficiency. In the recessive condition acaeruloplasminaemia, which presents

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with diabetes and dementia in middle adult life, there is no defect in copper transport, but a failure to mobilize iron from tissues, notably glial cells (Table 13.3). The low plasma caeruloplasmin concentrations seen in WD are not associated with an obvious disturbance of iron metabolism, although there is one report of an increase in hepatic iron concentration during penicillamine treatment and one ferrokinetic study showing increased cerebral iron uptake in Wilson’s disease. The prion protein Prion diseases such as bovine spongiform encephalopathy and Creutzfeldt–Jakob disease are characterized by the conversion of a normal cellular protein, the prion protein, to an abnormal isoform that is thought to be responsible for both pathogenesis and the infectious nature of the disease agent. There is now evidence that the prion protein is an antioxidant whose function may depend on its ability to bind copper. Once the prion protein binds Cu, it acts like a superoxide dismutase. Loss of this antioxidant protection could be responsible for neurodegeneration. In sporadic Creutzfeldt–Jakob disease (sCJD) there is a

decrease of up to 50% of copper and an increase in manganese of approximately 10-fold in the brain. Normal values Normal values for copper-related parameters are shown in Table 13.4. The neonate differs from these values in having a low plasma caeruloplasmin and copper, and a raised hepatic copper concentration, with values of up to 450 mg/g dry weight at birth falling to adult values (< 50 mg/g) by 6 months. The newborn thus resembles the patient with Wilson’s disease. This state presumably allows the fetus to store liver copper during gestation. It also makes a biochemical diagnosis of Wilson’s disease impossible before 3 months of age. The copper overload syndromes of man are shown in Table 13.5.

Wilson’s disease (WD, McKusick277900) The prevalence in Europe is reportedly 12–18 per million (see Hoogenraad (1996) for an account of the history of WD; Hoogenraad & Howen 1996) (approximately 1 in 50 000 to 1 in 80 000). Prevalences as high as 1 in 30 000 are

Table 13.3 Hereditary acaeruloplasminaemia. Inheritance Clinical features Pathology Biochemistry

Cause Gene locus Described mutations Treatment

Autosomal recessive Dementia, dysarthria, dystonia, diabetes mellitus, onset 40–60 years Iron deposition in liver, pancreas and brain Neuronal loss, gliosis Plasma caeruloplasmin and Cu very low: hepatic Cu normal Plasma Fe low; hepatic Fe raised Basal ganglia Fe deposition shown on magnetic resonance imaging Failure of caeruloplasmin synthesis 3q25 5-bp insertion in exon 7 nt2389delG in exon 13 None

Table 13.4 Biochemical diagnosis of Wilson’s disease. Parameter Plasma caeruloplasmin (mg/l) Urine Cu prepenicillamine (mmol/24 h) Urine Cu after penicillamine (mmol/24 h) Liver copper (mg/g dry weight) Serum copper (mM) Free copper* (mM)

Normal

Wilson’s disease

> 200 < 1.25 < 25 15–50 11–24 < 1.6

< 200 in 85–90% of cases > 3 in 65% of ‘hepatic ‘cases > 25 in 90% of ‘hepatic’ cases > 250 Low, normal or high (see text) Raised, > 7 mM suggests WD

*Free (non-caeruloplasmin) serum copper (mm) is calculated on the basis that caeruloplasmin contains 0.3% copper, and is approximately total Cu (mm)·–0.05 (caeruloplasmin mg/l).

Chapter 13: Disorders of Copper Metabolism

Cu

SEPHL

ATP

Cu

TGDN

NH2

DKTG

Cu

Pi

hinge

Cu Cu

247

Cu

trans-Golgi membrane

Fig. 13.2 The Wilson’s disease protein (ATP7B) is similar in structure to several other bacterial and eukaryotic cationic transporters which are collectively known as P-type ATPases because during the transport cycle there is reversible protein phosphorylation by ATP at an invariant aspartate residue, forming a co-valent phospho-protein intermediate. It is 57% homologous with the Menkes disease protein, with higher homology in functional regions. ATP7B contains the following

CPC

COOH

Cu

functional domains: 8 transmembrane sequences [1–8], in 1 of which (region 6) is the cys-pro-cys sequence found in all P-type ATPases and thought to form an ion channel; 6 copper binding regions [CXXC] containing cys-X-X-cys motifs at the amino terminal end; ATP binding, aspartyl kinase (DKGT) and phosphorylation domains. Alternatively, spliced forms of WND lacking transmembrane sequences 3 and 4 (exon 8) are expressed in brain.

Table 13.5 Hepatic copper overload states in man. State

Cause

Neonate Prolonged cholestasis (e.g. biliary atresia) Wilson’s disease

Physiological Impaired biliary Cu excretion Absent trans-Golgi Cu exporter

Infantile copper toxicosis (e.g. ICC, Tyrolean childhood cirrhosis)

Increased Cu ingestion,? + other genetic or toxic factors Unknown

Sporadic copper-related cirrhosis

reported from inbred communities. Wilson’s disease may present in many different ways (Table 13.6). Adding together various series, the relative proportions of the four major presentations in 400 patients were: hepatic 20%, hepatic and neurological 20%, neurological or psychiatric 50%, and 10% other causes. However, since these surveys were from adult neurological units they almost certainly underestimate the frequency of childhood hepatic cases, in particular failing to recognize cases of fulminant WD in childhood. Although Wilson’s disease may present as early as 3 years and as late as 60 years, the majority of cases

Animal model Most mammals Bile duct ligation LEC rat Toxic milk mouse None ?Bedlington terrier disease

present at 6–12 years with liver disease, or during adolescence or early adult life with neurological or psychiatric manifestations. Hepatic manifestations The hepatic manifestations of Wilson’s disease may be of almost any variety and severity (Table 13.6). The important practical message therefore is: suspect Wilson’s disease in any child with undiagnosed liver disease. Presentations include:

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Table 13.6 Modes of presentation of Wilson’s disease. Mode

Features

Asymptomatic

Detected during screening of family members

Hepatic

1 Insidious onset of vague symptoms followed (usually 4–12 years) by jaundice 2 Acute hepatitis 3 Fulminant hepatic failure with haemolysis 4 Portal hypertension: bleeding varices, ascites 5 Decompensated cirrhosis

Neurological (in second decade)

Deteriorating school performance Mood/behaviour changes Incoordination (handwriting deteriorates) Resting and intention tremors Dysarthria, excessive salivation Dysphagia, mask-like facies

Haematological

Acute haemolytic anaemia

Renal

Renal tubular dysfunction (Fanconi, RTA, aminoaciduria) Renal calculi

Skeletal

Rickets/osteomalacia Arthropathy

• Abnormal liver function tests, even as early as the first year of life. • Isolated hepatomegaly or identified during examination of a neurologically affected case. Only in neurologically affected cases are Kayser–Fleischer (KF) rings to be expected. • Acute hepatitis which appears to resolve. Failure to find a viral aetiology for an acute hepatitis, which has delayed or incomplete resolution, should raise the possibility of WD. • ‘Chronic hepatitis’, i.e. continuing abnormality of liver function tests, clinically indistinguishable from an autoimmune hepatitis, though usually not having raised plasma globulin. • Variceal haemorrhage from unsuspected portal hypertension. • Signs of decompensated chronic liver failure. • Fulminant liver failure (FHF). This, the most urgent presentation, causes the most difficulty in diagnosis and management. It usually occurs without antecedent illness but may occasionally be precipitated by an actual viral infection (hepatitis E, chickenpox or measles have been described) or an apparent infection. In some cases, previous episodes of haemolysis or ‘hepatitis’ may have occurred (see Plate 44a, Atlas: p. 455). KF rings will probably be absent (see Plate 44b, Atlas: p. 455). Other clues suggesting WD are: • the absence of other known causes • a relevant family history • a disproportionate rise in bilirubin (> 300 mmol/l) • haemolysis on blood film

• a relatively low alkaline phosphatase (< 600 IU/l) or transaminases (100–500 IU/l). Neurological presentation In older children the first symptoms may be neurological or psychiatric or both. They may develop insidiously or precipitously. Difficulty with speech is often reported. Neurological involvement tends to follow two general patterns: movement disorders or rigid dystonia. Movement disorders include tremors, poor coordination, and loss of fine-motor control, chorea, or choreoathe-tosis. The intention tremor may be initially unilateral, then becomes coarse generalized, and incapacitating (‘wing-beat’ tremor). Spastic dystonia presents with Parkinsonian-like mask-like facies, rigidity, and gait disturbance. Pseudobulbar involvement causes drooling, and dysphagia. The psychiatric disorders are highly variable. Depression is common. Neurotic behaviour includes phobias, compulsive behaviours, aggression, or antisocial behaviour. Cognitive deterioration may also occur with worsening school performance, poor memory, difficulty in abstract thinking, and shortened attention span. Pure psychotic disorders are uncommon. Neuropsychiatric findings in patients with a hepatic presentation include mood disturbance (mainly depression; occasionally poor impulse control), changes in school performance, and/or difficulty with fine motor skills, especially handwriting, or gross motor skills. The differential diagnosis of neuropsychiatric disease

Chapter 13: Disorders of Copper Metabolism associated with hepatic abnormalities in childhood and adolescence includes (i) late presentation of Niemann– Pick disease type C, (ii) Lafora disease, and (iii) congenital disorders of glycosylation. Haemolysis Haemolysis may be the initial presentation, sometimes apparently precipitated by infection or drugs. There may be a history of a previous undiagnosed haemolytic episode in cases presenting with hepatic or neurological features, and haemolysis is prominent in fulminant Wilson’s disease. Ophthalmic abnormalities The KF ring is a gold or grey-brown opacity in the peripheral cornea. It first develops superiorly in the cornea (12 o’clock), then inferiorly, and finally in the horizontal meridian. It represents a deposit of copper and sulphurrich granules in Descemet’s membrane, and is reversible with treatment. Additional later ocular findings in Wilson disease include sunflower cataracts, saccadic pursuit movements, loss of accommodation response, and apraxia of opening the eyelid. Renal abnormalities Renal tubular abnormalities are frequently found in WD if sought, comprising glycosuria, aminoaciduria, renal tubular acidosis, impaired phosphate reabsorption, or a full-blown renal Fanconi syndrome, and are the presumed consequence of tubular copper deposition. Glomerular dysfunction is less frequent, but proteinuria may be exacerbated by penicillamine. Recurrent hypokalaemic muscle weakness, hyperoxaluria, renal calculi and nephrocalcinosis are uncommon features. Skeletal manifestations Copper-mediated oxidative damage to collagen probably underlies the arthritis, which occurs in a small number of patients with Wilson’s disease. The secondary effects of renal tubular phosphate leak and hepatic osteodystrophy are likely to be the cause of the radiological abnormalities such as rickets or osteoporosis, which occur in a larger percentage. Skeletal complications appear to be more frequent in Asian/Indian patients.

249

intercristal spaces. The earliest histological changes comprise microvesicular and macrovesicular fatty deposition, glycogen-containing vacuoles in the nuclei of periportal hepatocytes, dense and enlarged peroxisomes. With progression, portal fibrosis and inflammation are seen. Children presenting with clinical liver disease may show a histological picture indistinguishable from autoimmune hepatitis with interportal fibrous bridging or frank cirrhosis (see Plates 45a, b, Atlas: p. 455). Features suggesting WD are: • fatty change • Mallory hyaline • glycogen-containing vacuoles in the nuclei • lipofuscin • copper staining • iron deposition in Kupffer cells in patients who have had haemolysis. In well-established liver disease, copper may be demonstrable by rhodanine or rubeanic staining. The elastin stains orcein and aldol fuchsin will then usually show granular staining thought to represent lysosomal copper-protein polymer (see Plate 45b, p. 455). It cannot be emphasized too strongly that these methods are negative in early cases, presumably because at that stage the copper is cytosolic and in low molecular weight complexes. The absence of histochemically demonstrable copper does not exclude a diagnosis of WD. Liver copper in presymptomatic children is higher [983.5 (SD 368) mg/g dry weight] than in older symptomatic children [583.3 (SD 304) mg/g] (Sternlieb & Schenberg 1968). This contradicts the common view that in WD copper builds up in the liver to a level which causes damage, and suggests that some other factor initiates damage in the copper-laden liver. The relationship between copper and organelle damage remains unclear. In particular, it is unknown why some patients develop severe hepatic necrosis, and others minimal damage. Isolated mitochondria from WD liver show lipid peroxidation and reduced respiratory chain activity, premature oxidative ageing shown by large mitochondrial DNA deletions, and bulky lesions of nuclear DNA. In contrast to haemochromatosis, WD is rarely associated with hepatoma. WD heterozygotes may have a hepatic Cu of the order of 100–200 mg/g dry weight and mild histological portal tract changes, but there is no evidence of progression of liver disease. Diagnosis

Pathology The earliest ultrastructural abnormalities are seen in mitochondria, which are pleomorphic and show increased matrix density, separation of the normally apposed inner and outer membranes, and widening of

The first essential in making the diagnosis is to think of it. KF rings, if present, are highly suggestive, but: • are usually absent in children below 10 years with WD • at an early stage, will only be detected by slit-lamp examination

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• are difficult to see in brown or green eyes • are not pathognomonic; they may rarely occur in copper overload due to chronic cholestasis. The biochemical diagnosis (Table 13.4) depends upon finding: 1 a low plasma caeruloplasmin 2 a raised urine copper, particularly after penicillamine 3 a raised liver copper concentration. However, there are numerous pitfalls in these laboratory parameters, as outlined below. Serum copper Most plasma copper is within caeruloplasmin. In WD, serum copper may therefore be low because caeruloplasmin is low, or raised because hepatic necrosis releases ‘free’ copper into the plasma, or somewhere in between. Anormal plasma copper should never exclude a diagnosis of WD. Free (non-caeruloplasmin) serum copper is a theoretically attractive parameter, reflecting the portion of copper which is non-protein-bound, presumably released from the damaged liver, and presumably available to cause toxicity. It is calculated (in mmol/l) on the basis that 1 mg caeruloplasmin contains 3 mg or 3/63.5 mmol copper, and is approximately total Cu mM – (0.047 ¥ caeruloplasmin mg/l). There are three major problems. First, it rests on the assumptions that one molecule of caeruloplasmin contains six atoms of copper. Second, immunologically measured caeruloplasmin comprises both holo- and apo-caeruloplasmin, and the assumption that the amount of apo-caeruloplasmin is so small that it can be ignored is probably incorrect in WD. Third, it is calculated from two measured parameters and is thus subject to large error. Caeruloplasmin Various factors that may affect plasma caeruloplasmin have to be considered: plasma caeruloplasmin exceeds 200 mg/l in approximately 10% of WD cases. It is an acute-phase reactant, and will be elevated by hepatic or other inflammation. In cases with chronic histologically active hepatitis, caeruloplasmin may therefore initially be in the normal range, falling below 200 mg/l with treatment. Plasma caeruloplasmin may be low if overall hepatic protein synthesis is low, whether acutely as in fulminant failure, or in decompensated cirrhosis or in other situations of hypoproteinaemia such as protein-losing enteropathy or severe malnutrition. A significant number of WD heterozygotes will have a plasma caeruloplasmin < 200 mg/l. Acaeruloplasminaemia may cause diagnostic confusion in neurological cases (Table 13.3) and an unknown percentage of normal individuals will be heterozygotes for acaeruloplasminaemia. Urine copper Basal urine copper is an unreliable parameter, showing both poor sensitivity and poor specificity, though values > 5 mmol/24 h are highly suggestive. A

penicillamine challenge test gives greater discrimination. In the original description of this test in children with liver disease penicillamine 0.5 g was given 12-hourly ¥ 2. Urine copper exceeded 25 mmol/24 h in 15/17 patients with WD and on 1/58 with other liver disorders. The difficulties in reliably collecting 24-h urines, and the fact that one dose is recommended for all ages, are limitations to this test. Further, in presymptomatic cases, post-penicillamine urine copper may not reach 25 mmol/24 h. It is therefore suggested that a post-penicillamine urine copper greater than 5 times the laboratory’s normal upper limit is strongly suggestive of, but not diagnostic of, WD. Liver histology Histological or electron microscopic (EM) appearances may support a diagnosis of WD, but are not pathognomonic (see above). Aclassic error is to rely upon histochemical demonstration of copper. It cannot be emphasized too strongly that the rhodanine, rubeanic acid and other stains for copper, and the orcein and aldol fuchsin stains for ‘copper-associated protein’, are usually negative in childhood WD despite the presence of copper measured by spectrometry (see Plate 45b, Atlas: p. 455). In suspected WD, a piece of the liver biopsy should be placed in a dry plastic copper-free container for subsequent analysis by atomic absorption analysis in a laboratory performing the measurement frequently. Attempted copper measurement in dewaxed paraffin-embedded tissue is likely to give erroneous results due to leaching during preparation, or contamination. Isotopic copper Following an oral dose of labelled copper, two peaks in plasma activity are seen. The first, peaking at around 4 h, represents newly absorbed copper which is associated with albumin. The second, a slower rise, represents copper incorporation into caeruloplasmin. The shape of these curves is similar whether the radioisotopes 64Cu or 67Cu or the stable isotope 65Cu are used. 64Cu or 67 Cu suffer from the disadvantages of short half-life, limited availability, and radiation dosage. 65Cu is infinitely stable and causes no radiation exposure. However, because of the relative natural occurrences of 65Cu and the more common 63Cu, the sophisticated technique of inductively coupled plasma mass spectrometry is required for analysis. This method is of value in the diagnosis of the difficult case. Following a 3-mg dose of 65Cu as copper sulphate in milk, blood samples are taken at 0, 4, 12 and 24 h. A 24 : 4 h activity ratio > 1 demonstrates normal caeruloplasmin synthesis and makes Wilson’s disease unlikely. Haplotype analysis By the identification of polymorphic microsatellite markers — varied lengths of repeated cytosine–adenosine sequences — near to the Wilson’s gene, a haplotype may be

Chapter 13: Disorders of Copper Metabolism constructed. In a family where it has not proved possible to identify mutations in a biochemically proven case, haplotype analysis makes it possible to determine with certainty whether the siblings are presymptomatic affected, heterozygote carriers, or unaffected. Mutation analysis Many WD mutations are now recognized. World-wide, the commonest of these is H1069Q (His1069Gln) in exon 14, which disrupts the ATP binding site. There is some evidence of a founder effect for H1069Q in Eastern Europe and consequently a high proportion of Eastern European patients are H1069Q homozygotes. This makes for an easy primary genetic diagnostic method. In other populations other particular mutations predominate, such as the 2010del7 Icelandic mutation. The UK and US WD populations show significant differences from this. They have a large number of different mutations. Most patients are compound heterozygotes, though immigrant patients of consanguineous parents are frequently homozygous. Third, His1069Gln is only found in 30–40%, usually in heterozygous dosage, and is absent in Asian patients. Because of these population differences, different molecular diagnostic strategies need to be adopted. For the UK, an appropriate strategy in a new patient is first to seek for H1069Q and a few other fairly common mutations; second, to sequence exons 8, 14 and 18, which are ‘hotspots’ for mutations; and finally to sequence remaining exons. If the patient has two readily identifiable mutations, the diagnosis is confirmed. If they have one readily identifiable mutation the diagnosis is likely, and it is worth hunting for the second. If no mutation is found, complete sequencing of the gene is justifiable if a mutational diagnosis is needed in order to screen siblings. Diagnosis in practice The practical conclusion to be drawn from the above is that the diagnosis of Wilson’s disease is difficult and depends on the clinical situation. In presymptomatic children, or neurological cases with mild abnormalities of liver function tests, expect caeruloplasmin to be low.

In active liver disease, caeruloplasmin is less reliable, but post-penicillamine urine copper should be high. In fulminant liver failure, calculated serum free copper, baseline urine copper, and post-penicillamine copper should be high. In all these situations, if a rapid test for H1069Q is available a positive result supports the diagnosis and justifies starting treatment. Treatment Five drugs are available to treat the copper overload of WD: D-penicillamine, triethylene tetramine hydrochloride (trientine), zinc, ammonium tetrathiomolybdate, and BAL (Table 13.7). There is much literature describing treatment with particular agents, but few randomised controlled clinical trials comparing agents. Penicillamine Although the rationale for using penicillamine was to achieve ‘decoppering’, it is clear that it does not act in this way. Penicillamine is not able to remove copper from cultured hepatocytes, and treatment does not cause liver copper levels to fall to normal. It is therefore thought to ‘detoxify’ the liver copper, possible mechanisms being: • induction of metallothionein, favouring lysosomal sequestration (like zinc) • augmenting the thiol pool, binding copper in other non-toxic complexes • a direct anti-inflammatory action, as demonstrated by the use of penicillamine in rheumatoid arthritis • reduction of hepatic fibrosis by impairing collagen cross-linking. Since the patient is not ‘decoppered’, they remain at high risk of deterioration if treatment is discontinued. Numerous reports of rapid decline in hepatic function within 18–24 months of stopping penicillamine emphasize the need to maintain compliance. Penicillamine has a reputation for toxicity because initially a mixture of the D and L isomers was used, which was associated with a high incidence of nephrotic syndrome and pyridoxine deficiency. D-Penicillamine is much less toxic, but nevertheless causes significant sideeffects in 5–10% of treated patients. These include:

Table 13.7 Drugs used in the treatment of Wilson’s disease. Drug D-Penicillamine

Triethylene tetramine dihydrochloride (trientine) Zinc sulphate or acetate Ammonium thiomolybdate

251

Dose 20 mg/kg/day with pyridoxine 25 mg/day 300 mg t.d.s. 150–300 mg t.d.s. 30 mg b.d.

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Section 6: Metabolic Liver Disease

• Skin rash, usually urticarial, occurring soon after commencing treatment, which usually responds to cessation of treatment and reintroduction gradually under steroid cover. • Proteinuria, which is in most cases mild and does not require cessation of treatment. In a small number of patients there may be an immune complex nephropathy leading to nephrotic syndrome. • Marrow depression, particularly affecting platelet count. • Systemic lupus erythematosus (SLE). • Pyridoxine deficiency, particularly during growth or pregnancy. • Effects on cutaneous collagen usually occurring after prolonged therapy, namely elastosis perforans serpiginosa and cutis laxa. The most worrying adverse effect of penicillamine (and trientine) is the appearance of, or deterioration in, neurological dysfunction on starting treatment — well described in the patient with neurological features, and reported in cases without neurological signs. Penicillamine is the agent for which we have the longest clinical experience and it remains the drug of first choice in many centres. Trientine Trientine was initially introduced as a second-line drug for patients intolerant of D-penicillamine. The majority of the above side-effects do not occur with trientine, except for SLE. The most commonly reported side-effect is sideroblastic anaemia, particularly when given with zinc. Colitis, resolving on cessation of trientine, is also reported (Dahlman et al. 1995). Having previously been difficult to obtain, trientine is now commercially available, but is significantly more expensive than penicillamine. Its use is justified because of its lower toxicity, but there are no long-term data on comparative efficacy. Zinc The rationale for using zinc is that induction of metallothionein in intestinal cells will bind copper in the enterocyte and reduce absorption. Since zinc also powerfully induces hepatic metallothionein, its mode of action may not be dissimilar to penicillamine. Zinc is an attractive drug because it is more physiological than penicillamine or trientine, is of apparently low toxicity, and zinc sulphate is cheap. In high doses in animals it may cause pancreatic atrophy, but this has not been reported in man. It may impair iron absorption. The principal practical problems are its unpalatability, and dyspeptic symptoms due to gastric irritation. Zinc acetate, which is less likely to cause these than zinc sulphate, is now commercially available and licensed (‘Galzin’), but is more expensive.

Tetrathiomolybdate (TM) TM has an interesting history. Sheep are very susceptible to copper poisoning, but this is less likely to occur on molybdenum-supplemented feeds. This effect is due to the formation of ammonium tetrathiomolybdate in the rumen. TM is a powerful copper chelator, and became an effective veterinary therapy for ovine copper poisoning. Unlike the above drugs, it is able rapidly to bind copper already in tissues in an inert complex. Its clinical use is limited by toxicity, namely marrow depression and, in growing animals, epiphyseal abnormalities. It may have a role in initial treatment of neurological cases. BAL (British anti-Lewisite, dimercaprol) was used for WD prior to the introduction of penicillamine. Given by intramuscular injection, it is painful and has many reported toxic side-effects. Some authorities recommend its use in neurological cases refractory to other therapy. Choice of drugs The choice of drugs will vary with the clinical situation. The child presenting with chronic liver disease with no neurological signs, haemolysis with or without abnormal liver function tests, acute liver dysfunction not proceeding to acute liver failure • Penicillamine or trientine are the drugs of choice combined with zinc. Penicillamine is commenced in a dose of 20 mg/kg/day increasing to 35 mg/kg/day, accompanied by pyridoxine 25 mg/day. Blood count and urine protein should be monitored weekly for the first month, monthly for 6 months, then 6-monthly. • Zinc sulphate or acetate should be started in a dose of 100–150 mg, doses being given 30 min before food. • If both zinc and penicillamine are to be used they should be given at different times. The rationale for combined therapy has been that as both drugs act in different ways there may be an additive effect. This is probably a misconception, but combination with zinc may produce an optimum response without using toxic levels of penicillamine. It remains to be proven that combined therapy has any advantage over zinc alone, but once remission has been obtained, then maintenance treatment with zinc alone is possible. There are reports that the combination of trientine and zinc predispose to sideroblastic anaemia, but these are not confirmed by other centres. Monitoring the effectiveness, and compliance with chelation therapy is difficult. Urine copper levels will rise to high values in the first 3 months, declining after 1 year of continued treatment. After this time, urine copper should be measured 6-monthly. A falling value suggests that the patient may have discontinued the drug, whilst an unexpectedly very high value may suggest that they

Chapter 13: Disorders of Copper Metabolism

253

As a ‘bridge to transplantation’ various strategies have been recommended: • Ultrafiltration is probably the most effective technique. • It is not yet clear if albumin dialysis or the Molecular Adsorbents Recirculating System (MARS) may be better than ultrafiltration for acute Wilson’s disease. (Sen et al. 2002). • There is limited experience with TM. By carefully titrating the dose against plasma free copper, one described patient was maintained 6 weeks until a donor liver became available. There are no reports of a child who needed transplantation being rescued by TM.

have restarted it recently in anticipation of the clinic visit. Effectiveness of therapy is monitored by biochemical liver function tests, which should show a steady improvement over the first months of treatment, and by serial liver biopsy. It is difficult to interpret liver copper levels in follow-up biopsies, since two effects are operative: (i) penicillamine removes that fraction of liver copper which is mobilizable, thus reducing liver copper; but (ii) both penicillamine and zinc induce metallothionein, which binds copper and may therefore cause liver copper concentration to rise. In interpreting serial liver copper levels it is also important to remember that the right lobe tends to have higher values. For this reason, changes in hepatic inflammation are of more significance than changes in liver copper. Likewise, liver histology may rapidly decline despite no significant change in hepatic copper concentration in the patient who discontinues treatment.

Neurological presentation Brewer et al. (1996) have argued that the neurological deterioration seen after commencement of penicillamine or trientine makes TM the initial treatment of choice, and in a large series report excellent results from a regimen of 8 weeks of TM followed by zinc.

Fulminant hepatic failure Despite prompt chelation therapy, the prognosis for this group remains poor without transplantation. An urgent decision should be made concerning referral and immediate listing for transplantation. Nazer et al. (1986) have produced a valuable scoring system (Table 13.8) and have shown that serial evaluation distinguishes those patients who are developing irreversible failure and should be listed for transplantation from those for whom medical treatment should be continued. Management, both initially and whilst awaiting a donor organ, includes standard care of the child with acute liver failure (Chapter 7). The therapeutic value of N-acetylcysteine for acute liver failure has been demonstrated, and this is a logical drug to use in fulminant Wilson’s disease, since maintenance of glutathione must be important in binding released copper. Because of the gravity of this situation, it is important to commence penicillamine as soon as the diagnosis is suspected. Durand et al. (2001) showed evidence that in WD patients with hepatic failure which had not progressed to encephalopathy, early administration of D-penicillamine was associated with survival without transplantation.

Presymptomatic cases With molecular methods, it is now easy to make the diagnosis of WD in unaffected siblings, even in the newborn period. It is likely that all genotypically affected patients are at risk of developing clinical disease at some time, and thus all need treatment. The risk is difficult to quantify because WD is so phenotypically variable, and some cases do not present until late adult life. Even within sibships there is phenotypic variability. Despite these caveats, treatment is recommended. Since clinically significant liver disease is not reported at ages < 3 years, treatment may logically begin at that age. Zinc, which is the least toxic and most physiological agent, is the treatment of choice. Presymptomatic treatment should prevent liver and neurological damage, but patients should be monitored for evidence of both disease, and for copper deficiency or pancreatic dysfunction. Pregnancy There are two issues, the care of the WD mother and the care of the fetus. There are numerous reports of successful pregnancy in women treated with

Table 13.8 Prognostic index in fulminant hepatic failure in Wilson’s disease. Score in points* Indicator Serum bilirubin (mmol/l) Serum AST (IU/l) Prothrombin time (seconds prolonged)

0

1

2

3

4

< 100 < 100 300 > 300 > 20

*Thus, a bilirubin of 170·mmol/l, an AST of 220·IU/l, and a prothrombin time of 21·s prolonged would score 2·+·3·+·4·=·9. A score >·7 is an indication to consider transplantation whilst commencing therapy. Deterioration of serial estimates of the score indicates need to list for transplantation.

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penicillamine. The danger of discontinuing treatment during pregnancy has been amply demonstrated. Early reports of unusual connective tissue changes in babies born to women who were receiving penicillamine for cysteinuria and rheumatoid arthritis suggest that zinc is a safer option during pregnancy. Assuming no consanguinity, the fetus will be an obligate heterozygote. The risk that the baby will have WD is of the order of 1 in 300 for a population with a disease frequency of 1 : 100 000. It is recommended that the baby is allowed to breast-feed, but the full blood count and caeruloplasmin are followed to exclude haematological evidence of copper deficiency and confirm the physiological rise in caeruloplasmin. Indications for liver transplantation Liver transplantation is indicated for those children who do not respond to therapy, or who have advanced liver failure (Table 13.8) and/or portal hypertension (Chapter 20). The results of liver transplantation in WD are good. Of 39 patients in Oklahoma transplanted during 1981–1991, survival at time of reporting was 79.4% (Bellary et al. 1995), although less in those with FHF (73% survival) than in those with chronic disease (100%). In another series of patients with FHF, those with WD had better results than the group as a whole (Devlin et al. 1995). A successful liver transplant restores biochemical indices of WD phenotype to normal. Living related liver transplantation from a parent phenotypically converts the patient to a heterozygote, clinically well but with a mildly reduced caeruloplasmin and a mildly increased hepatic copper concentration (Komatsu et al. 2002). There is no consensus as to whether liver transplant benefits the neurological features of WD, although a number of recent studies suggest that it may be beneficial (Schumacher et al. 1996) to patients with both hepatic and neurological disease and to those with neurological disease alone. The future In the LEC rat there are encouraging results from gene therapy and from hepatocyte transplantation. Successful but temporary adenovirus-mediated ATP7B gene transfer has been demonstrated (Ha-Hao et al. 2002), and transplantation of normal rat hepatocytes into the liver achieved correction of liver disease (Malhi et al. 2002). Transplanted cells have a survival advantage over native copper-laden cells, particularly in the presence of a second toxin, retrorsine. Exciting as these advances are, the real research need in WD is for randomized controlled therapeutic trials, and accurate documentation of outcome.

Non-Wilsonian copper-related cirrhosis in childhood This term encompasses the following entities, the common feature of which is a very high hepatic copper concentration: • A rapidly progressive and fatal disorder of infants and young children with characteristic liver pathology, and a history of excessive copper ingestion. This includes 1 Indian childhood cirrhosis (ICC), in which copper was acquired from milk which had been heated in brass utensils. 2 Tyrolean childhood cirrhosis, in which copper was acquired from diluted sweetened milk which had been boiled in copper utensils, and for which a strong genetic susceptibility was demonstrated. 3 Sporadic childhood copper-related cirrhosis, in which copper was acquired from water used to make up infant feeds, that water having taken up copper from plumbing. Characteristic of this group is the use of a private well for water. • Children with cirrhosis and copper accumulation, no identifiable source of dietary copper excess, but some evidence of a genetic abnormality, whether parental consanguinity or occurrence in siblings. ICC Definition and histology Amongst the many causes of cirrhosis in Indian children, ICC is best defined on histological grounds. The following features are seen: necrosis of hepatocytes with ballooning and Mallory’s hyaline; pericellular intralobular fibrosis; an inflammatory infiltration; poor regenerative activity, to the extent that there was often little nodular change; absence of fatty change; absence of cholestasis until an advanced stage; granular orcein staining was demonstrated. The copper-laden hepatocyte of ICC shows severe ultrastructural damage with prominent end-stage copper- and sulphur-rich lysosomes, and severe morphological abnormalities of mitochondria. Aetiology A retrospective review of children with ICC revealed that all had received animal milk, and that the age of introduction of animal milk was earlier than in other disease groups. A subsequent detailed comparison between the feeding history of 100 children with ICC and appropriate controls generated the hypothesis that ICC resulted from the early introduction of cow or buffalo milk feeds contaminated with copper from untinned brass utensils.

Chapter 13: Disorders of Copper Metabolism Clinical features In the early 1980s, ICC was the commonest chronic paediatric liver disorder seen in India, with a calculated incidence of 1 : 4000 rural live births. The mean age at presentation was 18 months (range 6 months to 5 years). Males outnumbered females 3 : 1. ICC affected rural families more frequently than urban ones, middle-income families more frequently than very poor ones, and Hindu ones more frequently than Muslim. The onset was usually insidious with abdominal distension, malaise and irritability, though some had a hepatitic onset. After weeks or months there was a rapid progression to jaundice, ascites, oedema and respiratory distress, and death usually occurred soon thereafter. The characteristic physical sign was hepatomegaly, the liver having an extraordinarily hard texture, smooth surface and sharp edge. The diagnosis was based on the characteristic histology (see above) and the grossly elevated liver copper.

study. The prevalence of ICC has now declined to near zero (Fig. 13.3a). (See also Chapter 22.) Tyrolean childhood cirrhosis Between 1900 and 1974 (Fig. 13.3b), 138 infants died in an area of the Austrian Tyrol (Muller et al. 1996). A pathological monograph described features similar to ICC, although neither copper stains nor copper assay were done. In its age of presentation (median 7 months), clinical features, short survival (median 2.75 months), and high mortality, the condition resembled ICC. Unlike ICC, sexes were affected equally. These infants came from isolated farming households where the practice was to make up an infant feed from cows’ milk, diluted and sweetened with sugar, and heated in a copper vessel. Siblings were often affected, parental consanguinity was common,

(a)

Prevention of ICC The feeding data suggested that Indian childhood cirrhosis was preventable by a change in infant feeding practice, and this proved to be the case in a large intervention

Number of cases

40 30 20 10 0

1980

1982

1984

1986

1988

1990

1992

Year (b) 40 35 30 25 20 15 10 5

0 –8 5 80 19

0

–8 70

19

0

–7

19

60

0

–6 50

19

0

–5

–4

40

30

19

19

0

–3 0

–2

20 19

10

19

00

–1 0

0

19

Some asymptomatic younger siblings proved to have hepatomegaly and subtle hepatic histological abnormalities comprising hepatocyte ballooning and portal inflammation. The liver copper was elevated in this group. Their parents were advised to avoid brass or copper contamination of infants’ feeds but penicillamine was not given. One child progressed to ICC whilst the others remained well.

ICC

50

Number of deaths

Siblings

Other liver disorders

60

Treatment Untreated, ICC had a mortality of 45% within 4 weeks, 74% within 8 weeks, and 86% within 6 months of presentation to hospital. Most of these cases presented at a very late stage, and it was common clinical experience that the appearance of jaundice, ascites and chest infection heralded a rapid terminal decline. A trial of penicillamine in such cases demonstrated no benefit. In subsequent studies, penicillamine in a dose of 20 mg/kg/day, with or without prednisolone, reduced mortality from 92% to 53%, with no additional benefit from prednisolone. Resolution of liver disease with normal growth but the development of inactive micronodular cirrhosis has been reported following penicillamine therapy. Liver copper concentrations fell to near normal levels.

255

Year

Fig. 13.3 (a) The number of cases of Indian childhood cirrhosis (ICC) presenting to one hospital in India fell from 30–50/year prior to 1985 to 1–2/year following a change in infant feeding practices. (b) The number of Tyrolean infants dying from a cirrhosis histologically identical to ICC peaked during the decade 1930–1940, and declined thereafter. No cases have been encountered in the Tyrol since 1974 (Muller et al. 1996).

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and the segregation ratio was 0.2159. Since some infants fed in the same way escaped the disease, it was hypothesized that both genetic and environmental factors were involved. Sporadic infantile copper toxicosis related to well water Individual cases from Australia (Walker-Smith & Blomfield 1973; Price et al. 1996), Germany (MullerHocker et al. 1987), and the UK (Baker et al. 1995) have presented with clinical and histological features indistinguishable from ICC. All have died or required transplantation, and all have had the following history. They have been born in a rural household, and have received milk made up with well water which has a low pH and has acquired high copper concentrations from copper plumbing or water heaters. The water copper concentration has in the well-documented cases been high — 7.6 mg/l in a 20-month-old Australian case (Price et al. 1996). No case has occurred in houses receiving a regulated water supply. Childhood copper toxicosis without excess copper ingestion Histological features resembling ICC, and raised hepatic copper, were seen in four siblings aged 4.5–6 years who died with progressive liver disease (Lefkowitch et al. 1982). Although these children were older than those with ICC, they had a similar clinical course and liver copper as high as 2083 mg/g dry weight. In these, and in other reports of an ICC-like disorder (Adamson et al. 1992), there was no identifiable cause of excess copper ingestion. Amongst the small number of infants with ICC now being seen in India are some with no history of exposure to copper-contaminated feeds. Copper-associated cirrhosis in older children A 7-year-old boy with decompensated cirrhosis and a liver copper of 2319 mg/g dry weight, whose 9-year-old brother had died with a similar illness, was treated successfully with penicillamine, liver copper falling to normal over 2 years (Horslen et al. 1994). Wilson’s disease was excluded. This and other copper-related cirrhoses in older children (Maggiore et al. 1987) are of unknown mechanism. Copper-associated cirrhosis in adults Cases of liver disease in adults attributable to copper ingestion are very rare. A 58-year-old psychiatric patient ingested 275 US coins which were largely made of copper. She died from profound haemolysis, but at post mortem

examination did not have cirrhosis (Yelin et al. 1987). There is a single report of a 26-year-old man who had ingested 10 times the maximum dose of dietary copper supplement for 2 years and who presented with acute liver failure requiring emergency liver transplant with successful outcome (O’Donohue et al. 1993). The rarity of such adult reports has led to the view that the infant is more susceptible to copper ingestion, perhaps because of the physiologically raised hepatic copper and the ‘physiological cholestasis’ of the newborn. However, there is no direct evidence in man or in other mammalian species that this is so. Genetic and environmental factors in copper intoxication syndromes Family data indicate that genetic factors contribute to both Indian and Tyrolean childhood cirrhoses. Loci for WD, metallothionein, and Bedlington terrier disease (MURR1) have been excluded. There is veterinary and experimental evidence that plant-derived pyrrolizidine alkaloids are synergistically hepatotoxic with copper. There is no direct evidence that this contributes aetiologically to the infantile copper toxicoses. However, the alkaloid retrorsine has been used experimentally to kill copper-laden liver cells in the LEC rat, allowing a selective advantage to transplanted normal hepatocytes. Conclusions and recommendations Unregulated water supplies should not be used to make up infant feeds. Whilst endemic ICC has largely disappeared, sporadic cases of an infantile ICC-like disorder continue to occur. Learning from ICC it is recommended that penicillamine is used early; and adverse prognostic factors, particularly jaundice, are recognized as indications for early transplantation.

References Adamson, M., Reiner, B., Olson, J.L. et al. (1992) Indian childhood cirrhosis in an American child. Gastroenterology 102, 1771–1777. Baker, A., Gormally, S., Saxena, R. et al. (1995) Copper-associated liver disease in childhood. Journal of Hepatology 23, 538–543. Bellary, S., Hassanein, T. & Van Thiel, D.H. (1995) Liver transplantation for Wilson’s disease. Journal of Hepatology 23, 373–381. Brewer, G.J., Johnson, V., Dick, R.D., Kluin, K.J., Fink, J.K. & Brunberg, J.A. (1996) Treatment of Wilson disease with ammonium tetrathiomolybdate. II. Initial therapy in 33 neurologically affected patients and follow-up with zinc therapy. Archives of Neurology 53, 1017–1025. Brewer, G.J. (2001) Zinc acetate for the treatment of Wilson’s disease. Expert Opinion in Pharmacotherapy 2, 1473–1477.

Chapter 13: Disorders of Copper Metabolism Brown, D.R. (2002) Copper and prion diseases. Biochemical Society Transactions 30, 742–745. Bull, P.C., Thomas, G.R., Rommens, J.M., Forbes, J.R. & Cox, D.W. (1993) The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nature Genetics 5, 327–337. Caca, K., Ferenci, P., Kuhn, H.J. et al. (2001) High prevalence of the H1069Q mutation in East German patients with Wilson disease: rapid detection of mutations by limited sequencing and phenotype-genotype analysis. Journal of Hepatology 35, 575–581. Curtis, D., Durkie, M., Balac (Morris), P. et al. (1999) A study of Wilson disease mutations in Britain. Human Mutations 14, 304–311. Dahlman, T., Hartvig, P., Lofholm, M., Nordlinder, H., Loof, L. & Westermark, K. (1995) Long-term treatment of Wilson’s disease with triethylene tetramine dihydrochloride (trientine). Quarterly Journal of Medicine 88, 609–616. Devlin, J., Wendon, J., Heaton, N., Tan, K.C. & Williams, R. (1995) Pretransplantation clinical status and outcome of emergency transplantation for acute liver failure. Hepatology 21, 1018–1024. Durand, F., Bernuau, J., Giostra, E. et al. (2001) Wilson’s disease with severe hepatic insufficiency: beneficial effects of early administration of D-penicillamine. Gut 48, 849–852. French, S. (2001) Mallory bodies, like the mutant of ATP7B seen in Wilson disease, are aggresomes. Gastroenterology 121, 1264–1266. Ha-Hao, D., Merle, U., Hofmann, C. (2002) Chances and shortcomings of adenovirus-mediated ATP7B gene transfer in Wilson disease: proof of principle demonstrated in a pilot study with LEC rats. Z Gastroenterology 40, 209–216. Harris, Z.L. (2002) Not all absent serum ceruloplasmin is Wilson disease: a review of aceruloplasminemia. Investigative Medicine 50, 236S–238S. Hoogenraad, T.U. (1996) The history of Wilson’s disease. In: Wilson’s Disease, Major Problems in Neurology, Vol. 30 (eds C. P. Warlow & J. van Gijn), pp. 1–13. W.B. Saunders, Philadelphia. Hoogenraad, T.U. & Howen, R.H.J. (1996) Prevalence and genetics. In: Wilson’s Disease, Major Problems in Neurology, Vol. 30 (eds C. P. Warlow & J. van Gijn), pp. 14–24. W.B. Saunders, Philadelphia. Horslen, S.P., Tanner, M.S., Lyon, T.D.B., Fell, G.S. & Lowry, M.F. (1994) Copper associated childhood cirrhosis. Gut 35, 1497–1500. Komatsu, H., Fujisawa, T., Inui, A. et al. (2002) Hepatic copper concentration in children undergoing living related liver transplantation due to Wilsonian fulminant hepatic failure. Transplantation 16, 227–232. Lefkowitch, J., Honig, C.L., King, M. & Hagstrom, J.W.C. (1982) Hepatic copper overload and features of Indian childhood cirrhosis in an American sibship. New England Journal of Medicine 307, 271–277. Lönnerdal, B. (1998) Copper autritias during infancy and childhood. American Journal of Clinical Nutrition 67, 1046S–1053S. Maggiore, G., Giacomo, C.D., Sessa, F. & Burgio, G.R. (1987) Idiopathic hepatic copper toxicosis in a child. Journal of Pediatric Gastroenterology and Nutrition 6, 980–983. Malhi, H., Irani, A.N., Volenberg, I., Schilsky, M.L., Gupta, S. (2002) Early cell transplantation in LEC rats modelling

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Wilson’s disease eliminates hepatic copper with reversal of liver disease. Gastroenterology 122, 438–447. Moore, S.D., Cox, D.W. (2002) Expression in mouse kidney of membrane copper transporters atp7a and atp7b. Nephron 92, 629–634. Muller, T., Feichtinger, H., Berger, H. & Muller, W. (1996) Endemic Tyrolean infantile cirrhosis: an ecogenetic disorder. Lancet 347, 877–880. Muller-Hocker, J., Weiss, M., Meyer, J. et al. (1987) Fatal copper storage disease of the liver in a German infant resembling Indian childhood cirrhosis. Virchows Archiv A 411, 379–385. Nazer, H., Ede, R.J., Mowat, A.P. & Williams, R. (1986) Wilson’s disease: clinical presentation and use of prognostic index. Gut 27, 1377–1381. O’Donohue, J.W., Reid, M.A., Varghese, A., Portmann, B. & Williams, R. (1993) Micronodular cirrhosis and acute liver failure due to chronic copper self-intoxication. European Journal of Gastroenterology and Hepatology 5, 561–562. Petrukhin, K., Fischer, S.G., Pirastu, M. et al. (1993) Mapping, cloning and genetic characterization of the region containing the Wilson disease gene. Nature Genetics 5, 338–343. Price, L.A., Walker, N.I., Clague, A.E. et al. (1996) Chronic copper toxicosis presenting as liver failure in an Australian child. Pathology 28, 316–320. Schiefermeier, M., Kollegger, H., Madl, C. et al. (2000) The impact of apolipoprotein E genotypes on age at onset of symptoms and phenotypic expression in Wilson’s disease. Brain 123, 585–590. Schneider, A.R., Stichling, F., Hoffmann, M., Scheler, R., Arnold, J.C., Riemann, J.F. (2001) Hepatosplenomegaly and progressive neurological symptoms — late manifestation of Niemann–Pick disease type C — a case report. Z Gastroenterol 39, 971–974. Schumacher, G., Müller, A.R., Platz, K.P., et al. (1996) Neurologic symptoms improve in patients with Wilson’s Disease despite immunosuppression. Transplantation Proceedings 28, 3099–3100. Schumacher, G., Platz, K.P., Müller A.R. et al. (1997) Liver transplantation: treatment of choice for hepatic and neurological manifestation of Wilson’s disease. Clinical Transplantation 11, 217–224. Sen, S., Felldin, M., Steiner, C. et al. (2002). Albumin dialysis and Molecular Adsorbents Recirculating System (MARS) for acute Wilson’s disease. Liver Transplantation 8, 962–967. Seniomicronw, J., Bak, T., Gajda, J., Poniatowska, R., Czlonkowska, A. (2002) Cognitive functioning in neurologically symptomatic and asymptomatic forms of Wilson’s disease. Movement Disorders 17, 1077–1083. Shah, A.B., Chernov, I., Zhang, H.T. et al. (1997) Identification and analysis of mutations in the Wilson Disease gene (ATP7B): population frequencies, genotype–phenotype correlation, and functional analyses. American Journal of Human Genetics 61, 317–328. Sternleib, I. & Scheinberg, I.H. (1968) Prevention of Wilson’s disease in asymptomatic patients. New England Journal of Medicine 278, 352–359. Tanner, M.S. (1998) The role of copper in Indian Childhood Cirrhosis. American Journal of Clinical Nutrition 67, 1074S–1081S.

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Tanzi, R.E., Petrukhin, K., Chernov, I. et al. (1993) The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nature Genetics 5, 344–350. Tsivkovskii, R., Eisses, J.F., Kaplan, J.H., Lutsenko, S. (2002) Functional properties of the copper-transporting ATPase ATP7B (the Wilson’s disease protein) expressed in insect cells. Journal of Biological Chemistry 277, 976–983. Walker, J.M., Tsivkovskii, R. & Lutsenko, S. (2002) Metallochaperone Atox1 transfers copper to the NH2-terminal domain of the Wilson’s disease protein and

regulates its catalytic activity. Journal of Biological Chemistry 277, 27953–27959. Walker-Smith, J. & Blomfield, J. (1973) Wilson’s disease or chronic copper poisoning? Archives of Disease in Childhood 48, 476–479. Wessling-Resnick, M. (2002) Understanding copper uptake at the molecular level. Nutrition Reviews 60, 177–179. Yelin, G., Taff, M.L. & Sadowski, G.E. (1987) Copper toxicity following massive ingestion of coins. American Journal of Forensic Medicine and Pathology 8, 78.

Chapter 14: Complications and Management of Chronic Liver Disease ROSS SHEPHERD

Mechanisms and causes of chronic liver disease, 259 Diagnostic considerations, 260 Clinical presentation, 261 Investigations, 262 Liver pathology, 262 Diagnostic dilemmas, 263 Prognostic considerations, 263

Management of complications of chronic liver disease, 264 Malnutrition and nutritional support, 264 Ascites and oedema, 267 Portal hypertension and variceal bleeding, 269 Hepatic encephalopathy, 274 Coagulopathy, 276

Mechanisms and causes of chronic liver disease Advances in the understanding of the basic mechanisms of liver injury have provided new insight into the complications of liver diseases in children, leading to new directions in the prevention and treatment of chronic liver disease. An understanding of these mechanisms provides a useful conceptual framework for the clinician dealing with young patients with chronic liver diseases. Most chronic liver diseases of childhood result in cirrhosis, and/or cholestasis, from which the complications of chronic liver disease are derived. Cirrhosis is a chronic diffuse liver disease characterized by widespread hepatic fibrosis with regenerative nodule formation. Cholestasis, the accumulation of hydrophobic bile acids toxic to hepatocytes, can be both a cause and an effect of cirrhosis. The liver appears to respond to injury in a stereotypic fashion with a complex but dynamic series of events (Fig. 14.1) including programmed cell death (apoptosis), cell necrosis, and fibrogenesis. Pathways to apoptosis following hepatocyte injury involve polarization of mitochondria, cytochrome c release, nuclear fragmentation, and formation of apoptotic bodies without inflammation. Pathways to necrosis involve depolarization of mitochondria, depletion of ATP, and cell lysis with inflammation. In response to any of these cellular events, there is oxidant stress, release of cytokines, activation of stellate cells, accumulation of collagens, increased turnover of components of the extracellular matrix, fibrosis, and replacement/regeneration of hepatocytes, resulting in nodule formation. The hepatic stellate cell (HSC) is widely regarded as the key fibrogenic cell co-ordinating hepatic extracellular matrix formation. HSC activation, and maintenance in the active

Pulmonary complications of chronic liver disease, 276 Hepatorenal syndrome, 277 Bacterial infections, 278 Hepatocellular carcinoma, 278 Future directions in management of complications of chronic liver disease, 279

state, is the basic prerequisite for hepatic fibrosis (Reeves & Friedman 2002). Activated HSCs express an intracellular microfilament protein, a-smooth muscle actin (SMA), which can be used as a marker protein of the activated phenotype. Activated HSCs also express a number of different cytokine receptors including transforming growth factor (TGF)-b1 receptor. TGF-b is a cytokine involved in tissue growth, differentiation, and the immune response, and is the dominant stimulus to extracellular matrix production by HSCs. Although the response appears stereotypic across a wide range of causes of liver disease, the cellular source of this stimulus to collagen production by HSCs can vary in different disease states, and there are few studies of this process to date in paediatric liver diseases. In biliary atresia, a rapidly progressive cause of biliary cirrhosis in infants, TGF-b1 is produced by both injured hepatocytes and bile duct epithelial cells (Ramm et al. 1998). In cystic fibrosis liver disease, which causes focal biliary cirrhosis, it is expressed predominantly in bile duct epithelium (Lewindon et al. 2002). As fibrosis and regenerative nodule formation advances there is distortion of the liver architecture (cirrhosis), with compression of hepatic vascular and biliary structures, resulting in altered hepatic blood flow, and the development of portal hypertension and shunting of blood from hepatic artery to portal vein branches, and to hepatic vein tributaries. These haemodynamic disturbances lead to irregular delivery of oxygen and nutrients to the hepatocytes, perpetuating a vicious cycle of events which may persist even if the original process causing liver injury has ceased. In children, a wide range of causes of hepatocellular injury may result in cirrhosis (Table 14.1), including re-

259

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Section 7: Management of Chronic Liver Disease Biliary

Inflammatory/ toxic

Hepatic stellate cells (SC)

Activation

Metabolic/ genetic

Vascular

Hepatocyte damage Necrosis

Hepatic Kupffer & endothelial cells (KC)

Activation

Cytokines Growth factors Soluble factors

TGF-β1

Activated SC Collagen I & III

Activated KC

Inflammation Fibrogenesis Apoptosis

Growth factors

Impaired hepatocyte function

Regeneration nodule formation

Haemodynamic disturbances

Liver failure

Cirrhosis

Portal hypertension

duced bile secretion or bile duct obstruction (cholestasis), infections, toxins, metabolic, vascular and nutritional disorders. The process of cirrhosis then superimposes on the primary liver disease, often eventually obscuring the nature of the original insult. The complications of chronic liver disease and cirrhosis (Table 14.2) are primarily due to impaired hepatic function and cholestasis, causing nutritional and metabolic disturbances, impaired protein synthesis and coagulopathy, as well as haemodynamic changes, causing portal hypertension, hepatorenal and hepatopulmonary syndromes. Encephalopathy and ascites occur as a result of both of these major pathophysiological events. Cholestasis is also associated with pruritus and malabsorption. In addition, impaired immunity with resulting bacterial infection may complicate cirrhosis. Hepatocellular carcinoma can complicate any cause of cirrhosis in childhood, particularly in chronic hepatitis B and tyrosinaemia type I.

Fig. 14.1 Pathogenesis of cirrhosis — a stereotypic response to liver injury.

Diagnostic considerations Diagnosis is essentially a stepwise process, involving a range of clinical, laboratory, radiological imaging, and pathological investigations: 1 Confirming the presence and type of liver disease. 2 Determining aetiology. 3 Assessing the extent of complications. Chronic liver disease may be either active or inactive, depending on the presence of biochemical or histological evidence of hepatocellular necrosis, apoptosis and inflammation; and either compensated, where there are no clinical or laboratory features of liver failure, or decompensated, where such features are evident. In general, morphological and histological classifications are often unhelpful in clinical settings, although certain features may help in determining the cause of the cirrhosis, as in biliary disease, hepatic venous outflow block and features specific for particular inherited or infective condi-

Chapter 14: Complications of Chronic Liver Disease Table 14.1 Causes of chronic liver disease in children. Biliary Extrahepatic biliary atresia Choledochal cyst, tumours, stones Alagille’s syndrome, biliary hypoplasia Familial intrahepatic cholestasis, drugs Sclerosing cholangitis Graft-vs.-host-disease Histiocytosis X Hepatic Neonatal hepatitis Hepatitis B ± delta Hepatitis C Autoimmune hepatitis Drugs/toxins Genetic/metabolic Carbohydrate defects Galactosaemia, fructosaemia, glycogen storage III and IV Amino acid defects Tyrosinaemia, urea cycle disorders Metal storage defects Neonatal haemochromatosis, Wilson’s disease Lipid storage diseases Gaucher’s disease, Niemann–Pick type C Fatty acid b-oxidation defects Peroxisomal disorders Zellweger’s syndrome Mitochondrial disorders Respiratory chain defects Cystic fibrosis Fibropolycystic disorders* Vascular Hepatic vein thrombosis Budd–Chiari syndrome Veno-occlusive disease Cardiac

*Do not cause cirrhosis.

Table 14.2 Complications of cirrhosis in children. Malnutrition and growth failure Portal hypertension and variceal bleeding Hypersplenism Ascites Encephalopathy Coagulopathy Hepatopulmonary syndrome Hepatorenal syndrome Bacterial infections, spontaneous bacterial peritonitis Hepatocellular carcinoma

tions. Grouping disorders which progress to cirrhosis by aetiology is helpful because of the framework this provides for diagnosis, prognosis, treatment and genetic counselling. Ultimately, the presence or absence of liver

261

failure provides the basis for transition from supportive therapy to considerations of liver transplantation when the condition of end-stage liver disease has been realized (Shepherd 1990). Clinical presentation In compensated liver disease there may be no symptoms and the child may not be jaundiced. The first indication of liver disease may be an incidental finding of hepatosplenomegaly, splenomegaly alone, increased hepatic transaminases or increased alkaline phosphatase. Commonly the liver is small and impalpable, but it can be enlarged, hard or nodular with, in some patients, a small right lobe or splenomegaly. Cutaneous features such as spider angiomata, prominent periumbilical veins, and palmar erythema may provide a clue to the presence of liver disease (see Plate 46, Atlas: p. 456). Spider angiomata may occur in healthy children under the age of 5 years and are thus not pathognomonic of liver diseases in children, but the appearance of new spiders or more than five or six may be indicative. They are frequently observed in the vascular drainage of the superior vena cava, and feature a central arteriole from which radiate numerous fine vessels, ranging from 2 to 5 mm in diameter. The presence of prominent veins radiating from the umbilicus is an indication of portal hypertension. Other cutaneous features include: easy bruising; fine telangiectasia on the face and upper back (see Plate 46, Atlas: p. 456); white spots, most often on buttocks and arms, which when examined with a lens show the beginnings of spider angiomata; and clubbing of the fingers. On intranasal examination, prominent telangiectasia of Little’s area is common, associated with recurrent epistaxis. While compensated cirrhosis in adults is mostly cryptogenic, metabolic liver diseases such as Wilson’s disease, cystic fibrosis, and a1-antitrypsin deficiency may present with compensated cirrhosis in children. In Wilson’s disease, specific features include haemolytic anaemia, subtle signs of encephalopathy such as personality changes, loss of memory or school failure, and Kayser–Fleischer rings, sought by an experienced examiner using a slit lamp. Children with cholestatic liver disease will have predominant signs or symptoms of persisting jaundice, or pruritus as in biliary cirrhosis (see Table 14.1). The liver is usually enlarged, and xanthelasma, malnutrition and deficiency of fatsoluble vitamins (particularly vitamins D and K) may be prominent features. Clubbing is more likely to occur in biliary cirrhosis, and malnutrition and decompensation occur earlier in this form of liver disease. Decompensated liver disease is characterized by clinical and laboratory findings of liver synthetic failure, and the occurrence of complications. As well as the features mentioned above, the major features (see Plate 46, Atlas: p. 456) include malnutrition, ascites, peripheral oedema,

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coagulopathy, and gastrointestinal bleeding. Signs of hepatic encephalopathy are subtle in children. Except for causes of biliary cirrhosis, jaundice is a late feature in other forms of cirrhosis and indicates very advanced disease. Malnutrition with reduced lean tissue and fat stores as well as poor linear growth is a well-recognized and important feature of chronic liver disease in children (Kaufmann et al. 1987; Shepherd et al. 1991; Chin et al. 1992). Spontaneous bruising caused by impaired hepatic production of clotting factors and thrombocytopenia due to hypersplenism are sign of advanced disease. Cirrhosis with decompensation may also be associated with changes in the systemic and pulmonary circulations, with arteriolar vasodilatation, increased blood volume, a hyperdynamic circulatory state and cyanosis due to intrapulmonary shunting. Renal failure is a late but serious event. Laboratory investigations may reveal elevated alkaline phosphatase, bilirubin, hepatic transaminases and ammonia, but in particular there is abnormal liver synthetic function, reflected by such findings as hypoalbuminaemia and prolonged prothrombin time.

Table 14.3 Investigation of chronic liver disease in children. General Bilirubin Aminotransferases Gamma-glutamyl transferase Alkaline phosphatase Albumin Cholesterol Urea and creatinine Ammonia Alpha-fetoprotein Full blood count Prothrombin time MEGX formation of caffeine clearance Chest X-ray Hepatobiliary and renal ultrasound Upper gastrointestinal endoscopy Electrocardiogram Electroencephalogram Liver biopsy

Investigations In all forms of suspected liver disease, confirmation will ultimately rest with the interpretation of liver biopsy findings, which may confirm the presence, type and degree of activity of cirrhosis, and contribute to a diagnosis of the cause of the liver disease. However, a full range of laboratory and imaging investigations should be performed prior to performing a liver biopsy. Such investigations may be diagnostic of the underlying cause and may allow appropriate handling of the liver biopsy specimen with respect to specific histological and biochemical analysis, particularly for metabolic disorders. Table 14.3 lists the diagnostic tests that should be considered for children with suspected cirrhosis or chronic liver disease. These tests focus on determining both the aetiology and the severity of the liver disease prior to further confirmation with a liver biopsy as indicated above. Liver pathology Classification of liver pathology is based on morphology, histology, aetiology and degree of activity. Morphological classification This divides cirrhosis into micronodular, macronodular and mixed types. Fibrosis is not synonymous with cirrhosis, and fibrosis without nodules occurs typically in congenital hepatic fibrosis and granulomatous liver disease. Micronodular cirrhosis is characterized by fibrous septa separating small (< 3 mm) regeneration nodules of almost uniform size, present throughout the liver. This is most

Specific (for diagnosis) Biliary Blood and liver tissue culture Operative cholangiogram ERCP/MRCP Hepatobiliary scan Colonoscopy Hepatic Viral serology (TORCH, hepatitis B, C, EBV) ESR Autoimmune antibodies, immunoglobulins Liver copper or iron deposition General/metabolic Urinary sugars, amino acids, organic acids, porphyrins, fatty acid degeneration products Blood sugar (fasting), lactate, pyruvate, urate Serum amino acids, copper, caeruloplasmin, a1-antitrypsin, iron ferritin, porphyrins, bile acids Serum acylcarnitine profile, CPK Sweat test, CF mutation studies Protease inhibitor phenotype Muscle biopsy, liver fibroblasts for specific enzymes Vascular Doppler images of hepatic venous blood flow Digital subtraction angiography Inferior venacavography Antithrombin III, protein C, protein S

CF, Cystic fibrosis; CPK, creatine phosphokinase; EBV, Ebolavirus; ERCP, endoscopic retrograde cholangiopancreatography; ESR, erythrocyte sedimentation rate; MEGX, monoethyl-glycinexylidide; MRCP, magnetic resonance cholangiopancreatography; TORCH, toxoplasma, rubella, cytomegalovirus, herpes simplex.

Chapter 14: Complications of Chronic Liver Disease commonly seen in children in the early stages of extrahepatic biliary atresia (see Plate 47, Atlas; p.456 ). Macronodular cirrhosis is characterized by nodules up to 5 cm in diameter, separated by irregular septa of varying widths. Regenerative nodules larger than 2 cm in diameter are evidence that the cirrhotic process has persisted for a number of years. This pattern is usually seen in a1antitrypsin deficiency, chronic active hepatitis and Wilson’s disease. Many cases, however, have characteristics of both types of cirrhosis (mixed), and it is known that micronodular cirrhosis can mature into macronodular or mixed cirrhosis. Percutaneous needle liver biopsy interpretation difficulties may arise because of small samples, fragmentation of the specimen or if the specimen is taken from a macronodule. A sample from a macronodule may look almost normal, but there may be hyperplasia of the hepatocytes or a relative excess of hepatic vein branches. In macronodular cirrhosis, the liver edge looks irregular on ultrasound (Chapter 2). Histological classification This is generally more helpful in defining aetiology and in management, defining cirrhosis as post necrotic, biliary (periportal) or hepatic venous outflow (cardiac) cirrhosis. Post-necrotic cirrhosis (Table 14.1) is the result of liver cell damage and is most commonly seen in chronic hepatitis due to viral, autoimmune factors or drugs. This type of cirrhosis is a common sequela of neonatal hepatitis. Features include piecemeal necrosis, bridging fibrosis, collapse of the hepatic lobules, and regeneration, with the development of macronodular cirrhosis. In biliary cirrhosis from cholestatic disorders (see Plate 47, Atlas; p. 456), there is fibrosis developing from within the portal tracts, extending out into the parenchyma linking adjacent portal tracts with little change in the hepatic parenchyma, and preservation of the lobular architecture (Table 14.1). In neonatal biliary disease, bile duct proliferation is a feature of extrahepatic biliary atresia, and bile duct paucity or hypoplasia is a feature of certain intrahepatic cholestatic syndromes. Obstruction to hepatic venous outflow secondary to cardiac lesions with increased right atrial pressure and vaso-occlusive disorders leads to centrilobular haemorrhagic necrosis, with fibrosis extending from central veins to portal tracts. In chronic cases, cirrhosis eventually develops and the initial distinguishing features may be obliterated. Specific histological patterns occur in Wilson’s disease (copper pigment deposition), a1-antitrypsin deficiency (intracellular periodic acid–Schiff-positive, diastaseresistant inclusions) and certain storage disorders.

263

Diagnostic dilemmas The process of cirrhosis in chronic liver disease may be superimposed on the primary cause and eventually obscure the nature of the original insult. Many forms of liver disease have specific histology patterns early in the disease, but as the disease progresses patterns merge, leaving morphological and histological classifications unhelpful. In many cases, particularly in cholestatic syndromes, causing jaundice, pruritus, dark urine and pale stools, the cause of the liver damage will be evident on the basis of history, examination and imaging techniques. A high index of suspicion is necessary for: • potentially treatable genetic disorders, such as Wilson’s disease, galactosaemia, hereditary fructosaemia and tyrosinaemia type I • potentially treatable acquired disorders, such as hepatitis B, hepatitis C and autoimmune chronic liver disease • surgically correctable disorders, such as choledochal cyst and biliary stenosis. Differentiation between cirrhosis and presinusoidal causes of portal hypertension such as congenital hepatic fibrosis and extrahepatic portal hypertension can sometimes cause diagnostic difficulties. In both of these conditions, there are no signs of chronic liver disease. In congenital hepatic fibrosis, the liver is enlarged and hard, splenomegaly is prominent, transaminases and synthetic tests are normal unless there is advanced disease. Histologically hepatocytes are normal, but there are prominent abnormal bile ducts in wide bands of fibrous tissue, but no nodules. Renal cysts on ultrasound or a suggestive family history may provide a clue to this diagnosis (Chapter 9). In extrahepatic portal hypertension due to portal vein malformation or obstruction, the liver is small but histologically normal, and transaminases are normal. There may be mild derangement of coagulation parameters secondary to an underlying coagulation disorder (e.g. protein C or S deficiency). Ultrasound will demonstrate a portal vein cavernoma or absence of blood flow in the portal system, which may be confirmed on angiography or splenoportography (Chapters 2, 3 and 18). The demonstration of a normal portal vein with good blood flow on ultrasound excludes this diagnosis.

Prognostic considerations With the advent of liver transplantation as definitive therapy for many causes of chronic liver disease, a redefinition of the diagnosis of end-stage liver disease is necessary with a view to predicted outcome, full and frank discussion of treatment options, and timely intervention if the transplant option is to be realized. Such an approach allows time for optimizing supportive therapy, to evaluate suitability for transplantation, and to maximize prospects for finding a suitable donor. In addition, com-

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plications such as malnutrition, gastrointestinal haemorrhage, encephalopathy, ascites and infection can be anticipated and prevented whenever possible. Unfortunately, most available liver function tests have poor predictive value until liver decompensation has taken place and the occurrence of specific complications such as gastrointestinal haemorrhage or encephalopathy is unpredictable. There have been few studies of prognostic factors in survival from chronic liver disease in children. For all causes of end-stage disease, McDiarmid et al. (2002) evaluated data from the Studies of Pediatric Liver Transplantation (SPLIT), a consortium of 29 US and Canadian centres, to develop the Pediatric EndStage liver disease (PELD) score. In the multivariate analyses, age, bilirubin, and international normalised ratio (INR) growth failure and albumin were significant for outcome, and a model using these five objective parameters has been developed and tested. In older studies (Chin et al. 1991; Shepherd et al. 1991), malnutrition was suggested as an important independent risk factor, possibly because major nutritional deficits in energy, protein, lipids, vitamins and minerals may independently compromise outcome and further compromise liver function per se. Quantitative dynamic liver function tests, such as monoethyl-glycinexylidide (MEGX) formation from lignocaine, and caffeine clearance, have also been evaluated as prognostic indicators of residual functional capacity of the liver (Oellerich et al. 1991; Baker et al. 1995; Mellon et al. 1997), but in general, expert clinical evaluation using a range of modalities, including the PELD score, and features listed in Table 14.4, remain superior in determining prognosis and predicting the need for transplantation. Knowledge of the natural history of particular disease states is of value. In biliary atresia, survival of the native liver after Kasai procedure is dependent on age and degree of fibrosis at the time of the procedure (Weerasoyia et al. 2002) and the surgical skill according to caseload for the procedure (McKiernan et al. 2000). The persistence of jaundice following a portoenterostomy is an indication for early referral for transplantation. Although a1-antitrypsin deficiency is the commonest metabolic disease leading to liver transplantation in children, only 10–15% of the protease-inhibitor type ZZ (PiZZ) population develops liver disease, and 5–10% of them will re-

Table 14.4 Adverse prognostic features of chronic liver disease in children. Bilirubin > 300 mmol/l Prolonged prothrombin time unresponsive to intravenous vitamin K Partial thromboplastin time > 20 s Malnutrition (Wt. SD score < 1.5) Low plasma cholesterol Ascites

quire liver transplant in childhood. Duration of jaundice, severity of histological features and biochemical abnormalities may predict outcome at an early stage of the disease (Francavilla et al. 2000). In tyrosinaemia type I, unless controlled by diet and NTBC (2(2-nitro-trifluoromethylbenzoyl)-1,3-cyclohexenedione) (Lindstedt et al. 1992, Holme & Lindstedt (2000)), progressive hepatocellular damage is associated with a high incidence of hepatoma by 5 years of age, and ≥ 60% of those presenting by 2 months of age and 25% of those with onset between 2 months and 6 months of age die by 12–15 months of age.

Management of complications of chronic liver disease The primary aims of management are: 1 To minimize or prevent progressive liver damage by treating the cause, if possible. 2 To anticipate, prevent or control the complications. 3 To predict outcome in order to deliver definitive therapy by liver transplantation. In many cases the complications of chronic liver disease can be minimized, and it is necessary carefully to monitor patients with chronic liver disease even if the disease appears to be compensated. Malnutrition and nutritional support The liver has a central role in regulating fuel and metabolism, nutrient homeostasis, and absorption of a number of nutrients. These factors, combined with the common symptoms of anorexia and a poor dietary intake, make malnutrition common in chronic liver disease, particularly if the onset is in infants, who are more vulnerable to the debilitating effects of malnutrition because of their higher energy and growth requirements (Sokol & Stall 1990). A wide range of nutrient deficits occurs in most chronic liver diseases in children (Table 14.5). Malnutrition itself may further derange liver function because the liver requires energy for a number of synthetic, storage and detoxification functions. Nutritional support is an area of management of chronic liver diseases in children where significant gains are to be made (Beath et al. 1993). The rational implementation of nutritional therapy depends on the assessment of the severity of the malnutrition and specific nutrient deficits so that adequate nitrogen and other calories can be provided and vitamin and mineral deficiencies can be prevented or treated. Dietary manipulation for treatment of encephalopathy and management of ascites may result in a protein intake insufficient for somatic growth in children, and care should be taken to concentrate feeds. Nutritional therapies specific for liver disease, providing adequate energy and nitrogen for protein synthesis in children by supplementing metabolic derangements

Chapter 14: Complications of Chronic Liver Disease

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Table 14.5 Nutritional deficits and their management in paediatric liver disease. Deficit

Evaluation

Management

Energy

Energy balance Intake Absorption Expenditure Nutritional status Anthropometry Body cell mass (TBK) DEXA

Energy supplements to achieve 120–130% RDI Nocturnal enteral nutrition

Protein

Plasma proteins (albumin) BCAA/AAA ratio Protein stores Muscle mass TBN

Provide adequate protein (3–4 g/kg/day) BCAA-enriched protein Regular albumin infusion (if serum albumin < 25 g/l)

Fat

Skinfolds, body composition EFA deficiency Plasma lipid profile Absorption

Optimize fat absorption (MCT/LCT) Provide saturated fats high in EFA

Fat-soluble vitamins

Plasma 25-OH-D Skeletal X-rays and DEXA (rickets) Prothrombin time Plasma vitamin e and a

Light exposure Vitamin D–1–a (50 ng/kg) Vitamin K (2.5–5 mg/day) Vitamin E (50–400 IU/day) (as TPGS) Vitamin A (5000–10 000 IU/day)

Water-soluble vitamins

Specific levels Blood count

Supplement as requested

Minerals

Specific levels Cardiac evaluation

Supplement as requested

AAA, Aromatic amino acids; BCAA, branched-chain amino acids; DEXA, dual energy X-ray absorptiometry; EFA, essential fatty acids; LCT, long-chain fatty acids; MCT, medium-chain fatty acids; RDI, recommended daily intake; TBK, total body potassium; TBN, total body nitrogen; TPGS, tocopherol polyethyleneglycol-1000 succinate.

at a macronutrient and micronutrient level, are being evaluated. Effective strategies are emerging and advances include supplemental enteral nutrition, branched chain amino acids, docosahexaenoic acid and structured lipids. The key to optimal nutritional management is a multidisciplinary approach to nutritional surveillance and intervention, including a paediatric dietitian, nurse co-ordinator, feeding psychologist, and clinician (Chapter 1). Pathophysiology Protein–energy balance and macronutrients The body composition of malnourished children with paediatric liver disease is similar to that of protein-energy malnutrition (Chin et al. 1992a,b; Greer et al. 2003), with depletion of metabolically active cell mass and body fat stores, resulting from combined disturbances of intake, absorption and metabolism of nutrients. Importantly, because many of the above changes are energy-linked, overall energy metabolism is compromised in children with chronic

liver disease (McKiernan et al. 1991; Shepherd & Trocki 1995; Greer et al. 2003). Children with biliary atresia (Greer et al. 2003), are hypermetabolic and catabolic during fasting, compared with controls with reduced respiratory quotient (an index of altered substrate oxidation). It is likely that energy metabolism varies with the cause and severity of the disease, and adjusting for body composition makes studies of energy metabolism difficult (Crawford et al. 1994; Greer et al. 2003). Chin et al. (1992a) found that in 27 children with chronic liver disease, mean ad libitum protein energy intake was only 70% of recommended requirements. Protein synthesis of circulating proteins Albumin, transferrin and clotting factors are also impaired in chronic liver disease. An abnormal serum amino acid profile is seen, with elevations in plasma aromatic amino acids (AAA) and depression in branched-chain amino acids (BCAA) (Weisdorf et al. 1987). BCAA comprise 40–50% of the minimum daily requirement for essential amino acids in humans, playing an important regulatory role in protein

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synthesis. Neither growth nor positive nitrogen balance is possible without these amino acids. In cholestatic liver diseases, intestinal malabsorption secondary to reduced delivery of bile salts to the small intestine and exocrine pancreatic dysfunction results in malabsorption of fat and fat-soluble vitamins. Carbohydrate metabolism is abnormal and is characterized by carbohydrate intolerance, peripheral insulin resistance, hyperinsulinaemia and reduced hepatic glycogen stores. Chronic liver disease also alters the synthesis of lipids, including very-low-density lipoproteins and cholesterol, and hypocholesterolaemia is an adverse factor in the outcome of liver transplantation. Disturbances of the growth hormone (GH)–insulinlike growth factor (IGF-1) axis may also contribute to wasting and growth failure in children with liver disease, by virtue of IGF-1 deficiency (Quirk et al. 1994) and GH resistance (Greer et al. 1998). Vitamins and trace elements Abnormalities of intake, absorption and metabolism of vitamins and trace elements are common. Vitamin K is a necessary cofactor for the conversion of inactive precursors of prothrombin and factors VII, IX and X into their active forms. Dietary vitamin K requires bile and pancreatic juice for uptake, and thus in cholestasis vitamin K malabsorption is the primary cause of a prolonged prothrombin time. In parenchymal liver disease the synthesis of liver-dependent clotting factors is reduced. If vitamin K deficiency is a result of malabsorption, parenteral vitamin K normalizes the prothrombin time, but in advanced liver disease vitamin K only partially corrects the prolonged prothrombin time, suggesting poor hepatic synthetic function (Yanofskyi et al. 1984). Vitamin E deficiency is common, particularly in infants with cholestatic liver diseases resulting in a distinctive progressive but preventable neurological disorder associated with peripheral neuropathy, ophthalmoplegia and ataxia (Guggenheim et al. 1982; Sokol et al. 1983). Patients with cholestatic syndromes who have little or no exposure to sunlight, depend primarily on dietary vitamin D to maintain body stores and are particularly likely to develop rickets (defective mineralization) and osteopenia (reduced formation of matrix), with low serum 25-hydroxy vitamin D levels (Andrews et al. 1981). Both these complications result from vitamin D and calcium malabsorption, with secondary hyperparathyroidism. Total 25(OH)D and osteocalcin levels are low, suggesting that decreased bone formation and not increased bone resorption is the main determinant of bone disease (Klein et al. 2002). Vitamin D treatment does not easily reverse bone disease. Signs of vitamin A deficiency are uncommon but abnormalities of the regulation of metabolism of retinolbinding proteins and biochemical vitamin A deficiency

have been reported in infants with biliary atresia (Mourey et al. 1990). Biochemical deficiencies of water-soluble vitamins, including thiamine and pyridoxine, may occur and cases of nutritional cardiomyopathy and peripheral neuropathy have been reported (Rossouw et al. 1978). Of the trace elements, iron, zinc and selenium deficiencies have been reported in children with end-stage liver disease (Chin et al. 1992a). Importantly, these can be associated with growth failure and poor protein synthesis. Nutritional assessment Conventional techniques of assessment, such as body weight and weight adjusted for height, may not be accurate in patients with liver disease because of fluid retention manifest by ascites and oedema masking the underlying loss of bulk in crucial body compartments. Thus, assessment of malnutrition is best performed using several parameters, particularly those less affected by fluid retention such as triceps, skinfolds and arm muscle measurements (Sokol & Stall 1990), biochemical tests for vitamin and micronutrient deficiency, and serial evaluation of growth parameters. Gold standard methods for measuring body composition, such as metabolically active cell mass by total body potassium (Chin et al. 1992a; Crawford et al. 1994), are expensive and limited to research methodology. Other simple body composition measures, such as body impedance analysis, are not reliable in liver disease in children (Holt et al. 1994). Nutritional management The ideal goals of nutritional support include the provision of adequate calories and nitrogen for protein synthesis, restoration and prevention of plasma amino acid imbalance, prevention of vitamin and trace element deficiency, and the achievement of normal growth and activity. The clinical evaluation and approach to management for specific nutritional deficits is given in Table 14.5. Daily intakes of ≥ 130% of the recommended allowances for age and sex are usually necessary to compensate for increased energy expenditure, increased requirements and malabsorption. Enteral supplements are indicated if the child cannot sustain reasonable growth and nutrition via the oral route. Because of poor oral intake and evidence associating fasting with catabolism, nocturnal nutritional supplements are useful means of providing sufficient protein/energy for growth in young children with chronic liver disease (Chin et al. 1990; Beath et al. 1993). Parenteral nutrition is rarely required unless there is feed intolerance, or gastrointestinal bleeding. The use of specialized defined formulae for nutritional supplements in liver disease is receiving some attention.

Chapter 14: Complications of Chronic Liver Disease The carbohydrate and the fat composition (a mix of medium-chain triglycerides and long-chain triglycerides) can provide sufficient absorbed energy, but the protein sources of standard formulae have some disadvantages with regard to abnormalities of protein and BCAA metabolism. Previous recommendations for protein restriction, derived from experience of encephalopathy in adults, are not applicable to small children. There is some evidence in controlled trials that diets with a normal protein intake but relatively rich in BCAA confer nutritional advantages in children with liver disease (Chin et al. 1992c), and that BCAA-enriched normal to high protein intakes (2–3 g/kg/day) do not invoke hepatic encephalopathy (Charlton et al. 1992). BCAA have important regulatory rules in protein synthesis and neither growth nor positive nitrogen balance is possible without these amino acids. They enhance muscle synthesis (Buse & Reid 1975), as well as hepatic structural and secretory protein synthesis (Base et al. 1987). Complete ‘hepatic’ formulae rich in BCAA-containing medium-chain triglycerides and high carbohydrate as well as vitamin and mineral supplements are available (Generaid Plus; Scientific Hospitals Supplies Ltd, Liverpool, UK). For older children, the use of oral supplements rich in BCAA is recommended (Generaid, SHS Ltd; Nutrihep, Nestle Clinical Nutrition, Deerfield, IL 60015, USA; Aminoleban, Otsuka Pharmaceuticals, Tokyo, Japan). Specific vitamin and mineral therapy should also be considered, including both water- and fat-soluble vitamins and specific trace elements (Table 14.5). If steatorrhoea is marked it may be necessary to give vitamin K parenterally on a weekly basis, and vitamin D on a monthly basis, but this must be controlled by regular clinical assessment, radiographs of the wrist, and measurement of serum phosphate, calcium and alkaline phosphatase. Fatsoluble vitamin preparations in water-miscible form are best in cholestasis. Vitamin E deficiency can usually be prevented with vitamin E in water-miscible form (D-alpha tocopheryl polyethyleneglycol-1000 succinate, 25 IU/ kg/day; Sokol et al. 1985). Most children with chronic cholestatic liver disease require 600–3000 IU/day of water-soluble vitamin A(Andrews et al. 1981), but as vitamin Atoxicity can produce cerebral side-effects and hepatotoxicity, the dose should be monitored in patients who do not have significant cholestasis. It is important to recognize that certain specific therapies for liver disease, such as cholestyramine, used for controlling pruritus, penicillamine, used in Wilson’s disease, and diuretics, used for ascites, may cause deficiency of trace elements. Fluid and electrolyte homeostasis is an important part of nutritional management of children with chronic liver disease. Diminished effective circulating blood volume may explain many of the secondary findings of salt and water retention related to portal hypertension, and reduced oncotic pressure due to hypoalbuminaemia. Nor-

267

mally, the diminished circulatory blood volume triggers compensatory hormonal and renal responses to conserve water and sodium. Measures to stabilize and restore effective circulating blood volume help to maintain optimal volume of fluid and sodium balance. This can be achieved by maintaining serum albumin levels by infusions of albumin on a regular basis once significant hypoalbuminaemia ensues, the avoidance of excessive diuretic therapy, and the use of paracentesis with albumin replacement. These measures help to prevent dilutional hyponatraemia and water overload, which may compromise growth and cause other alterations in nutrient metabolism. Ascites and oedema The development of ascites and oedema are common complications of cirrhosis, and a sign of advanced liver disease. Extravascular fluid accumulation in chronic liver disease represents a breakdown of intravascular volume homeostasis, which is controlled by capillary hydrostatic pressure and plasma colloid osmotic pressure. This process may develop insidiously or be precipitated by events such as gastrointestinal bleeding, infection, or the development of hepatoma. Fluid may accumulate as peripheral oedema, in the peritoneal cavity as ascites, or in the pleural cavity. It is manifest by pitting oedema, abdominal distension, and/or the development of hernias. In the majority of patients, judicious use of diuretics, and maintenance of plasma oncotic pressure will control ascites. Pathophysiology The two important factors in extravascular fluid accumulation are portal venous pressure and plasma oncotic pressure, both of which interact in chronic liver disease. These processes result in fluid redistribution between intra- and extravascular spaces, affected by portal venous pressure, hypoalbuminaemia and increased sodium and water retention. Several theories as to the formation of ascites exist. The under filling hypothesis suggests that there is increased sinusoidal pressure leading to a cascade of events resulting in fluid retention from elevated portal venous pressure, increased splanchnic volume, decreased systemic vascular resistance, and decreased effective plasma volume. The decreased plasma volume results in increased activity of plasma renin and aldosterone, resulting in renal retention of sodium and water, leading to the accumulation of ascites. This hypothesis is supported by the fact that expansion of the plasma volume by methods such as albumin infusion may reverse ascites, decrease levels of renin and aldosterone, and result in a diuresis. The overflow hypothesis speculates that inappropriate

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renal sodium and water retention is the primary abnormality triggered by the hepatorenal reflex. Although some animal models support this hypothesis, the fact that the renin–angiotensin–aldosterone system is activated in decompensated cirrhosis is rather against it. Finally, the peripheral arterial vasodilation hypothesis suggests that peripheral arterial vasodilation is the initiating event in ascites formation. The fact that patients with chronic liver disease are prone to the development of arteriovenous connections implies the presence of vasoactive hormones. These connections are known to be associated with peripheral vasodilatation and renal sodium retention. These various models for the development of ascites are not necessarily mutually exclusive. Early overflow secondary to renal sodium retention may be the initiating factor, but in later phases of chronic liver disease diminished effective plasma volume with its accompanying hormonal changes may predominate, leading to peripheral arterial vasodilatation and further increase in sodium and water retention. Thus, sodium retention seems to be fundamental to the occurrence of ascites and oedema. In some patients, sodium retention occurs despite normal activity of the renin–aldosterone and sympathetic nervous systems, and despite increased circulating plasma levels of natriuretic peptides and activity of the so-called natriuretic hormone. These patients have an impairment in circulatory function which, although less intense, is similar to that of patients with increased activity of the renin– aldosterone and sympathetic nervous systems. This suggests that antinatriuretic factors, more sensitive to changes in circulatory function, may be important in the pathogenesis of sodium retention. The development of drugs that inhibit the tubular effect of antidiuretic hormone and increase renal water excretion without affecting urine solute excretion is of interest for the management of water retention and dilutional hyponatraemia in cirrhosis. Two families of drugs, the V2 vasopressin receptor antagonists which block the tubular effect of antidiuretic hormone (Decaux 2001) and the k-opioid agonists which block the tubular effect of antidiuretic hormone (Gadano et al. 2000), improve free water clearance and correct dilutional hyponatraemia in human and experimental cirrhosis with ascites. Treatment Mild ascites causing minimal discomfort or difficulties with mobility or breathing requires no specific treatment in most cases. Salt restriction, an aldosterone antagonist, maintenance of effective plasma volume by albumin infusions for hypoalbuminaemia are effective in most circumstances. Fluid and salt restriction to reduce ascites in children may have deleterious effects on growth and

Table 14.6 Treatment of ascites. Nutritional support Avoid excessive sodium intake (< 1–2 mmol/kg) Spironolactone: < 3 years 12.5 mg q.i.d. 4–7 years 25 mg q.i.d. 8–11 years 37.5 mg q.i.d. 11 years + 50 mg q.i.d. ± Chlorothiazide + vitamin K supplement Albumin infusion (if serum albumin < 25 g/l) 2 g/kg or 10 ml/kg + frusemide 2 mg/kg Paracentesis + albumin infusion for refractory symptomatic ascites

should be balanced by an increase in calorie content of feeds. This is an important consideration in children with chronic liver disease for whom liver transplantation may be the long-term therapeutic option. Indeed, nutritional support, with maintenance of adequate protein homeostasis, is a key factor in the management of ascites (Table 14.6). Patients with gross or refractory ascites resulting in breathing difficulties, abdominal pain or limitation of movement may require paracentesis which involves large-volume paracentesis plus albumin infusion. Paracentesis is also indicated for the diagnosis of unexplained fevers, spontaneous bacterial peritonitis (protein concentration < 20 g/l, leukocytosis), and in the diagnosis of Budd–Chiari syndrome where an acute onset of ascites is associated with protein concentrations > 20 g/l. The diuretic of choice is the aldosterone antagonist, spironolactone, which requires a flexible dosage regimen, often using doses which are higher than in other disorders causing fluid retention in children. The goal of diuretic treatment is a negative fluid balance of ≥ 10 ml/kg/day. If a diuresis occurs at a faster rate than this then there is the risk of plasma volume depletion resulting in decline in renal function. Spironolactone takes 2–4 days to take effect using initial dosages as shown in Table 14.6. The initial response to spironolactone is so reliable that the plasma volume status of the patient should be investigated if no significant diuresis is achieved within 2–4 days. The most significant side-effect of spironolactone therapy is hyponatraemia, which, with hyperkalaemia, is an indication for discontinuing spironolactone. Loop diuretics may be added to if there is only a partial response to spironolactone and no reduction in plasma volume. Frusemide (1–2 mg/kg) is most commonly used, particularly with albumin infusion, but chronic use is accompanied by excessive losses of urinary potassium and chloride, which can exacerbate hepatic encephalopathy and plasma volume depletion. Routine replacement of potassium is recommended except with spironolactone. Because of the higher toxicity of loop diuretics, thiazide diuretics such as chlorothiazide are preferable for chronic use, often resulting in a satisfactory diuresis in a dose initially of 2–3 mg/kg/day. Serum elec-

Chapter 14: Complications of Chronic Liver Disease trolytes, creatinine and urea nitrogen should be measured frequently during diuretic therapy. Refractory ascites This is fortunately uncommon in children, but may occur occasionally in older children and adolescents. The combination of frequent albumin infusions and large-volume paracenteses has become the preferred intervention for ascites refractory to diet and diuretic therapy, based on controlled trials demonstrating relative safety and efficacy (Tito et al. 1990). In severe refractory or recurrent cases where portal hypertension is also an issue, a transjugular intrahepatic portosystemic stent shunt (TIPSS) temporarily decreases portal pressure, decompresses the liver and reduces sinusoidal and splanchnic pressure. This procedure is increasingly being used in paediatric liver centres when a bridging procedure before transplantation is required (Heyman et al. 1997). Refractory ascites in adults has been treated with peritoneal venous shunts (Leveen or Denver), which permit flow of ascitic fluid into the venous system causing resolution of ascites and improved urinary output, but coagulopathy, infection and cardiac failure may develop due to the shunt. Their use has not been reported in children. Liver transplantation is the only treatment which improves long-term survival. Portal hypertension and variceal bleeding (see also Chapter 18) Portal hypertension is one of the major causes of morbid-

ity and mortality in children with chronic liver disease. In general, it is the result of a combination of increased portal blood flow and increased portal resistance, and occurs when portal pressure rises above 10–12 mmHg. Signs and symptoms are the result of decompression of this elevated portal blood pressure through portosystemic collaterals. The main clinical features are splenomegaly, the occurrence of oesophageal, gastric and rectal varices, and the development of ascites. Splenomegaly and hypersplenism rarely require specific intervention. The major problems are bleeding from oesophageal and other varices, considered below, and ascites and nutritional disturbances, considered in detail above. Pathophysiology An understanding of portal hypertension requires knowledge of the anatomy of the portal system (Fig. 14.2). Portal capillaries originate in the mesentery of the intestine and spleen and in the hepatic sinusoids. Capillaries of the superior mesenteric and splenic veins supply the portal vein with a nutrient and hormone-rich blood supply. At the hilum of the liver the portal vein divides into two major trunks supplying the right and left lobes of the liver, and these trunks undergo a series of divisions supplying segments of the liver terminating in small branches which pierce the limiting plate of the portal tract and enter the sinusoids through short channels. The partly oxygenated portal venous blood supplements the oxygenated hepatic arterial blood flow to give the liver unique proLeft branch

Liver

Right branch

Short gastric veins

Po

Left gastric vein

l rta

Umbilical vein

ic

Splen

Spleen

Pancreas Inferior mesenteric vein

Superior mesenteric vein

Fig. 14.2 Anatomy of portal venous system (reproduced with permission from Sherlock & Dooley 1998).

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Section 7: Management of Chronic Liver Disease

Azygos and hemiazygos system Pulmonary Diaphragmatic

Intercostal

Gastro-oesophageal

Lumbar

Splenorenal

Umbilical

I V C

Spermatic or ovarian

Rectal

tection against hypoxia. Blood flow from both the hepatic artery and the portal vein is well regulated, allowing the liver to withstand thrombosis of either one of these major vessels. Portal hypertension due to chronic liver disease may arise due to prehepatic or intrahepatic block, where the block may be presinusoidal, sinusoidal or postsinusoidal. The major pathological effect from portal hypertension is the development of collaterals carrying blood from the portal venous system to the systemic circulation (Fig. 14.3). These develop around the upper part of the stomach and the oesophagus and in the rectum, in the falciform ligament, and may drain into the inferior vena cava or the left renal vein. Only the submucosal collaterals, such as in the oesophagus and stomach and rarely in other parts of the intestine, are associated with gastrointestinal bleeding (see Plate 48b, Atlas: p. 457). Collaterals in other parts of the intestine occur at sites of surgery in

Fig. 14.3 Sites of collateral circulation in portal hypertension (reproduced with permission from Sherlock & Dooley 1998).

the gastrointestinal tract, particularly stoma and anastomotic sites. Portal hypertensive gastropathy, which is suggested by dilated mucosal veins and capillaries and mucosal congestion in the stomach, develops particularly in patients who have had variceal obliteration. While changes in vascular resistance to blood flow between the splanchnic bed and the right atrium appear to be the initial events in the development of portal hypertension, a number of other haemodynamic changes contribute to and amplify the increased portal blood pressure. There is a hyperdynamic circulatory state with increased cardiac and decreased splanchnic arteriolar tone, both of which increase portal inflow. Studies in animal models indicate that a number of humoral mediators are involved including glucagon, prostaglandins, nitrous oxide and endothelium-derived relaxing factor. Changes in intravascular volume also play an important part in

Chapter 14: Complications of Chronic Liver Disease pathophysiology of the hyperdynamic circulation, as do alterations in adrenergic tone in the splanchnic system. All of these observations have led to new experimental and clinical studies suggesting possible pharmacological treatments for portal hypertension (Boyer 2001), although direct treatment of variceal haemorrhage remains the major approach.

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Emergency therapy Bleeding oesophageal varices in children requires emergency treatment (Fig. 14.4 and Chapter 18) (see Plate 48b, Atlas: p. 457) However small the haemorrhage, admission to the nearest hospital with blood transfusion facilities is advised. As soon as the patient has blood transfusion available and a secure intravenous infusion line, and is haemodynamically stable, referral to a tertiary unit with experience in the management of variceal haemorrhage in children is recommended. In patients with chronic liver disease an initial melaena or sentinel bleed may precede sudden haematemesis and shock requiring rapid blood transfusion to prevent death. Significant bleeding with hypotension impairs hepatic perfusion, often causes deterioration of liver function and precipitates ascites and encephalopathy. Vital signs such as tachycardia and hypotension and a reduction in splenomegaly can be helpful in assessing blood loss. Beta-blocker therapy may mask significant hypotension. In patients with cirrhosis, hepatic encephalopathy must be anticipated and lactulose should be given. In such cases, nasogastric intubation is an essen-

Therapy Therapy is primarily directed at the prevention and/or management of variceal haemorrhage, except in cases of hepatic venous outflow block where surgically treatable causes, such as vena caval webs or constrictive pericarditis, need to be considered. Variceal haemorrhage clinically presents as a need for emergency therapy, or as a need for prophylaxis of initial or subsequent rebleeding after an initial bleed. Most of the data concerning the management of variceal haemorrhage have come from large controlled trials in adults, and the paediatric literature is generally descriptive or anecdotal.

Bleeding varices Secure haemostasis (vitamin K, plasma) Treat hypovolaemia IV octreotide or vasopressin Refer to appropriate centre Medical/surgical liaison Endoscopy and sclerotherapy or banding

Bleeding stops

Bleeding continues >4–48 hours

Evaluate measures to minimize or prevent recurrence

TIPSS portal vein ultrasound

Endoscopy ± sclerotherapy Sengstaken tube

Emergency surgery or transplantation

Persistent bleeding

Fig. 14.4 Algorithm for management of bleeding varices. TIPSS, Transjugular intrahepatic portosystemic stent shunt.

TIPSS if portal vein patent

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tial part of management, allowing the documentation of ongoing bleeding, and the removal of blood which might precipitate encephalopathy. Initial fluid management in the form of crystalloids followed by red blood cell transfusion is important, and any coagulopathy should be corrected with vitamin K, fresh frozen plasma, or occasionally in the case of thrombocytopenia, platelet infusion. Pharmacological treatment Pharmacological therapy is directed towards reduction of hepatic vascular resistance using prostacyclin, adrenergic antagonists, calcium channel blockers or nitric oxide, or reducing portal blood flow with splanchnic vasoconstrictors or propranolol. In practice, if the bleeding is severe, a short-acting splanchnic vasoconstrictor may be useful (Table 14.7) (Moitinho et al. 2001). Somatostatin (Burrough et al. 1990) or its longeracting analogue octreotide (maximum dose 1 mg/kg/h i.v., or 2–4 mg/kg/dose subcutaneously 8-hourly) have fewer side-effects and are the drugs of choice, although there has not been a systematic evaluation in children. The other major splanchnic vasoconstrictors are vasopressin (0.3 U/kg as a bolus over 20 min followed by continuous infusion of the same amount on an hourly basis, usually for 24 h or until the bleeding has ceased) or its inactive precursor glypressin (0.01 mg/kg bolus 4- to 6hourly or 0.05 mg/kg infusion over 6 h for 24–48 h). Common side-effects include skin pallor, abdominal colic and chest pain. Studies in adults have indicated that adjunctive vasodilator, such as nitroglycerine in the form of a 10-mg patch, may reduce these haemodynamic complications (Bosch et al. 1989). Endoscopic treatment (see also Chapter 18 for technical details) As soon as the patient is haemodynamically stable, an experienced endoscopist should document the cause of the haemorrhage. A significant percentage of patients with known varices have bleeding from sources other than varices, including duodenal/gastric ulceration. In addition, meta-analysis of multiple controlled adult studies clearly show that endoscopic treatment plus pharmacological treatment is currently the best measure to achieve initial control of significant acute variceal bleeding (Banares et al. 2002). Episodes of minor variceal haemorrhage may spontaneously terminate, but endoscopic treatment by sclerotherapy or band ligation is often necessary. Both techniques are well-described in children (Fox et al. 1995; Howard et al. 1988; Goenka et al. 1993; Goncalves 2000). In adults, comparative trials of sclerotherapy and ligation indicate equal efficacy in controlling bleeding, reducing rebleeding, and ablating varices, but there are fewer adverse effects with banding (Stiegmann et al. 1992). However, the two procedures can be complementary and access to both procedures may be warranted

(Fox et al. 1995; McKiernan et al. 2002), particularly in small infants, where entrapment of part of the oesophageal wall with perforation or bleeding is possible. In these circumstances, sclerotherapy is appropriate. Sclerotherapy involves injection of sclerosants such as ethanolamine, or tetradecyl sulphate para- or intravariceally, in volumes of 0.5–1.0 ml just above the gastro–oesophageal junction. It is associated with bacteraemia and broad-spectrum antibiotics should be prescribed (amoxycillin, cefuroxime and metronidazole). Complications, which should be uncommon in experienced centres, include oesophageal ulceration, stricture and pain. The use of mucosal protecting agents such as sucralfate (1–4 g 6-hourly) may minimize the risk of ulceration and/or stricture formation. More severe complications are rare but include perforation, thrombotic phenomena, respiratory complications and rarely pericardial problems. Sengstaken–Blakemore tube In rare cases, if the above measures fail to control bleeding, temporary cessation of bleeding can be achieved using mechanical compression of oesophageal and gastric varices using a paediatric Sengstaken–Blakemore tube or a Linton tube. These devices are best inserted under anaesthesia at the time of attempted sclerotherapy. The Sengstaken–Blakemore tube consists of a rubber tube with two balloons, which is passed into the stomach where the first balloon is inflated and withdrawn against the gastro–oesophageal junction. The second balloon may be inflated in the oesophagus at a pressure of 20–30 mmHg but is rarely required as the pressure on the gastro–oesophageal junction is usually sufficient to control the bleeding. A Linton tube is a single balloon device with a pear-shaped single balloon, which is inflated in the stomach and then pulled up against the gastro–oesophageal junction. Both tubes may be useful temporarily to control bleeding to allow for resuscitation and prevent exsanguination, but neither can be used for longer than 24 or 48 h because of the risk of ulceration, particularly in the oesophagus. There is a high incidence of rebleeding when the tubes are removed. Portosystemic shunts Emergency creation of portosystemic shunts or other surgical therapy is usually a last resort for persisting exsanguinating acute variceal haemorrhage. Those patients who come to emergency shunts often have gastric variceal bleeding (Millar et al. 1991). Considerations in these circumstances include potential mortality, and the range of techniques available, including TIPSS, surgical shunts, oesophageal trans-section, oesophagogastric devasculation and splenectomy (Chapter 18). TIPSS is an attractive approach because it does not require major surgery. It has been used effectively in critically ill adults to control bleeding prior to liver transplan-

Chapter 14: Complications of Chronic Liver Disease tation (Ring et al. 1992), and in some children with bleeding stomal varices (Lagier et al. 1994). The procedure appears to decrease portal pressure acutely, although 60% occlude within 3–12 months, so it is best viewed as a bridging procedure only. Paediatric application is limited by size constraint (Marx & Williams 1992), but in experienced hands, in selected children over the age of 2–5 years, the procedure has application and is preferable to major shunt surgery for hepatic causes of portal hypertension (see Plate 48(b), Atlas: p. 457). Ultimately the approach to acute variceal haemorrhage in paediatric patients is a progression from the least invasive to the most invasive, and the outcome for the patient relies on the particular strengths of the team, the facilities available for the care of the patient, and the development of particular approaches for this problem in individual institutions. Primary prophylaxistinal bleed In recognized cases of portal hypertension with varices, primary prophylaxis is controversial. However, it is reasonable to prepare for the possibility by ensuring that the child’s caregivers understand the importance of seeking early medical advice by attending the nearest hospital for blood cross-matching and appropriate referral to a tertiary unit. Long-acting vasoactive drugs that reduce splanchnic pressures may be useful in these circumstances (Table 14.7). Betablockers, such as propranolol and the more selective atenolol, reduce hepatic arterial and portal vein blood flow and have been studied with respect to reduction in

Table 14.7 Pharmacotherapy in portal hypertension. Short-acting splanchnic vasoactive agents Growth hormone inhibiting factors Somatostatin Octreotide (25 mg/h i.v. infusion or 50 mg/8 h s.c.) Vasoconstrictors Vasopressin (0.3 units/kg/h infusion for 24 h) Glypressin (0.3–1.0 unit/kg/h infusion) Long-acting splanchnic vasoactive agents Beta-adrenergic receptor blockers Propranolol (1–5 mg/kg/day in three divided doses) Atenolol (1 mg/kg/day in two doses) Alpha-adrenergic receptor blockers Clonidine* (10–20 mg/kg/day in three doses) 5HT receptor antagonists Retanserin Nitrovasodilators Nitroglycerin* (5–10 mg patches) Isosorbide 5 nitrate Diuretics Spironolactone (1.5–3.0 mg/kg/day in three doses)

*Reported adjunctive effect with propranolol. 5HT, 5-hydroxy trypramine tryptophan.

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portal pressures to < 12 mmHg, thereby reducing the risk of an initial bleed in adults (Lebrec 2001). Two small uncontrolled clinical trials have been performed in children which suggest a benefit for both primary and secondary prophylaxis (Shasidhar et al. 1999). Prophylactic sclerotherapy or propranolol may also be indicated, if there are cherry-red spots on the varices, which indicate imminent risk of bleeding. Prevention of recurrent gastrointestinal bleeding Direct obliteration of the varices is the treatment of choice for bleeding due to cirrhosis. Randomized controlled trials in adults have shown a reduction in the frequency of bleeding and improved survival (Westaby et al. 1992), and although no randomized controlled trials have been performed in children, several large studies of sclerotherapy (Howard et al. 1988; Goenka et al. 1993; Goncalves et al. 2000), and smaller studies of banding (Fox et al. 1995; McKiernan et al. 2002) in children with portal hypertension indicate that this procedure is safe and reduces the chance of rebleeding. Neither technique reduces portal pressure, and both may cause some interference with the vascular haemodynamics. In some cases hypersplenism and portal gastropathy get worse temporarily. Several vasoactive drugs have also now been documented in multiple controlled trials in adults to reduce the risk of rebleeding by reducing portal and systemic pressures (Poynard et al. 1991; Lebrec 2001). At present, a combination of a non-selective b-blocker and certain nitrates (e.g. isosorbide 5-mononitrate) are the drugs of choice, aiming at a 25% reduction in resting heart rate (Table 11.7). Major adverse effects of b-blockers include reactive airway disease and heart block. Surgical management of portal hypertension Where there is active liver disease but a significant risk of mortality from bleeding, surgical management of portal hypertension is feasible. Such patients should ideally be evaluated and treated in a transplant centre. Surgical portosystemic shunts can reduce the risk of gastrointestinal bleeding but cause a decrease in portal blood flow and decreased hepatic perfusion, and carry the risks of hepatic decompensation, hepatic encephalopathy, and precluding or enhancing difficulty with liver transplantation. Randomized controlled trials in adult patients have not shown any significant improvement in survival with portosystemic shunts in patients with intrahepatic causes of portal hypertension. If a shunt operation is contemplated in critically ill patients, then the use of a TIPSS is probably the procedure of choice. Ultimately the procedure of choice for uncontrolled portal hypertension due to intrahepatic disease is liver transplantation. In nonshunt, non-transplant candidates, a Sugiura procedure (oesophageal disconnection/devascularization procedure) may be life-saving, with the added advantage of a

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low risk of encephalopathy. Special consideration should be given to shunt surgery in some cases of congenital hepatic fibrosis and portal vein thrombosis, which are presinusoidal causes of portal hypertension not associated with the occurrence of liver synthetic dysfunction (Chapters 9 and 18). Hepatic encephalopathy Hepatic encephalopathy is a major neuropsychiatric complication of chronic liver disease. It tends to develop slowly in cirrhotic patients, starting with altered sleep patterns and eventually progressing through asterixis to stupor and coma. Precipitating factors are common and include an oral protein load, gastrointestinal bleeding and the use of sedatives. It is common following shunts for portal hypertension. Hepatic encephalopathy is difficult to recognize in children, particularly in infants. Early symptoms of encephalopathy are subtle and include neurodevelopmental delay, school problems, lethargy or sleep reversal. Intellectual impairment and personality change may occur in older children, while clouding of consciousness, progressing to stupor and coma are late signs. Clinical signs such as ataxia, tremor and dysdiadochokinesia are difficult to determine in small children. Pathogenesis The occurrence of hepatic encephalopathy appears to be related to four major events: portosystemic shunting; hepatocellular dysfunction; interaction of nitrogen metabolites from the intestine with the central nervous system; and altered neurotransmitter function (Fig. 14.5) (see also Chapter 7). From clinical observations and from studies in experimental models, nitrogenous products such as ammonia derived from the gastrointestinal tract appear to be of primary importance. Hepatic encephalopathy is rare when liver function is able to remove nitrogenous intestinal metabolites, although portosystemic shunting alone can result in encephalopathy if the subject is given a high-protein diet. However, serum ammonia levels, which are usually elevated in encephalopathy, do not directly correlate with cerebral state and experimental evidence suggests that such changes are not the only ones responsible for the encephalopathy. Neuropathologically, there is astrocytic (rather than neuronal) alteration. Magnetic resonance imaging reveals bilateral signal hyperintensities particularly in globus pallidus on T(1)weighted imaging, a phenomenon which may result from manganese deposition. Proton (1H) magnetic resonance spectroscopy shows increases in the glutamine resonance in brain, reflecting increased brain ammonia removal. Although the exact molecular mechanisms are not known, excitatory/inhibitory neurotransmitter imbalance leading to dysfunction of the glutamate-nitric oxide (NO) sys-

tem is thought to play a major role. Activation of glutamate receptors leads to increase in intracellular calcium, which initiates several calcium-dependent processes including NO formation. NO is a gaseous, highly reactive, freely diffusible molecule with a short half-life. Increased expression of the neuronal isoform of NO synthase and the uptake of L-arginine (the obligate precursor of NO) has been demonstrated. Hyperammonaemia associated with liver dysfunction results in increased NO, which may lead to learning and memory impairments. Other metabolic factors, which have been implicated, are shortchain fatty acids such as butyrate, valerate and octanoate, which are increased in the plasma and cerebrospinal fluid in encephalopathy, and may act synergistically with ammonia. Hepatic encephalopathy may also be affected by the accumulation of inhibitory neurotransmitters in the brain. Neurotransmitters mediate the post-synaptic action of neurones. Inhibitory neurotransmitters may be false (not ordinarily present in the brain) or true [such as the amino acid g-aminobutyric acid (GABA)], which is produced in the brain by the decarboxylation of glutamic acid. False transmitters may be produced by metabolism of amines by gastrointestinal tract bacteria and are normally removed by the portal circulation by the liver. False neurotransmitters have not been found to induce encephalopathy in experimental animals. In contrast, GABAhas an important role in central nervous system inhibition and GABA-like activity has been found in portal blood in both animal models and subjects with chronic liver failure after gastrointestinal haemorrhage. In experimental models, GABA may produce coma. The GABA receptor is activated not only by GABA but by benzodiazepines. The reversal of encephalopathy in some patients after the administration of a benzodiazepine antagonist supports this hypothesis, although the effect is not entirely consistent. Alterations in neurotransmitter function may also occur as a result of disturbances of amino acid metabolism, particularly the deficiency of branched-chain amino acids and excess of aromatic amino acids. Further alterations in brain function can be induced by hypoglycaemia, common even with fasting in young children, or respiratory alkalosis leading to a decrease in cerebral perfusion, and hypoxaemia due to haemodynamic changes. Aggravating factors include gastrointestinal haemorrhage, hypovolaemia, hypokalaemia, sedatives, anaesthetics, sepsis and high protein intake, which increase the endogenous nitrogen load, thus precipitating overt encephalopathy. Diagnosis Diagnosis of hepatic encephalopathy in children involves

Chapter 14: Complications of Chronic Liver Disease

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Cerebral disturbance

Aorta

Inferior vena cava

Portal collateral vein Hepatic vein

Hepatocellular disease

Fig. 14.5 Mechanisms of hepatic encephalopathy. In the presence of hepatic dysfunction and/or portosystemic shunts, nitrogenous and other metabolites from the gastrointestinal tract interact directly with the central nervous system which appears sensitized due to altered neurotransmitter function. (Reproduced with permission from Sherlock & Dooley 1998.)

a high index of suspicion and careful clinical assessment. While there are agreed criteria with neuropsychiatric tests in adults, these are not applicable to children, and there is no specific laboratory test for encephalopathy. Changes on EEG may provide objective evidence of cerebral dysfunction, but the changes are non-specific and do not correlate with the severity of encephalopathy. Slow waves are prominent on EEG at stage II to III encephalopathy but may occur in normal children (Yen & Liaw 1990). In chronic encephalopathy, the degree of encephalopathy varies with protein intake, which is an important clue to early diagnosis.

Source of nitrogen

Portal vein

Food protein Ingested blood Drugs and bacterial action

Intestine

Treatment Treatment of hepatic encephalopathy is directed at identifying and treating any precipitating factors, the avoidance of fasting, sedatives, and reducing the nitrogen load from the intestine. While standard therapy in adults for chronic hepatic encephalopathy includes protein restriction, this may result in growth failure and nutritional depletion in children, which may further aggravate glucose and amino acid disturbances. Thus, restriction of dietary and/or intravenous protein to 1–2 g/kg should be used only in acute or very symptomatic encephalopathy, and

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protein may be reintroduced as the encephalopathy subsides. A reduction in intestinal protein load and bacterial flora in the gastrointestinal tract can be achieved in the short term by enemas, particularly if an acute episode of encephalopathy is precipitated by gastrointestinal haemorrhage, and in the long term by use of broad-spectrum antibiotics and/or lactulose. Antibiotics reduce the amount of bacterial urease available by directly suppressing ammonia-forming bacteria. In children, neomycin is commonly used, although its long-term use has resulted in deafness. Vancomycin hydrochloride has been successfully used in resistant cases. Lactulose, a non-absorbable synthetic disaccharide, is the mainstay of treatment for hepatic encephalopathy, and should be first-line therapy as, in theory, its mode of action may be counteracted by antibiotics. In the colon, the unabsorbed lactulose is metabolized by bacteria, producing lactic acid, causing a drop in pH in the colon and a reduction in ammonia reabsorption (Mortensen et al. 1990). Recommended paediatric doses are 0.3–0.4 ml/kg three times a day sufficient to acidify the stools (pH < 6.0), without significant diarrhoea. Therapy with lactulose or with a combination of lactulose and neomycin is successful in reducing encephalopathy in the majority of patients (Conn et al. 1977). Similar results have been found with sorbitol (Morgan & Hawley 1987). BCAA-enriched nutritional supplements may be a useful adjunctive therapy for hepatic encephalopathy by reducing muscle protein breakdown and normalizing plasma amino acid profiles, although double-blind randomized studies of BCAAs for chronic encephalopathy in adults have conflicting results. BCAA supplements have been used as an enteral protein supplement in randomized crossover trials in children with advanced cirrhosis and malnutrition, demonstrating improvement in nutritional status and safety with respect to the development of hepatic encephalopathy (Charlton et al. 1992; Chin et al. 1992c). Similarly, benzodiazepine antagonists might ameliorate some symptoms of hepatic encephalopathy. Flumazenil has been the subject of limited and unblinded trials suggesting dramatic improvements in encephalopathy with reversal after discontinuation (Ferenci et al. 1989), although randomized controlled trials have yet to be performed. In addition, sodium benzoate, useful in treating episodic hyperammonaemia in urea-cycle disorders (Brusilow et al. 1984), may have application in hepatic encephalopathy unresponsive to lactulose (Uribe et al. 1988).

Table 14.8 Coagulation disturbances and altered haemostasis in chronic liver disease. Vitamin K malabsorption/deficiency Vitamin K dependent coagulation protein deficiencies (factors II, VII, IX, X) Hypofibrinogenaemia and dysfibrinogenaemia Thrombocytopenia Consumption

factors. Thus, coagulation disorders are common in chronic liver disease (Table 14.8) due to a combination of vitamin K malabsorption and deficiency, reduced synthesis of coagulation factors and inhibitors of coagulation, thrombocytopenia secondary to hypersplenism, or from intravascular coagulopathy. These disturbances are particularly important in prognostic assessment, and in the genesis and management of gastrointestinal bleeding, and may lead to serious complications such as intracerebral bleeding and intravascular coagulopathy. Management Management is directed at prevention or correction of vitamin K deficiency by administration of parenteral vitamin K if necessary. All patients should have oral vitamin K supplements (Table 14.5). Parenteral vitamin K (2–10 mg i.v. daily for 3 days or 5–10 mg per week i.m.) should be given to any patient with a prolonged prothrombin time. Infusions of fresh frozen plasma (5– 10 ml/kg), cryoglobulin and/or platelet transfusions are effective for transient correction, and should be reserved for invasive procedures such as liver biopsy and for bleeding episodes. However, in children awaiting liver transplantation, the regular use of fresh frozen plasma and platelets, if the prothrombin time is > 40 s prolonged or the platelet count is < 40 ¥ 109/l, may reduce the risk of haemorrhage. Where there is persistent severe coagulation disturbance or persisting bleeding, reduction in prothrombin time and bleeding time may be achieved by the use of desmopressin, which increases levels of factors VIII and IX (Burroughs et al. 1985). Pulmonary complications of chronic liver disease Chronic liver disease and cirrhosis have a number of potential pulmonary complications (Table 14.9).

Coagulopathy The liver plays an important role in the maintenance of haemostasis by a complex balance between the production of coagulation proteins, inhibitors of coagulation and removal of fibrin degradation products and coagulation

Hepatopulmonary syndrome The hepatopulmonary syndrome is defined as a triad of liver dysfunction, intrapulmonary arteriovenous shunts, and arterial hypoxaemia. The hepatopulmonary syn-

Chapter 14: Complications of Chronic Liver Disease Table 14.9 Pulmonary complications of chronic liver disease. Intrapulmonary shunts and hypoxaemia Pulmonary hypertension Pleural effusions Pneumonia Restrictive or obstructive airways disease

drome causing hypoxaemia is relatively common in childhood liver disease. Oxygen saturations of < 90% and cyanosis appear unrelated to the severity of liver damage, but are associated with the occurrence of clubbing. The pathogenesis appears to be multifactorial, including intrapulmonary shunts, arteriovenous shunts, ventilation–perfusion mismatch, and portopulmonary venous anastomoses. In some cases the degree of cyanosis may be proportionally greater than the hypoxaemia. In infants, hypoxaemia can be aggravated by poor respiratory effort related to ascites or hepatomegaly. Such patients have dyspnoea at rest, particularly when upright, often relieved by lying down. The diagnosis is established by ensuring that there is no underlying cardiac defect (ECHO, ECG or cardiac catheterization). Simple transcutaneous techniques of oxygen monitoring can be of most diagnostic value (Santamaria et al. 2001). Ventilation perfusion scans will demonstrate the presence of extrapulmonary isotope in the cerebral blood and other organs; lung function tests are usually normal. While no specific treatment for this syndrome has been proven, the degree of hypoxaemia is improved by oxygen administration, attention to nutrition support and control of ascites. The hepatopulmonary syndrome may seriously limit tolerance to anaesthesia. During or after transplantation, worsening hypoxaemia may be improved by using inhaled NO. Liver transplantation will reverse the systemic and pulmonary vascular changes, although recovery may be slow. Pulmonary hypertension This may occur in cirrhosis as a result of failure of degradation of vasoactive substances in the splanchnic circulation associated with portopulmonary venous anastomoses and para-oesophageal portosystemic collaterals within the pulmonary venous system. The presenting feature is cyanosis, but early signs include right ventricular hypertrophy or accentuation of the pulmonary vessels on chest X-ray. Pleural effusions and pneumonia These are common in end-stage liver disease. Pleural effusions have a similar aetiology to ascites (see above)

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and in association with an increased risk of bacterial infection, increase the risk of pneumonia. The occurrence of fever, cough or dyspnoea indicates the need for appropriate respiratory investigations and management. Obstructive and restrictive pulmonary abnormalities A variety of these have been detected in patients with chronic liver disease, particularly in a1-antitrypsin deficiency and in liver disease associated with cystic fibrosis where the aetiology of these pulmonary complications is due to the primary disease. Hepatorenal syndrome This syndrome is a functional progressive renal failure of unknown cause occurring in patients with severe liver disease. It is a serious complication of cirrhosis and carries a poor prognosis. While the pathogenesis is not understood, abnormalities of renal cortical blood flow are central to the pathogenesis. A high incidence of glomerulosclerosis and membranoproliferative glomerulonephritis has been documented in children with end-stage liver disease at the time of liver transplantation (Chin et al. 1992b), probably secondary to chronic reduction in renal cortical blood flow. Studies in adult cirrhotics have suggested that those without hepatorenal syndrome have systemic vasodilatation, whereas those with hepatorenal syndrome have evidence of peripheral vasoconstriction, leading to the hypothesis that patients with the hepatorenal syndrome have increased splanchnic blood pooling resulting in decreased renal blood flow (Fernandez-Seara et al. 1989), possibly related to up-regulated endothelial nitric oxide synthase (Editorial 1992). Administration of vasopressin, which causes splanchnic vasoconstriction, has been shown to increase glomerular filtration and renal blood flow in such patients (Lenz et al. 1989), and forms the basis of current approaches to medical therapy. Renal vasoconstriction is also possibly related to an increase in the production of thromboxane, a potent vasoconstrictor, and a decrease in prostaglandin2, a dilatory metabolite (Moore et al. 1991). Clinical features and diagnosis Acute renal failure in children with liver disease may be due to renal, prerenal or hepatorenal syndrome. It is possible to differentiate them by urinary indices, such as urinary sodium concentrations (< 20 mmol/l in prerenal) and ratio of urinary to plasma creatinine (> 40 in prerenal). Functional renal failure (the hepatorenal syndrome) presents in two forms. The onset may be acute, precipitated by gastrointestinal haemorrhage, aggressive diuresis, or an associated deterioration of liver function.

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It is associated with oliguria, uraemia, hyperkalaemia, hyponatraemia and a low urinary sodium concentration (< 10 mmol/l). Initial serum creatinine levels double in less than 2 weeks. These features are difficult to distinguish from prerenal failure, which responds to an acute volume expansion, or acute tubular necrosis, where tubular casts and high urinary sodium (> 30 mmol/l) are found. Plasma volume expansion does not improve renal function in hepatorenal syndrome. The second form is characterized by a slower development of oliguric renal failure with a marked reduction in glomerular filtration rate and hyponatraemia, again with a low urinary sodium concentration. Serial measurements of urinary sodium concentration and urinary osmolarity help distinguish the condition of acute tubular necrosis, where the urinary sodium concentration may rise and the urine osmolarity is usually equal to plasma osmolarity. These measurements are unreliable if the patient is on diuretics, particularly frusemide. Treatment Renal failure has a mortality of ≥ 90% in the setting of severe liver disease, but is effectively reversed by liver transplantation. Increased understanding of the pathogenesis has led to preliminary attempts to reverse hepatorenal syndrome with combinations of splanchnic vasocontrictors (octreotide, 3–5 mg/kg/day), or vasopressin analogues [terlipressin (0.04 mg/kg/day)], colloid volume expansion with regular albumin infusions (1–2 g/kg/day), insertion of transjugular intrahepatic portovenous shunts, and improved forms of dialysis (Moreau 2002). Liver transplantation is tolerated reasonably well in patients with hepatorenal syndrome, although the glomerular abnormalities, and the nephrotoxic effects of cyclosporin may explain the high rates of renal dysfunction post transplant (Chin et al. 1992b). Bacterial infections Bacterial infections are common in chronic liver disease, and may precipitate other complications, such as encephalopathy, ascites, and hepatorenal syndrome. Urinary and respiratory tract infections are frequent, and bacteraemia commonly results from invasive investigations. Spontaneous bacterial peritonitis is a common serious complication of ascites and should always be excluded in all children with sepsis. Immune deficits associated with chronic liver disease include abnormalities of complement and opsonization, impaired function of Kupffer cells, neutropenia, and alterations in mucosal barriers, particularly the gastrointestinal tract. Portal hypertension makes patients susceptible to frequent bacteraemia, perhaps by inducing bacterial translocation of the

gut. The specific risk factors for infection are low serum albumin, gastrointestinal bleeding, intensive care unit admission for any cause, and therapeutic endoscopy. Certain infectious agents are more virulent and more common in patients with liver disease. These include Klebsiella, Escherichia coli, Vibrio, Campylobacter, Yersinia, Plesiomonas, Enterococcus, Aeromonas, Capnocytophaga, and Listeria species, as well as organisms from other species. Preventative measures such as pneumococcal and Haemophilus influenzae vaccination, prophylactic antibiotics for invasive procedures, and nutritional support, may reduce the risk of specific infection. Spontaneous bacterial peritonitis This is a potentially fatal complication of ascites in children (Larcher et al. 1985). The condition should always be suspected in a patient with ascites and concurrent fever, abdominal pain or neutrophilia. Common signs in paediatric patients include abdominal distension, vomiting and diarrhoea. Examination may reveal abdominal tenderness with rebound and decreased or absent bowel sounds. Occasionally spontaneous bacterial peritonitis may be relatively asymptomatic except for fever. The diagnosis is established by abdominal paracentesis, which reveals cloudy fluid with a neutrophil leucocyte count of > 250/mm, and a low protein concentration < 20 g/l. Characteristically, spontaneous bacterial peritonitis is caused by a single species, often enteric bacteria such as Klebsiella spp., E. coli and enterococcus, although Streptococcus pneumoniae predominated in one series (Larcher et al. 1985). The presence of multiple species suggests the possibility of bowel perforation and secondary peritonitis. While the final choice of antibiotics is dictated best by the bacteriology, early institution of therapy with a thirdgeneration cephalosporin, such as ceftriaxone or cefotaxime, is recommended (Felisart et al. 1985). Prophylaxis against this disorder has not been subjected to definitive trials (Soares-Weiser et al. 2001), but clinical experience suggests that may be achieved by the use of prophylactic antibiotics during invasive procedures, immunization (as above) and in recurrent cases a prophylactic oral antibiotic such as cotrimoxazole, ciprofloxacin or norfloxicin (Gines et al. 1990). Hepatocellular carcinoma Hepatocellular carcinoma may occur in the setting of chronic liver disease in cirrhosis in childhood. Frequent associations include hepatitis B, in which children with neonatally acquired hepatitis B have developed hepatocellular carcinoma from the age of 7 or 8 years (Hsu et al. 1987). There is also a close association of the development of hepatocellular carcinoma with tyrosinaemia type I,

Chapter 14: Complications of Chronic Liver Disease with one study (Weisdorf et al. 1987) suggesting an occurrence rate of 37% in patients surviving beyond 2 years of age. Patients may present with abdominal pain and/or abdominal mass or an increase in a-fetoprotein, but hepatocellular carcinoma may be found incidentally at liver transplantation. If hepatocellular carcinoma is associated with chronic liver disease, liver transplantation may be the treatment of choice (Iwatsuki et al. 1991) (see also Chapter 19).

Future directions in management of complications of chronic liver disease The traditional view of prevention and treatment of the major complications of liver disease, as delineated above, is being challenged by newer concepts of management arising out of improved knowledge of the basic mechanisms of liver injury and developments in cell and molecular biology. Examples include: therapy aimed at slowing/preventing progressive liver injury due to cholestasis, such as antioxidants and ursodeoxycholic acid, measures aimed at preventing fibrogenesis, thus slowing progression of liver fibrosis and cirrhosis; and hepatocyte transplantation and gene therapy, where animal models show that hepatocytes survive, function and participate in regeneration when transplanted into liver or spleen, and clinical studies suggest a possible role in gene therapy protocols or bridging to transplantation.

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Fernandez-Seara, J., Prieto, J., Quiruga, J. et·al. (1989) Systemic and regional haemodynamics in patients with liver cirrhosis and ascites with and without functional renal failure. Gastroenterology 97, 1304–1312. Fox, V.L., Carr-Locke, D.L., Connors, P.J. & Leichtner, A.M. (1995) Endoscopic ligation of oesophageal varices in children. Journal of Paediatric Gastroenterology and Nutrition 20, 202–208. Francavilla, R., Castellaneta, S.P., Hadzic, N. et al. (2000) Prognosis of alpha-1-antitrypsin deficiency-related liver disease in the era of paediatric liver transplantation. Journal of Hepatology 32, 986–992. Gadano, A., Moreau, R., Pessione, F. et al. (2000) Aquaretic effects of niravoline, a kappa-opioid agonist, in patients with cirrhosis. Journal of Hepatology 32, 38–42. Gines, P., Rimola, A., Planas, R. et al. (1990) Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis results of a double-blind, placebo-controlled trial. Hepatology 12, 716–724. Goenka, A.S., da Silva, M.S., Cleghorn, G.J., Patrick, M.K. & Shepherd, R.W. (1993) Therapeutic upper gastrointestinal endoscopy in children: an audit of 443 procedures. Journal of Gastroenterology and Hepatology 8, 44–57. Goncalves, M.E., Cardoso, S.R., Maksoud, J.G. (2000) Prophylactic sclerotherapy in children with esophageal varices: long-term results of a controlled prospective randomized trial. Journal of Pediatric Surgery 35, 401–405. Greer, R.M., Lehnert, M., Lewindon, P., Cleghorn, G.J. & Shepherd, R.W. (2003) Body composition and components of energy expenditure in children with end-stage liver disease. Journal of Pediatric Gastroenterology and Nutrition 3, 358–363. Greer, R.M., Quirk, P., Cleghorn, G.J. & Shepherd, R.W. (1998) Growth hormone resistance and somatomedins in children with end-stage liver disease awaiting transplantation. Journal of Pediatric Gastroenterology and Nutrition 27, 148–154. Guggenheim, M.A., Ringel, S.P., Silverman, A. et·al. (1982) Progressive neuromuscular disease in children with chronic cholestasis and vitamin E deficiency. Journal of Pediatrics 100, 51–57. Heyman, M.B., LaBerge, J.M., Somberg, K.A. et al. (1997) Transjugular intrahepatic portosystemic shunts (TIPS) in children. Journal of Pediatrics 131, 914–919. Holme, E. & Lindstedt, S. (2000) Nontransplant treatment of tyrosinemia. Clinical Liver Disease 4, 805–814. Holt, T.L., Cui, C.T., Thomas, B.J. et·al. (1994) Clinical applicability of bioelectric impedance as a measure of body composition in health and disease. Nutrition 10, 221–224. Howard, E.R., Stringer, M.D. & Mowat, P. (1988) Assessment of injection sclerotherapy and the management of 152 children with oesophageal varices. British Journal of Surgery 75, 404–408. Hsu, H.C., Wu, M.Z., Chang, M.H., Su, I.J. & Chen, D.S. (1987) Childhood hepatocellular carcinoma developed exclusively in hepatitis B surface antigen carriers in three decades in Taiwan: a report of 51 cases strongly associated with rapid development of liver cirrhosis. Journal of Hepatology 5, 260–267. Iwatsuki, S., Starzel, T., Sheahan, D.G. et·al. (1991) Hepatic resection versus transplantation for hepatocellular carcinoma. Annals of Surgery 214, 221–229. Kaufmann, S.S., Murray, N.D., Wood, P. et·al. (1987) Nutritional support for the infant with extrahepatic biliary atresia. Journal of Pediatrics 10, 679–683.

Klein, G.L., Soriano, H., Shulman, R.J., Levy, M., Jones, G. & Langman, C.B. (2002) Hepatic osteodystrophy in chronic cholestasis: evidence for a multifactorial etiology. Pediatric Transplantation 6, 136–140. Lagier, E., Rousseau, H., Maquin, P. et·al. (1994) Treatment of bleeding stomal varices using transjugular intrahepatic portosystemic shunt. Journal of Pediatric Gastroenterology and Nutrition 18, 501–503. Larcher, V.F., Manolaki, N., Vegnente, A., Vergani, D. & Mowat, A.P. (1985) Spontaneous bacterial peritonitis in children with chronic liver disease: clinical features and etiological factors. Journal of Pediatrics 106, 907–910. Lebrec, D. (2001) Primary prevention of variceal bleeding. What’s new? Hepatology 33, 1003–1004. Lenz, K., Hortnagel, H. & Proml, W. (1989) Beneficial effect of 8 ornithine vasopressin on renal dysfunction in decompensated cirrhosis. Gut 30, 90–96. Lewindon, P.J., Pereira, T.N., Hoskins, A.C. et al. (2002) The role of hepatic stellate cells and transforming growth factor-beta (1) in cystic fibrosis liver disease. American Journal of Pathology 160, 1705–1715. Lindstedt, S., Holme, E., Lock, E.A., Hjalmarson, O. & Strandvik, B. (1992) Treatment of hereditary tyrosinaemia by inhibition of 4-hydroxy phenyl pyruvate dioxygenase. Lancet 340, 813–817. Marx, M.V. & Williams, D. (1992) Percutaneous transjugular portosystemic shunt: Commentary on the technical aspects of this new procedure. Hepatology 15, 557–558. McDiarmid, S.V., Anand, R. & Lindblad, A.S. (2002) Development of a pediatric end-stage liver disease score to predict poor outcome in children awaiting liver transplantation. Transplantation 74, 173–181. McKiernan, P.J., Beath, S.V. & Davison, S.M. (2002) A prospective study of endoscopic esophageal variceal ligation using a multiband ligator. Journal of Pediatric Gastroenterology and Nutrition 34, 207–211. McKiernan, P., Glasgow, J.F.T., Guiney, E.J. et·al. (1991) Total energy expenditure in extrahepatic biliary atresia. Journal of Pediatric Gastroenterology and Nutrition 13, A318. McKiernanP.J., Baker, A.J. & Kelly, D.A. (2000) The frequency and outcome of biliary atresia in the UK and Ireland. Lancet 1, 25–29. Millar, A.J.W., Brown, R.A., Hill, I.D. et·al. (1991) The fundal pile: bleeding gastric varices. Journal of Pediatric Surgery 26, 707–709. Moitinho, E., Planas, R., Banares, R. et al. (2001) Multicenter randomized controlled trial comparing different schedules of somatostatin in the treatment of acute variceal bleeding. Journal of Hepatology 35, 712–718. Moore, K., Ward, P.S., Taylor, G.W. et·al. (1991) Systemic and renal production of thromoboxane A2 and prostacyclin in decompensated liver disease and hepatorenal syndrome. Gastroenterology 100, 1069–1077. Moreau, R. (2002) Hepatorenal syndrome in cirrhosis. Journal of Gastroenterology and Hepatology 17, 739–747. Morgan, M.Y. & Hawley, K.E. (1987) Lactitol versus lactulose in the treatment of acute hepatic encephalopathy in cirrhotic patients: a double blind randomized trial. Hepatology 7, 1278–1284. Mortensen, P.B., Holtug, K., Bonnen, H. et al. (1990) The degradation of amino acids, proteins, and blood to shortchain fatty acid in colon is prevented by lactulose. Gastroenterology 98, 353–360.

Chapter 14: Complications of Chronic Liver Disease Mourey, M.S., Siegenthaler, G., Amed, E.E. et·al. (1990) Regulation of metabolism of retinol binding protein by vitamin A in children with biliary atresia. American Journal of Clinical Nutrition 51, 638–643. Oellerich, M., Burdelski, M., Lautz, H.U., Binder, L. & Pichlmayr, R. (1991) Predictors of one year survival in patients with cirrhosis. Hepatology 14, 1029–1034. Poynard, T., Cales, P., Pasta, L. et·al. (1991) Beta adrenergic antagonist drugs and the prevention of gastrointestinal bleeding in patients with cirrhosis and oesophageal varices: an analysis of data and prognostic factors in 589 patients from four randomized clinical trials. New England Journal of Medicine 324, 1532–1538. Quirk, P., Owens, T., Moyse, H. et·al. (1994) Insulin-like growth factors are reduced in plasma from growth retarded children with liver disease. Growth Regulation 4, 35–38. Ramm, G.A., Nair, V.G., Bridle, K.R., Shepherd, R.W. & Crawford, D.H. (1998) Contribution of hepatic parenchymal and nonparenchymal cells to hepatic fibrogenesis in biliary atresia. American Journal of Pathology 153, 527–535. Reeves, H.L. & Friedman, S.L. (2002) Activation of hepatic stellate cells — a key issue in liver fibrosis. Frontiers of Bioscience 7, 808–826. Ring, E.J., Lake, A.R., Roberts, J.P. et·al. (1992) Using transjugular intra hepatic portosystemic shunts to control variceal bleeding before liver transplantation. Annals of Internal Medicine 116, 304–309. Rossouw, J.E., Labadarous, D., Davis, M. et·al. (1978) Water soluble vitamins in severe liver disease. South African Medical Journal 54, 183–190. Santamaria, F., Sarnelli, P., Celentano, L. et al. (2002) Noninvasive investigation of hepatopulmonary syndrome in children and adolescents with chronic cholestasis. Pediatric Pulmonology 33, 374–379. Shepherd, R.W. (1990) Liver transplantation in children. Medical Journal of Australia 153, 509–510. Shepherd, R.W., Chin, S.E., Cleghorn, G.J. et·al. (1991) Malnutrition in chronic liver disease in children accepted for transplantation, clinical profile and effect on outcome. Journal of Paediatrics and Child Health 27, 295–299. Shepherd, R.W. & Trocki, O. (1995) Resting energy expenditure is elevated in children with endstage liver disease. Journal of Paediatrics and Child Health 31, A10. Sherlock, S. & Dooley, J. (1998) Diseases of the Liver and Biliary System, 10th edn. Blackwell Science Ltd, Oxford.

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Chapter 15: The Liver in Systemic Illness SUSAN V. BEATH

Cardiac disease and the liver, 282 Hypoxia, 282 Hepatic congestion, 283 Low cardiac output, 283 Cardiac–hepatic syndromes, 283 Investigation, 284 Management, 284 Gastrointestinal disease, 284 Impaired enterohepatic circulation of bile, 285 Cystic fibrosis, 285 Shwachmann’s disease, 285 Inflammatory bowel disease, 285 Intestinal failure, 286 Autoimmune liver and joint disease, 286 Obesity, 287 Renal disease, 287

Alagille’s syndrome, 287 Infantile polycystic disease, 287 Cirrhosis and renal dysfunction, 287 Hepatorenal syndrome, 287 Respiratory disease, 288 a1-Antitrypsin deficiency, 288 Hepatopulmonary syndrome, 288 Endocrine disorders, 288 Diabetes mellitus, 288 Hypopituitarism, 288 Hypothyroidism, 289 Hypoparathyroidism, 289 Haematological disease, 289 Sickle-cell disease, 289 Thalassaemia, 290 Haemophilia A, 290 Haemolytic anaemia, 290

The liver inevitably plays a major role in systemic illness. It is the largest organ in the body and takes up to 25% of cardiac output. The presence of a double vascular input from the coeliac axis and portal vein exposes the liver to high concentrations of inflammatory mediators, hormones, nutrients, food antigens, drugs and intestinal microorganisms. The hepatic veins drain into the inferior vena cava or directly into the right atrium which means that cardiac dysfunction rapidly leads to hepatic congestion. In addition, the liver is composed of many different cell types, e.g. hepatocytes, endothelial cells, Kupffer cells, biliary epithelial cells, stellate cells and immune regulatory cells. These cells produce an enormous range of bioactive molecules, including glucose, inflammatory mediators, growth factors, hormones, bilirubin, coagulation factors, albumin and products of drug metabolism. There is a great potential for extrahepatic disease to influence liver function and for impaired liver function to influence the course of systemic disease.

Cardiac disease and the liver The pathophysiology of hepatic dysfunction in heart disease is related to hypoxia, congestion and low cardiac output (Mathie 1993). Dextrocardia and pulmonary stenosis may also be associated with liver disease.

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Aplastic anaemia, 290 Haemophagocytic lymphohistiocytosis (erythrocytosis), 291 Post-bone marrow transplantation, 291 Malignancy, 292 Infiltration by tumour, 292 Cytotoxic therapy, 293 Impaired immune system, 293 Immune deficiency, 293 CD40 ligand deficiency, 293 Acquired immunodeficiency (HIV infection), 294 Chronic granulomatous disorders, 294 Multisystem pathology, 295 Sepsis, 295 Malnutrition, 295 Investigations, 296

Hypoxia This type of injury is frequently seen after coronary bypass surgery, especially if the bypass operation has taken longer than 2 h. The evidence that the injury is primarily hypoxic is based on liver histology in which zone III (around the central vein, which is furthest away from arterial blood) changes are characteristic. A dramatic rise in transaminases, which may be > 10 000 IU/l, occurs 24–48 h after the cardiac surgery. Cholestasis after bypass surgery may occur if the bypass time exceeds 2 h, as demonstrated by a study in which 18.5% of adults who underwent heart valve surgery under bypass developed cholestasis (Michalopoulos et al. 1997). Coagulopathy is rare, although clotting may be prolonged because of heparin/warfarin treatment. The liver function tests usually return to normal within weeks unless hypoxia or a low cardiac output state persist. Biliary sludge, which may lead to obstructive jaundice, is a recognized complication of major cardiac surgery, especially if the child has required a major blood transfusion and is not permitted enteral feeding for more than a few days (Michalopoulos et al. 1997). The differential diagnosis includes drug toxicity — e.g. both amiodarone and verapamil may cause a cholestatic hepatitis (Morse et al. 1988) — systemic sepsis, viral hepatitis, congenital risk factors such as a1-antitrypsin deficiency, Alagille’s syndrome, hypopituitarism and biliary obstruction.

Chapter 15: The Liver in Systemic Illness Hepatic congestion

Cardiac–hepatic syndromes (Table 15.1)

The liver becomes congested when there is an increase in right atrial or ventricular pressure as in pulmonary atresia, constrictive pericarditis or tetralogy of Fallot. Sinusoidal engorgement usually causes modest elevations of transaminases while alkaline phosphatase and bilirubin are typically normal, although there may be a rise in unconjugated hyperbilirubinaemia. The clinical features are those of hepatic vein outflow obstruction and include: hepatomegaly, which may be tender; unconjugated hyperbilirubinaemia; transaminases 80–200 IU/l; and sinusoidal dilatation around the central vein on histology. Later the clinical picture includes: hypoalbuminaemia exacerbated by protein-losing enteropathy, ascites, cirrhosis and portal hypertension. If constrictive pericarditis is the underlying cause of hepatic congestion, the diagnosis may be missed as cardiac signs and symptoms are minimal. Cardiac catheterization may be required to confirm the diagnosis. The differential diagnosis includes Budd–Chiari syndrome, veno-occlusive disease and tuberculous pericarditis (see Plate 49, Atlas: p. 458).

Biliary atresia

Low cardiac output States secondary to hypoplastic left heart or cardiomyopathy reduce blood flow within the liver parenchyma, producing chronic hypoxia. There may be a compensatory increase in portal vein blood flow to balance the reduction in hepatic arterial flow, so hepatic dysfunction may be minimal unless multiorgan failure has developed due to the low output state (Mathie 1993). Jaundice and elevated transaminases (100–10 000 IU/l) are usual and tend to be worse with prolonged low-output states. As in acute hypoxic injury, biliary sludge may develop, causing biliary obstruction and an increase in cholestasis (Lee et al. 1994) (see Plate 50, Atlas: p. 458). The differential diagnosis includes drugs such as amiodarone, viral hepatitis and, in neonates, congenital liver disease (e.g. biliary atresia, a1-antitrypsin deficiency; see Chapter 4).

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In approximately 10% of patients biliary atresia is associated with congenital heart disease, which may include atrial septal defect, ventricular septal defect, aortic stenosis, pulmonary stenosis and dextrocardia with or without situs inversus. If severe, the cardiac lesion should be corrected before liver transplantation (Chapter 20). Alagille’s syndrome Alagille’s syndrome is classically associated with cardiac disease (Chapter 4). This multisystem autosomal dominantly inherited disease consists of a characteristic triangular-shaped face, failure to thrive, cholestasis often accompanied by severe pruritus, hypoplasia of intrahepatic bile ducts, butterfly vertebrae and posterior embryotoxon. The cardiac disease usually consists of peripheral pulmonary stenosis or atresia, but other congenital defects such as Fallot’s tetralogy may occur (Table 5.1). The clinical phenotype is variable and 10% of patients (Alagille et al. 1987) have cardiac symptoms only. The diagnosis is usually obvious clinically, but confirmed by electrocardiography (ECG), which may show right ventricular overload, or by echocardiography. Cardiac catheterization will document pulmonary artery pressures and indicate whether balloon dilatation or surgery is required or feasible. Surgery may be necessary before liver transplantation. It is not clear whether the defect regresses after liver transplantation. Cardiomyopathy Cardiomyopathy may be associated with inherited metabolic disease. Hypertrophic cardiomyopathy may develop as a result of the abnormal tyrosine metabolism in tyrosinaemia type I (Kvittingen 1991). It is not usually clinically significant and regresses with NTBC [2-(2-nitrotrifluoromethylbenzoyl)-1,3-cyclohexenedione] therapy or liver transplantation (Chapters 5 and 20). Cyclosporin

Table 15.1 Features of cardiac–hepatic syndromes. Condition

Hepatic features

Cardiac features

Biliary atresia Alagille’s syndrome Hyperaldosteronism Mitochondrial cytopathy and tyrosinaemia type I

Cholestasis and cirrhosis Cholestasis, pruritus Bounding pulses Fulminant or subacute liver failure

Dextrocardia, ASD, VSD Peripheral pulmonary stenosis Volume-overloaded ventricles Hypertrophic cardiomyopathy

ASD, Atrial septal defect; VSD, ventricular septal defect.

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and the immune suppressant tacrolimus have been reported to cause dose-dependent hypertrophic cardiomyopathy (Atkison et al. 1995). Mitochondrial disease may present with either fulminant liver failure in the neonatal period or progressive neurological deterioration and hypertrophic cardiomyopathy (Poulton & Brown 1995). The diagnosis may be confirmed by ECG, echocardiography, cardiac biopsy or be suspected biochemically by an elevated plasma lactate and an inability to metabolize a glucose load (Chapters 5 and 12). Cardiomyopathy may also develop as a consequence of cirrhosis in which one of the mediators appears to be a natriuretic peptide. A study of 36 adult patients with and without ascites demonstrated a relationship between higher levels of brain natriuretic peptide in the group with ascites and also with thickness of the interventricular septum. All 36 patients with cirrhosis had detectable changes in cardiac function as assessed by trans-thoracic two-dimensional echocardiography and radionuclide angiography compared with age-matched volunteers, which included increased mean ejection fraction, prolonged deceleration times, left atrial enlargement and interventricular septal thickening (Wong et al. 2001).

Table 15.2 Investigations of liver function in children with cardiac disorders. Liver function tests

Aspartate transaminase g-Glutamyl transferase Coagulation tests

Blood culture and viral serology

Hepatitis A, B and C Adenovirus, coxsackie virus titres

Screen for congenital disease

a1-Antitrypsin level and phenotype Urinary amino acids and organic acids

Screen for biliary obstruction

Hepatic ultrasound Biliary scintigraphy (e.g. TEBIDA scan)

Liver biopsy ± muscle biopsy if diagnostic uncertainty remains

Table 15.3 Management of cholestasis secondary to cardiac disease. Fat-soluble vitamins Vitamin A: Aravit A (5000–25 000 IU/day) Vitamin D: alpha-calcidol (50 ng/kg/day) Vitamin E: alpha-tocopheryl (50–500 IU/day) Vitamin K: phytomendiol (1–10 mg/day) Ursodeoxycholic acid (20–50 mg/kg/day)

Chronic fluid retention Portal hypertension leads to subclinical sodium retention causing an increase in circulating blood volume and all body fluid compartments (Chapter 14). Initially this process suppresses the renin–angiotensin–aldosterone system, but as liver disease progresses the system becomes activated, resulting in further fluid retention. Failure to clear vasodilatating molecules such as nitric oxide and hyperaldosteronism in chronic liver disease lead to an increase in cardiac output and a high-output state with bounding peripheral pulses is apparent (Blendis & Wong 2001). Systemic hypertension is common post-liver transplantation secondary to immunosuppression with steroids, cyclosporin or tacrolimus, and may also be associated with left ventricular hypertrophy. Investigation Various tests are recommended in order to determine the extent and severity of hepatic dysfunction and to screen for coexisting liver disease (Table 15.2) (see also Chapter 2).

Calorie supplements Medium-chain triglyceride: Liquogen (Scientific Hospital Supplies) Specialized feed containing medium-chain triglyceride Pepti-junior (Nutricia) Pregestimil (Mead Johnson Nutritionals)

liver function (Table 15.3). As the formation of biliary sludge is a risk with complex cardiac surgery and major blood transfusion, parenteral nutrition is best avoided or combined with enteral feeding to stimulate bile flow. Ursodeoxycholic acid (20–50 mg/kg/day) may be a useful choleretic in children with impaired biliary drainage as it stimulates bile flow and reduces the formation of insoluble cholesterol and phospholipid aggregates. The development of the inspissated bile syndrome may be resistant to ursodeoxycholic acid, and surgical or radiological intervention with biliary lavage may be necessary (Chapter 18). If cholestasis is prolonged, fat-soluble vitamins, calorie supplements and medium-chain triglycerides should be prescribed (Chapter 4). The prognosis depends on the underlying cardiac condition and is good unless a low cardiac output state persists and multiorgan failure develops.

Management Hepatic dysfunction secondary to heart disease requires supportive management only, since effective treatment of the underlying cardiac lesion leads to improvement of

Gastrointestinal disease The gastrointestinal tract is intimately related to the liver anatomically and physiologically. The presence of food in

Chapter 15: The Liver in Systemic Illness the stomach and duodenum triggers a cascade of hormones responsible for digestion, absorption and metabolic processing of nutrients. For example, emptying of the gall bladder can be induced by cholecystokinin, which is released from neuroendocrine cells in the duodenum in response to fat or amino acids present in the duodenum. Impaired enterohepatic circulation of bile Lack of stimulation to bile flow caused by enteral starvation after major surgery is considered to be the reason for the development of biliary sludge and stones postoperatively (Hofman 1995). Impaired reabsorption of bile salts in the terminal ileum depletes the bile acid pool, altering the composition of bile and making it more lithogenic. Crohn’s disease, cystic fibrosis or surgical resection of the terminal ileum may be associated with impaired bile acid circulation and gallstone formation. Clinical features of terminal ileal disease include: steatorrhoea, watery diarrhoea secondary to bile salt colitis, intermittent abdominal pain, obstructive jaundice secondary to inspissated bile, gallstones, fat-soluble vitamin deficiency, and anaemia secondary to vitamin B12 deficiency. Management The management of liver disease in children with terminal ileal disease is difficult, as the condition is usually chronic. Metronidazole (20 mg/kg/day), which selectively decontaminates the intestinal tract and reduces deconjugation of bile salts by bacteria, may be useful in reducing abnormalities in liver function tests in patients with Crohn’s disease (Capron et al. 1983). Cystic fibrosis This is associated with bile salt malabsorption and up to 25% of adolescents have evidence of biliary cirrhosis. The liver function tests typically demonstrate transient increases in alkaline phosphatase, g-glutamyl transferase (GGT) and transaminases. The plasma bilirubin is usually normal unless a gallstone obstructs the common bile duct. The extent of liver disease may be underestimated by liver function tests and abdominal ultrasound, but biliary radioisotope excretion scans may show focal delayed excretion, and liver histology shows portal tract pathology rather than parenchymal changes (Colombo et al. 1992). Ursodeoxycholic acid has an important role in stimulating bile flow and making the composition of the bile less lithogenic, which appears to protect against further deterioration in liver function in cystic fibrosis (Balistreri 1997) (Chapter 11).

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Shwachman’s disease This rare inherited condition is characterized by exocrine pancreatic dysfunction and growth failure secondary to malabsorption. It presents in the first year of life. There may be multisystem involvement, particularly bone marrow (cyclical neutropenia), skeleton (metaphyseal dyschondroplasia of femoral and humoral head) and liver. Hepatomegaly and moderately elevated hepatic transaminases (80–300 IU/l) were present in over 50% of patients at the time of presentation, although there was some resolution with time (Aggett et al. 1980; Mack et al. 1996). Histology is nonspecific with macrovesicular fatty change. Inflammatory bowel disease All forms of inflammatory bowel disease (Crohn’s disease, ulcerative colitis and indeterminate colitis) are associated with chronic hepatitis and/or autoimmune sclerosing cholangitis (ASC) (Mieli-Vergani & Vergani 1996; Gregorio et al. 1997). The pathogenesis of hepatic involvement is not understood but is probably related to immune mechanisms such as exposure to cytokines produced in the lamina propria of the intestine and transferred via the portal vein to the liver; the production of autoantibodies; and a reduction in suppressor T-cells. The bowel disease usually precedes the liver disease, although chronic active hepatitis and ASC may occur in isolation (see Chapter 8). Hepatomegaly with or without jaundice or stigmata of chronic liver disease such as telangiectasia and splenomegaly is the commonest clinical feature. In ASC, jaundice and abdominal pain are more common. Biochemical liver function tests demonstrate elevated transaminases (100–500 IU/l) and elevated alkaline phosphatase and GGT if cholangitis is present (Chapter 8). Table 15.4 outlines the recommended hepatic investigations and differential diagnosis for inflammatory bowel disease. Management Inflammatory bowel disease is a chronic condition, with considerable morbidity, which is potentially fatal, and should be supervised in a regional centre by a multidisciplinary team. Remission of both bowel and liver disease can be induced with prednisolone and maintained with azathioprine. Immunosuppression is reduced slowly over months and years while monitoring liver function tests and full blood count carefully. The course of the liver disease is variable, as the disease may have many relapses and remissions (Maggiore et al. 1993), and is not necessarily associated with the severity of the bowel disease. The prognosis is also variable, but children who

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Table 15.4 Differential diagnosis of liver disease and inflammatory bowel disease.

Table 15.5 Complications of children maintained on parenteral nutrition.

Diagnosis

Investigations

Complication

Drug toxicity (e.g. azathioprine)

Full drug history, blood levels, liver biopsy

Viral hepatitis

Serology (hepatitis A, B and C, EBV, CMV, adenovirus human herpesvirus 6, parvovirus, coxsackie)

Liver disease Pulmonary thromboembolism Restricted venous access

Abnormal enteropathic circulation of bile salts

Stool colour, trial of ursodeoxycholic acid Small bowel contrast study to assess terminal ileum Hepatic ultrasound

Autoimmune disease

Autoantibodies (SMA, ANA, ANCA) Immunoglobulins Complement levels Endoscopic cholangiogram MRI cholangiogram Liver biopsy

ANA, Antinuclear autoantibodies; ANCA, antinuclear cytoplasmic antibodies; CMV, cytomegalovirus; EBV, Epstein–Barr virus; MRI, magnetic resonance imaging; SMA, smooth muscle autoantibodies.

present before the onset of liver failure have a 5-year survival of over 90% (Mieli-Vergani & Vergani 1996). Liver transplantation may be necessary in a small number of children with aggressive disease or who present late with subacute liver failure. Inflammatory bowel disease may deteriorate or present for the first time post-liver transplantation. Intestinal failure Intestinal failure and dependence on parenteral nutrition (PN) have significant effects on hepatic function. The reduced mucosal integrity of the abnormal gut, the increased risk of sepsis, and the absence of a normal enterohepatic circulation all contribute to portal and pericellular fibrosis which are characteristic of PN-induced liver disease (see Chapters 4 and 21). Children should be referred before life-threatening complications develop (Table 15.5). In children referred for intestinal transplant assessment, hepatomegaly is common and splenomegaly almost invariable. Elevations of biliary enzymes, alkaline phosphatase and GGT occur early and jaundice is a late sign (Black et al. 1981; Hofman 1995). The differential diagnosis includes gallstones, sepsis and viral hepatitis. Manganese levels should be measured as manganese has been associated with PN-related liver disease, and toxic concentrations causing a Parkinsonian syndrome may develop in cholestatic infants because manganese depends on biliary excretion (Fell et al. 1996).

Incidence 15% 35–50% 15%

Authors Colomb et al. (1994) Dollery et al. (1994) Pollard et al. (1995) Ricour et al. (1990)

Management Children with chronic intestinal failure should be evaluated in a specialist centre. Intestinal adaptation should be encouraged, episodes of sepsis treated aggressively and the children managed at home whenever possible (Bisset et al. 1992; Stringer & Puntis 1995). Treatment with ursodeoxycholic acid, and selective decontamination of the gut with metronidazole also have a role. The prognosis is universally poor once bilirubin is consistently > 100 mmol/l, and small bowel transplantation should be considered (Beath et al. 1995, 1997; Kaufman et al. 2001).

Autoimmune liver and joint disease As the liver is rich in major histocompatibility complex (MHC) antigen-presenting cells, there is considerable potential for recognition by effector T-cells and macrophages with subsequent inflammation. Whilst primary autoimmune liver disease in children has been well defined (see Chapter 8) (Maggiore et al. 1993; MieliVergani & Vergani 1996; Gregorio et al. 1997), there are many overlap syndromes (Gohlke et al. 1996) in which liver dysfunction is part of a systemic illness, for example juvenile chronic arthritis (JCA) or systemic lupus erythematosus (SLE). JCA, which affects 1 in 1000 children before the age of 16, rarely presents with systemic features and hepatic involvement is even more uncommon. In SLE, hepatic disease may be associated with other multiorgan involvement including fibrosing alveolitis, pericarditis and autoimmune gut disease. Clinical features include elevated transaminases, cholestasis, pruritus and, rarely, acute liver failure (Pearson et al. 1989). Immunoglobulin subclasses may be raised nonspecifically in any active autoimmune condition, including JCA and SLE. Complement levels may also be raised, but C4 deficiency is associated with autoimmune chronic active hepatitis. Specific autoantibodies such as liver/kidney microsomal antibodies (LKM) are typically found in autoimmune hepatitis type II, but may develop in an overlap syndrome with arthritis. Liver histology is often not diagnostic, demonstrating non-

Chapter 15: The Liver in Systemic Illness specific portal inflammatory changes that are common in many chronic inflammatory diseases affecting the liver. Demonstration of extensive necrosis or fibrosis may contribute prognostic information. The differential diagnosis of liver dysfunction with joint disease should include: sepsis, especially if the child is on steroids; autoimmune hepatitis type I or II; drug toxicity (see below) and viral hepatitis. Management The management of liver disease in systemic JCAor other severe autoimmune conditions is first to treat the underlying condition, which may include nonsteroidal antiinflammatory drugs or steroids and, second, azathioprine to induce and maintain remission. Methotrexate and cyclophosphamide should be avoided if possible because of potential hepatic toxicity. The prognosis is unclear and is related to the course of the joint disease. The anti-inflammatory drugs used to manage JCA and SLE, especially azathioprine and methotrexate, may also cause hepatic dysfunction, which varies from a lowgrade transaminitis of little clinical significance to more severe hepatic dysfunction with cholestasis, pruritus and impaired synthetic function. Liver histology typically shows fatty change and portal fibrosis in more severe cases (Tang & Neuberger 1996). The hepatic lesions subside within days or weeks when the offending drug is withdrawn, although fulminant liver failure has been described.

Obesity Obesity is associated with fatty liver, which may cause abnormalities of liver function. Areview of 310 obese Japanese schoolchildren in whom other forms of liver disease had been excluded, found that 24% had an alanine aminotransferase (ALT) level at least 30 IU/l above the upper limit of normal, and that children who had been obese for more than 7 years were more likely to have an abnormal ALT. Most of the patients (83%) with a raised ALT also had an abnormal abdominal ultrasound suggesting fatty infiltration (Tazawa et al. 1997). The pathogenesis of fatty liver in obesity is unknown, but may be due to hyperinsulinaemia or insulin resistance. In another Japanese study of 228 obese children, fatty liver as measured by the serum level of glutamic pyruvic transaminase correlated more closely with high levels of immunoreactive insulin than with skinfold thickness or other anthropometric variables (Kawasaki et al. 1997). There may be an important relationship between fatty liver and the more serious entity non-alcoholic steato-heaptitis (NASH). The natural history of the two conditions is being evaluated currently (Rashid & Roberts 2000), and some authors recommend treatment with ursodeoxycholic acid or vitamin

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E for biopsy-proven NASH, particularly if fibrosis is present (Manton et al. 2000) (Chapter 10).

Renal disease Alagille’s syndrome Alagille’s syndrome (Chapter 4) may be associated with renal abnormalities including renal tubular dysfunction, glomerular nephritis or cystic changes (Martin et al. 1996). Occasionally the renal disease may predominate, but the hepatic and cardiac manifestations are usually more significant clinically (Berrocal et al. 1997). Infantile polycystic disease Infantile polycystic disease is an autosomal recessive condition which may be associated with congenital hepatic fibrosis. The clinical phenotype is variable and hepatomegaly usually develops before the age of 10 years. Earlier onset of symptomatic hepatosplenomegaly is associated with worse prognosis (Chapter 9). Polycystic kidney disease may also occur in association with Caroli’s disease (see Plate 30, Atlas: p. 450). Combined liver and kidney transplantation may be necessary in patients with severe symptoms related to recurrent cholangitis and renal failure. Cirrhosis and renal dysfunction A variety of glomerular disorders, including increased number of sclerotic glomeruli and mesangial proliferation, have been reported in a morphometric study of 17 adult patients with cirrhosis and normal renal biochemistry who were compared with normal controls. This may explain the rapidity of onset and severity of hepatorenal syndrome in patients with end-stage liver disease (Wagrowska-Danilewicz et al. 1996). Similar findings have been observed in children with a1-antitrypsin deficiency (Noble-Jamieson et al. 1990). Hepatorenal syndrome Hepatorenal syndrome occurs in fulminant and chronic liver disease. Portal hypertension in association with severe hepatic decompensation results in inappropriate activation of the renin–angiotensin–aldosterone system, the sympathetic nervous system and arginine vasopressin, all of which contribute to sodium and water retention and the development of ascites. The redistribution of fluid between compartments may reduce renal blood flow, setting in motion several intrarenal events such as increased renal sympathetic activity and vasoconstricting prostaglandins, which precipitate hepatorenal syndrome (Davison 1996). Acute tubular necrosis and

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functional renal failure are accompanied by severe oliguria, and inappropriately low sodium excretion may occur. Hepatorenal syndrome has recently been classified into two types based on the clinical course, a distinction which is important in the context of evaluating new treatment. Type 1 hepatorenal syndrome is the severe acuteonset form in which there is nearly 100% mortality unless a timely liver transplant is carried out. N-acetylcysteine (150 mg/kg over 2 h followed by 100 mg/kg daily for 5 days) may be useful in type 1 hepatorenal syndrome. Renal function improved from 25 ml/min to a mean of 43 ml/min in 12 adult patients, treated with Nacetylcysteine, without an improvement in hepatic parameters, or other intervention such as haemofiltration (Holt et al. 1999). The type 2 hepatorenal syndrome is less severe, more insidious and appears responsive to transintrahepatic portosystemic stent shunt (TIPSS) (Wong & Blendis 2001). Management of both types includes careful fluid balance including the use of splanchnic vasoconstrictors and colloid volume expansion, renal dialysis, or haemofiltration in order to maintain perfusion of vital organs (Chapters 7 and 14). Recovery from hepatorenal syndrome usually occurs when portal hypertension is reduced either by TIPSS, or successful liver transplant, or spontaneous recovery of liver function (Moore 1997).

Respiratory disease Respiratory dysfunction does not usually affect liver function, possibly because the liver has a double vascular blood flow and tolerates modest hypoxia (arterial oxygen saturations > 85%). a1-Antitrypsin deficiency Deficiency of a1-antitrypsin, which is an important cause of neonatal jaundice, may present in adolescence when respiratory symptoms related to pulmonary emphysema coincide with hepatitis and hepatic fibrosis/cirrhosis. The diagnosis is made by detecting low levels of a1antitrypsin in plasma and establishing the phenotype (Pi ZZ) (see Chapter 4). The clinical phenotype is extremely variable (Schwarzenberg & Sharp 1990), with some individuals having mild symptoms related to reduced functional residual capacity and hyperinflation (Greenough et al. 1988), while others may require heart, lung and liver transplantation (Prachalias et al. 2000). Hepatopulmonary syndrome Cyanosis secondary to arteriovenous shunting may develop in infants and older children with any form of chronic liver disease. Severe intrapulmonary shunting may be an indication for liver transplantation even in children with compensated cirrhosis (Lange & Stoller 1995)

(Chapters 14 and 20). The chronic hypoxia leads to increased erythropoietin production and an increased red cell mass which persists for some time after liver transplantation. The diagnosis is made by excluding a cardiac cause and establishing that there is intrapulmonary arteriovenous shunting on perfusion scans of pulmonary and systemic circulation. Angiography is rarely indicated. It is important to differentiate arteriovenous shunting secondary to liver disease from poor respiratory function from other causes (e.g. cystic fibrosis or pulmonary hypertension), as it is reversible after liver transplantation (Abrams et al. 1995).

Endocrine disorders Diabetes mellitus Diabetes mellitus causes profound metabolic instability and wide variations in plasma glucose and lipids even with good insulin control. Hepatic manifestations in diabetes mellitus include hepatomegaly due to excess glycogen and fat stores. This may occur acutely in diabetic ketosis, or chronically if diabetic control is suboptimal. Abdominal pain may occur and is associated with rapid enlargement of the liver and stretching of the liver capsule (Lecomte et al. 1997). Gallstones are another complication of diabetes, which may lead to abdominal pain and abnormal liver function. Hepatic transaminases may be raised, typically up to 80–150 IU/l (Falchuk & Conlin 1997). Mauriac syndrome, which is now rare, is when poor diabetic control is associated with hepatomegaly due to fatty liver, growth retardation, a moon-shaped face, fat deposition on shoulders and abdomen, and chronic hepatitis (Lorenz & Barenweld 1979). Cirrhosis may develop as a result of severe steatosis and pericentral hepatic fibrosis, but these changes occur gradually and are not likely to present in childhood (Nagore & Scheur 1988). Hypopituitarism Hypopituitarism is a rare disorder in which partial or total failure to produce adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone, growth hormone and gonadotropins is present. It may present within weeks of birth with neonatal hepatitis, causing elevated transaminases and conjugated hyperbilirubinaemia (Chapter 4). Hypoglycaemia, failure to thrive and micropenis are characteristic features which should raise clinical suspicion (see Plate 5, Atlas: p. 441) (Kaufman et al. 1984; Spray et al. 2000). Septo-optic dysplasia may be present, in which case infants may present with roving eye movements and poor vision. Treatment with hydrocortisone and thyroxine is associated with improvement in liver function and growth. Although growth hormone

Chapter 15: The Liver in Systemic Illness levels are low, it is usually possible to maintain a normal growth velocity by ensuring a good calorie intake until the child is 2 years old. After the age of 2, linear growth is more dependent on growth hormone, which is therefore given by subcutaneous injection. The prognosis for septooptic dysplasia depends on the severity of the initial lesion and is not related to hormone replacement. Hypothyroidism Hypothyroidism leads to a mild unconjugated hyperbilirubinaemia, although neonatal hepatitis may develop (Chapter 4). Hypoparathyroidism Chronic active hepatitis is associated with type I polyglandular syndrome in which hypoparathyroidism, adrenal insufficiency and mucocutaneous candidiasis may occur. This syndrome is rare and in any single individual only two or three features are present. Onset is usually in infancy or childhood, and the condition may be autosomal recessive. Patients with this syndrome should be screened for abnormalities of liver function, as chronic hepatitis may remain clinically silent until the onset of liver failure, which is the major cause of mortality (Michele et al. 1994).

Haematological disease Sickle-cell disease Sickle-cell disease is a chronic haemolytic anaemia, secondary to a defect in the b polypeptide chain of haemoglobin A, which leads to production of haemoglobin S (HbS). HbS forms insoluble polymers particularly in conditions of low oxygen saturation. The HbS polymers damage the red cell membrane, which shortens the life of the red cell. HbS increases viscosity of the blood and capillary obstruction and sequestration become more likely, which may trigger further HbS polymerization and provoke a ‘sickling crisis’. The hepatic sinusoids are a common site for sequestration of red blood cells in sickle-cell anaemia because of sluggish blood flow and relatively low oxygen saturation in zone 3 around the central vein. Clinical features The clinical features vary depending on phenotype: • haemolytic anaemia with unconjugated hyperbilirubinaemia • splenomegaly develops between 6 months and 5 years, reducing with age and repeated infarction; 10% of children have persistent splenomegaly

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Table 15.6 Lesions of the liver in sickle-cell disease (from Charlotte et al. 1995). Pathology

Number

%

Sinusoidal dilatation Perisinusoidal fibrosis Ischaemic necrosis Chronic persistent hepatitis Cirrhosis Gall-bladder stones Common bile duct stone

23 19 5 11 2 20 1

89 73 19 42 8 77 4

• hepatomegaly due to sickling, haemosiderosis or congestive failure • enlargement of both liver and spleen during sickle-cell crises • progressive liver disease due to anoxic necrosis and hepatic infarction • pigment gallstones and cholecystitis • viral hepatitis. The phenotype varies considerably in severity. In a series of 510 adult patients, only 26 had hepatic symptoms (gallstones/hepatomegaly/abnormal liver function tests). Biliary tract lesions were uncommon (Table 15.6). Although low-grade haemolysis is almost invariable, hepatic lesions are a result of recurrent ischaemia and vascular occlusion secondary to sinusoidal sickling during systemic viral infections (Koduri et al. 1994), rather than biliary lithiasis. Patients with a severe phenotype who have multiple sequestration crises and require repeated blood transfusions may develop iron overload and viral hepatitis (Nation et al. 1985). Diagnosis and management Biochemical liver function tests may demonstrate a rise in transaminases, alkaline phosphatase and conjugated bilirubin, particularly during a sickle-cell crisis. Gallstones and/or cholecystitis will be obvious on ultrasonography. Liver biopsy is only required if there is difficulty in diagnosis, or for prognostic reasons. Histology may show evidence of vascular lesions including sinusoidal dilatation, perisinusoidal fibrosis, and ischaemic necrosis (Charlotte et al. 1995). Portal fibrosis and cirrhosis are particularly associated with iron overload. There may be difficulty in differentiating abdominal pain due to sickle-cell sequestration from cholelithiasis, as in both situations there may be right-sided abdominal pain and tenderness. If biliary symptoms persist in the presence of gallstones, cholecystectomy is recommended (Chapter 18), ensuring that perioperative hypoxia is prevented.

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Bone marrow transplantation is available for patients who are likely to die in childhood (Walters et al. 1996), although it is advisable to evaluate the extent and severity of liver disease first. Thalassaemia Thalassaemia is caused by deficient production of either a or b globin chains and results in a greatly reduced red cell life span (days rather than weeks). Unlike sickle-cell disease, sequestration crises do not occur. The main problems in thalassaemia are related to the effects of chronic anaemia (fatigue, hyperplasia of sites of red cell production such as liver and skull, infections, impaired growth and absent sexual maturation), haemolysis and iron overload. Patients with b-thalassaemia usually die unless transfused within the first year of life, but if the haemoglobin is maintained above 10.5 g/dl by monthly transfusions, given with an iron-chelating agent, desferrioxamine, survival into adult life is possible. Liver disease in thalassaemia Liver disease is usually secondary to: • haemosiderosis, which develops despite iron chelation treatment and may progress to fibrosis and cirrhosis (see Plate 51, Atlas: p. 458) • viral hepatitis, which may be secondary to hepatitis B, C or non-A-G (acquired from blood transfusion); patients are also at increased risk of human immunodeficiency virus (HIV) (Chapter 8) • gallstones are also common, although usually asymptomatic unless impacted in the common bile duct. The development of extensive iron overload can be predicted in patients with high transfusion requirements (> 100 transfusions). These patients should be evaluated for bone marrow transplantation before they develop cirrhosis and other major complications of iron overload (Lucarelli et al. 1996). Treatment of chronic viral hepatitis is under evaluation (Chapter 8). Haemophilia A Liver disease in classical haemophilia is related to viral hepatitis from infected blood products or factor VIII concentrate. Screening of blood products and prophylactic immunization have greatly reduced the risk of hepatitis B, but many children have been infected with hepatitis C and HIV prior to adequate screening in the 1980s. These children are at risk of chronic hepatitis, cirrhosis and hepatocellular carcinoma (Chapter 8), which may be more aggressive in this group of children (Tong et al. 1995) (see Plate 25b, Atlas: p. 447). Treatment with interferon-a and ribavirin is effective in approximately 45% of children, depending on genotype (Chapter 8). Liver trans-

plantation is indicated for liver failure, and will also cure the haemophilia. HIV infection commonly produces abnormal liver function caused by opportunistic infections, lymphoproliferative disease or AIDS-related neoplasm (Lefkowitch 1994). The availability of combinations of retroviral drugs in recent years has changed the prognosis of HIV dramatically. The effects of HIV infection can be modified by treatment with three classes of retroviral drugs (nucleoside analogues, non-nucleoside analogues, protease inhibitors), which reduce the viraemia, restore the CD4 : CD8 ratio and prolong life for many years (Mocroft et al. 1998). Haemolytic anaemia Immune related Rhesus incompatibility directed against fetal erythrocytes causes brisk haemolysis which leads to anaemia, unconjugated hyperbilirubinaemia and kernicterus if bilirubin levels are not controlled with phototherapy and exchange transfusion if necessary. Rhesus and ABO blood group incompatibility are self-limiting, but a more severe form is described in which Coombs’-positive autoantibodies are directed against hepatocytes as well as red cells. Coombs’-positive autoimmune hepatitis produces a clinical picture of progressive neonatal hepatitis which often causes death from sepsis and/or liver failure within the first year of life. Steroids may slow the progression of the disease and although liver transplantation has been attempted, the disease may recur in the graft (PerezAtayde et al. 1994). Theoretically, bone marrow transplantation may be more effective treatment for children who do not respond to prednisolone and azathioprine. Red cell fragility Hereditary spherocytosis commonly presents in the neonatal period as an episode of unconjugated hyperbilirubinaemia, or during intercurrent sepsis because hypoglycaemia and acidosis increase red cell fragility. Infection with parvovirus B19 is associated with an aplastic crisis (Smith et al. 1994). Hepatic disease consists of cholelithiasis secondary to pigment stones and occasionally cholecystitis. Splenectomy is indicated in children older than 5 years as this restores the red cell life span to around 100 days, normalizes the plasma haemoglobin and reduces the risk of obstructive jaundice caused by bile pigment stones. Aplastic anaemia Aplastic anaemia may be a presenting symptom of fulminant liver failure or may develop after successful liver

Chapter 15: The Liver in Systemic Illness transplantation. The common factor may be a virus (e.g. parvovirus, Epstein–Barr virus (EBV)), but often the cause is unknown. It is important to consider the possibility of a viral aetiology causing simultaneous bone marrow and liver failure, as many drugs used therapeutically after liver transplantation will exacerbate the bone marrow disease (e.g. tacrolimus, cotrimoxazole). Some patients have received successful bone marrow transplantation after successful liver transplantation where the aplastic anaemia has been refractory and continuing viral infection has been excluded (Perkins et al. 2001). Haemophagocytic lymphohistiocytosis (erythrocytosis) Haemophagocytic lymphohistiocytosis is primarily a haematological disease in which macrophages, including hepatic Kupffer cells, become excessively activated and phagocytose neighbouring cells, such as erythrocytes and leucocytes. The disorder may be sporadic or familial or associated with viruses, for example parvovirus 19, echovirus or EBV. The clinical picture includes hepatosplenomegaly and jaundice which may resemble neonatal hepatitis, although fulminant liver failure with coagulopathy is more common and may be difficult to distinguish from septicaemia. The diagnosis is made by demonstrating erythrophagocytosis in liver or bone marrow (see Plate 16, Atlas: p. 449). In the familial type of haemophagocytic lymphohistiocytosis, atypical lymphocytes or histiocytes may be found in the cerebrospinal fluid, which also contains excess protein. Management consists of support for acute liver failure (Chapters 5 and 7) and cytotoxic therapy. Remission can be achieved with etoposide, methylprednisolone and methotrexate in at least a third of cases, but mortality may be as high as 75% in some groups, which has prompted the use of allogeneic bone marrow transplantation in high-risk patients (less than 2 years old, familial pattern) (Hirst et al. 1994). Liver transplantation is not indicated.

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Post-bone marrow transplantation Bone marrow transplantation (BMT) is indicated for many disorders, ranging from acute leukaemia to immunodeficiency. Some of the patients may have liver disease with their original disease, others may have been treated with hepatotoxic drugs as part of their treatment or conditioning pre-BMT. It is not surprising therefore that abnormal liver function develops in approximately 30% of patients undergoing BMT (McDonald et al. 1987). There are many potential causes, including infection, non-A-G hepatitis, graft-vs.-host-disease (GVHD), venoocclusive disease (VOD) and drug toxicity (Farthing et al. 1982). Graft-vs.-host-disease GVHD is a systemic disorder involving skin, gut, lung, eye, pancreas and liver, typically occurring 7–50 days after BMT (and occasionally after liver or small bowel transplantation). The acute form presents with a desquamating skin rash, diarrhoea and, if the liver is involved, mild jaundice and hepatomegaly (see Plate 52a, Atlas: p. 458). The immune damage in the liver is directed towards the small bile ducts. The biliary epithelium becomes irregular with nuclear pleomorphism and vacuolated cytoplasm. There may also be endothelitis, and mild portal tract inflammation with bile duct loss and cholestasis; the parenchyma is relatively spared. Chronic GVHD is defined as continuing poorly controlled acute GVHD after 100 days. Eighty percent of patients are cholestatic and have complete loss of all bile ducts. Histology of the liver shows bile duct loss, bridging fibrosis and occasionally cirrhosis (Knapp et al. 1987) (Table 15.7) (see Plate 52b, Atlas: p. 458). The differential diagnosis of both acute and chronic GVHD includes: • viral hepatitis (cytomegalovirus (CMV), EBV, hepatitis A, B, C, other) • drug toxicity (including parenteral nutrition) • biliary obstruction from biliary sludge • hepatobiliary infection • veno-occlusive disease.

Table 15.7 Clinical features of graft-vs.-host-disease (GVHD) and veno-occlusive disease (VOD). Acute GVHD

Chronic GVHD

VOD

Onset

7–50 days

> 100 days

1–30 days

Clinical

Skin rash Diarrhoea

Skin rash Pale stools

Tender hepatomegaly Ascites, elevated jugular venous pressure

Biochemistry

Bilirubin > 50 mmol/l

Bilirubin > 200 mmol/l Raised alkaline phosphatase

Bilirubin > 35 mmol/l Raised alkaline phosphatase

Histology

Vanishing bile ducts

Bile ducts absent

Narrow or occluded vessels

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Investigations should include: viral serology; abdominal ultrasound to detect sludge, biliary dilatation and portal vein flow; blood, bone marrow and hepatic culture; and skin, gut and liver biopsy. The diagnosis is made on the clinical features and the characteristic changes in skin, jejunum, rectal or liver biopsies, although the liver biopsy may be almost normal in the early stages. Management The management of GVHD irrespective of organ involvement is to increase immunosuppression with high-dose corticosteroids, cyclosporin (trough levels 200–400 ng/ml monovalent assay) and tacrolimus (trough levels 8–15 ng/l). In addition, azathioprine, antithymocyte globulin and thalidomide may be useful if the patient has a history of GVHD. Ursodeoxycholic acid is frequently used to encourage enterohepatic recirculation of bile acids and to treat pruritus (Fried et al. 1992). The prognosis is related to the control of GVHD and success of the bone marrow graft. In rare circumstances progression to cirrhosis and liver failure may occur. Liver transplantation may be considered if disease in other organs is minimal and the bone marrow graft has been successful. Veno-occlusive disease VOD is a serious complication of BMT that occurs in 28% of patients and presents within 30 days of BMT. The clinical features mimic the Budd–Chiari syndrome and include: • jaundice (bilirubin > 35 mmol/l) • tender hepatomegaly • elevated jugular venous pressure • ascites or unexpected weight gain (McDonald et al. 1984; Reiss et al. 2002). Patients with a history of pretransplant viral hepatitis, radiotherapy or busulphan conditioning are more likely to develop VOD. In a retrospective, multivariate analysis the use of ciprofloxacin and vancomycin prophylaxis, methotrexate treatment for GVHD, and abnormal transaminases and alkaline phosphatase pre-BMT, were also associated with an increased risk of VOD (Styler et al. 1996). The diagnosis is based on clinical criteria: • Exclusion of other causes of hepatic dysfunction postBMT (Table 15.7). • Abdominal ultrasound of the portal vein flow to identify retrograde flow and or an increase in hepatic resistance. • Liver biopsy, if coagulation permits. Liver histology demonstrates narrowing or occlusion of the terminal hepatic venules, sinusoidal congestion and necrosis of hepatocytes with a mild inflammatory infiltrate in the centilobular zone. Fibrosis and cirrhosis may develop (see Plate 53, Atlas: p. 459).

The management is supportive, including management of cholestasis and diuretics for ascites. The prognosis is poor for such patients, especially if they have previously received busulphan conditioning. Liver failure may contribute to the mortality of 50%. However, the new thrombolytic, defribrotide, is promising and has produced resolution of symptoms in advanced cases (Richardson et al. 2002). The lack of serious toxicity with defribotide, which is a polydeoxyribonucleotide, is attributed to its lack of systemic anticoagulant effect at the same time as a local thrombolytic and antithrombotic action. Defribotide has also been used to treat VOD after liver transplantation (Mor et al. 2001). Hepatobiliary infections Hepatobiliary infections, especially candidiasis and CMV, are well-recognized features after BMT (Haron et al. 1987). Risk factors for fungal infection include neutropenia, recent treatment with myelosuppressive agents, use of broad-spectrum antibiotics and immunosuppression. Patients present with fever, hepatic dysfunction and rarely tender hepatomegaly. Investigations should include: C-reactive protein, fungal and bacterial culture of blood, and bone marrow or liver biopsy, although fungi are notoriously difficult to culture when present in low numbers. Abdominal computed tomography scan and ultrasound may show characteristic multiple low attenuation or hypoechoic areas which may represent fungal infection. In the context of immunosuppression and fever unresponsive to broad-spectrum antibiotics probable fungal infection is likely and should be treated with liposomal amphotericin (1–3 mg/ kg/day) and/or flucytosine (100–200 mg/kg/day) in severe infections. CMV infection may occur either as a primary infection or a reactivation causing hepatitis or other systemic disease such as CMV enteritis or pneumonitis. Treatment is with intravenous ganciclovir and hyperimmune gammaglobulin. EBV infection may occur but does not usually cause significant hepatic disease. If high levels of immune suppression are maintained for > 6 months there is a risk of B-cell lymphoproliferative disease developing (Forman et al. 1987).

Malignancy Infiltration by tumour Primary tumours such as hepatoblastomas or hepatocellular carcinoma may cause clinically obvious abdominal distension and may be associated with chronic hepatitis B infection or tyrosinaemia type I (Chapter 19). Abnormal liver function tests (elevated alkaline phosphatase and transaminases) are found in up to 30% of

Chapter 15: The Liver in Systemic Illness patients with Hodgkin’s disease and may represent increased Kupffer cell activity in the portal tracts. Tumours such as rhabdomyosarcoma may infiltrate the liver causing thrombosis of the portal vein or obstruction of the biliary tree. Other tumours such as peritoneal mesothelioma may simulate end-stage liver failure and present with jaundice, coagulopathy, wasting and gross ascites (Harrison et al. 1996). Acute leukaemia may present with hepatosplenomegaly and elevated transaminases (100–400 IU/l) due to infiltration by malignant clones of lympho-cytes. Histology will demonstrate leukaemic infiltration of the portal tract, which usually reverses following therapy. Cytotoxic therapy Cytotoxic treatment for malignancy inevitably affects the liver, which is one of the most metabolically active tissues in the body, but these effects are rarely apparent clinically because of the capacity for hepatic regeneration. Thus, hepatic damage due to chemotherapy is more likely in children who are debilitated by chronic disease or receiving prolonged therapy (Tang & Neuberger 1996). The clinical features are variable and related to the drug involved; for example, actinomycin, which is frequently used in the management of Wilms’ tumour, may be associated an intense hepatitis sufficient to induce subacute hepatic failure, as in the case of a 10-year-old boy who had an additional risk factor of being a carrier for a1-antitrypsin deficiency (Ruchelli et al. 1990). Radiotherapy of the liver is another risk factor for actinomycin toxicity, especially in small children (Ludwig et al. 1999). Actinomycin has also been reported as a rare cause of VOD in a series of six children, three of whom died (D’Antiga et al. 2001) and as a cause of hepatic fibrosis and cirrhosis (Plate 28, Atlas: p. 449) Methotrexate hepatotoxicity is usually dose related, and liver biopsy may show steatosis and portal tract fibrosis in children who have received prolonged courses, and in rare cases fulminant liver failure has ensued. 6Mercaptopurine (6-MCP), used in maintenance treatment of acute lymphocytic leukaemia, is also hepatotoxic and is associated with hepatic necrosis and cholestasis. Fatalities have been reported (Laidlaw et al. 1995). Patients on 6-MCP should have regular liver function tests as hepatic damage is reversible if treatment is stopped promptly. Doxorubicin is more often associated with cardiomyopathy, but may cause a chemical hepatitis (Coker et al. 1993). In patients with pre-existing abnormalities of liver function the dose should be reduced (50% of the normal dose if the bilirubin > 20 mmol/l, 25% of normal dose if bilirubin > 50 mmol/l). Azathioprine is no longer commonly used in regimens for treating cancers, but it remains a cytotoxic agent widely used in the management of inflammatory condi-

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tions such as ulcerative colitis, arthritis, and following solid organ transplantation. Rare but serious adverse effects have been reported including VOD and the development of a hepatocellular carcinoma (Russman et al. 2000). The mechanism may be via the metabolite of azathioprine, 6-mercaptopurine, which is a dose-dependent hepatotoxin. Impaired immune system Children treated for malignancy are immunocompromised, which increases the incidence of bacterial, viral and fungal infections, which may involve the liver causing liver dysfunction, especially cholestasis. Clinically, fungal infections are insidious in onset, evolving over many days and weeks, usually in the context of neutropenia, serum C-reactive protein > 50 mg/l, malnutrition, broad-spectrum antibiotics and a high swinging fever (temperature typically 39–40°C) (Stone et al. 1974; Anttila et al. 1994). Visceral candidiasis has been reported in which Candida species invaded the liver, biliary tract and portal vein producing cholestasis and gross hepatosplenomegaly (Hacking et al. 1989). The positive identification of fungi is very difficult (Rolando et al. 1991), except in overwhelming infections, so treatment with amphotericin (1–3 mg/kg/day) and/or flucytosine (100–200 mg/kg/day) is often empirical, based on risk factors and clinical suspicion (de Repentigny & Reiss 1984). In systemic candidiasis prolonged treatment may be required (see Plate 54, Atlas: p. 459).

Immune deficiency Children with inherited immunodeficiency syndromes may have associated liver dysfunction because of recurrent bacterial, viral or opportunistic infection (see Plate 55, Atlas: p. 459) CD40 ligand deficiency This X-linked inherited immunodeficiency is associated with chronic hepatitis, cirrhosis and opportunistic infections of the biliary tree. Recurrent ascending cholangitis, often due to atypical organisms such as cryptosporidia, eventually causes a sclerosing cholangiopathy that leads to liver failure (see Plate 56, Atlas: p. 460) It may be age related as the incidence of liver disease increases with age: by the age of 20 years 75% of survivors with CD40 ligand deficiency have liver disease (Hayward et al. 1997), which recurs following liver transplantation. The role of BMT prior to the development of advanced liver disease has been evaluated in eight boys, four of whom survived. Better outcome was associated with younger age at transplant and normal liver histology (Khawaja et al. 2001).

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Acquired immunodeficiency (HIV infection) Twenty-six percent of babies acquire HIV from their mothers and approximately 90% of these infants have hepatomegaly and abnormal liver function tests (Lefkowitch 1994), usually from opportunistic infection. These babies are also at risk of hepatitis B and C. Other potential causes of hepatic disease include Mycobacterium avium-intracellulare, CMV, lymphomas and Kaposi’s sarcoma, all of which may develop in children with HIV. Recurrent or chronic infection of the biliary tree with cryptosporidiosis or other organisms may produce a clinical picture resembling sclerosing cholangitis (Lefkowitch 1994). Myocarditis and congestive cardiac failure can occur in HIV-infected patients and produce secondary changes in the liver (abnormal liver function tests and fibrosis of the central vein) (Hardman & Purdon 2002). Perinatal transfer of HIV may be reduced to 8% by giving oral zidovudine antenatally or intravenously during labour to the mother, and oral zidovudine to the baby until 6 weeks old (Connor et al. 1994). The long-term medical outlook for children with HIV has improved considerably in countries which can afford the cost of triple treatment with nucloside analogues, non-nulceoside analogues and protease inhibitors (Palella et al. 1998).

Numerically the most important causes of granuloma in the liver are tuberculosis, sarcoid, schistosomiasis and intrinsic liver disease (James & Sherlock 1994). Hepatic granulomas are often clinically silent, but established disease may present as a chronic intrahepatic cholestatic syndrome, portal hypertension and Budd–Chiari. Even in patients with no respiratory symptoms exclusion of tuberculosis is extremely important. The further management of patients with granuloma depends on the final diagnosis, which will become apparent through a systemic evaluation of intestine, chest, joints, eyes and skin, and will usually require the input of other specialists such as rheumatologist, ophthalmologist, immunologist and gastroenterologist. Appropriate investigation includes: serology for hepatitis viruses, HIV, chest radiograph, Mantoux test, lung function tests, drug history, liver function testing including organand non-organ-specific autoantibodies, immunoglobulin subclasses, full blood count and film, erythrocyte sedimentation rate, angiotensin converting enzyme level, microscopic assessment of stool for ova of schistosomiasis, abdominal ultrasound, oro-gastroduodenoscopy to assess portal hypertension, colonoscopy to evaluate inflammatory bowel disease, and liver biopsy. Sarcoidosis

Chronic granulomatous disorders Granulomas are collections of specialized immune cells such as Kupffer cells, macrophages, or neutrophils which in response to infection, toxic injury (drugs and alcohol) or abnormal regulation of the immune system fuse to form large epithelioid cells with multiple nuclei. Granulomas may appear anywhere in the body, although particular diseases have characteristic patterns (Table 15.8).

Granulomatous disease secondary to sarcoidosis is an uncommon but important cause of liver dysfunction. In adults respiratory symptoms are prominent, but extrapulmonary sites, especially joints, eyes and liver, are more usual in children (Rizzato 2001). There is often a long delay between the onset of symptoms such as malaise, weight loss, stiffness and muscle pain, and diagnosis. Hepatic sarcoidosis can mimic juvenile chronic arthritis

Table 15.8 Granulomatous conditions affecting the liver: common sites and characteristics. Primary site

Associated sites

Special features

Tuberculosis

Lung, lymph node

Intestine, liver

Caseating granulomas secondary to infection with Mycobacterium tuberculosis

Sarcoidosis

Lung, ocular, joints

Liver, spleen, bone, heart

Extrapulmonary disease more common in paediatric age group, 40% have elevated angiotensin converting enzyme, unknown aetiology

Schistosomiasis

Veins of the colon

Portal veins infested by S. mansonii

Ova from adult worms evoke delayed type hypersensitivity and portal hypertension, so called ‘pipe stem’ fibrosis

Crohn’s disease

Intestinal tract

Liver, skin, oral mucosa

May be part of overlap syndrome including chronic active hepatitis, juvenile chronic arthritis

Wegener’s granulomatosis

Naso-oro cavity

Liver, skin, intestine, heart, kidney

Fibrinoid necrosis of medium sized arteries especially of mid-line structures resulting in ulcerating granulomas

Chronic granulomatosis disease

Lung, neutrophil dysfunction

Intestine (diarrhoea), skin, nodes, liver

X-linked disorder of neutrophil hydrogen peroxide dismutase, Aspergillus pneumonia

Chapter 15: The Liver in Systemic Illness (Sarigol et al. 1999) and the international registry of sarcoid arthritis has recorded data in 53 children over 5 years in which 10 had non-caseating granuloma of the liver, 38 had persistent arthritis and 44 had an inflamed uveal tract, including one child who was blind (Lindsley & Petty 2000). Diagnosis depends on excluding other causes of granulomas, although the presence of elevated angiotensin enzyme is helpful sometimes (in the patients reported to the international sarcoid arthritis registry only 14 out of 37 patients exhibited a high level of angiotensin converting enzyme). Treatment depends on the site and effect of granulomas, but the most usual approach is oral prednisolone (1–2 mg/kg/day). Methotrexate has been used to treat pulmonary disease with some success in adults; however, some hepatic toxicity can be expected so caution is advised in using this agent in children with hepatic sarcoidosis (Lower & Baughman 1995). Chronic granulomatous disease This disorder is an uncommon primary immunodeficiency disease with an estimated incidence of about 1 in 200 000 births inherited in an X-linked recessive fashion, although autosomal recessive modes of inheritance are described. Chronic suppurative infections are the most common manifestation, with up to 27% of patients developing liver abscess with staphylococcus being the most usual causative organism (Winkelstein et al. 2000). An unusual hepatic manifestation of chronic granulomatous disease (CGL) is ascites, which has been reported as a consequence of primary bacterial peritonitis, and also separately as a result of portal hypertension secondary to chronic hepatic granulomatosis (Castro et al. 1992). The hepatic pathology is described in a review of male patients aged 5–41 years (Nakhleh et al. 1992) in which foamy macrophages containing a fine granular golden brown pigment were seen in all seven cases predominantly in the portal tract areas. Granulomas and associated giant cells were seen in four cases which when cultured grew Staphylococcus aureus. Abscesses are frequently resistant to simple medical treatment with antibiotics and a multidisciplinary approach is necessary in which precise imaging and percutaneous drainage are often successful. Interferon-gamma, which has been used prophylactically, may also be useful in acute infective episodes (Hague et al. 1993).

Multisystem pathology Sepsis Liver dysfunction commonly develops secondary to severe sepsis (Gimson 1987). The infection may involve the liver directly, as in hepatitis B, herpes simplex virus, Kawasaki’s disease, Gram-negative septicaemia, and

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candidiasis (Kimura et al. 1996), or indirectly as part of the toxic shock and hypoperfusion caused by the inflammatory response, for example in meningococcal septicaemia. Jaundice and hepatomegaly are early signs, with nonspecific elevation in transaminases. Coagulopathy may develop either as part of the liver failure or due to disseminated intravascular coagulation. Ultrasound scanning of the abdomen is helpful in identifying abscesses, fluid collections or an obstructed biliary tree secondary to biliary sludge or gallstones. The commonest ultrasonic finding in septicaemia is an ‘echo-bright’ liver due to hyperplasia of the reticuloendothelial system or fatty change which may be confirmed histologically. In Kawasaki’s disease acute hydrops of the gall bladder may be detected on ultrasound in addition to hepatomegaly, abnormal liver function tests and elevated serum total bile acids. Aspiration of the gall bladder may be required to prevent perforation. In shocked patients with hypoperfusion, ischaemic necrosis with high transaminases (> 500 IU/l) coagulopathy may develop, which is reversible if supportive treatment for septic shock is commenced promptly. The differential diagnosis includes: • An inborn error of metabolism which has become apparent because of septicaemia (Waggoner et al. 1990). Biochemical markers for inborn errors of metabolism include a high plasma lactate, increased free fatty acids, especially short-chain species (C6, C8, C10) and relatively low ketone production suggesting a disorder of boxidation (Morris & Leonard 1997) (Chapters 5 and 12). • Drug ingestion. Paracetamol, rifampicin, azathioprine, augmentin, solvent abuse, cocaine and heroin have been associated with liver failure and septicaemia (Marks & Chapple 1967; Meadows & Verghese 1996). The diagnosis is based on establishing the source of infection and excluding other causes of liver disease. Management is directed towards treating the sepsis and providing support for the liver failure (Chapter 7). The prognosis depends on the aetiology of the sepsis. Liver transplantation is only indicated if sepsis is confined to the liver and will not recur post transplant (e.g. echovirus). Malnutrition Malnutrition has profound effects on the functioning of all organs, including the liver (Alleyne et al. 1969). Drug and toxicant clearance is reduced (Bidlack & Hamilton Smith 1984) and myocardial and respiratory function are significantly impaired in malnourished intensive care patients (Meakins et al. 1979; Sheldon & Petersen 1980). Hepatic and plasma concentrations of glutathione and associated antioxidant systems are reduced in protein energy malnutrition (Shi et al. 1982; Becker et al. 1995). The

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liver has a large population of Kupffer cells and therefore has a major role in the immune system, which is depressed in malnutrition. In particular, cell-mediated responsiveness and peripheral T-cell counts are reduced, rendering malnourished patients with acute or chronic liver disease especially susceptible to fungal and enteric infections (Gross & Newberne 1980; Rolando et al. 1991). Malnutrition also appears to be a risk factor in major surgical procedures with an increased operative morbidity and mortality after liver transplantation (Shaw et al. 1985; Beath et al. 1994). The consequences of malnutrition are profound, so it is important to institute appropriate nutritional support as soon as possible (Beath et al. 1993; Protheroe & Beath 1997) (see also Table 15.3).

Investigations Abnormal liver function requires systematic investigation. In the setting of systemic disease evaluation should include: • a careful history noting details of drug exposure, blood product transfusion and family history (see Table 15.2) • previous evidence of chronic liver disease, e.g. palmar erythema, splenomegaly or obstructive jaundice (e.g. pale stools and dark urine) • blood culture, urinalysis, chest X-ray • total and unconjugated bilirubin, hepatic transaminases, alkaline phosphatase (low in Wilson’s disease, high in biliary diseases and some metabolic diseases, e.g. tyrosinaemia), albumin • prothrombin time, activated partial thromboplastin time, fibrinogen and D-dimers • viral serology (hepatitis A, B, C; EBV; CMV; adenovirus; echovirus; parvovirus) level, ferritin (for neonatal • a1-antitrypsin haemochromatosis) • urinalysis for reducing substances, organic acids and amino acids to screen for inborn errors of metabolism • an ultrasound of the abdomen noting the size and echogenicity of the liver, abnormalities of the biliary tree and gall bladder, patency and size of hepatic vessels, portal vein flow, spleen size and the presence of ascites • liver biopsy may be justified if diagnostic and prognostic uncertainty remains.

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Moore, K. (1997) The hepatorenal syndrome. Clinical Science 92, 433–443. Mor, E., Pappo, O., Bar-Nathan, N. et al. (2001) Defribotide for the treatment of veno-occlusive disease after liver transplantation. Transplantation 72, 1237–1240. Morris, A.A.M. & Leonard, J.V. (1997) Early recognition of metabolic decompensation. Archives of Disease in Childhood 76, 555–556. Morse, R.M., Valenzuela, G.A., Greenwald, T.P., Eulie, P.J., Wesley, R.C. & McCallum, R.W. (1988) Amiodarone-induced liver toxicity. Annals of Internal Medicine 109, 838–840. Nagore, N. & Scheur, P. (1988) Pathology of diabetes mellitus. Journal of Pathology 156, 155–160. Nakhleh, R.E., Glock, M. & Snover, D.C. (1992) Hepatic pathology of chronic granulomatous disease of childhood. Archives of Pathological Laboratory Medicine 116, 71–75. Nation, C.S.R., Bonch, C. & Weatherall, D.J. (1985) Hepatic sequestration in sickle cell anaemia. British Medical Journal 290, 744. Noble-Jamieson, G., Mowat, A.P., Thiru, S. & Barnes, N. (1990) Severe hypertension after liver transplantation in children with alpha-1-antitrypsin deficiency. Archives of Disease in Childhood 65, 1217–1219. Palella, F.J., Delaney, K.M., Moorman, A.C et al. (1998) Declining morbidity and mortality among patients with advanced HIV infection. New England Journal of Medicine 338, 853–860. Pearson, R.D., Swenson, I., Schenk, E.A., Klish, W.J. & Brown, M.R. (1989) Fatal multisystem disease with immune enteropathy heralded by juvenile rheumatoid arthritis. Journal of Pediatric Gastroenteroloy and Nutrition 8, 259–265. Perez-Atayde, A.R., Sirlin, S.M. & Jonas, M. (1994) Coombspositive autoimmune hemolytic anemia and post infantile giant cell hepatitis in children. Pediatric Pathology 14, 69–77. Perkins, J.L., Neglia, J.P., Ramsay, N.K. & Davies, S.M. (2001) Successful bone marrow transplantation for severe aplastic anemia following orthotopic liver transplantation: long term follow-up and outcome. Bone Marrow Transplantation 28, 523–526. Pollard, A., Sreeram, N., Wright, J.G., Beath, S.V., Booth, I.W. & Kelly, D.A. (1995) ECG and echocardiographic diagnosis of pulmonary thromboembolism associated with central venous lines. Archives of Disease in Childhood 73, 147–150. Poulton, J. & Brown, G.K. (1995) Investigation of mitochondrial disease. Archives of Disease in Childhood 73, 94–96. Prachalias, A.A., Kalife, M., Francaville, R. et al. (2000) Liver transplantation for alpha-1-antitrypsin deficiency in children. Transplant International 13, 207–210. Protheroe, S.M. & Beath, S.V. (1997) Nutritional support in liver disease. In: Baillière’s Clinical Paediatrics — Nutritional Support, Vol. 5 (ed S. W. Ryan), pp. 215–231, W.B. Saunders, London. Rashid, M. & Roberts, E.A. (2000) Nonalcoholic steatohepatitis in children. Journal of Gastroenterology and Nutrition 30, 48–53. Reiss, U., Cowan, M., McMillan, A. & Horn, B. (2002) Hepatic venoocclusive disease in blood and bone marrow transplantation in children and young adults: incidence, risk factor, and outcome in a cohort of 241 patients. Journal of Pediatric Hematological Oncology 24, 746–750. de Repentigny, L. & Reiss, E. (1984) Current trends in immunodiagnosis of candidiasis and aspergillosis. Review of Infectious Disease 6, 301–312. Richardson, P.G., Murakami, C., Jin, Z. et al. (2002) Multiinstitutional use of defribrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and

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Chapter 16: Skin Disorders in Liver Disease INDRA D. M. VAN MOURIK AND CELIA MOSS

Structure and function of normal skin, 300 Skin structure, 300 Skin function, 301 Dermatological manifestations of liver disease, 301 Jaundice, 301 Palmar erythema, 301 Spider naevi, 301 White nails (Terry’s nails), 301 Pruritus, 301

Xanthelasma, 302 Purpura, 302 Photosensitivity, 302 Carotenaemia, 302 Angiomatous naevi, 302 Gianotti–Crosti syndrome, 302 Skin manifestations of malnutrition, 302 Dermatological complications of liver transplantation, 303

Paediatric skin disorders account for 10–15% of GP consultations. Their prevalence in children with liver disease is unknown, but may be even higher. The enormous variety of skin diseases poses a considerable diagnostic challenge to the non-dermatologist and appropriate treatment may be delayed (Morelli & Weston 1993). In the context of paediatric hepatology, skin disorders can be separated into three groups: 1 Common incidental skin conditions such as acne, warts, eczema, drug rashes and infections due to common bacteria, viruses or fungi. 2 Dermatological manifestations of an underlying systemic disorder such as xanthelasma associated with cholestasis or spider naevi in chronic liver disease. 3 Skin disorders following liver transplantation, including: (i) side-effects of immunosuppressant drugs (ii) direct results of immunosuppression, including bacterial, viral, fungal and protozoal infections (iii) graft-vs.-host-disease (iv) cutaneous malignancies. This chapter first deals with the structure and function of normal skin as a basis for understanding skin pathophysiology, dermatological manifestations of liver disease in general, and skin conditions in the immunocompromised host.

The skin in the immunocompromised host, 303 Cutaneous side-effects of immunosuppressive drugs, 303 Cutaneous lesions in immunocompromised hosts, 304 Approach to diagnosis of dermatological lesions, 310 Techniques, 310

dermis and subcutaneous layer (Graham-Brown & Burns 1990). Epidermis The epidermis is a multilayered structure which renews itself continuously by cell division in the basal layer. It consists of: • keratinocytes, which move peripherally from the basal layer, giving rise to successive layers of cells that lose their nuclei and eventually die as they reach the surface • melanocytes, melanin-producing dendritic cells • Langerhans cells, important antigen-presenting cells bearing major histocompatibility (MHC) class II antigens • Merkel cells, involved in sensation and mainly seen on digital pads, lips and in the oral cavity. The epidermal appendages are apocrine sweat glands, hair, sebaceous glands, nails and teeth. Dermis The dermis forms the bulk of the skin and contains connective tissue fibres (mainly collagen with some elastin and reticulin) lying beneath the epidermis, giving the skin its ability to stretch and mould. Blood vessels, nerves, lymphatics and muscles as well as cells such as leucocytes, histiocytes, fibroblasts and mast cells are found in this layer.

Structure and function of normal skin Subcutaneous layer Skin structure The skin is divided into three layers: the epidermis,

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The subcutaneous layer mainly contains fat, sweat glands and blood vessels.

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Skin function

White nails (Terry’s nails)

The skin is a vital part of our body with numerous functions including: • physical barrier to antigens or bacteria (intact stratum corneum, lipids in sebaceous glands, suppressant effect of normal skin flora on pathogens, presence of granulocytes, macrophages and killer T-cells) • prevention of excessive absorption or loss of water and regulation of internal temperature (sweat glands) • pigmentation prevents injury from ultraviolet light • vitamin D synthesis by sunlight in the epidermis • sensation of pain, touch and temperature • Involvement in immunological reactions (Langerhans cells, secretory IgA, T- and B-cells).

White nails are a common feature of chronic liver disease (cirrhosis) in adults, but are less frequently seen in children.

Dermatological manifestations of liver disease Jaundice Jaundice (icterus), a yellow discoloration of the skin and mucous membranes, is the most obvious sign of liver disease and is best seen in the conjunctivae. It is detectable when the serum level of bilirubin exceeds 2 mg/dl (34 mmol/l), although in neonates it may not be detected unless the level exceeds 5 mg/dl (85 mmol/l). The differential diagnosis and management have been discussed elsewhere in this book (see Chapter 4). Palmar erythema Palmar erythema, or ‘liver palms’, is a nonspecific red discoloration of the palms and fingertips of the hand indicative of a hyperdynamic circulation which is associated with chronic liver disease and cirrhosis. Spider naevi Spider naevi, or spider angiomata, are telangiectases consisting of a central arteriole with superficially radiating small vessels, resembling spiders’ legs, and are mainly observed in the superior vena cava distribution area (i.e. above the nipple line). Characteristically the whole lesion will blanche when pressure is applied to the centre of the spider, and during episodes of severe or prolonged hypotension they may disappear. Although spider naevi do occur in healthy people, the presence of more than five is suggestive of chronic liver disease. An increase in number or size of spider naevi may suggest progressive liver damage (cirrhosis), but also occurs in pregnancy.

Pruritus Pruritus is a distressing symptom of cholestasis or inborn errors of bile acid metabolism. Symptoms range from mild to severe intractable pruritus, which interferes with the patient’s daily activity and sleep. Intractable pruritus may be an indication for liver transplantation. The exact mechanism of pruritus is uncertain. Cholestasis leads to an accumulation in plasma of substances which are normally excreted into bile (e.g. bilirubin, cholesterol and bile acids). High levels of bile acids may damage hepatocyte membranes, triggering the release of pruritogenic substances, which interact with nerve endings in the skin (Gregoria et al. 1993; Jones & Bergasa 1996). The skin in patients with generalized pruritus is often very dry and varies from normal appearance, through mild flakiness with a few scratch marks, to severe excoriation with scars and nodules. Treatment of pruritus is empirical and unsatisfactory. Good skin care is essential. As dryness of the skin is a prominent feature, avoidance of soap and liberal use of emollients are strongly recommended. Alternative treatments such as evening primrose oil and aromatherapy, and a wide range of drugs and therapies including ursodeoxycholic acid, phenobarbitone, rifampicin, cholestyramine, histamine antagonists, ondansetron, plasmapheresis and phototherapy (Chapter 4), are used with variable success. Partial external diversion of bile has been attempted in patients with pruritus unresponsive to medical treatment, again with highly variable success rates (Connolly et al. 1995). More recent studies have implicated increased opioid neurotransmission/neuromodulation in the central nervous system as a contributor to pruritus in cholestasis, suggesting that oral opiate antagonists, for example naloxone, may provide long-term relief from pruritus (Jones & Bergasa 2000). Although the exact mechanism of opiate involvement is still unknown, the beneficial effects of opiate antagonists have been shown in different randomized, blinded, placebo-controlled trials (Bergasa et al. 1991, 1993). Finally, subjective amelioration of pruritus following intravenous administration of ondansetron to cholestatic patients may suggest that altered serotonergic neurotransmission may also contribute to this form of pruritus (Jones & Bergasa 2000).

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Xanthelasma

Angiomatous naevi

Orange-yellow lipid deposits of cholesterol in the skin are known as xanthelasmata. They are seen in children with elevated plasma cholesterol due to chronic cholestasis secondary to intrahepatic biliary hypoplasia such as Alagille’s syndrome. They rarely present before the age of 16 months. The commonest sites are areas of mild trauma, elbows, knees and at flexures. Xanthelasmata regress with management of hypercholesterolaemia and following liver transplantation.

Rarely, infants are born with multiple angiomas of the skin and internal organs. The skin lesions look like small ‘strawberry naevi’, which are present at birth or arise shortly afterwards and, although they may appear anywhere on the body, have a predilection for the head, neck and napkin area. The lesions contain both capillary and ‘cavernous’ vascular elements, rapidly increase in size to often dome-shaped, red/purple extrusions, and may bleed if traumatized. Although the skin lesions would normally undergo spontaneous resolution with time, the associated hepatic and intestinal angiomas may lead to severe complications and, depending on the extent of disease and organs affected, often have a poor prognosis.

Purpura Purpura is extravasation of red cells in the skin, which presents with red patches that do not blanche on pressure. Purpura in liver disease usually reflects thrombocytopenia secondary to hypersplenism and portal hypertension, or skin fragility due to steroids. Photosensitivity Photosensitivity with abnormal liver function may be due to porphyria cutanea tarda. Early cutaneous features are blister formation and erosions on the backs of the hands, the forearms and the face following exposure to sunlight. The areas heal with scarring and milia formation. Later there may be hyperpigmentation, hypertrichosis and pseudosclerodermatous thickening of the skin. Similar photosensitive blistering eruptions, associated with elevated plasma and urinary porphyrins (raised coproporphyrin isomer I and III fraction), have been described in children with Alagille’s syndrome (see Plate 57, Atlas: p. 460). It is unclear whether the elevated porphyrins are secondary to liver dysfunction or associated with the deletion of chromosome 20 in this condition. The lack of similar lesions in other hepatic disorders associated with comparable porphyrin abnormalities does suggest that other factors may be involved in the pathogenesis of these cutaneous lesions (Poh-Fitzpatrick et al. 1990). Carotenaemia This yellow/orange discoloration of the skin, in particular of the palms, soles and feet, may occur in otherwise healthy children due to excess dietary b-carotene. Its importance is that it may be mistaken for jaundice. In some children it may be associated with low serum retinolbinding protein (RBP4) levels resulting in slow uptake and release of vitamin A by the liver and subsequent inhibition of conversion of carotene to vitamin A. The resulting hypercarotenaemia and low vitamin A levels do not respond to vitamin A supplementation (Attard-Moltano et al. 1992).

Gianotti–Crosti syndrome Gianotti–Crosti syndrome, or papular acrodermatitis of childhood, is a nonspecific viral exanthema which may accompany hepatitis B infection. There are erythematous, non-itchy papules on the face and extremities. Other clinical findings are generalized lymphadenopathy, and in children with hepatitis there is hepatomegaly and biochemical and histological evidence of acute or chronic hepatitis. Skin manifestations of malnutrition Infants with chronic liver disease are particularly at risk of malnutrition (Beath et al. 1993) (Chapters 4 and 14). Deficiencies in calories, protein, essential fatty acids, minerals and trace elements (particularly zinc and selenium) may eventually lead to skin abnormalities. Dietary protein deficiency (kwashiorkor) may result in nonspecific skin changes ranging from pigmentary changes (hyper- or hypopigmentation) to flexural erosions, desquamation and dry, depigmented and pluckable hair. In children with reduced calorie intake (marasmus) the skin may appear dry and wrinkled. Similar changes can be found as a result of longstanding essential fatty acid deficiency (see Plate 58, Atlas: p. 460), but the main feature is a dry flaky skin (ichthyosis) with hyperpigmentation. Zinc deficiency occasionally complicates liver disease and may lead to exudative eczematous lesions around the orifices and on the hands and feet similar to those found in acrodermatitis enteropathica, an inborn error of zinc metabolism. Selenium deficiency may lead to loss of hair pigment. All these conditions are reversible with appropriate dietary supplementation.

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which is frequently used post-liver transplantation (Chapter 17).

The skin in the immunocompromised host

Eczema

Environmental conditions and skin microorganisms, which have little significance in the normal host, may have quite devastating effects in the immunocompromised patient. Protection by an intact well-functioning skin is essential but may be compromised by various factors uniquely associated with the immunosuppression. In the first place, the integrity of the skin may be breached by the use of long-term central lines, intravenous devices and invasive diagnostic procedures, allowing easy invasion of pathogens. Second, immunosuppressant drugs such as corticosteroids cause atrophy of the skin, thus compromising the first-line barrier, while other immunosuppressant drugs (cyclosporin, FK506, etc.) lead to granulocytopenia, neutropenia and neutrophil defects, or alteration of T-cell and B-cell function, thereby reducing the second-line defences against pathogens. Finally, longstanding antimicrobial therapy may alter the normal skin flora (e.g. staphylococci, coryneforms and some Gramnegative bacilli such as Acinetobacter spp.), allowing colonization with potential pathogens. Once colonized, the immunocompromised host is at continuous risk of acquiring infection with these organisms (Fritsch et al. 1989).

Atopic dermatitis, or eczema, is a common skin disorder in infancy and childhood, affecting 5–7% of children before the age of 5 years. It may be particularly troublesome in children with liver disease before or after transplantation. In infants and younger children the main affected areas are the face and extensor surfaces of the extremities, while in older children and adults the flexural areas are predominantly involved. Chronic eczema (see Plate 60, Atlas: p. 461) appears red, scaly and lichenified (thickened, with exaggerated skin markings), while acute exacerbations are characterized by oedema, oozing, crusting and excoriation. The main symptom is pruritus, which may be not only difficult to manage, but also to differentiate from pruritus due to cholestasis in children with both conditions. Immunocompromised children with atopic dermatitis have an increased risk of secondary bacterial infection of the eczematous lesions leading to crusting and weeping. Occasionally eczema appears for the first time or becomes more severe in children post transplant on cyclosporin. This is paradoxical because cyclosporin is used to treat eczema, and may indicate a role for infection in the pathogenesis of eczema. There is no clear relationship with cyclosporin dose, but the eczema may improve when immunosuppression is reduced. First-line treatment of eczema involves soap substitutes, bath oils and emollient creams (e.g. aqueous cream and combinations of white soft paraffin and liquid paraffin) to moisturize the skin and reduce pruritus secondary to xeroderma (dry skin). More inflamed areas should be treated with topical steroids, which are available in increasing strengths from hydrocortisone 0.5–1%, to Eumovate (clobetasone butyrate 0.05%) or Betnovate (betamethasone 0.1%). In superimposed bacterial or fungal infection an ointment combining a steroid and antibacterial or anticandidal agent is necessary, such as Canesten HC, Terra-Cortril or Vioform HC. A body suit made of tubular bandages is comforting at night. Sometimes a double layer of bandages, with the inner layer wet (‘wet wraps’), is helpful for extreme pruritus. Ichthammolimpregnated bandages are useful for lichenified eczema on the limbs. In more resistant cases of chronic eczema, long-term use of topical and systemic corticosteroids is limited because of numerous side-effects. In recent years other, immunomodulatory forms of treatment have been explored, including topical tacrolimus ointment. Large multicentre studies have recently shown that its longterm use in both adults and children with severe atopic

Cutaneous side-effects of immunosuppressive drugs Hypertrichosis (hirsutism) Cyclosporin A therapy causes a reversible dosedependent increase in growth of body hair (see Plate 59, Atlas: p. 461). Vellus hair (thin, short hair without pigment, which takes over from lanugo hair in hair follicles after birth) converts to terminal hair, which is longer, coarser and darker, and existing terminal hair becomes thicker. The mechanism of this follicular stimulation is unknown. It may be exacerbated by the use of systemic steroids (Tosi et al. 1994; Yamamoto & Kato 1994). Retrospective studies in adult renal transplant recipients receiving cyclosporin found that 40–60% had hirsutism, with a slightly higher incidence in dark-skinned patients suggesting predisposing genetic factors (Bencini et al. 1986; Chugh et al. 1994). The incidence of hypertrichosis in children on cyclosporin post-liver transplantation is approximately 30% (Van Mourik et al. 1997) and the impact of its cosmetic effect, particularly in teenagers, is substantial.

Gingival hyperplasia Gingival hyperplasia is a recognized side-effect of cyclosporin and of the antihypertensive drug nifedipine,

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eczema is both efficacious and safe (Assmann et al. 2000, 2001; Reitamo et al. 2000). Acne vulgaris Acne vulgaris affects most adolescents during puberty, when changes in the hair follicle and sebaceous glands are stimulated by hormones. Drug-induced acne rarely occurs before puberty, in the ‘unprimed’ prepubertal follicles. Adolescents and adults treated with high-dose corticosteroids for autoimmune hepatitis or post transplant may develop acne for the first time, or experience an exacerbation of pre-existing acne (Munro 1997). Steroid-induced acne (see Plate 61, Atlas: p. 461) is reversible and generally appears 2–3 weeks after initiation of high-dose prednisolone therapy. It may be mild or severe, extending beyond the usual distribution sites to the arms, the whole central back and down to the buttocks. Acne vulgaris is characterized by comedones, papules and pustules, nodules and cysts, and finally scar formation. In steroid-induced acne pustules predominate and the eruption is often strikingly monomorphic. Cyclosporin may also provoke acne, as part of its effect on the hair follicle. Mild forms of acne should be treated with topical preparations such as benzoyl peroxide or retinoic acid alone or in combination with topical antibiotics (tetracyclines, erythromycin or clindamycin). In moderate cases treatment should include a combination of topical preparations with systemic oxytetracycline or erythromycin. Minocycline, an oral preparation of tetracycline, should be avoided as it can cause a lupus-like hepatitis. The more potent antiacne drugs, cyproterone acetate and isotretinoin, are potentially hepatotoxic and therefore contraindicated. Other steroid-induced skin manifestations Striae, facial erythema, atrophic and friable skin, purpura and telangiectasia are all well-recognized cutaneous sideeffects of prolonged high-dose steroid use. Apart from erythema these changes are irreversible.

Cutaneous lesions in immunocompromised hosts Viral infections Cutaneous viral infections in healthy subjects are common, benign and self-limiting but may be devastating in immunocompromised hosts, so early diagnosis and treatment are vital. The most important cutaneous virus infections in the context of liver transplantation are human papillomaviruses (HPV), molluscum contagiosum, herpes simplex virus (HSV), varicella-zoster virus (VZV) and cytomegalovirus (CMV).

Human papillomavirus Viral warts (verrucae) are one of the commonest cutaneous manifestations of long-term immunosuppressive therapy and may be so numerous as to be disfiguring (Chugh et al. 1994). The warts may reflect primary infection or reactivation of previously acquired latent virus (see Plate 62, Atlas: p. 461). Studies in adult renal transplant recipients showed a link between HPV and cutaneous malignancies, although other factors such as UV exposure and type of immunosuppressive drug also play a role. Warts and verrucas (plantar warts). Warts can be treated conservatively with keratolytic paints or destructively by cryotherapy. In immunosuppressed children cryotherapy is often ineffective, as well as painful. If the child requires a general anaesthetic for another reason, the warts may be curetted or frozen at the same time, but unfortunately they may recur. Repeated treatment may be required until immunosuppression can be reduced. If the warts are asymptomatic treatment may not be indicated. Plane warts. These are tiny, flat, flesh-coloured warts, usually occurring on the back of hands and on the face. They usually resolve spontaneously and treatment is not indicated. Condyloma acuminatum. These are genital warts, located on the penis, vulva or perianal area, which usually present as small cauliflower-like lesions. They are common in childhood, particularly in children undergoing immunosuppression. They are best treated with podophyllin paint under general anaesthetic if there are numerous warts. Molluscum contagiosum Molluscum contagiosum is caused by a poxvirus. The umbilicated, white or whitishyellow papules occur anywhere on the body and may be very extensive in immunosuppressed patients, responding to reduction in immunosuppressive therapy. There is no specific treatment as they eventually resolve spontaneously. If symptomatic, cryotherapy or individual enucleation with a needle is possible. Herpes simplex virus Primary herpes simplex infection due to HSV type 1 presents in immunocompetent children as a cold sore with mild to moderate stomatitis. Immunocompromised patients suffer primary HSV-1 infection as severe herpetic gingivostomatitis with extensive blisters and erosions on buccal mucosa and lips. Conjunctivitis and keratitis may also occur. As the virus persists in sensory ganglia the patient remains at risk of recurrent herpes infection, usually presenting as cold sores on the lips with occasional spread to the oesophagus. Diagnosis is based on the clinical features and positive electron microscopy of cultured fluid from vesicles. Serology is helpful only in primary HSV infection. Cutaneous HSV infection in immunosuppressed pa-

Chapter 16: Skin Disorders

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Table 16.1 Drug doses in dermatological conditions. Drug

Dose

Frequency (route)

25–100 mg/kg/dose (max. 5 g) 2.5 mg/kg/dose 10–25 mg/kg/dose 25–50 mg/kg/dose (max. 2 g) 10 mg/kg/dose (max. 250 mg) 7.5 mg/kg/dose 250–500 mg/dose (NOT/kg)

4–6 h (i.m./i.v.) 12 h (i.v./oral) 6–8 h (oral) 4–6 h (i.v.) 6 h (oral) Single (i.v./i.m.) 6 h (oral)

30–60 mg/kg/dose (max. 3 g) 7.5–15 mg/kg/dose (max. 500 mg) 50 mg/kg/dose (max. 3 g) 15 mg/kg/dose (max. 500 mg)

4–6 h (i.v.) 6 h (oral) 4–6 h (i.v.) Single (i.v. over 2 h)

Flucytosine Griseofulvin Ketoconazole Miconazole

1 mg/kg Then increase over 2–4 days to 2–3 mg/kg 4 (or 8) mg/kg (max. 200 mg) Then 2 (or 4–8) mg/kg (max. 100 mg) 400–1200 mg/m2/dose (max. 2 g) 10–20 mg/kg (max. 1 g) 3–5 mg/kg/dose (max. 400 mg) 7.5–15 mg/kg/dose (max. 1.2 g)

Daily (i.v. over 1 h) Daily (i.v.) Stat. (oral/i.v.) Daily (oral/i.v.) 6 h (oral./i.v.) Daily (oral) 12–24 h (oral) 8 h (i.v. over 1 h)

Antiviral Acyclovir

250–500 mg/m2/dose

8 h (i.v. over 1 h)

Ganciclovir

2.5–5 mg/kg/dose

8–12 h (i.v. over 1 h)

Antibacterial Carbenicillin Cotrimoxazole Erythromycin Flucloxacillin Gentamicin Oxytetracycline Penicillin: Benzylpenicillin (penicillin G) Phenoxymethylpenicillin (penicillin V) Ticarcillin Vancomycin Antifungal Amphotericin (liposomal) Fluconazole

tients should always be treated systemically (acyclovir), with reduction of immunosuppression in more extensive infections. Varicella-zoster virus The presentation of varicella (chickenpox) in immunosuppressed patients resembles that in healthy children, with fever, malaise and a characteristic skin rash, but the disease may be more severe and lead to serious complications such as haemorrhagic varicella, post-infectious encephalomyelitis and pneumonia. The virus remains dormant in dorsal root ganglia and may reactivate leading to herpes zoster (shingles). In immunosuppressed hosts reactivation is more likely and may lead to recurrent varicella and/or disseminated disease with visceral involvement, which may be fatal. Treatment of both forms of varicella include a reduction in immunosuppressive therapy, intravenous acyclovir and zoster immunoglobulin (ZIG). Cytomegalovirus CMV infection in immunocompromised hosts rarely presents with cutaneous manifestations, but as a febrile illness with arthralgia and myalgia or disseminated disease with visceral involvement. A few patients with primary or reinfection with CMV have presented with erythema multiforme with the typical ‘target lesions’ or blisters.

Fungal infections of the skin Fungal infections are common in immunocompromised patients, some reviews reporting an incidence as high as 70–85%. They include (i) infections that commonly affect normal individuals but in immunocompromised hosts present in a more severe and extensive form; and (ii) ‘opportunistic’ fungal infections with organisms unlikely to invade a normal host (Denning 1994; Philpot 1993). This chapter covers only the superficial mycoses involving the outermost layers of the skin, the nails, the hair and mucous membranes. The main pathogens in this group are the dermatophytes and yeasts (Richardson et al. 1993). Dermatophytoses Infections with dermatophytes, or ringworm fungi, are confined to the superficial stratum corneum, nails and hair, and are usually acquired from contact with keratin debris carrying fungal spores. There are three genera of dermatophytes, Trichophyton, Microsporum and Epidermophyton, of which more than 40 species are recognized world-wide. Some are anthropophilic (i.e. transmitted from person to person), while others are zoophilic (i.e. passed from animals to humans). Diagnosis is confirmed by microscopic detection of fungal hyphae in skin scrapings, nail clippings or plucked

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hair or a positive culture. Treatment includes topical broad-spectrum antifungal agents such as miconazole (Daktarin) or clotrimazole (Canesten) in cases of very limited infection, or oral griseofulvin where the fungal infection is more extensive. More potent systemic antifungals include itraconazole and terbinafine, but these are not licensed in children at present and are potentially hepatotoxic. For drug doses see Table 16.1. Tinea pedis (athlete’s foot). This presents as scaling, itchy skin between the toes, often spreading to the entire sole. A foul odour may be present. Vesicles may occur, particularly during warm weather, rupturing to leave a ring-like ragged border. It is a relatively uncommon condition in immunocompetent prepubertal children, where the diagnosis of contact dermatitis is more likely. However, the incidence is increasing in immunosuppressed children in this age group. The condition may resolve without treatment, but often recurs. Tinea corporis. Dermatophyte infection of the trunk, legs, arms or face produces annular scaly, itchy lesions with an inflammatory edge and central clearing (see Plate 63, Atlas: p. 462). It may have spread from another site (e.g. tinea cruris) or from an external source, animal or human. Tinea capitis. Dermatophyte infection of the scalp and hair produces varying degrees of scaling, patchy hair loss and areas of suppuration (kerion). The few hairs in the affected areas are usually broken just above the surface of the scalp and in some cases the fungi can be detected by their yellow-green fluorescent appearance under the Wood’s light (longwave UV light). This infection always requires systemic treatment for at least 6 weeks. Tinea unguium. Onychomycosis due to dermatophyte infection more often affects toenails than fingernails and is frequently associated with tinea pedis. It usually starts as yellow-white, irregular distal nail dystrophy, which spreads slowly proximally, eventually producing a thickened, friable, opaque, yellow nail. If treatment is required it must be systemic. Tinea cruris. Uncommon in children and usually occurring in young adult males, tinea cruris is a symmetrical, red, itchy eruption with a scaly edge and central clearing which spreads from the groin and pubic region to the inner thighs. Superficial yeast infections Pityriasis (tinea) versicolor. This common condition is characterized by light-brown scaly patches on the trunk, neck, shoulders and upper arms. In immunosuppressed patients the rash may extend to the scalp, face, abdomen, groin and legs. The causative organism, Malassezia furfur, is a normal skin commensal. Diagnosis is clinical and includes demonstration of a greenish, golden-yellow or pink fluorescence under the Wood’s light. Treatment with topical agents such as selenium sulphide, miconazole, clotrimazole or econazole is

usually effective, although the infection may relapse in places where the topical agents have not been applied properly. Candidiasis. Candida albicans is a normal commensal of the human digestive tract and can be isolated from the mouth and intestinal tract in 30–50% of the normal population and from the genital tract of up to 20% of normal women. Infection of skin and mucous membranes (candidiasis) is usually derived from the patient’s own reservoir. Topical and systemic steroid treatment, immunosuppression and long-term use of broadspectrum antibiotics predispose to candidiasis. Adequate treatment of superficial candidiasis is usually achieved with topical antifungal preparations such as nystatin, clotrimazole, amphotericin or miconazole. In more widespread infections systemic antidermatophytes such as ketoconazole, miconazole and fluconazole (Table 16.1) are indicated. Griseofulvin is ineffective against Candida spp. Liposomal amphotericin is the drug of choice for severe or intractable candidiasis. Flucytosine, a synthetic antifungal drug, is only active against yeasts but has been demonstrated to have a synergistic effect with amphotericin. Oral candidiasis. This is characterized by white, curdlike plaques inside the mouth which can be scraped off leaving inflamed and friable mucosa. In severe cases the disease may spread to the oropharynx and oesophagus. Localized lesions should clear within 2 weeks of commencing topical treatment with nystatin oral suspension, amphotericin or miconazole gel (Daktarin). In extensive infections systemic treatment is indicated. Chronic paronychia. This is a chronic inflammatory process affecting the proximal nail fold and nail matrix, caused by bacteria or C. albicans. Treatment should be with topical or, if this is unsuccessful, with oral preparations. Cutaneous candidiasis. Cutaneous candidiasis occurs in moist areas, such as body flexures (intertrigo) and skin that has been occluded with bandages or adhesive tape. Lesions start as vesicles or pustules, which may coalesce and erupt, leaving an erythematous area surrounded by an irregular scaling margin. The clinical diagnosis of candidiasis is confirmed by microscopic demonstration of C. albicans in scrapings of the lesions or by culture from swabs. Topical treatment is usually adequate, but systemic therapy is indicated for widespread infection. Pityrosporum folliculitis. In this acneiform condition, which is seen frequently in immunosuppressed children, small follicular papules and pustules are present on the trunk, in the absence of other features of acne (see Plate 64, Atlas: p. 462). It responds well to treatment with antifungal agents such as miconazole. Other opportunistic fungal infections Cutaneous aspergillosis. Aspergillosis is a common fungal infection in immunocompromised hosts. The primary

Chapter 16: Skin Disorders cutaneous form of aspergillosis, however, is uncommon and in most cases develops at entry sites of intravenous catheters or where splints were strapped to the skin. The lesions are erythematous or violaceous, oedematous, indurated plaques that evolve into necrotic ulcers covered with a black eschar. They may be painful and pruritic, in contrast to ecthyma gangrenosum, which looks identical and evolves in quite a similar way. The diagnosis is confirmed by demonstrating dermal hyphae in a skin biopsy. Cultures of biopsied lesions may yield Aspergillus flavus, A. fumigatus, A. niger or, less commonly, A. terreus. Blood cultures are rarely positive. Secondary cutaneous aspergillosis may follow haematogenous spread of invasive aspergillosis in immunocompromised hosts, and presents as cutaneous maculopapular lesions, which eventually become pustular and evolve into ulcers covered with a black eschar. Diagnosis is again made by microscopy and culture of a skin biopsy, and blood cultures are more likely to be positive. Serological tests for the presence of Aspergillus antibodies (precipitin test to detect precipitating antibodies) or Aspergillus antigens (latex particle agglutination test for Aspergillus galactomannan, a cell wall glycoprotein) in immunocompromised hosts are not very helpful in establishing the diagnosis and are frequently false negative due to delayed or absent immune response. Treatment includes removal of any foreign body such as intravenous lines and catheters, local wound care and intravenous antifungal treatment with liposomal amphotericin B (Table 16.1). Cutaneous cryptococcosis. This uncommon condition in immunocompromised patients may present as primary cutaneous cryptococcosis or the more common secondary cutaneous disease, which occurs in 10–15% of patients with disseminated disease. There may be single or multiple nodules, vesicles, ulcers or abscesses, predominantly located on the head, trunk or limbs, or small maculopapular lesions resembling molluscum contagiosum. Diagnosis is confirmed by demonstrating the organism, Cryptococcus neoformans, in aspirates from blister fluid and in cultured fluid, ulcer drainage or skin biopsy specimens. In most cases with disseminated disease latex agglutination tests for the presence of cryptococcal antigen in body fluids will be positive, although serology is usually negative. All patients with cutaneous cryptococcosis should be investigated for disseminated infection. Treatment with systemic antifungal preparations such as amphotericin B with or without flucytosine should be commenced as soon as possible. Cutaneous histoplasmosis. This very rare infection with Histoplasma capsulatum is usually self-limiting in the general population, but in immunocompromised hosts it frequently progresses to disseminated disease. Cutaneous involvement is rare and presents as papules, plaques and

307

ulcers, which may progress to purpuric lesions and abscesses. Occasionally aggressive erysipelas or cellulitislike eruptions develop. The diagnosis is confirmed by demonstrating the organism in skin biopsies as culture growth is too slow to establish an early diagnosis. Serological precipitin and agglutination assays are unreliable and often negative in immunocompromised patients. Treatment should consist of amphotericin B, often given in combination with flucytosine for its additive and synergistic effect. Unusual fungal skin infections Cutaneous trichosporonosis. In its mild form infection with Trichosporon beigelii causes a superficial hair infection, which presents as firmly attached, irregular, soft, light-brown nodules along the midshafts of the hairs (white piedra). It particularly affects young adults and is found world-wide, although it is most common in tropical and subtropical regions. Diagnosis is confirmed by microscopic detection of the hyphae on the hairs as well as culturing the organism. The simplest treatment option is to shave or clip the hair in the affected area, followed by topical application of lotrimazole or miconazole cream. Secondary cutaneous trichosporonosis usually presents as multiple, erythematous, maculopapular lesions, which may develop into necrotic ulcers. Histopathological examination of skin biopsies reveals the organism, and the diagnosis can be confirmed by positive blood cultures. Serological tests are often false negative. Intravenous amphotericin B is an effective treatment provided the patient is not neutropenic. Others. Cutaneous infections in the immunocompromised host may also be caused by an array of unusual fungi which, in the past, were often considered as contaminants and whose classification creates great confusion. Examples are certain yeasts, such as Geotrichum candidum, Rhodotorula, Saccharomyces and Torulopsis species, dermatophytic fungi such as Alternaria, Curvularia and Drechslera, and hyaline moulds such as Fusarium, Penicillium and Paecilomyces. Skin lesions vary enormously but many begin as a pigmented papule or vesicle, which subsequently progresses to necrosis. A positive culture is essential for the correct diagnosis, as on histological examination of skin biopsies it is often impossible to differentiate between the various types of fungal organisms. Amphotericin B is the drug of choice, with imidazoles for amphotericin-resistant cases (Vartivarian et al. 1993). Bacterial skin lesions Gram-negative infections Gram-negative bacilli such as Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa are responsible for most serious skin infections in immunocompromised patients. Skin manifestations

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include cellulitis, subepidermal bullae, subcutaneous abscesses and rarely toxic epidermal necrolysis (TEN). Ecthyma gangrenosum, usually due to P. aeruginosa, is commonest in severely neutropenic patients. It begins as a painless, round, erythematous macule, which may have a small vesicle on its surface. Later it becomes indurated and bullous or pustular, and subsequently the skin sloughs and forms a gangrenous ulcer with a grey-black eschar surrounded by an erythematous halo. It is commonest in intertriginous regions, but may also appear on the extremities, face or trunk. It may be associated with a high temperature, tachycardia, tachypnoea and hypotension. The diagnosis is confirmed by positive cultures from a skin biopsy specimen or blood cultures. Treatment is aggressive with high doses of intravenous carboxypenicillins, such as carbenicillin or ticarcillin, in combination with an aminoglycoside (Table 16.1). Persistent neutropenia during treatment and multiple skin lesions are poor prognostic features (Kuhls & Leach 1992). Gram-positive infections Skin infections by Gram-positive bacteria do not differ in character from those in immunocompetent patients, but may be more severe and are more often associated with systemic involvement. Streptococcal infections. Streptococcal infection of the skin and subcutaneous tissue presents as cellulitis, an erythematous, hot, swollen area, often on the leg. There may be blisters and even skin necrosis with malaise, high fever and rigors. Treatment consists of intravenous penicillin, although in some cases surgical debridement of severely necrotic areas may be necessary. Staphylococcal infections. These can take various forms, as outlined below. • Folliculitis. This is an infection of the superficial part of a hair follicle with Staphylococcus aureus leading to a small pustule on an erythematous base, centred on the follicle. In mild forms treatment consists of topical preparations (e.g. benzoyl peroxide, alone or in combination with topical antibiotics similar to those used in the treatment of acne). In severe cases systemic antibiotics such as flucloxacillin or erythromycin may be required (Table 16.1). • Furunculosis (‘boils’). This is characterized by painful, inflammatory nodules due to deep infection of hair follicles by S. aureus. Over a period of time the lesion becomes fluctuant and once the central necrotic core has been discharged the boil resolves. In immunosuppressed patients treatment is with intravenous flucloxacillin. • Impetigo. This is a superficial skin infection caused by S. aureus alone or in combination with haemolytic streptococci. There is an initial small blister or pustule which rapidly increases in size, ruptures and leaves a raw, exuding surface which then dries and forms the typical golden-yellow crust. Impetigo may appear anywhere on the body, even in immunocompetent patients, and in

immunosuppressed patients should be treated with systemic flucloxacillin or erythromycin. • Staphylococcal scalded skin syndrome (SSSS). This is generally thought of as a disease of healthy infants and children, but when seen in adults it predominantly occurs in immunosuppressed individuals. It is caused by the production of a toxin by some staphylococcal phage types which splits the dermis, causing the superficial epidermis to peel off and leaving a skin resembling severe scalding. In immunocompromised patients it is often associated with severe sepsis, with positive blood cultures for S. aureus, and treatment should include a course of intravenous antibiotics (flucloxacillin). Corynebacterial infections. Coryneforms, or diphtheroids, are normal skin commensals which cause minor problems in healthy individuals (e.g. erythrasma). Cutaneous infections in immunocompromised patients occur in severely neutropenic patients previously treated with broad-spectrum antibiotics. They mainly present as cellulitis or subcutaneous abscess at the site of a puncture wound or intravenous catheter. A few cases have been reported where corynebacteria infection presented as an erythematous maculopapular rash, initially on the trunk, followed by diffuse spread and a more pustular appearance. Clinical diagnosis requires confirmation from blood and skin biopsy cultures. Treatment is difficult as the organism is resistant to most antibiotics except vancomycin. Mycobacterial infections Both Mycobacterium tuberculosis and atypical mycobacteria may cause cutaneous disease. Primary skin infections, usually caused by the atypical mycobacteria M. marinum, M. cheloni, M. kansasii and M. haemophilium, occur in normal and immunosuppressed hosts. The commonest presentation is a pigmented, granulomatous nodule with an erythematous halo on an extremity, although a wide variety of lesions, such as cellulitis or panniculitis, may occur. Systemic symptoms are not usually present although in immunocompromised hosts the infection may disseminate to multiple cutaneous sites or ulcerate, leading to superinfection. Skin manifestations of disseminated M. tuberculosis infection in immunocompromised hosts include recurrent episodes of skin and soft tissue abscesses of the extremities with symptom-free intervals in between and often minimal systemic symptoms. The diagnosis is confirmed by histological identification of acid-fast bacilli and positive cultures. Treatment should be with appropriate antituberculous chemotherapy. Nocardial infections Nocardia spp. infection, especially with N. asteroides, is strongly associated with immunosuppression and may be focal or disseminated. Skin manifestations include pustules, cellulitis or ulcers, and are usually secondary to disease in the lungs. The diagno-

Chapter 16: Skin Disorders sis is often difficult as Nocardia is not easily detected in cultures or histological sections. Treatment consists of adequate surgical drainage, if required, in combination with cotrimoxazole. Cutaneous malignancies Susceptibility to skin cancer after transplantation is multifactorial. Predisposing risk factors include older age at time of transplant, lighter skin type, solar keratosis, greater sunlight exposure, higher rejection rate in the first year after transplant, and level of immunosuppression (Haagsma et al. 2001; Mithoefer et al. 2002). More recent research, mainly in renal transplant recipients, indicated that genetic variation in enzymes involved in free radical metabolism in the skin could also be associated with the development of skin cancer (Marshall et al. 2000). Cutaneous lymphomas occur with increased incidence in transplant recipients (Pascual et al. 1992). They are predominantly of B-cell origin and, in many cases, are associated with Epstein–Barr virus infection (McGregor et al. 1993). Cutaneous T-cell lymphomas have been rarely described in this group and their aetiology is ill understood. Reduced immune surveillance, chronic antigenic stimulation caused by transplant grafts, and the direct oncogenic effect of immunosuppressive drugs have all been suggested as mechanisms (Ward et al. 2001). It is likely that immunosuppressive treatment (cyclosporin, tacrolimus) causes an imbalance in the T-cell regulatory systems, resulting in an expanded T-cell subpopulation. In both conditions the early skin changes are nonspecific (see Plate 65a, Atlas: p. 462), but the later stages are characterized by exfoliative generalized erythroderma and lymphadenopathy. The definitive diagnosis is made by skin biopsy (see Plate 65b, Atlas: p. 462). Non-melanoma skin cancer (NMSC) is increasingly recognized as a complication of longterm immunosuppression in solid organ transplant recipients (Penn & Brunson 1988). Studies in adult renal transplant recipients have shown that as patients survive longer, the risk of developing dysplastic (i.e. premalignant or malignant) lesions within 5 years of transplantation is as high as 40% (Leigh & Glover 1995a,b). Major contributing factors are exposure to ultraviolet radiation (i.e. high levels of sun exposure), drug-induced immunosuppression and HPV infection. Although still rare in childhood, these lesions occur at a younger age and lead to a higher morbidity and mortality than in immunocompetent individuals. Dysplastic skin lesions in adult transplant recipients include actinic or solar keratosis, Bowen’s disease, squamous cell carcinoma and, less commonly, basal cell carcinoma and malignant melanoma, all of which are uncommon in children. Warts, following infection with HPV, are common in both groups and rarely become

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malignant (warty dysplasia), particularly on sunexposed skin areas (Blohme & Larko 1990, 1994). Early detection and treatment of skin malignancies is necessary to avoid metastatic spread. Management strategies should focus on regular full-skin check and nodular examination, aggressive treatment of established malignancies (including reduction in immunosuppression), and prophylactic measures to reduce the risk of additional photodamage and malignant transformation (Otley & Pittelkow 2000). Preventative measures include minimizing immunosuppression and avoiding excessive sun exposure, and this advice should be routinely provided to parents and children undergoing transplantation. Children should be advised to use adequate sun block. As it may be difficult to differentiate between benign and dysplastic lesions, any skin lesion that suddenly appears, changes colour or size, becomes itchy or painful, or starts bleeding, oozing or crusting, should be seen by a dermatologist and a skin biopsy performed to confirm the diagnosis and commence appropriate treatment (see Chapter 20). Graft-vs.-host disease (GVHD) Acute GVHD remains a major cause of morbidity and mortality following bone marrow transplantation, affecting the liver, skin and gut (Chapter 15). It is very rare following liver or small bowel transplantation (Vogelsang et al. 1998). Cutaneous acute GVHD presents between 7 days and 7 weeks after transplant with a maculopapular rash, which may look like measles, accompanied by palmar and plantar erythema and sometimes oedema. The rash may be pruritic or feel like sunburn. The lesions coalesce and spread to the trunk, face and extremities. Sometimes the rash becomes bullous and progresses to toxic epidermal necrolysis. The diagnosis can be confirmed by skin biopsy, which shows dermo-epidermal clefts, necrosis of keratinocytes surrounded by lymphocytes (‘satellite cell necrosis’), vacuolization of basal epidermal cells and oedema. Cutaneous lesions in chronic GVHD are itchy, flattopped, red-purple shiny papules resembling lichen planus. Later the skin may thicken and look like scleroderma, with hyper- and hypopigmentation. Nonspecific skin rashes Rashes in immunosuppressed patients vary enormously in their presentation, and represent a wide variety of underlying diagnoses (Chren et al. 1993). Histopathological interpretation is difficult without an informed dermatological differential diagnosis. In some cases the diagnosis may become more obvious at a later stage, and

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History

1 Dermatological and family history 2 Drug history, including immunosuppression status

Examination

1 Site and distribution of lesion(s) 2 Characteristics of individual lesions

Illustration

1 Photograph of lesion(s)

Investigations

1 ?Fungal

Skin scrapings Nail clippings Wood's light (if scalp involvement)

2 ?Bacterial/viral

Direct swab from pus or vesicle fluid EM-examination of blister base (if blisters present) Blood cultures/viral serology (if systemic involvement)

3 ?Malignancy

Refer to dermatologist

4 Unknown aetiology

Dermatological opinion Skin biopsy

careful documentation, including medical illustration and review by a dermatologist, are therefore essential.

Approach to diagnosis of dermatological lesions A practical approach to the diagnosis of skin disorders in immunosuppressed children post transplantation is outlined in Fig. 16.1. A dermatological history is essential, including past and family history as well as a detailed review of systemic and topical therapy the child is receiving at the moment. This, in combination with a careful documentation of site and/or distribution of lesions and description of the characteristics of individual lesions, may in many cases offer sufficient information to make a correct diagnosis. Further investigations and/or referral to a dermatologist are indicated if the patient is systemically unwell, if the diagnosis is not clear, or if there is suspicion of skin malignancy (Allen et al. 1986). Techniques

Fig. 16.1 Practical approach to diagnosis of skin lesions.

Nail clippings Nail clippings should be taken as proximally as possible to optimize the chances of identifying fungus on microscopy or culture. Scalp lesions Scalp lesions should be examined under ultraviolet light (Wood’s light) to detect fluorescence, although some ringworm species do not fluoresce. Plucked hairs from the edge of a lesion can be sent for microscopic examination and culture. Skin cultures Pus or vesicle fluid can be swabbed directly. Samples for bacteriological examination should be sent either dry or in a transport medium, while virological samples should be sent in a special viral transport medium. In the case of blisters the base should be scraped for electronmicroscopic examination.

Skin scrapings for mycology The scaly edge of the lesion should be carefully scraped with a scalpel blade onto black paper and sent to the microbiology laboratory for microscopic examination and mycological culture.

Skin biopsies A punch or wedge biopsy technique should be applied, preferably under local anaesthesia. Select a fresh lesion for biopsy, as older lesions may show secondary

Chapter 16: Skin Disorders changes, which make histological interpretation more difficult (Parham et al. 1992). Establish beforehand from the laboratory what transport medium is required. Formaldehyde is routine for light microscopy, but is unsuitable for fat-containing lesions, for example xanthomas. Glutaraldehyde is usual for electron microscopy. If in doubt, and for skin to be cultured for microorganisms, place the specimen on a salinesoaked gauze swab and convey directly to the laboratory.

References Allen, U., Smith, C.R. & Prober, C.G. (1986) The value of skin biopsies in febrile, neutropenic, immunocompromised children. American Journal of Disease in Childhood 140, 459–461. Assmann, T., Homey, B., Ruzaicka, T. (2001) Topical Tacrolimus for the treatment of inflammatory skin diseases. Expert Opinion on Pharmacotherapy 2, 1167–1175. Assmann, T., Homey, B. & Ruzicka, T. (2000) Applications of tacrolimus for the treatment of skin disorders. Immunopharmacology 47, 203–213. Attard-Moltano, S., Evans, N. & Sherwood, R.A. (1992) Carotinaemia with low vitamin A levels and retinol-binding protein. Journal of Inherited Metabolic Disease 15, 929–930. Beath, S.V., Booth, I.W. & Kelly, D.A. (1993) Nutritional support in liver disease. Archives of Disease in Childhood 69, 545–549. Bencini, P.L., Montagnino, G., Sala, F., De Vecchi, A., Crosti, C. & Tarantino, A. (1986) Cutaneous lesions in 67 cyclosporintreated renal transplant recipients. Dermatologica 172, 24–30. Bergasa, N.V., Alling, D.W., Talbot, T.L. et·al. (1991) Relief from the intractable pruritus of chronic cholestasis associated with oral nalmefene therapy. Hepatology 14, 154A. Bergasa, N.V., Alling, D.W., Talbot, T.L. et·al. (1993) Nalmefene therapy is associated with the relief of pruritus of cholestasis: results of a double-blind randomised placebo-controlled trial. Hepatology 18, 177A. Blohme, I. & Larko, O. (1990) Skin lesions in renal transplant patients after 10 years of immunosuppressive therapy. Acta Dermato-Venereologicca (Stockholm) 70, 491–494. Blohme, I. & Larko, O. (1994) Premalignant and malignant skin lesions in renal transplant patients. Transplantation 37, 165–167. Chren, M.-M., Lazarus, H.M., Bickers, D.R. & Landefeld, S. (1993) Rashes in immunocompromised cancer patients. Archives of Dermatology 129, 175–181. Chugh, K.S., Sharma, S.C., Singh, V., Sakhuja, V., Jha, V. & Gupta, K.L. (1994) Spectrum of dermatological lesions in renal allograft recipients in a tropical environment. Dermatology 188, 108–112. Connolly, C.S., Kantor, G.R. & Menduke, H. (1995) Hepatobiliary pruritus: what are effective treatments? Journal of the American Academy of Dermatology 33, 801–805. Denning, D.W. (1994) Pocket Reference to Opportunistic Fungal Infections. Science Press Ltd, London. Fritsch, P., Schuler, G. & Hintner, H., eds. (1989) Current Problems in Dermatology: Immunodeficiency and Skin. Karger, Basel. Graham-Brown, R. & Burns, T., eds. (1990) Lecture Notes on Dermatology. Blackwell Scientific Publications, Oxford. Gregoria, G.V., Ball, C.S., Mowat, A.P. & Mieli-Vergani, G. (1993) Effect of Rifampicin in the treatment of pruritus in

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hepatic cholestasis. Archives of Disease in Childhood 69, 141–143. Haagsma, E.B., Hagens, V.E., Schaapveld, M., van den Berg, A.P., de Vries, E.G., Klompmaker, J.B. et·al. (2001) Increased cancer risk after liver transplantation: a population based study. Journal of Hepatology 34, 84–91. Jones, E.A. & Bergasa, N.V. (1996) Why do cholestatic patients itch? Gut 38, 644–645. Jones, E.A. & Bergasa, N.V. (2000) Evolving concepts of the pathogenesis and treatment of pruritus of cholestasis. Canadian Journal of Gastroenterology 14, 33–40. Kuhls, T.L. & Leach, C.T. (1992) Infections in pediatric liver transplant recipients. In: Infections in Immunocompromised Infants and Children. (ed. C. C. Patrick), pp. 231–250. Churchill Livingstone, New York. Leigh, I.M. & Glover, M.T. (1995a) Cutaneous warts and tumours in immunosuppressed patients. Journal of the Royal Society of Medicine 88, 61–62. Leigh, I.M. & Glover, M.T. (1995b) Skin cancer and warts in immunosuppressed renal transplant recipients. Recent Results in Cancer Research 139, 69–86. Marshall, S.E., Bordea, C., Haldar, N.A. et al. (2000) Glutathione S-transferase polymorphisms and skin cancer after renal transplantation. Kidney International 58, 2186–2193. McGregor, J.M., Yu, C.C., Lu, Q.L., Cotter, F.E., Levison, D.A. & MacDonald, D.M. (1993) Post transplant cutaneous lymphoma. Journal of the American Academy of Dermatology 29, 549–554. Mithoefer, A.B., Supran, S. & Freeman, R.B. (2002) Risk factors associated with the development of skin cancer after liver transplantation. Liver Transplantation 8, 939–944. Morelli, J.G. & Weston, W.L. (1993) Skin. In: Current Paediatric Diagnosis and Treatment, 11th edn (eds W. E. Hathaway, W. W. Hay, J. R. Groothuis & J. W. Paisley), pp. 372–391. Prentice Hall International, London. Munro, C.S. (1997) CME Dermatology II. Acne. Journal of the Royal College of Physicians of London 31, 360–363. Otley, C.C. & Pittelkow, M.R. (2000) Skin cancer in liver transplant recipients. Liver Transplantation 6, 253–262. Parham, D.M., Wilson, R.T. & Callihan, T.R. (1992) Skin biopsies. In: Infections in Immunocompromised Infants and Children (ed. C. C. Patrick), pp. 787–804. Churchill Livingstone, New York. Pascual, J., Torrelo, A., Teruel, J.L., Bellas, C., Marcen, R. & Ortuno, J. (1992) Cutaneous T cell lymphomas after renal transplantation. Transplantation 53, 1143–1145. Penn, I. & Brunson, M.E. (1988) Cancers after cyclosporin therapy. Transplantation Proceedings 3 (Suppl. 3), 885–892. Philpot, C. (1993) Mycological examination of skin. In: Clinical Signs and Procedures in Dermatology (eds R. Marks, P. Dykes & R. Motley), pp. 158–172. Martin Dunitz Ltd, London. Poh-Fitzpatrick, M.B., Zaider, E., Sciales, C. et·al. (1990) Cutaneous photosensitivity and coproporphyrin abnormalities in the Alagille syndrome. Gastroenterology 99, 831–835. Reitamo, S., Wollenberg, A., Schopf, E., Perrot, J.L., Marks, R., Ruzicka, T. et al. (2000) Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. The European Tacrolimus Ointment Group. Archives in Dermatology 136, 999–1006. Richardson, M.D. & Warnock, D.W., eds. (1993) Fungal Infection, Diagnosis and Management. Blackwell Scientific Publications, Oxford.

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Tosi, A., Misciali, C., Piraccini, B.M., Peluso, A.M. & Bardazzi, F. (1994) Drug-induced hair loss and hair growth. Incidence, management and avoidance. Drug Safety 10, 310–317. Van Mourik, I.D.M., Nagle, A. & Kelly, D.A. (1997) Conversion from Sandimmun to Neoral in stable paediatric liver transplant recipients. Hepatology 26, 432. Vartivarian, S.E., Anaissie, E.J. & Bodey, G.P. (1993) Emerging fungal pathogens in immunocompromised patients: classification, diagnosis and management. Clinical Infectious Diseases 17 (Suppl. 2), S487–S491.

Vogelsang, G.B., Hess, A.D. & Santos, G.W. (1988) Acute graftversus-host disease: clinical characteristics in the cyclosporin era. Medicine 67, 163–174. Ward, H.A., Russo, G.G., McBurney, E., Millikan, L.E. & Boh, E.E. (2001) Posttransplant primary cutaneous T-cell lymphoma. Journal of the American Academy of Dermatology 44, 675–680. Yamamoto, S. & Kato, R. (1994) Hair growth-stimulating effects of cyclosporin A and FK506, potent immunosuppressants. Journal of Dermatological Science 7 (Suppl.), S47–S54.

Chapter 17: Dental Care of Children with Liver Disease MARIE-THERESE HOSEY

Formation and composition of enamel and dentine, 313 Dental disease, 313 Dental caries, 313 Periodontal disease, 314 Prevention of dental disease, 314

Intrinsic dental pigmentation, 314 Enamel hypoplasia in children with liver disease, 315 Guidelines for the dental management of children with liver disease, 315

Children with liver disease and liver grafts require specialist dental care. Their inadequate drug and protein metabolism and tendency towards prolonged bleeding means that even simple dental treatment requires careful management. Children with liver disease and liver grafts are more likely to have hypoplastic defects of the enamel of their teeth, delayed eruption of the primary dentition, intrinsic green staining of both primary and permanent teeth and the oral soft tissues, and cyclosporin-induced gingival overgrowth, and to suffer from an increased susceptibility to dental caries (Shapiro et al. 1975; Seow et al. 1991; Funakoshi et al. 1992; Zaia et al. 1993; Hosey et al. 1995; Sheehy et al. 2000). In this chapter a brief discourse on the relevant areas of dental development and disease will be presented, and then the oral implications of liver disease and liver transplantation will be examined and guidelines suggested.

Formation and composition of enamel and dentine Mature enamel is a crystalline material, in the form of hydroxyapatite, that is 96% by weight mineral and, as such, is the hardest calcified tissue in the human body. Enamel is laid down in an incremental fashion from the tip of the cusp to the cervical margin, and it is possible to see a microscopic neonatal line marking the border between the enamel matrix that is formed before birth and that formed after (Bath-Balogh & Fehrenbach 1997). Hard tissue formation in the crowns of primary incisor teeth starts between the 13th and 16th weeks of intrauterine life and continues until enamel calcification is completed 3 months after birth (Lunt & Law 1974).

Dental disease There has been little change in the proportion of children

Care of transplant recipients, 316 Guidelines for the dental management of paediatric liver graft recipients, 318

with actively decayed primary teeth over the last 10 years. The incidence of dental disease is higher in Northern Ireland and Scotland, in ethnic minority groups, and in children from low-income and single-parent families (Attwood et al. 1990; O’Brian 1993; Shaw 1997; Pitts 1998). The frequent administration of liquid medicines sweetened with sucrose has significantly contributed to an increased incidence of dental caries in children with chronic medical disorders (Roberts & Roberts 1979, 1981). Unfortunately, there is also evidence to suggest that medically compromised children have a much higher proportion of untreated carious lesions than the average child, brush their teeth less often and seldom use fluoride supplements (Franco et al. 1996). In addition, children who have had invasive dental or medical procedures are more likely to be afraid of dental treatment and either avoid attending the dentist altogether or co-operate poorly (Wright & Alpern 1971; Kleinknecht et al. 1973; Cuthbert & Melamed 1982; Kent & Blinkhorn 1991). Dental caries Children with liver disease have been reported to have ‘generalized dental discomfort’, ‘chronic marginal gingivitis and advanced carious destruction’ and ‘absent oral hygiene’ (Shapiro et al. 1975). Seow et al. (1991) reported a high prevalence of untreated dental caries and also noted that the teeth had enlarged pulp chambers. This latter finding is a morphological feature, which could render pulpal exposure and subsequent loss of vitality of the carious tooth more likely. Therefore, children with liver disease not only appear to have a predilection for tooth decay but they may also be more likely to lose their teeth as a result. Although the paediatric dentist is skilled in the management of anxious children, behavioural management techniques require care, patience and time. For many children with liver disease the time avail-

313

314

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able for completion of the dental treatment is limited by the overriding urgency of transplant surgery. Therefore, dental treatment under general anaesthesia is often the only option, even though this does little to foster a positive attitude towards dental care. To avoid this, these children are best referred before problems arise to a specialist paediatric dentist who can then institute preventative and acclimatization therapies in good time. It has been recommended that high-speed suction is used for children with liver disease during operative dental procedures to guard against ingestion of blood Glassman et al. 1993; Svirsky 1989; Little 1992) and that the dose of amide local anaesthetic solutions (lignocaine) used during operative dental procedures is reduced (Welbury 1997). These children might also require antihaemolytic agents to aid haemostasis following dental surgery or tooth extraction. General anaesthesia is best provided by an anaesthetist suitably experienced in managing children with compromised liver function, in a hospital facility. Broad-spectrum antibiotic cover is required if children are having associated procedures such as liver biopsy. Periodontal disease Diseases of the periodontal tissues begin in childhood. Dental plaque initiates an inflammatory reaction, modulated by the immune response, microbial species and genetic predisposition. Periodontal disease progresses from gingivitis to gradual loss of the attachment of the tooth to the surrounding connective tissues and bone, causing tooth mobility, bleeding, pocketing and eventual abscess and tooth loss. Prevention of dental disease Many children with liver disease require nutritional supplementation, and such supplements often contain high proportions of non-milk extrinsic sugars that are highly cariogenic. It is important that parents are not confused by contradictory messages about diet; this requires a degree of pragmatism by the dental team and places a greater burden upon them to deliver stringent preventive care together with the restorative treatment that will doubtless ensue. It is helpful if the dietician and physician can, where possible, limit the frequency of the dietary supplements to mealtimes and prescribe sugar-free medications in order to reduce the incidence of dental caries. Teeth should be brushed twice daily with a 1000 p.p.m. fluoride toothpaste, which is then spat out rather than rinsed to reduce caries. The use of fluoride, either professionally applied or prescribed as supplements or rinses, is also recommended for these high-risk children. Chlorhexidine delivered as a gel, varnish or rinse reduces

the bacterial load, and possibly also the risk of bacteraemia (Sheehy et al. 1999, 2000) as well as preventing caries and periodontal disease. All susceptible fissures should be sealed using fissure sealants, and the use of xylotol chewing gum should be considered (Shaw 1997; Sheehy et al. 1999; Scottish Intercollegiate Guidelines Network 47 2000). Intrinsic dental pigmentation Dental discoloration can arise from extrinsic sources such as chromogenic bacteria, food pigment, dye and tobacco. Intrinsic discoloration is found in many conditions including: fluorosis, tetracycline ingestion, lepromatous leprosy, and haemolytic diseases of the newborn and congenital erythropoietic porphyria. The earliest reports of intrinsic green pigmented primary teeth were published over 30 years ago in children with hyperbilirubinaemia caused by rhesus incompatibility (Langmead 1912; Thursfield 1912; Farquhar 1951; Miller 1951; Tank 1951). Intrinsically pigmented green primary and permanent teeth, alveolar bone and oral mucosa have been widely reported in children with liver disease (Marsland & Gerrard 1953; Shapiro et al. 1975; Herbert & Delcambre 1987; Morisaki et al. 1990; Vancleynen & Demars-Fremault 1990; Seow et al. 1991; Majewski et al. 1993; Zaia et al. 1993; Hosey et al. 1995). It is thought that this pigment is deposited in the enamel organ during tooth formation as biliverdin, the oxidation product of the bilirubin molecule, in those areas of dentine and enamel which were undergoing calcification during the period that the child was jaundiced (Miller 1951; Zaia et al. 1993). Indeed, Seow et al. (1991) reported that the green pigment extended into the roots of the affected primary teeth but stopped at the stage of root development that corresponded to the time when the child received a liver graft. However, owing to the very high mineral content of enamel and dentine, biochemical and histological examination is difficult and there are no radiographic or histological abnormalities associated with the pigmentation (Funakoshi et al. 1992; Majewski et al. 1993). As yet, the exact nature of the pigment is unknown but it is conceivable that it might not be equally distributed in both enamel and dentine (Tank 1951; Marsland & Gerrard 1953; Funakoshi et al. 1992). The deposition of intrinsic stain may occur during hard tissue formation postnatally or in utero (Miller 1951; Marsland & Gerrard 1953; Brearley & Storey 1968; Genot et al. 1970; Shapiro et al. 1975; Rosenthal et al. 1986; Herbert & Delcambre 1987; Vancleynen & Demars-Fremault 1990; Seow et al. 1991; Funakoshi et al. 1992; Zaia et al. 1993), but recent clinical evidence strongly suggests that the pigment is deposited after birth (Hosey 1997), as primary molar teeth are more deeply stained than the primary in-

Chapter 17: Dental Care cisors since a greater proportion of the primary molar crown is formed after birth (Marsland & Gerrard 1953; Rosenthal et al. 1986). Treatment of discoloured teeth Adhesive dental materials are now widely used to restore the aesthetics of a child’s discoloured permanent incisor teeth. Composite restorations (white fillings) and porcelain veneers can easily be applied to the labial surface of the incisor teeth to camouflage unsightly intrinsic discoloration. There are many colour-modifying adhesive materials which, used singly or in combination, can restore a child’s smile throughout their formative years (Reid 1988; Harley & Ibbetson 1991). These techniques are non-destructive of tooth tissue and the technique does not require local anaesthesia. These veneers extend into the space between the teeth and underneath the gingival margin, therefore it is imperative that the child has scrupulous oral hygiene, otherwise there will be increased plaque retention leading to caries and periodontal disease. In adulthood, porcelain crowns may be the treatment of choice fully to mask the discoloration, but these cannot be provided sooner than the third decade of life because not only is the immature dental pulp too large, risking exposure during crown preparation, but also the gingival contour shrinks back during adolescence, leaving unsightly crown margins visible if the definitive restoration is provided too early. Enamel hypoplasia in children with liver disease The mineralized enamel contains a history of the child’s early life. Enamel does not remodel and so disturbances during development remain in the tooth as a permanent record (Fearne et al. 1994). Enamel hypoplasia is a quantitative defect of enamel, visually and morphologically identified as involving the surface of the enamel and associated with a reduced thickness. The defective enamel may have shallow or deep pits or wide or narrow grooves, arranged horizontally in a linear fashion or generally distributed around all or part of the enamel surface (Ainamo & Cutress 1982). Enamel defects can be hereditary or acquired and can be associated with numerous systemic disorders. The presence of enamel defects in permanent teeth has been reported to be between 30% (Suckling et al. 1976) and 49% (Dummer et al. 1986). Enamel hypoplasia is much less common in primary teeth than in their permanent successors (Goodman et al. 1987). It has been attributed to various factors such as fever, local infection (Pindborg 1982), nutritional deficiency (Skinner et al. 1994), prolonged hypocalcaemia (Ranggard et al. 1995) and steroid therapy (Bublitz et al. 1981). Trauma to the mineralizing primary teeth caused

315

by pressure of the laryngoscope on the alveolar ridge during intubation has also been suggested as an aetiological factor (Noren et al. 1993). Enamel hypoplastic defects may be more prevalent in children with liver disease. Seow et al. (1991) found enamel hypoplasia in each of the nine children in their study, and reported that these defects ranged from minor breaks in the enamel to large areas where the enamel was missing altogether. However, in a more recent study, Hosey et al. (1995) found hypoplastic defects in only six of their 55 paediatric liver graft recipients, despite the fact that many of the children lived in a fluoridated area, but this could be attributable to the high proportion of children with a primary dentition in the sample. These hypoplastic primary teeth are more susceptible to caries, necessitating stringent preventive therapy. Dental treatment of hypoplastic teeth Hypoplastic first permanent molars are more susceptible to caries and so the dental management is focused on caries prevention through the limitation of sugar frequency, motivation towards good oral hygiene and the use of topical fluorides and fissure sealants (British Society of Paediatric Dentistry 1993, 1996). Even though these teeth are sometimes extracted as part of an elective orthodontic treatment plan (Mackie et al. 1989), this is not always the treatment of choice and many have to be restored so that masticatory function and pleasing aesthetics are maintained. Unaesthetic hypoplastic permanent incisor teeth can be restored using the same adhesive techniques as previously described.

Guidelines for the dental management of children with liver disease The following are suggested guidelines for the dental management of children with liver disease. 1 Children with liver disease are at risk of dental caries. They need early referral to a specialist paediatric dental service for co-ordination of their preventive therapy. 2 Preventive management will include dietary control, fluoride supplements, fissure sealants and oral hygiene instruction. 3 Parents need active encouragement to ensure that their child receives lifelong dental care. Parents can become so overwhelmed by the medical treatment that they simply forget that continued dental care is vital to the health of the child. Early involvement of the dental team helps to overcome this problem and enables parents and children to benefit fully from preventive care and acclimatization therapy. 4 Invasive dental treatment such as extractions needs to be carried out in consultation with a physician to ensure that the appropriate medical precautions are taken, e.g.

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Section 8: The Liver and other Organs

antihaemolytic agents, broad-spectrum antibiotics. If in association with another invasive procedure, such as liver biopsy, intravenous antibiotics (amoxycillin, metromidozole and cefotaxime) should be given for 24–48 h (Table 17.2). 5 Children who require treatment under general anaesthesia need to be treated in a hospital environment where there are medical facilities and trained medical staff available. Where possible, medical and dental therapies should be combined under the same general anaesthetic, e.g. extractions and liver biopsy. 6 High-speed suction during operative dental procedures should be used to guard against ingestion of blood. 7 The dose of amide local anaesthetic solutions (lignocaine) should be reduced. 8 Where nutritional support is required, it is helpful if the dietician and physician can, where possible, limit the frequency of the dietary supplements to mealtimes and prescribe sugar-free medications. Since this is rarely possible, it is vital that these children are referred early to a paediatric dentist so that rigorous preventive therapy can be provided. 9 Parents should be made aware of the likelihood of the occurrence of intrinsic green discoloration and enamel hypoplasia, but reassured that there are techniques available that can alleviate compromised dental aesthetics.

Care of transplant recipients Delayed eruption in paediatric liver transplantation Delayed eruption of the primary dentition has been reported in 29–40% of paediatric liver graft recipients (Seow et al. 1991; Hosey et al. 1995). The prevalence has been found to be as high as 48% in malnourished children (Hosey et al. 1997). Plate 66 (see Atlas: p. 463) shows delayed emergence of upper primary incisors in a 22month-old liver graft recipient. There is little variation in primary tooth eruption times between different populations or between sexes (Roche et al. 1964; Lavelle 1979; Magnusson 1982; Hitchcock et al. 1984; Ountstead et al. 1987; Ramirez et al. 1994). Delayed eruption of the primary dentition is found in children with chromosomal abnormalities, such as Down’s syndrome, and in hypothyroidism and hypopituitarism, but there are also local causes such as ectopic crypt position, supernumerary teeth and lack of space (Welbury 1997). Tooth eruption ultimately depends upon the imbalance of forces acting upon the tooth and the forces resisting its movement (Kardos 1996). In this way, the resilience, texture or thickness of the overlying oral mucosa may counteract the forces of eruption (Di Biase 1971) and impede the emergence of the tooth. The timing of primary tooth emergence is related to general somatic growth, nutritional status, prematurity and birth weight (Infante &

Owen 1973; Fadavi et al. 1992; Reilly et al. 1992). Moreover, studies of severely malnourished children in Peru showed that these children not only suffer from delayed eruption but are also more susceptible to dental caries (Alvarez et al. 1990, 1993). Although children with delayed eruption of the primary dentition ‘catch up’ on the population norms after the second year of life, once the medical difficulties have been resolved (Delgado et al. 1975; Loevy et al. 1989; Fadavi et al. 1992), malnourished children post-liver transplantation still fail to ‘catch up’ on their dental eruption despite nutritional support. Corticosteroid therapy and delayed eruption Corticosteroid therapy is known to slow the rate of statural growth and skeletal maturation in children (Blodgett et al. 1956) and to cause delayed eruption of the permanent dentition (Luyk et al. 1985). There have been no direct reports of delayed eruption in the primary dentition attributable to steroid therapy, but it is possible that this is due to the hitherto small number of infant transplant recipients. Cyclosporin and delayed eruption of the primary dentition Increased thickening of the overlying oral mucosa can cause delayed eruption of the primary dentition (Galili et al. 1974). Cyclosporin causes gingival overgrowth and has also been reported to delay eruption of both primary (Reich et al. 1981; Church & Brandt 1984) and permanent teeth (Appleton & Leach 1991), in addition to malnutrition, i.e. cyclosporin might have been the impediment to ‘catch-up’ in primary tooth eruption (Hosey 1997). Management of delayed eruption Palliative treatment such as the use of teething rings, hard and fibrous foods on which to gnaw, teething gels and systemic analgesia are recommended to the parents of children with delayed primary tooth eruption. Forewarning parents, especially of children who have been severely malnourished, of the likelihood of delayed eruption also helps to allay parental anxiety. The correction of the underlying medical condition, e.g. discontinuation of corticosteroid medication and nutritional support, is often sufficient to facilitate eruption of previously delayed teeth. Surgical intervention may be necessary in some cases, but fortunately most of the delayed primary teeth appear to erupt eventually. Indeed, the adoption of a ‘wait and see’ approach might avoid unnecessary and traumatic surgical therapy. Cyclosporin-induced gingival overgrowth in transplant recipients The supporting tissues of the teeth are comprised of the marginal and attached gingiva, the periodontal ligament, cementum covering the dentine on the root, and the alveolar bone.

Chapter 17: Dental Care Periodontal diseases are a group of acute and chronic infections that affect these tissues. Such conditions often begin during childhood as inflammation of the gum margin, with redness, swelling and bleeding on brushing. Chronic gingivitis increases steadily between the ages of 5 and 9 years and is closely associated with the amount of plaque, debris and calculus (O’Brian 1993). The severity of the gingivitis is increased when oral hygiene is impaired but it can be reversed with effective plaque control. Gingival overgrowth deepens the pocket between the gingival tissues and the teeth and therefore increases plaque retention. The overgrowth of gingival tissue caused by cyclosporin often has marked inflammatory changes and consequently bleeds readily. Thus liver graft recipients are predisposed to diseases of the periodontal tissues. Gingival overgrowth is the only known oral side-effect of cyclosporin therapy and was first reported in the early 1980s (Calne 1979; Starzl et al. 1989a,b; Starzl et al. 1981; Seymour 1991; Seymour & Jacobs 1992). The reported prevalence of cyclosporininduced gingival overgrowth in transplant recipients is between 8% and 100% (Ross et al. 1989; Seymour & Jacobs 1992; Thomason et al. 1993; Somacarrera et al. 1994; Hosey et al. 1995). This variation in the prevalence of gingival overgrowth could be at-tributed to differences in individual sensitivity, either between different HLA-B37 phenotypes or between different fibroblast populations (Hassell & Stanek 1983; Daly 1992; Thomason et al. 1996). Donor–host HLA mismatching may be an important factor (Seymour et al. 1996; Thomason et al. 1998; Thomas et al. 2000; Das et al. 2001; Wright et al. 2001) (Table 17.1). It is not related to coincident cytomegalovirus infection (Hosey et al. 2000).

317

Pathogenesis of gingival overgrowth Cyclosporin-induced gingival overgrowth is firm and pink, with focal lobulations and a stippled surface consisting primarily of a highly vascularized connective tissue with an overlying irregular, multilayered, parakeratinized epithelium of variable thickness. The predominant feature is a proliferation of collagen fibres in the corium which are lightly distributed in a foamy basophilic ground substance. There is a marked plasma cell, macrophage and T-cell infiltrate, and modification of the appearance of gingival fibroblasts (Lambertenghi et al. 1986; Yamasaki et al. 1987; McGaw & Porter 1988; Seymour & Jacobs 1992; Mariani et al. 1993). Gingival overgrowth may be caused by cyclosporin creating an imbalance between tissue formation and degradation, thereby inducing connective tissue accumulation or inhibition of matrix breakdown and associated with various other mediators of inflammation, growth and soft tissue modelling. Although the relationships between both cyclosporin dose and serum trough level and gingival overgrowth have been extensively investigated, the results are controversial. Animal (Fu et al. 1995) and in vitro (Coley et al. 1986) studies have confirmed a relationship, but although some clinical studies have supported these findings (Seymour et al. 1987; Somacarrera et al. 1994), others have not (Daley et al. 1986; Seymour & Smith 1991; Pernu et al. 1992; Thomason et al. 1993; Hosey et al. 1995; Lowry et al. 1995). It has been suggested that there is a ‘threshold dose’ below which the biological effect of the drug or one of its metabolites on the gingival tissues is dispelled (Daly 1992; Seymour & Jacobs 1992). The Neoral preparation of cyclosporin improves

Table 17.1 The prevalence of gingival overgrowth in previous studies of liver graft recipients. Mean age in months (range)

Medical diagnosis

Prevalence of gingival overgrowth (%)

Authors

Date

Number of subjects

Svirsky Ross et al.

1989 1989

1 21

37 100 (24–192)

OLT OLT

100 Not reported

Seow et al.

1991

7

39 (1–34)

OLT

86

Funakoshi et al.

1992

5

53

OLT

100

Zaia et al. Hosey et al.

1993 1995

1 55

84 56 (8–194)

OLT OLT

100 51

Other comments

Increased plaque index in subjects but no correlation between trough cyclosporin, therapy duration or comitant nifedipine medication Gingival overgrowth worsened with therapy duration No relation between gingival overgrowth and dose or therapy duration No relation between trough cyclosporin level and the severity of gingival overgrowth or between concomitant nifedipine therapy and presence of gingival overgrowth. Significant inverse relation between cyclosporin duration and overgrowth severity

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bioavailability of cyclosporin following liver grafting, but the increased exposure to cyclosporin might increase drug-related adverse effects (Trull et al. 1993, 1994; Bennett et al. 1996; Dunn et al. 1996; Grant et al. 1996). The risk of cyclosporin-induced gingival overgrowth is greatest in adolescents (Daley et al. 1986; Hosey 1997), which may be due to the added effect of growth hormone on the fibroblastic response, or the effect of oestrogen and progesterone on gingival tissues or periodontal vasculature (Seymour & Heasman 1992). The effect of the duration of cyclosporin therapy on gingival overgrowth in humans has not been established (Fu et al. 1995), although in young children this might be the most critical factor (Karpinia et al. 1996). There is resolution of the gingival response once the drug has been discontinued (Daly 1992). Concomitant nifedipine medication and gingival overgrowth Not only does nifedipine cause gingival overgrowth (Singer & Zebrowski 1988; Salo et al. 1990), but it also acts synergistically with cyclosporin on the gingival tissues (McGaw et al. 1987; Slavin & Taylor 1987; Thomason et al. 1993). This may be due to similarities in the mechanism of action of both drugs at the cellular level (Nishikawa et al. 1991), although recent studies have failed to demonstrate an association between nifedipine medication and either the presence or the severity of gingival overgrowth (Hosey et al. 1995; Lowry et al. 1995). Plates 67a,b (Atlas: p. 463) show a child with severe gingival overgrowth and poor oral hygiene, treated with both cyclosporin and nifedipine. The influence of plaque on cyclosporin-induced gingival overgrowth The severity of cyclosporin-induced gingival overgrowth is related to gingival irritants, such as dental plaque, calculus, imperfections in dental restorations, orthodontic appliances and the effects of mouth breathing (Daley et al. 1986; Bartold 1987; McGaw et al. 1987; Wilson et al. 1998). Transplant recipients medicated with cyclosporin have a significantly increased level of plaque, which might explain why gingival overgrowth is more prominent in areas where dental plaque has accumulated (Daley et al. 1986; Bartold 1987; Ross et al. 1989; Pernu et al. 1992). There is a correlation between poor oral hygiene and the presence of gingival overgrowth. The mild chronic irritation caused by dental plaque may promote the hyperplastic effect of cyclosporin on the gingiva and act as a reservoir for the drug (Daley et al. 1986; McGaw et al. 1987). However, not all studies have demonstrated that dental plaque is a significant aetiological factor (Seymour et al. 1987; Margiotta et al. 1996). Indeed, Tyldesley and Rotter (1984) reported that even frequent oral hygiene procedures were insufficient to eliminate gingival over-

growth. Nevertheless, Ross et al. (1989), in a controlled study, found that levels of both plaque and gingivitis were increased in liver graft recipients. Management of gingival overgrowth Children with liver grafts need to be taught to acquire and then retain excellent oral hygiene skills. The health of their periodontal tissues needs to be monitored throughout their lives and they need constant encouragement to keep up the best possible standard of oral cleanliness. Poor oral hygiene and periodontal disease predispose to transient bacteraemia, therefore excellent oral hygiene, possibly augmented with a chlorhexidine oral rinse, is beneficial. For a few, surgical excision of the overgrown tissue (gingivectomy) or gingival recontouring (gingivoplasty) may be required to improve aesthetics and to reduce plaque retention by allowing adequate access for effective plaque removal. Alternatively, a change of immunosuppression to tacrolimus or mycophenolate mofetil, neither of which cause gingival overgrowth, may be indicated (Chapter 20). Prophylactic antibiotic therapy Bacteraemia of dental origin follows even the simplest dental procedure, but especially all minor oral surgical procedures in children, with multiple tooth extractions causing the greatest proportion of positive blood cultures. The antibiotics that are commonly used orally and parenterally are likely to be effective on at least 85% of occasions (Roberts et al. 1998; Al Karaawi et al. 2001). Oral amoxycillin (50 mg/kg, given 1 h preoperatively) will almost always eliminate odontogenic bacteria (Roberts et al. 1987). For invasive procedures, such as subgingival scaling, dental extractions and surgery that involve the gingival tissues, antibiotic prophylaxis is sometimes recommended (Sheehy et al. 1999). The American Academy of Paediatric Dentistry (2000) recommends prophylactic antibiotic therapy for organ transplant and immunocompromised patients since they may be at risk from bacteraemia produced by invasive dental procedures. They advise a course of amoxicillin 50 mg/kg (maximum 2 g) orally, 1 h before the dental procedure. Clindamycin 20 mg/kg (maximum 600 mg) orally, 1 h before the dental procedure is recommended for children who are allergic to penicillin (American Academy of Paediatric Dentistry 2000). Guidelines for the dental management of paediatric liver graft recipients The dental management of paediatric recipients of liver transplants should be based on the following guidelines.

Chapter 17: Dental Care Before liver transplantation 1 Intensive oral hygiene therapy, preventive care and careful parental counselling are of paramount importance if good oral health is to be maintained. This is best achieved when liver transplantation is first contemplated, since dental care is then seen by the family as being an integral part of the child’s treatment. 2 It is important that each child who is likely to be scheduled for liver grafting has a full dental examination so that potential sources of infection can be treated and preventive therapy commenced. Where possible, active treatment should be completed before transplant; this includes the removal of any teeth that are of dubious prognosis, since these may become a nidus of infection in the immunocompromised child. 3 Children who already attended their local general dental practice regularly should be advised to continue in order to ‘normalize’ their lives as much as possible. Nevertheless, oral care still needs to be co-ordinated by a specialist paediatric dentist who is not only skilled in the management of medically compromised children but also capable of co-ordinating the various medical and dental specialties into a framework for the better oral care of the child (Consultants in Paediatric Dentistry 1997). After liver transplantation 1 Following liver transplantation patients require routine dental check-ups, frequent topical fluoride application and reinforcement of preventive advice. Tooth brushing can be complemented with chlorhexidine oral rinse or gel, and fluoride supplementation should be considered, especially if the child lives in a non-fluoridated area, to reduce the risk of tooth decay. 2 Parents should be made aware that delayed eruption of the primary dentition sometimes occurs and palliative treatment, for example the use of teething rings, should be recommended. The development of the dentition should be monitored, but parents can be reassured that these teeth generally do erupt eventually and often without recourse to surgical intervention. 3 Gingival overgrowth in liver graft recipients is most common and severe in adolescents. Good oral hygiene is vital to reduce the risk of periodontal disease. Although gingivectomy and gingivoplasty are rarely required in younger children, these procedures may be necessary in adolescents. 4 Antibiotic prophylaxis should be considered for invasive dental procedures, since such patients may be at risk from bacteraemia produced by invasive dental therapy. Oral amoxycillin (50 mg/kg in a single dose 1 h prior to the procedure) will eliminate most odontogenic bacteria.

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Clindamycin is recommended for children who are allergic to penicillin. 5 Regular surveillance of the head and neck region should be performed.

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Ross, P.J., Nazif, M., Zullo, T., Zitelli, B. & Guevara, P. (1989) Effects of cyclosporin A on gingival status following liver transplantation. Journal of Dentistry for Children 56, 56–59. Salo, T., Oikarinen, K.S. & Oikarinen, A.I. (1990) Effect of phenytoin and nifedipine on collagen gene expression in human gingival fibroblasts. Journal of Oral Pathology and Medicine 19, 404–407. Scottish Intercollegiate Guideline Network (SIGN), 47. (2000) Prevention of Dental Caries in Children of High Caries Risk. SIGN Executive, Royal College of Physicians, Edinburgh. Seow, W.K., Shepherd, R.W. & Ong, T.H. (1991) Oral changes associated with end-stage liver disease and liver transplantation: implications for dental management. Journal of Dentistry for Children 58, 474–480. Seymour, R.A. (1991) Calcium channel blockers and gingival overgrowth. British Dental Journal 17, 376–379. Seymour, R.A. & Heasman, P.A., eds (1992) Drugs, Diseases and the Peridontium. Oxford University Press, Oxford. Seymour, R.A. & Jacobs, D.J. (1992) Cyclosporin and the gingival tissues. Journal of Clinical Periodontology 19, 1–11. Seymour, R.A. & Smith, D.G. (1991) The effect of a plaque control programme on the incidence and severity of cyclosporin-induced gingival changes. Journal of Clinical Periodontology 18, 107–110. Seymour, R.A., Smith, D.G. & Rogers, S.R. (1987) The comparative effects of azathioprine and cyclosporine on some gingival health parameters of renal transplant patients. Journal of Clinical Periodontology 14, 610–613. Seymour, R.A., Thomason, J.M. & Ellis, J.S. (1996) The pathogenesis of drug-induced gingival overgrowth. Journal of Clinical Periodontology 23, 165–175. Shapiro, B.M., Gallagher, F.E. & Needleman, H.L. (1975) Dental management of the patient with biliary atresia. Oral Surgery Oral Medicine Oral Pathology 40, 742–747. Shaw, L. (1997) Prevention of dental caries in children. International Journal of Paediatric Dentistry 7, 267–272. Sheehy, E.C., Heaton, N., Smith, P. & Roberts, G.J. (1999) Dental management of children undergoing liver transplantation. Pediatric Dentistry 21, 272–280. Sheehy, E.C., Roberts, G.J., Beighton, D. & O’Brien, G. (2000) Oral health in children undergoing liver transplantation. International Journal of Paediatric Dentistry 10, 109–119. Singer, D.L. & Zebrowski, E.J. (1988) Nifedipine: effects in vitro on gingival fibroblasts. Journal of Dental Research 67, 332. Skinner, M.F., Hadaway, W. & Dickie, J. (1994) Effects of ethnicity and birth month on localised enamel hypoplasia of the primary canine. Journal of Dentistry for Children 61, 109–113. Slavin, J. & Taylor, J. (1987) Cyclosporin, nifedipine and gingival hyperplasia. Lancet ii, 739. Somacarrera, M.L., Hernandez, G., Acero, J. & Moskow, B.S. (1994) Factors related to the incidence and severity of cyclosporin induced gingival overgrowth in transplant patients. A longitudinal study. Journal of Periodontology 65, 671–675. Starzl, T.E., Demetris, A.J. & Vanthiel, D. (1989a) Liver transplantation I. New England Journal of Medicine 321, 1014–1022. Starzl, T.E., Demetris, A.J. & Vanthiel, D. (1989b) Liver transplantation II. New England Journal of Medicine 321, 1092–1099.

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Chapter 17: Dental Care Yamasaki, A., Rose, G.G., Pinero, G.J. & Mahan, C.J. (1987) Ultrastructure of fibroblasts in cyclosporin A-induced gingival hyperplasia. Journal of Oral Pathology 16, 129–134.

Zaia, A.A., Graner, E., De Almeida, O.P. & Scully, C. (1993) Oral changes associated with biliary atresia and liver transplantation. Journal of Pediatric Dentistry 18, 39–42.

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Chapter 18: Surgical Disorders of the Liver and Bile Ducts and Portal Hypertension MARK D. STRINGER AND EDWARD R. HOWARD

The bile ducts, 324 Biliary atresia, 324 Choledochal cysts, 332 Spontaneous perforation of the bile duct, 335 Inspissated bile syndrome, 336 Benign bile duct strictures, 336 Bile duct tumours, 336

Cholelithiasis, 337 Acalculous cholecystitis, 340 Congenital vascular abnormalities, 340 Congenital portocaval shunts, 341 Hepatoportal arteriovenous communications, 341 Portal hypertension, 341 Definition and pathophysiology, 342

The bile ducts Biliary atresia, choledochal cysts, spontaneous perforation of the bile duct and the inspissated bile syndrome are the most common ‘surgical’ causes of jaundice in infants. Biliary atresia is the most common abnormality presenting in the neonatal period. Early diagnosis is essential as delay in treatment may result in irreversible liver damage. Biliary atresia Congenital atresia of the bile ducts is a unique pathological entity, which has no analogy with any disease process in the bile ducts of older patients. It is characterized as ‘a destructive inflammatory process of unknown aetiology which affects a variable length of the biliary tract’, and untreated infants die of liver failure within a few months of life. The first clear report of the natural history of the condition was published by the Edinburgh paediatrician John Thomson (1891), but it was not until 1928 that Ladd described surgical correction of a small number of cases of the so-called ‘correctable’ type of atresia, in which the atretic segment is limited to the common bile duct whilst the proximal biliary tree is patent. Ladd performed anastomotic procedures in six out of the 11 cases he explored (Ladd 1935). Amajority of affected infants, however, have a surgically ‘uncorrectable’ type of biliary atresia in which the atresia extends into the proximal bile ducts. All of these children died within a year or two of their disease until a novel method of treatment was introduced from Japan in the late 1950s (Kasai & Suzuki 1959). Kasai reported the identification of microscopic biliary channels within the proximal atretic tissue in the porta hepatis and showed that exposure of these channels, by radical resec-

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Classification, aetiology and clinical features, 342 Investigation, 344 Management, 345 Liver trauma, 350 Presentation and investigation, 351 Management, 352

tion of the bilary tract, could result in effective drainage of bile. Although this work was initially greeted with a considerable degree of scepticism outside of Japan, successful results were eventually achieved in centres worldwide and the ‘Kasai portoenterostomy’ is now accepted as a standard operation for the condition. Incidence Biliary atresia is a rare disease with a frequency of approximately 1 per 16 000 live births. The incidence is similar in many countries, as shown by recent studies from France and the UK (Chardot et al. 1999; McKiernan et al. 2000). There is a slight female preponderance in most large series (Davenport et al. 1997), but only rarely is there any significant family history of liver or biliary disease. Cunningham and Sybert (1988) collected 11 instances of familial biliary atresia from the literature and added two further families, each with two siblings affected. Aetiology The true aetiology of biliary atresia is unknown, although embryological, infective, and anatomical hypotheses have been suggested. 1 Embryological and genetic abnormality. Approximately 10% of children with biliary atresia have associated extrahepatic abnormalities that include polysplenia, situs inversus, interrupted inferior vena cava and cardiac defects. These associations, which have been reported in 7.5% of 308 cases of atresia, have been termed the ‘biliary atresia splenic malformation (BASM) syndrome’ (Davenport et al. 1993) (Table 18.1). The critical period of early development for all the affected components of this

Chapter 18: Surgical Disorders

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Table 18.1 Associated abnormalities of the biliary atresia splenic malformation (BASM) syndrome (Davenport et al. 1993). Anomaly

Frequency

Preduodenal portal vein Polysplenia Situs inversus Malrotation Interruption of inferior vena cava Cardiac anomalies Intrapulmonary shunting Double spleen/splenunculi Asplenia Pancreatic anomalies Immotile cilia syndrome

75% 90% 50% 50% 30% 30% 5% 2–5% 2–5% 2–5% 1%

syndrome (biliary, inferior vena cava, portal vein, splenic) is from 25 to 40 days of gestation, and hence an embryopathic ‘insult’ at this early stage of development would help to explain the coincident anomalies. Davenport et al. (1993) also described a possible relationship between BASM and antenatal events in the mother, the most common of which was maternal diabetes, a condition that is known to cause fetal malformations such as transposition of the great vessels and hypoplastic femur. The embryological development of the biliary tree and liver is complex. There are histological and immunohistochemical similarities between the developing hepatobiliary system between 11 and 13 weeks’ gestation and the appearance of established biliary atresia. Bile is produced by hepatocytes from 12 weeks’ gestation and coincident with this there are remodelling, selection and deletion of fetal bile ducts originating from the ductal plate membrane to form the definitive pattern of proximal intrahepatic bile ducts. Tan et al. (1994b) have suggested that biliary atresia without syndromic features may represent an arrested development of these biliary radicals. A small number of cases of biliary atresia have been detected antenatally on maternal ultrasound scans. Three cases with cystic biliary atresia had gestational ultrasound anomalies from 17 weeks (Redkar et al. 1998) and Casaccia et al. (2002) identified two cases in five fetal ultrasound scans which had shown evidence of ‘subhepatic cysts’. Gamma-glutamyl transpeptidase (GGT) is an enzyme of fetal liver origin, which may be found in amniotic fluid from the 2nd trimester onwards and relates to in utero bile production and fetal defecation (MacGillivray & Adzick 1994). Muller et al. (1988) reported a large study of amniotic fluid sampling and showed that cases born with biliary atresia had minimal levels of amniotic fluid GGT dating back to 18 weeks’ gestation. There are reports of isolated cases of biliary atresia associated with trisomy 17, 18, and 21 (Danks 1965; Alpert et al. 1969; Strauss et al. 1972). The frequency of twinning in biliary atresia is not greater than that ex-

Comment

Usually with normal position of heart Venous drainage by azygos veins May be mode of presentation Increasingly apparent in long-term survivors

e.g. annular pancreas Bronchiectasis, sinusitis

pected in a normal population, with most being discordant for the disease (Schweizer & Kerremans 1988; Silveira et al. 1991). 2 Infective factors Isolated cases of biliary atresia have followed infection with rubella (Strauss 1968) and the Epstein–Barr virus (Weaver et al. 1984), but much of the interest in infection has focused on experimental work with the hepatotropic RNA viruses, reovirus and rotavirus. Phillips et al. (1969) induced liver disease and hyperbilirubinaemia in 21-day-old weanling mice after inoculation with reo-3 virus and similar experiments have reproduced some of the intrahepatic histological features of biliary atresia — although not usually the typical extrahepatic appearance and sequelae (Parashar et al. 1992; Riepenhoff-Talty et al. 1993). The animals themselves, although jaundiced, do not develop chronic liver disease since the biliary tract regenerates almost completely. Although some clinical studies have suggested that there is a high incidence of positive serology against reovirus type III in infants with biliary atresia (Morecki et al. 1982), others (Dussaix et al. 1982; Brown et al. 1988) have disputed this. Viral-like particles have only been identified from a single case of biliary atresia (Morecki et al. 1984), and further studies using sophisticated techniques such as polymerase chain reaction (PCR) have proved negative (Iwami et al. 1991; Parashar et al. 1992). Seasonal variation and winter predilection for biliary atresia has been identified in some cohort studies (Strickland & Shannon 1982; Yoon et al. 1997) and provides some evidence for a possible viral aetiology. However, larger, less well-controlled studies have failed to confirm this observation (Mowat et al. 1976; Houwen et al. 1988). 3 Anatomical factors A common pancreatico-biliary channel has been demonstrated in 60% of cases of biliary atresia (Chiba et al. 1990) and in over 80% of children with congenital choledochal cysts (Miyano et al. 1979).

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Chiba et al. (1990) compared endoscopic retrograde cholangiography (ERCP) findings in 28 infants with biliary atresia with seven infants with neonatal hepatitis syndrome. The mean length of the pancreatico-bilary channels in the former was 5.1 mm compared with 1.3 mm in the latter, suggesting a possible role for the malformation in aetiology. 4 Animal observations Harper et al. (1990) described the occurrence of biliary atresia in lambs and calves in New South Wales, Australia. A common factor in this, and in previous outbreaks of the disease, was the restriction of grazing to particular areas of land when the maternal animals were in early stages of pregnancy. The authors suggested that perhaps a plant toxin might be involved in the aetiology of the bilary atresia, although they failed to identify a specific substance during their investigation. Pathogenesis Biliary atresia is a cholangiopathic panductular disease, which, in most infants, is present at birth. Progression of the condition results in cholestasis, hepatic fibrosis and cirrhosis. Bile duct plugging, ductular proliferation, portal oedema, a small-cell infiltrate and variable giant-cell formation characterize the histological appearances of the liver (Haas 1978). A pronounced inflammatory reaction, particularly at the porta hepatis, with a dense smallcell infiltrate is not uncommon (Dillon et al. 1994). This feature seems to be related to the child’s age, as older infants may show a diminution in the inflammatory change (Davenport & Howard 1996). Dillon et al. (1994) detected an aberrant expression of cellular mediators of inflamma-

Type 1

Type 3

tion, such as intercellular adhesion molecules (ICAM) and vascular adhesion molecules (VCAM), in cases of biliary atresia but not in other cases of neonatal cholestasis. On the other hand, Davenport et al. (2001), in a study of the inflammatory infiltrate and its relationship with clinical outcome, did not find that the immunohistochemical patterns of immune-mediated inflammation in biliary atresia differed significantly from those observed in infants with non-biliary atresia cholestatic jaundice. They did note that an improved prognosis in biliary atresia was associated with a reduction in the expression of the macrophage marker CD68 in the liver and biliary remnants, and a reduction in ICAM expression on infiltrating cells within bile duct tissue. The inflammatory process affects the intrahepatic ducts in all cases of biliary atresia and intrahepatic ducts do not show dilatation on ultrasonography or cholangiography. Radiologically they have the appearance of a ‘cloud’ radiating from the porta hepatis (see Plate 68, Atlas: p. 463). This appearance does not change in the long term, even in those who have had a good response to portoenterostomy and satisfactory bile drainage. The lumen of the extrahepatic duct is obliterated by inflammatory tissue at a variable level and this macroscopic appearance forms the basis for the commonest pathological classification. There are three main types of obliteration (Fig. 18.1), of which type 3 (obliteration at the level of the porta hepatis) is the commonest, occurring in 85–90% of cases. Obstruction at the level of the common hepatic duct (type 2) or common bile duct (type 1) is much less common but carries a better prognosis. Occasionally cysts can occur proximal or distal to the obliterated duct. How-ever, the wall in such cases is invariably thickened

Type 2

Fig. 18.1 Classification of biliary atresia. (After Japanese Association of Paediatric Surgeons.) Type 1: atresia affecting common bile duct, often associated with proximal biliary cyst. Type 2: atresia affecting common hepatic duct. Type 3: obliteration and atresia affecting whole of extrahepatic biliary tree.

Chapter 18: Surgical Disorders and communicates poorly with intrahepatic ducts, and this appearance should not be confused with true choledochal cystic dilatation. Role of screening There has been interest in a screening programme for biliary atresia because of the delay that may occur before these infants reach specialist centres (Mieli-Vergani et al. 1989). Using tandem mass spectrometry to measure conjugated bile acids in dried blood spots obtained from newborn infants has proved disappointing (Mushtaq et al. 1999). Although screening for conjugated bilirubin in liquid blood was both sensitive and specific for the diagnosis of biliary atresia (Powell et al. 2003), it has not proved possible to transfer this technique to dry blood spots. There is as yet no satisfactory screening test which will provide the necessary sensitivity or specificity in the general population (Logan & Stanton 1993) and it is imperative that paediatricians investigate and exclude biliary atresia in all infants who have persistent conjugated jaundice after 14 days of age (Hussein et al. 1991; Mowat et al. 1995). Clinical features and diagnosis (Chapter 4) Infants with biliary atresia present with • conjugated hyperbilirubinaemia • dark urine • pale, acholic stools. These signs are present from birth, although birth weight and gestation are usually normal. At first the infants feed and thrive appropriately. Lack of fat-soluble vitamin K absorption may eventually result in a coagulopathy, and a number of the infants present with abnormal bleeding, which may be intracranial. On examination, the liver is enlarged and in older infants there may be ascites and splenomegaly. An accurate diagnosis of biliary atresia is established preoperatively in approximately 95% of cases by excluding medical causes of conjugated hyperbilirubinaemia (particularly a1-antitrypsin deficiency) and identifying the characteristic histological appearances of a percutaneous liver biopsy (see Chapter 4). The following investigations may be particularly helpful: • Hepatobiliary ultrasound will exclude other surgical causes of jaundice such as choledochal cyst and obstructed extrahepatic ducts due to inspissated bile. An absent gall bladder or one with an irregular outline is suggestive of biliary atresia (Farrant et al. 2000). In some cases a well-defined triangular area of high reflectivity corresponding to fibrotic ductal remnants at the porta hepatis may be seen on ultrasound (the ‘triangular cord’ sign) (Park et al. 1999). • Radionuclide hepatobiliary imaging using iminodi-

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acetic acid (IDA) derivatives fails to show bile excretion into the bowel within 24 h in cases of biliary atresia and discriminates between this condition and most causes of the neonatal hepatitis syndrome. • Magnetic resonance cholangiography (MRC) may be used to visualize the bile ducts and gall bladder of nonbiliary atresia infants with cholestatic jaundice and therefore exclude biliary atresia. Han et al. (2002) have reported a diagnostic accuracy of 98%, sensitivity of 100% and specificity of 96% in the diagnosis of 23 cases of biliary atresia. • If the diagnosis remains unclear, even after liver biopsy, then consideration should be given to ERCP. This is technically possible in about 90% of infants and biliary atresia can be confidently excluded if the whole of the biliary tree is imaged, although false-positive results may follow from technical failures in cannulation. Iinuma et al. (2000) were successful in demonstrating normal bile ducts in 43 out of 50 ERCPs and six of the seven ‘failed’ cases were proven to be cases of bilary atresia at subsequent laparotomy. • An alternative to ERCP is provided by a formal laparotomy and operative cholangiography • The role of endoscopic ultrasound in the diagnosis of biliary atresia has not yet been evaluated (Chapter 2). Surgery (Fig. 18.2) The biliary tree is approached via a right-sided transverse incision extended across the midline (Howard 1995). If the diagnosis has not been established preoperatively then an operative cholangiogram is obtained via a catheter in the gall bladder. It must be emphasized that only complete visualization of the whole of the biliary tree will exclude biliary atresia at this stage. The hepatic suspensory ligaments are divided and the liver rotated to expose its inferior surface in the incision. This manoeuvre gives maximal exposure of the porta hepatis. The obliterated biliary tract is divided distally and elevated to separate it from the underlying portal vein and adjacent hepatic artery. It is then dissected free and transected high at the level of the porta hepatis. A complete resection of the extrahepatic biliary tree is advisable in all types of biliary atresia except for the uncommon case in which there is a significant remnant of patent bile duct in the porta hepatis. Biliary continuity is restored using a Roux loop, which is anastomosed to the transected tissue in the porta hepatis as a portoenterostomy. In some cases of biliary atresia operative cholangiography may show a patent lower common bile duct in continuity with the gall bladder, the atretic process being restricted to the common hepatic and hepatic ducts. Reconstruction of the biliary tract using the gall bladder (portocholecystostomy) after resection of the remnants of

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(b)

(a)

Fig. 18.2 Three stages in the operation of portoenterostomy for biliary atresia (Kasai operation). (a) The gall bladder and remnants of the bile ducts are mobilized completely into the porta hepatis. (b) All residual bile duct tissue is excised and a Roux loop of jejunum is prepared for anastomosis to the cut surface in the porta hepatis. (c) The Roux loop is anastomosed to the porta hepatis.

the bile ducts has been suggested as an effective method of preventing postoperative cholangitis. Unfortunately, postoperative complications are not uncommon with this technique. Matsuo et al. (2001), for example, performed the operation in five cases. One died of bile leakage, two were converted to standard portoenterostomies because of poor bile drainage, and one developed a bile duct stricture at 19 years of age. Currently, a revision or re-do portoenterostomy is not recommended in the UK as it is associated with only a small chance of success. It also increases the technical difficulty of any subsequent liver transplantation. Infants tolerate portoenterosomy very well and early postoperative complications are unusual.

(c)

Postoperative care and longterm complications after portoenterostomy Intravenous antibiotics are given in the immediate postoperative period, and are replaced by 1 month of oral antibiotic prophylaxis after the return of bowel activity. Choleretics (cholestyramine and phenobarbitone) and vitamins A, D, E, and K are prescribed for at least 1 year. Steroids have been recommended in the belief that they might reduce scar tissue formation, but no controlled trials have been published to confirm or refute their value (Table 18.2). Complications of the portoenterostomy operation include:

Chapter 18: Surgical Disorders

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Table 18.2 Protocol for management of biliary atresia. Preoperative management (commencing 24–48·h before surgery) Medication • neomycin 12.5 mg/kg/dose t.d.s. oral • metronidazole 7.5 mg/kg/dose t.d.s. oral • lactulose 5 ml b.d. oral Blood tests Full blood count, liver function tests, clotting screen, group and cross match Operation Operative cholangiogram if bile in gall bladder Portoenterostomy Postoperative management Pain relief: Epidural for first 36–48 h followed by paracetamol I.v. fluids: Oral feeding with return of bowel activity Steroids (optional 2-week course — value not yet proven) e.g. Day 1, methylprednisolone i.v. 20 mg, decreasing 2.5 mg daily to 15 mg/day, then prednisolone 5 mg daily orally for 1 week Antibiotics: i.v. for 5 days Gentamicin i.v. 2.5 mg/kg/dose t.d.s. (levels needed) Amoxicillin i.v. 25 mg/kg/dose t.d.s. Antibiotic prophylaxis (started on postoperative day 6) Cephalexin 12.5 mg/kg/dose b.d. for 1 month ± Cycles of cephalexin (12.5 mg/kg/dose b.d.), trimethoprim (2 mg/kg o.d.) and amoxil 25 mg/kg/dose t.d.s. (each cycle of 12 weeks). Longer term oral medication Ranitidine 1 mg/kg/dose t.d.s. phenobarbitone 5 mg/kg/dose nocte ursodeoxycholic acid 10 mg/kg/dose b.d. vitamin A 5000 IU o.d. vitamin D 50 ng/kg o.d. (alfacalcidol) vitamin E 50 mg o.d. vitamin K 1–2 mg o.d. Management of postoperative cholangitis Septic screen Liver biopsy for culture I..v. antibiotics Ceftazidime 30 mg/kg t.d.s. for 10 days Amoxicillin 20 mg/kg t.d.s. for 10 days

• ascending bacterial cholangitis • cirrhosis and portal hypertension • metabolic and nutritional consequences of cholestasis • intrahepatic cyst formation • hepatopulmonary syndrome and pulmonary hypertension • malignant change in the liver (rare). Ascending bacterial cholangitis This serious complication occurs most commonly in the first year following surgery, perhaps because bile flow may not become maximal until 1 year after surgery. Episodes of infection have been recorded in approximately 40–50% of the infants in most series and occur in those who have achieved at least some degree of bile flow (Ecoffey et al. 1987). It is characterized by worsening jaundice, fever and acholic stools.

The diagnosis is confirmed by blood culture or by percutaneous liver biopsy. A wide range of organisms may be identified, including Escherichia coli, Proteus and Klebsiella species but it is important to treat suspected cases early and empirically with broad-spectrum antibiotics such as ceftazidime, amoxicillin, and gentamicin or piperacillin, before the detailed results of investigation are available. A number of operative modifications have been made to Kasai’s original portoenterostomy operation to try to reduce the incidence of cholangitis. These have included diversion stomas and the formation of antireflux valves in the Roux loop (Saeki et al. 1991). However, despite the theoretical benefits of such modifications, in practice they confer little additional benefit and equally good results are obtained from the use of a long Roux loop (Ohi 1991).

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Cholangitis may occur some years after a portoenterostomy procedure in a child with otherwise good liver function. It is important in such a case to exclude a partial obstruction of the Roux loop, perhaps secondary to an adhesion, as this can be relieved by surgery. Percutaneous transhepatic cholangiography (PTC) and radionuclide hepatic imaging are essential diagnostic measures to identify the site of the obstruction in these cases. Prolonged antibiotic prophylaxis is necessary, particularly if there is no obstruction of the Roux loop. If cholangitis recurs frequently despite these measures with deteriorating liver function, then liver transplantation should be considered. Portal hypertension Hepatic fibrosis is always present at the time of portoenterostomy and is reflected in an increase in portal venous pressure (Kasai et al. 1981; Ohi et al. 1986). Approximately 60% of children who survive to 2 years will have endoscopic evidence of oesophageal varices, although only about half of these will ever bleed (Kang et al. 1993). The severity of the varices in older children is not related to the original degree of liver fibrosis (Kang et al. 1993) or to the number of episodes of cholangitis (Ecoffey et al. 1987). As the average age at first bleed is about 3 years (Howard et al. 1988), some centres recommend endoscopic assessment of the upper gastrointestinal tract from 2 years of age. Stringer et al. (1989) observed the development of varices in 67% of 61 children 2.5 years or more after portoenterostomy and bleeding had been recorded in 17 (28%). Bleeding was more common in those who were persistently jaundiced and in those who had suffered recurrent attacks of cholangitis. The initial treatment of bleeding varices is supportive, with restoration of blood volume plus correction of coagulopathy and thrombocytopenia. Endoscopic sclerotherapy or variceal banding (Hall et al. 1988; McKiernan et al. 2002), with or without a Sengstaken tube, may be required for the control of severe bleeding. A new innovation increasingly used in adults with bleeding oesophageal varices is the interventional radiological procedure known as transjugular intrahepatic portosystemic shunt (TIPSS). Schweizer et al. (1995) reported the results in seven patients with biliary atresia. Metabolic and nutritional consequences of cholestasis postKasai Persisting cholestasis and diminished bile flow may cause malabsorption of fat and fat-soluble vitamins. This may manifest as vitamin K-dependent coagulopathy. Intestinal absorption of calcium may be impaired and hydroxylation of vitamin D reduced as a consequence of hepatic fibrosis or cirrhosis, and it is not surprising therefore that changes in bone mass and clinical evidence of osteomalacia and rickets may occur. Chongsrisawat et al. (2001) found evidence of osteoporosis and low levels of serum 25-hydroxyvitamin D in 16 out of 20 jaundiced and

three out of 22 non-jaundiced patients with biliary atresia. The role of vitamin E malabsorption in postportoenterostomy children is unclear, although neurological signs such as abnormal eye movements have been reported in cases of long-term vitamin E deficiency associated with cholestatic syndromes. Usually, vitamin deficiencies can be avoided by adequate oral supplementation. In severe cholestasis, parenteral supplements may be necessary. Malabsorption of long-chain triglycerides and fatty acids occurs in cholestatic patients and replacing formula feeds with medium-chain triglyceride-enriched feeds often improves weight gain and steatorrhoea. However, an adequate intake of essential fatty acids must be maintained. Copper and zinc metabolism may be abnormal in children after portoenterostomy (Endo et al. 1991) and high serum copper and low serum zinc levels have been reported in long-term survivors both with and without cholestasis (Suita et al. 1987) (Chapter 14). Intrahepatic cyst formation Biliary cystic change may occur within the livers of longterm survivors and may be associated with recurrent attacks of cholangitis. Tsuchida et al. (1994) classified the morphological appearances of the cysts into: • discrete cysts not communicating with the enterostomy — type A • discrete cysts communicating with the enterostomy — type B • diffuse cystic dilatations of the bile ducts — type C. Bu et al. (2002) reviewed 154 patients who had undergone portoenterostomies between 1992 and 2000 and found that 39 (25.3%) had intrahepatic cystic change. Single cysts were present in 23 cases, and multiple cysts in 16. Jaundice and cholangitis were presenting signs in 13 and 15 cases in the respective groups. Interestingly, the cysts in seven patients decreased in size during courses of prolonged antibiotic treatment. Single large cysts may be drained either percutaneously or via a cystoenterostomy operation, but repeated cholangitis in children with cystic change is an indication for liver transplantation. Hepatopulmonary syndrome and pulmonary hypertension As in other types of chronic liver disease, hypoxia with cyanosis on standing (platypnoea) and exertion, dyspnoea and finger clubbing may be presenting features of diffuse intrapulmonary shunting and vascular dilatation in long-term survivors of portoenterostomy. The mechanism responsible for these abnormalities is not known, although they appear to be more common in children with BASM (Valayer 1996). Routine monitoring of peripheral oxygen saturation is essential to detect this syndrome early. The diagnosis is confirmed using arterial blood gas estimations with and without inspired oxygen. Ventilation/perfusion radionuclide lung scans are used

Chapter 18: Surgical Disorders to quantify the degree of shunting. This severe complication is resistant to conventional therapy and liver transplantation is the only treatment. Pulmonary hypertension can also develop in biliary atresia patients (Soh et al. 1999) and may be caused by vasoactive substances such as endothelin and prostaglandin F2, which are either not metabolized in the liver or are secreted by endothelial cells. Assessments of pulmonary function and pulmonary haemodynamics should be part of the long-term follow-up of these children. Malignant change in the liver Malignant change (both cholangiocarcinoma and hepatocellular carcinoma) in cirrhotic livers of post-portoenterostomy children has been reported (Kulkarni & Beatty 1977; Valayer 1996). Results of portoenterostomy The results of portoenterostomy have improved remarkably since 1974 when median survival times were < 1 year. After 1975 the survival times, aided by earlier diagnosis and improved surgical technique, increased to a median of 18 years, and this has now been achieved in up to 60% of patients (Howard et al. 2001). A number of variables have been studied in an attempt to predict the effectiveness of the portoenterostomy procedure; some have been derived from perioperative data, e.g. age at surgery (Mieli-Vergani et al. 1989), macroscopic appearance of the bile ducts (Davenport et al. 1996) and microscopic analysis of the resected specimen. The surgeon’s experience has also been implicated as an important prognostic factor (McClement et al. 1985; McKiernan et al. 2000). The age at which surgery is carried out is the single most widely quoted prognostic variable, although some observers have shown little relationship in the majority of infants who are < 10 weeks of age (Tagge et al. 1991). However, uncorrected atresia of the bile ducts does result in progressive intrahepatic disease and a clear detrimental effect of age on survival has been demonstrated in infants who are older than 100 days at the time of the portoenterostomy operation (Davenport et al. 1997). In summary, the postoperative volume of bile flow is probably related to the size of bile ductules at the porta hepatis (Suruga et al. 1972; Tan et al. 1994a; Davenport et al. 1996), whilst the long-term quality of survival in those with adequate bile flow is dependent on the severity of secondary liver damage at the time of surgery. Approximately 70–80% of infants will show evidence of bile flow after surgery, which will be adequate to ensure survival to 5 years of age in more than 50% (Mieli-Vergani et al. 1989; Davenport & Howard 1996). Furthermore, series from Japan (Ohi 1991), France (Laurent et al. 1990; Valayer 1996), the USA (Karrer et al. 1996) and the UK (Davenport et al. 1997) suggest that

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about 30–40% of the children may survive to 10 years of age with their native liver intact. Saeki et al. (1987), for example, reported 26 long-term survivors, 14 of whom were over 15 years of age, although abnormal liver function tests were detected in approximately 40% of the group. Quality of life Ohi (2002) summarized the clinical status of 80 patients who survived for more than 10 years with their native liver. One or more complications were recorded in 23 (29%) patients and included: • increased fatigue 23 (29%) • pruritus 10 (12.5%) • abdominal pain 4 (5%) • hepatopulmonary syndrome 3 (4%) • jaundice 3 (4%) • recurrent pyrexia 2 (2.5%) An assessment of the occupations of 82 cases showed that 44 were at school or college, 34 in work and four described themselves as housewives. Six had married. Four women had children. Valayer (1996) analysed 25 patients over 15 years of age and did not find any specific problem related to puberty or to sexual development, which was normal in all cases. Detailed Quality-of-Life (QoL) assessments of a cohort of 25 Japanese patients were compared with an agematched cohort of 21 from the UK (Howard et al. 2001). The results showed that there were no significant differences between the assessments of the Japanese and British patients in physical and social functioning, bodily pain and emotional status, although there were marginal differences in indices of general health and vitality. Importantly, the study showed the similarity of results that can be achieved after portoenterostomy in different centres in the world. Transplantation (see Chapter 20) Biliary atresia is the commonest indication for liver transplantation during childhood (Salt et al. 1992). Transplantation was initially used for survivors of the Kasai operation with life-threatening complications (e.g. variceal bleeding and chronic liver failure). However, with increasing experience in transplantation, early liver replacement has been undertaken in infants who have failed to respond to portoenterostomy (Beath et al. 1993). Some authors (Sandler et al. 1997) have suggested that transplantation should be performed as a primary procedure during infancy as an alternative to the portoenterostomy operation, but this ignores the potential for long-term survival in a significant proportion of children. The general view at the moment is that portoenterostomy should remain the first operation of choice and that

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primary transplantation should be reserved for patients with advanced liver disease who present with hepatosplenomegaly, low albumin levels and significant ascites. Choledochal cysts Choledochal ‘cysts’ are rare congenital localized dilatation(s) of the bile ducts. They are more common in Oriental races and their incidence is estimated to be about 1 in 100 000 live births in western countries. More than twothirds of cases are diagnosed in children under 10 years of age and girls outnumber boys by about 3 : 1. Anatomy and classification Classification of choledochal cysts is based on that proposed by Todani et al. (1977) (Fig. 18.3). Type I cysts may be either cystic or fusiform and account for more than 70% of cases in most series. Next in frequency are type IVa cysts,

i.e. multiple cystic dilatations of the extra- and intrahepatic ducts. Type II (diverticulum), type III (choledochocele), type IVb (multiple extrahepatic cysts) and type V [multiple (Caroli’s disease) or single intrahepatic duct cysts] are very rare. Pancreaticobiliary malunion (see below) without cystic biliary dilatation has been termed a ‘forme fruste’ choledochal cyst (Lilly et al. 1985) but should be treated in a similar way to a fusiform choledochal cyst. Pancreaticobiliary malunion Choledochal cysts are frequently associated with an abnormal junction between the terminal common bile duct and the pancreatic duct, whereby the ducts unite well outside the duodenal wall and are not therefore surrounded by the normal sphincter mechanism (Iwai et al. 1992) (see Plate 69, Atlas: p. 463). This abnormal long common channel, which often exceeds 5–10 mm in length (Guelrud et al. 1999), encourages reflux of pancreatic juice into the

Type Ic

Type If

Type II

Type III

Type IVa

Type V

Fig. 18.3 Classification of choledochal cysts. Type 1 dilatations may be cystic (1c) or fusiform (1f) and typically associated with pancreaticobiliary malunion. Other types are: II (diverticulum), III (choledochocele), IVa (multiple cystic dilatations of extra- and intrahepatic ducts), IVb (multiple extrahepatic cysts) and V (single or multiple intrahepatic duct cysts).

Chapter 18: Surgical Disorders biliary tree and high concentrations of pancreatic enzymes are then found in the bile. This may predispose to the development of bile duct and gall-bladder cancer in adults (Yamauchi et al. 1987). Less frequently, bile refluxes into the pancreatic duct precipitating pancreatitis. Pancreaticobiliary malunion is common in type I and IVa choledochal cysts but is rarely seen with other varieties. Pathology In type Ic cysts, the choledochal dilatation typically starts just above the duodenum and ends abruptly just below the bifurcation of the common hepatic duct. The gall bladder is often normal in size. The wall of a choledochal cyst is thickened and composed of fibrous tissue with occasional elastic and smooth muscle fibres. The epithelial lining may be ulcerated, particularly in older children. In adults, epithelial metaplasia and dysplasia occur (Komi et al. 1986). Hepatic histology varies from normal to mild periportal fibrosis through to biliary cirrhosis. Hilar duct strictures may be found with type IVa cysts (Todani et al. 1984). Other biliary abnormalities are uncommon (Stringer 2002a). Portal hypertension may develop secondary to portal vein compression or from hepatic fibrosis or cirrhosis. Malformations outside the biliary tree are rare (Stringer et al. 1995; Samuel & Spitz 1996). Aetiology and pathogenesis There are two principal theories. The first suggests that a choledochal cyst arises because of an acquired weakness of the wall of the bile duct secondary to reflux of pancreatic juice (Babbitt 1969; Han et al. 1997). However, pancreaticobiliary malunion is not found in all patients with a choledochal cyst and it may occur in others without duct dilatation. The second theory proposes that obstruction of the distal common bile duct is the key event (Spitz 1977). A stenosis is often seen just below a type I cyst, but whether this is congenital or acquired is unclear. Genetic factors seem likely in view of the female preponderance and geographical distribution of the condition. However, familial choledochal cysts have rarely been reported, and twin studies have not identified any clear genetic predisposition (Lane et al. 1999). Clinical presentation Choledochal cysts can present at any age but most are diagnosed before 10 years (Stringer et al. 1995). Specific age groups present in different ways: • Prenatal diagnosis. Choledochal cysts may be detected by ultrasound scan as early as 15 weeks’ gestation (Stringer et al. 1995; Redkar et al. 1998). Most are type I cystic lesions. Postnatally, affected infants who are otherwise well should be treated by early surgery (< 3 months), par-

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ticularly if they are jaundiced. Some will have a cystic variant of biliary atresia, but progressive enlargement of the cyst during gestation and the subsequent demonstration of dilated intrahepatic bile ducts favour true choledochal pathology (Matsubara et al. 1997; Kim et al. 1998). Liver fibrosis may develop rapidly and is reversible by early surgery (Lugo-Vincente 1995). Early treatment also reduces the risks of cholangitis, progressive jaundice and cyst perforation. Results of surgical treatment at this age are generally excellent (Redkar et al. 1998; Suita et al. 1999). • Infants typically present with obstructive jaundice. Vomiting, fever, failure to thrive and an abdominal mass may be noted. Even with pancreaticobiliary malunion, hyperamylasaemia is not found because the amylase concentration in pancreatic juice is low until about 1 year of age (Davenport et al. 1995; Todani et al. 1995). However, biliary concentrations of pancreatic lipase, elastase and trypsin are significantly elevated in infants with a common channel (Todani et al. 1995; Urushihara et al. 1995). • Older children often present with abdominal pain. Of 72 children in the King’s College Hospital series, 50 (69%) presented with jaundice, which was associated with abdominal pain in half and a palpable mass in seven (Stringer et al. 1995). In infants the jaundice is frequently persistent but in older children it is often intermittent. In this same series, 13 (18%) children presented with recurrent abdominal pain alone and plasma and/or biliary amylase values were elevated in all. The classic triad of jaundice, pain and a right hypochondrial mass was present in only four (6%). Diagnostic delay is common highlighting the need for adequate investigation of jaundice, pancreatitis or a dilated common bile duct (Stringer et al. 1995). A choledochal cyst should always be included in the differential diagnosis of jaundice and pancreatitis. By ultrasound, the common bile duct diameter measures up to 3.5 mm in healthy children and up to 2 mm in infants (HernanzSchulman et al. 1995). A persistently dilated bile duct needs to be investigated further. Children with recurrent, severe abdominal pain should have a plasma amylase level measured. The hyperamylasaemia associated with pancreaticobiliary malunion can be accompanied by acute pancreatitis but some children have only ‘biochemical’ pancreatitis (Todani et al. 1995; Urushihara et al. 1995). In these cases, hyperamylasaemia may result from either diffusion of pancreatic amylase through the denuded epithelium of the cyst or from cholangiovenous reflux of amylase-rich fluid induced by a high choledochal pressure. Complications Choledochal cysts are prone to complications, which may be the presenting feature. These include:

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• Cholangitis — presents with progressive jaundice, abdominal pain, fever and often rigors. The causative organism is usually a Gram-negative organism. • Rupture — typically occurs spontaneously in children under 4 years of age (Stringer et al. 1995; Ando et al. 1998). Intraperitoneal rupture causes biliary peritonitis whereas retroperitoneal rupture is less dramatic. Clinical features include abdominal pain and distension, vomiting, fever, mild jaundice and biliary ascites. Definitive surgery may be possible at the time of diagnosis but temporary T-tube drainage of the choledochal cyst and delayed surgery once the inflammation has subsided and after the anatomy has been clarified is a safe alternative. • Pancreatic disease — pancreaticobiliary malunion may be associated with recurrent acute pancreatitis, chronic pancreatitis, pancreatic duct protein plugs and calculi. • Gallstones — Yamaguchi (1980) reported an 8% prevalence in 1433 Japanese cases. • Portal hypertension — may be secondary to portal vein compression, hepatic fibrosis or cirrhosis. • Malignant change — a well-recognized complication, mainly affecting adults but older children are also at risk (Yamaguchi 1980; Bismuth & Krissat 1999). Iwai et al. (1990) reported a 12-year-old girl with a type IVa cyst and a long common channel complicated by carcinoma. The age-related cancer risk has been estimated to be 0.7% in the first decade, 7% in the second decade and 14% after 20 years of age (Voyles et al. 1983). Pancreaticobiliary ductal malunion is an important predisposing factor. The risk of malignancy is greatest in patients who have been treated by internal drainage of a choledochal cyst (cystenterostomy) (Todani et al. 1987). Even after cyst excision, malignancy may affect incompletely excised extrahepatic ducts or dilated intrahepatic ducts, indicating the need for lifelong surveillance (Kobayashi et al. 1999). Malignant change carries a poor prognosis. Investigations Biochemical liver function tests may be normal or show evidence of obstructive jaundice. Hyperamylasaemia may be detected during episodes of abdominal pain. Clotting abnormalities should be excluded in jaundiced patients. Ultrasonography is the initial investigation of choice. The size, contour and position of the cyst, the proximal bile ducts, vascular anatomy and hepatic echotexture can all be accurately assessed together with signs of any complications. ERCP gives excellent visualization of the cyst, ductal anatomy and the pancreaticobiliary junction (see Plate 70, Atlas: p. 464). PTC is an alternative. Both investigations are invasive and associated with a small risk of complications such as iatrogenic pancreatitis or biliary sepsis, and both are best performed under general anaesthesia in children. ERCP should be avoided during an

episode of acute pancreatitis. Magnetic resonance cholangiopancreatography (MRCP) is non-invasive and does not require the use of contrast agents or irradiation (Matos et al. 1998). Bile and pancreatic secretions have a high signal intensity on T2-weighted images. However, definition of the pancreatic duct and common channel may be suboptimal, especially in infants, and calculi may be overlooked (Lam et al. 1999). Ongoing developments may overcome these problems (Kim et al. 2000). Hepatobiliary scintigraphy may be useful in selected cases, e.g. in the jaundiced infant where a cystic variant of biliary atresia is suspected or in some cases of cyst rupture. Radioisotope scanning is also useful for assessing biliary drainage after surgery. Computed tomography (CT) is helpful in evaluating pancreatitis. Laparoscopy and angiography are rarely necessary. In many patients a detailed ultrasound scan supplemented by intraoperative cholangiography provides sufficient anatomical information, but ERCP or MRCP offer more definitive preoperative imaging. Surgical management Radical cyst excision and hepaticoenterostomy is the optimum treatment for the more common types of choledochal cyst (Miyano et al. 1996; Stringer 2002a). In experienced centres, the procedure can be performed safely at all ages with minimal morbidity. Simple anastomosis of the cyst to a loop of bowel (cystenterostomy) should rarely, if ever, be undertaken because of the inevitable long term morbidity (cholangitis, cholelithiasis, pancreatitis, anastomotic stricture, biliary cirrhosis and malignancy) (Kaneko et al. 1999). Intravenous vitamin K is given to correct any coagulopathy and prophylactic intravenous broad-spectrum antibiotics are given at the start of surgery. If the anatomy of the choledochal cyst has not been defined in detail preoperatively, an operative cholangiogram is performed. A sample of bile is aspirated from the cyst for culture and measurement of pancreatic enzyme concentrations. The extrahepatic cyst is completely excised, oversewing the distal common bile duct just above its junction with the pancreatic duct. The common hepatic duct is divided at the level of the bifurcation and a wide hilar bilioenteric anastomosis is constructed with either a Roux loop of jejunum or the duodenum. Any dilated proximal intrahepatic ducts and a dilated common channel should be inspected and cleared of debris. Aliver biopsy is performed. Preliminary T-tube drainage of a choledochal cyst is occasionally required for patients with cyst rupture or uncontrolled cholangitis. Cyst excision can then be performed when the patient is fit. Occasionally, portal hypertension or dense inflammation make radical excision hazardous when intramural resection of the inner layer of the posterior wall of the cyst avoids damaging the

Chapter 18: Surgical Disorders portal vessels (Lilly 1978). Patients with advanced biliary cirrhosis should be considered for liver transplantation. In fusiform choledochal dilatations, endoscopic sphincterotomy or transduodenal sphincteroplasty have been reported to provide short-term relief of symptoms, but this approach fails to address the longterm hazards of pancreaticobiliary malunion. Types II and III cysts have been successfully managed by more conservative approaches (O’Neill et al. 1987; Dohmoto et al. 1996). Localized, symptomatic type V cysts can be treated by hepatic resection but more diffuse disease complicated by recurrent cholangitis and stone formation may need liver transplantation (see Caroli’s disease, Chapter 9). Results and complications Radical cyst excision and hepaticoenterostomy achieves consistently good results (Stringer et al. 1995; Miyano et al. 1996; Todani 1998). Regression of hepatic fibrosis and early biliary cirrhosis has been recorded after surgery (Yeong et al. 1982). Early postoperative complications such as anastomotic leakage, bleeding, acute pancreatitis and intestinal obstruction are rare. Long-term complications may be evident clinically or from routine biochemical liver function tests and ultrasound scan. An anastomotic stricture may develop up to 10 or more years postoperatively (Saing et al. 1997). Todani (1998) reported a 10% reoperation rate in 103 children followed for a median of 14 years and Yamataka et al. (1997) a 9% complication rate in another Japanese series of 200 children followed for a mean of 11 years. Revisional surgery was necessary for cholangitis due to anastomotic or ductal strictures, common channel calculi and adhesive bowel obstruction. Biliary complications were more likely with type IVa cysts or after anastomosis to the common hepatic duct. Reoperation was not required after hilar hepaticoenterostomy for type I choledochal cysts. There were no instances of malignancy. Anastomotic strictures were very rare in children undergoing surgery before 5 years of age. Late postoperative cholangitis should be investigated by a combination of ultrasound, MRC, biliary scintigraphy and/or PTC (with antibiotic prophylaxis). Although interventional radiological techniques may be able to remove stones and dilate strictures, surgery is usually required to revise a bilioenteric anastomotic stricture. Pancreatitis may develop years after cyst excision in patients with a common channel containing protein plugs or calculi, but this is rare after appropriate primary surgery. Endoscopic sphincterotomy may be valuable in such cases. Malignancy has been reported after choledochal cyst excision (see above), but adequate primary surgery should minimize this risk (Yoshikawa et al. 1986; Yamamoto et al. 1996).

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Spontaneous perforation of the bile duct Spontaneous perforation of the bile duct was first described in 1932 by Dijkstra, and since then over 70 cases have been reported in the literature (e.g. Lilly et al. 1974; Fitzgerald et al. 1978; Hammoudi & Alauddin 1988; Davenport et al. 1991). The perforation occurs at the junction of the cystic and common hepatic ducts and is usually described as ‘punched out’. There is usually no obvious cause, although transient biliary obstruction, perhaps due to inspissated bile and a sudden increase in biliary pressure, seems likely in some cases. A developmental weakness of the bile duct has been suggested (Johnston 1961) but embryological studies of the development of the biliary tract have not identified any possible cause for this (Tan & Moscoso 1994). Presentation and diagnosis Clinical presentation is from 2 to 24 weeks of age, with abdominal distension accompanied by jaundice and acholic stools (Davenport et al. 1991). Differential diagnoses include perforation associated with choledochal cysts (Ohkawa et al. 1977), trauma, and Ascaris infestation of the bile duct (Witcombe 1978). The infants usually have unremarkable birth histories and development until a rapid onset of generalized peritonitis, or an insidious onset of obstructive jaundice, pale stools and dark urine. Chardot et al. (1996) defined three types of presentation from their experience of 11 cases, which they described as acute peritonitis, localized peritonitis and bile duct stenosis. Of the three, localized peritonitis is the commonest type of presentation manifesting as abdominal distension, intermittent vomiting, failure to thrive and ascites. The vomiting may be severe enough to suggest an erroneous diagnosis of gastric outlet obstruction (Kumar et al. 2001). Often the infant is not pyrexial. Bile in the peritoneal cavity presents with greenish staining of hydroceles, hernial sacs and the umbilicus. Bile leakage in the porta hepatis results in severe inflammatory change that can rarely cause a secondary stenosis of the lower portion of the common bile duct (Davenport et al. 1996). Abdominal ultrasound may show a complex mass around the bile duct and duodenum, free intraperitoneal fluid and, in some cases, dilated intrahepatic ducts. Biochemical liver function tests are abnormal with a mild, conjugated hyperbilirubinaemia, and raised alkaline phosphatase and GGT levels. Biliary radionuclide imaging may show isotope within the peritoneal cavity, or a PTC will demonstrate a leak (see Plate 71, Atlas: p. 464). Treatment The treatment is surgical in all cases. A laparotomy and

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cholangiogram performed with a catheter placed in the gall bladder, which may be thick-walled from the surrounding inflammation, will confirm the site of perforation and indicate whether there is any distal common bile duct obstruction from inspissated bile or stricture formation. Lilly et al. (1974) suggested a conservative surgical approach using peritoneal drainage alone. However, except in cases with very small perforations and with no evidence of distal bile duct obstruction, a more interventional method is preferable, as deaths have occurred from persistent bile leaks when peritoneal drainage has been used as the sole technique. A small T tube may be placed in the common bile duct to provide a controlled biliary fistula and to allow recovery from the biliary peritonitis. This is left in situ for 2 weeks and then removed if repeat T-tube cholangiography shows no evidence of distal obstruction. In late presenting cases it may be necessary to resect a secondary bile duct atresia and re-establish biliary drainage via a hepaticojejunostomy (Spigland et al. 1996). Inspissated bile syndrome (IBS) Bile duct obstruction caused by plugs of thickened bile was first described by Ladd (1935). The incidence increased during the 1950s and 1960s, perhaps because of the prevalence of untreated rhesus disease of the newborn associated with prolonged haemolysis and precipitation of bilirubin within the common bile duct (see also Chapter 15). Infants with IBS may have a history of episodes of dehydration, parenteral nutrition (St-Vil et al. 1992), prematurity, or diuretic therapy. A prospective ultrasound study of neonates receiving parenteral nutrition visualized biliary sludge in 44% and discrete gallstones in 5% of cases (Schirmer et al. 1989). Occasionally there are cholangiographic anomalies such as an abnormal entry of the common bile duct into the duodenum, which may explain why some infants seem predisposed to develop IBS. Although intraluminal obstruction is caused by inspissated bile, the two older patients in a series of nine cases were obstructed by distinct gallstones (at 4 and 6 months) (Heaton et al. 1991). Diagnosis and treatment The differential diagnosis of IBS in the neonatal period includes biliary atresia, but the diagnosis is usually obvious on abdominal ultrasonography, which may reveal dilated intra- and extrahepatic bile ducts secondary to impacted inspissated bile in the distal common bile duct. Radionuclide scans will confirm biliary obstruction but are not diagnostic. The definitive investigation is PTC and occasionally this can be therapeutic after flushing the biliary tree via a small catheter introduced through the

track (Heaton et al. 1991). In some cases irrigation can be similarly achieved with ERCP. If this fails then a laparotomy is indicated to decompress the biliary tree. The common bile duct is opened, the inspissated material washed out and free distal drainage re-established (confirmed by cholangiography). The use of choleretic agents (e.g. ursodeoxycholic acid 20 mg/kg/d) and biliary motility drugs (e.g. cholecystokinin) has recently been introduced to help avoid the need for surgery as there is evidence that the lack of gall-bladder activity during prolonged parenteral nutrition may potentiate the development of inspissated bile. Benign bile duct strictures Strictures of the extrahepatic bile ducts in children may result from trauma, surgery, radiotherapy for malignant disease, and spontaneous perforation (Howard 2002a). Another type of benign stricture was reported by Bowles et al. (2001) who described lesions in seven children (six girls and one boy) that were not associated with any obvious aetiological factor and which were designated by the authors as ‘idiopathic’. These were characterized by a specific combination of histological features, which included fibrosis and chronic inflammation of the wall of the bile duct, loss of epithelium and epithelial hyperplasia and regenerative change. At least three of these four features were present in each case. These isolated strictures (see Plate 72, Atlas: 465) differ from the multiple strictures observed in sclerosing cholangitis, a condition in which the epithelium remains intact. Furthermore, long-term follow-up of the children with idiopathic lesions did not reveal any recurrence after resection or the development of any other disease. A similar condition has been described in adults (Verbeek et al. 1992) and hepaticojejunostomy is the treatment of choice in all age groups. Bile duct tumours Painless obstructive jaundice is the presenting feature of these very rare lesions that may be misdiagnosed as choledochal cysts or cholelithiasis. The diagnosis depends on accurate imaging of the biliary tract using a combination of ultrasonography, CT, MRCP and ERCP. Malignant tumours occur more frequently than benign lesions (Table 18.3). Malignant 1 Rhabdomyosarcoma Lack et al. (1981) pointed out that rhabdomyosarcoma is the commonest primary tumour of the bile duct in children and that it should always be considered in the differential diagnosis of obstructive

Chapter 18: Surgical Disorders Table 18.3 Tumours of the extrahepatic bile ducts in children. Benign Inflammatory ‘pseudotumour’ Papilloma Granular cell tumour Malignant Rhabdomyosarcoma Carcinoma Liposarcoma

jaundice. Approximately 100 cases have been reported to date. The median age at presentation is 3.4 years and there is no gender predominance. Clinical signs include obstructive jaundice, fever, weight loss and abdominal distension. Scanning of the biliary tract shows solid material within dilated intra- and extrahepatic bile ducts and PTC is useful in defining the extent of the tumour within the bile ducts. Local or distant spread is present in 30–40% of cases at the time of presentation (Spunt et al. 2000). Macroscopically the tumours are polypoid with grapelike projections filling the lumen of the bile duct. Histological examination shows typical features of embryonal rhabdomyosarcoma with botryoid features. The cells are of mesenchymal origin and have a myxomatous appearance with eosinophilic cytoplasm. The botryoid polyps are hypocellular and oedematous. The tumour infiltrates beneath the bile duct epithelium and into liver parenchyma and it may also infiltrate surrounding structures such as the stomach and inferior vena cava. Until recently the survival of these patients was dismal, with an average life expectancy of 6 months. However, an aggressive approach to treatment using a combination of chemotherapy, surgery and radiotherapy has improved the outlook and Spunt et al. (2000) have reported an estimated overall 5-year survival rate of 66% in a series of 25 children treated since 1972. The survival rate for the children who did not have metastatic disease at the time of presentation was 78%. 2 Carcinoma Carcinoma may arise in the bilary tracts of patients with untreated choledochal cysts. It has also been reported in residual extrahepatic and intrahepatic bile ducts after successful cyst excision (Yoshikawa et al. 1986; Watanabe et al. 1999). The youngest case of carcinoma in a patient with no predisposing cause was a girl who was 17 years of age (Czaja et al. 1985). Surgical resection is required, if possible. 3 Liposarcoma One case of this tumour has been reported in a child aged 2 years and 4 months, who had presented with jaundice and fever. The diagnosis was confirmed at post mortem (Soares et al. 1989).

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Benign 1 Inflammatory ‘pseudotumour’ The aetiology of inflammatory pseudotumours of the bile duct is not known, although it has been suggested that they may arise in response to a local chemical or infective irritant. The macroscopic appearance of a resected lesion is of an encapsulated mass of yellow-brown tissue surrounding a compressed bile duct. Histological features consist of a mass of collagenous tissue with a mixed inflammatory cell infiltrate (Stamatakis et al. 1979). Surgical resection and reconstruction of the biliary tract with a Roux loop of jejunum is curative. 2 Papilloma Papillomas of the bile duct have been reported twice in children (Khan et al. 1996). Surgical excision is essential as they may develop areas of dysplasia and carcinoma. 3 Granular cell tumour There are four reports of granular cell tumours in children under 15 years of age (Reynolds et al. 2000). These lesions are thought to arise from Schwann cells and they are positive for S100 protein immunoreactivity, which is a neural marker (CheslynCurtis et al. 1986). Clinical presentation is of a stricture of the bile duct and histology shows cells containing granular eosinophilic cytoplasm. Infiltration of surrounding structures may complicate surgical resection. Cholelithiasis Epidemiology Estimates of the prevalence of gallstones in children vary according to geography and age: 0.5% of neonates in Germany (Wendtland-Born et al. 1997), 0.13–0.2% of infants and children in Italy (Palasciano et al. 1989; Toscano et al. 2001), and less than 0.13% of children in Japan (Nomura et al. 1988). Most studies of cholelithiasis in childhood show a bimodal distribution with a small peak in infancy and a steadily rising incidence from early adolescence onwards. In early childhood boys and girls are similarly affected, but a clear female predisposition emerges during adolescence. Studies in western children have shown a consistent increase in both the prevalence of gallstones and the incidence of cholecystectomy for cholelithiasis during the last three decades (Takiff & Fonkalsrud 1984; Bailey et al. 1989; Grosfeld et al. 1994; Waldhausen & Benjamin 1999; Kumar et al. 2000; Miltenburg et al. 2000). This may reflect improved detection from the widespread use of diagnostic ultrasonography and/or a genuine increase in the incidence of cholelithiasis.

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Section 9: Surgical Management of Liver Disease are biliary stasis, excess bilirubin load and lithogenic bile (Afdhal 2000).

Pathogenesis There are four major types of gallstone: mixed cholesterol, pure cholesterol, black and brown pigment stones. Mixed cholesterol stones are the commonest variety in adults but are also found in obese adolescent girls. They develop from cholesterol supersaturation of bile in the presence of bile stasis; non-cholesterol components include calcium salts and proteins. In children, all four stone types may occur but black pigment stones are relatively common and are seen in haemolytic disorders and in association with total parenteral nutrition (Takiff & Fonkalsrud 1984; O’Brien et al. 1986). Black pigment stones are formed from supersaturation of bile with calcium bilirubinate. Brown pigment stones are associated with biliary stasis and infection and form more often in the bile ducts than the gall bladder. Rarely, calculi are composed of pure calcium carbonate (Wu et al. 2001). Biliary sludge is composed of mucin, calcium bilirubinate and cholesterol crystals and appears echogenic on ultrasound but does not cast an acoustic shadow. Gall-bladder sludge is typically found in association with total parenteral nutrition/fasting, pregnancy, sickle cell disease, treatment with Ceftriaxone or Octreotide, and after bone marrow transplantation. The natural history of biliary sludge is variable; it may disappear spontaneously or progress to gallstone formation. Persistent sludge may cause biliary tract complications. Many aetiological factors have been associated with cholelithiasis in children (Table 18.4). The dominant ones

Haemolytic disorders These include sickle cell disease, hereditary spherocytosis, and thalassaemia major. In each, the incidence of gallstones increases with age. The prevalence of pigment stones in sickle cell anaemia is approximately 10–15% in children under 10 years of age but up to 40% in those aged 10–18 years (Bond et al. 1987; Webb et al. 1989). About 10–20% of children with hereditary spherocytosis have evidence of cholelithiasis (Croom et al. 1986). In thalassaemia, gallstones are rare before 5 years of age but thereafter between 4 and 14% of children are affected (Kalayci et al. 1999). Pigment stones may also complicate haemolytic uremic syndrome, ABO or Rhesus incompatibility, and cardiac valve replacement. In the newborn, an excessive bilirubin load combined with an immature bilirubin excretion mechanism has been linked to pigment stone formation. Ileal resection/disease Ileal resection or disease is an unequivocal risk factor for cholelithiasis (Davies et al. 1999). Symptomatic gallstones occur in 10–20% of children with short bowel syndrome (Georgeson & Brown 1998). Children with Crohn’s disease affecting the terminal ileum are similarly at risk. The most likely mechanism is a disturbance of the normal enterohepatic circulation of bile salts causing a relative

Table 18.4 Specific conditions associated with childhood cholelithiasis (Stringer 2002b). Condition

Aetiological factors

Reference

Cystic fibrosis

Abnormalities of biliary lipid and mucin composition. Common bile duct stenosis

Anagnostopoulos et al. (1993)

Down syndrome

Prenatal factors may be important since calculi have been detected soon after birth

Toscano et al. (2001)

Cardiac/liver transplantation

Multifactorial (haemolysis, cyclosporin-induced changes in bile and lipid metabolism, gall-bladder stasis, frusemide therapy)

Sakopoulos et al. (2002)

Childhood cancer

Multifactorial (ileal conduit, parenteral nutrition, abdominal surgery, repeated blood transfusions and abdominal radiation therapy)

Mahmoud et al. (1991)

Bone marrow transplantation

Blood transfusions/chemotherapy

Safford et al. (2001)

Spinal surgery/injury

Immobilization, disturbed calcium haemostasis, blood transfusion

Teele et al. (1987)

Hepatobiliary trauma

Haemobilia

Reif et al. (1991)

Selective IgA deficiency

Gall-bladder sepsis. Decreased bile acid pool from intestinal losses

Danon et al. (1983)

Dystrophia myotonica

Impaired gall-bladder emptying

Schwindt et al. (1969)

Chronic intestinal pseudo-obstruction

Impaired gall-bladder motility

Shimotake et al. (1993)

Cholestatic/cirrhotic liver disease

Alagille’s syndrome, PFIC, Gilbert syndrome and Wilson disease

Lykavieris et al. (2001)

Congenital duodenal anomalies

Fibrosis around the distal common bile duct after surgical repair

Tchirkow et al. (1980)

Chapter 18: Surgical Disorders bile salt deficiency, which leads to incomplete solubilization of unconjugated bilirubin and calcium bilirubinate stones. Total parenteral nutrition (TPN) The association between TPN and biliary sludge/ cholelithiasis is well established. Fasting and TPN promote biliary stasis by impairing both the enterohepatic circulation of bile acids and cholecystokinin-induced gall-bladder contraction (Jawaheer et al. 1995). Premature infants are particularly susceptible to this complication. In a prospective sonographic study of 41 infants receiving TPN, Matos et al. (1987) detected gall-bladder sludge in 18 (44%) after a mean period of 10 days. In 12 infants, the sludge cleared within 1 week of enteral feeding, but two of the remaining patients went on to develop asymptomatic gallstones. Other risk factors Adolescents with cholelithiasis typically have an adult pattern of risk factors, i.e. female gender, obesity and sometimes teenage pregnancy (Reif et al. 1991). Oestrogens increase cholesterol excretion whilst progesterone reduces bile acid excretion and slows gall-bladder emptying (Afdhal 2000). Rapid weight loss is a risk factor in adults. Biliary obstruction and stasis from choledochal cysts and biliary strictures are known to promote gallstone formation. Numerous specific disorders have been associated with an increased incidence of gallstones in children (Table 18.4). Clinical features These are age dependent. • Infancy. In recent years, the number of reports of infants with gallstones has increased significantly. Gallstones have even been detected in the fetus (Stringer et al. 1996a). Premature infants are more at risk, probably because of impaired gall-bladder contractility (Lehtonen et al. 1993), repeated blood transfusions, frusemide therapy, phototherapy, decreased bile acid output (Halpern et al. 1996) and systemic or biliary infection (Debray et al. 1993). Gallstones are frequently asymptomatic in infants but they may cause nonspecific symptoms such as poor feeding and vomiting or give rise to acute cholecystitis, obstructive jaundice or biliary perforation (St-Vil et al. 1992; Debray et al. 1993). • Childhood. Haemolytic disorders, ileal resection and total parenteral nutrition are among the conditions predisposing to cholelithiasis in this age group (Grosfeld et al. 1994). Symptomatic children usually complain of abdominal pain in the right upper quadrant or epigastrium associated with nausea and vomiting. Occasionally presentation is with obstructive jaundice or pancreatitis.

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• Adolescence. More often these are girls who are overweight with a positive family history (Grosfeld et al. 1994), but cholelithiasis from other causes may also present in this age group. There does not appear to be an association with the oral contraceptive pill (Vessey & Painter 1994). Fatty food intolerance, biliary colic and acute or chronic cholecystitis are reported in most cases with symptomatic stones. Diagnosis Clinical suspicion of cholelithiasis is readily confirmed by an ultrasound scan in a fasting patient. Gallstones are solitary or multiple, mobile, and typically cast an acoustic shadow; stones as small as 1.5 mm can be detected by ultrasound. Gall-bladder wall thickness and common bile duct dilatation can also be assessed. The sensitivity and specificity of ultrasound exceeds 95% for gallbladder cholelithiasis but only 50–75% of common bile duct stones are detected. Between 20% and 50% of stones in children are radiopaque. Radioisotope scanning with 99mTc-diisopropyl iminodiacetic acid (DISIDA) is highly sensitive and specific in the diagnosis of acute cholecystitis. Non-visualization of the gall bladder in an otherwise patent biliary system suggests acute cholecystitis. MRC is being increasingly used to investigate complicated gallstone disease. With common bile duct stones, endoscopic retrograde cholangiography offers the additional advantage of therapeutic intervention. Management 1 Non-operative Infants with spontaneously resolving cholelithiasis have been reported by several authors (St-Vil et al. 1992; Debray et al. 1993; Miltenburg et al. 2000). Early surgery should therefore be avoided in the asymptomatic infant with gall-bladder calculi. Clinical and ultrasound monitoring is appropriate provided the infant has no other evidence of biliary tract disease. In infants remaining dependent on TPN, cholecystokinin or ursodeoxycholic acid may be helpful in clearing biliary sludge (Rintala et al. 1995). In older children, the management of asymptomatic gall-bladder calculi of non-haemolytic origin is controversial because the natural history is poorly defined. Many children remain asymptomatic for at least a few years (Bruch et al. 2000). However, the likelihood of spontaneous resolution of cholelithiasis in older children is low (particularly if stones are calcified) and the child is at risk of gallstone complications for life. Dissolution therapy for gallstones in children is of doubtful benefit. Despite prolonged treatment, low dissolution rates and high recurrence rates have been observed in adults with cholesterol stones. Calcified and pigment stones and patients with a non-functioning gall

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bladder are not amenable to treatment. Ursodeoxycholic acid is ineffective in children with radiolucent calculi complicating cystic fibrosis (Colombo et al. 1993). Extracorporeal shock wave lithotripsy of gallstones has rarely been reported in children. Sokal et al. (1994) documented successful treatment of a child with a single obstructing 7-mm stone in the distal common bile duct. 2 Surgical Symptomatic or complicated gallstone disease usually requires surgery. Cholecystectomy, either laparoscopic (Holcomb et al. 1999) or through a small incision, is the standard treatment for gall-bladder stones. In the haemolytic disorders, asymptomatic calculi deserve special consideration. In hereditary spherocytosis, cholecystectomy is indicated for children with asymptomatic calculi who are undergoing splenectomy for haematological reasons (Croom et al. 1986). Prophylactic cholecystectomy at the time of splenectomy is not indicated in those who do not have gallstones (Sandler et al. 1999). In sickle cell anaemia opinion is divided. Reasons for favouring elective cholecystectomy for asymptomatic stones include the increasing risk of complications with age, the higher morbidity of emergency surgery and the difficulty of distinguishing cholecystitis from a sickle cell abdominal crisis (Alexander-Reindorf et al. 1990; Winter et al. 1994). Perioperative complications are minimized by preoperative blood transfusion to correct anaemia and reduce the proportion of haemoglobin S together with avoidance of acidosis, hypovolaemia and hypothermia. Laparoscopic cholecystectomy is advantageous in these patients, and may obviate the need for preoperative blood transfusion in some cases. 3 Choledocholithiasis Common bile duct stones are relatively uncommon (Newman et al. 1997) but children with sickle cell disease (Ware et al. 1988) and infants (Debray et al. 1993; Kumar et al. 2000) have a higher incidence. Obstructive jaundice, cholangitis and/or acute pancreatitis may occur. MRC may be helpful in diagnosis but ERC also offers the opportunity for intervention. There are several approaches to managing choledocholithiasis. ERC and sphincterotomy with stone retrieval can be undertaken before or after laparoscopic cholecystectomy, even in small infants (Guelrud et al. 1992). Early ERC is recommended for common duct stones causing obstructive jaundice or cholangitis. Gallstone pancreatitis is less straightforward since the stone usually passes spontaneously, after which laparoscopic cholecystectomy can be undertaken (Holcomb et al. 1999). Surgical approaches to choledocholithiasis include cholecystotomy and irrigation in small infants or, in older children, choledochotomy and stone removal or transduodenal sphincteroplasty. Some centres have used percutaneous retrieval techniques. In infants with a com-

mon bile duct stone, a short period of observation is often worthwhile if the infant is well, since spontaneous passage has been described (St-Vil et al. 1992). Acalculous cholecystitis Severe acute distension of the gall bladder in the absence of any other biliary tract disease is rare. If infection, ischaemia, or chemical irritation supervene, acute acalculous cholecystitis may occur. In western countries, acute acalculous cholecystitis may develop after shock, trauma, cardiac surgery, burns, systemic sepsis, Salmonella infection, and parenteral nutrition (Tsakayannis et al. 1996). In the tropics, Salmonella typhi infection and Ascariasis should be considered, although no aetiological factors are identifiable in some cases (Ameh 1999). Acalculous cholecystitis has also been described in Kawasaki disease. Clinical features include abdominal pain, vomiting, fever, localized tenderness and, in half of the cases, a palpable right upper quadrant mass. Laboratory investigations reveal a leucocytosis, raised acute-phase reactants, hyperbilirubinaemia and mild hyperamylasaemia. Differential diagnosis includes appendicitis but this is readily distinguished by ultrasound, which shows a markedly distended gall bladder. Initial management is conservative with antibiotics, intravenous fluids and bowel rest. Cholecystectomy or cholecystostomy is indicated if there is progressive clinical deterioration, a persistent tender mass and/or increasing gall-bladder distension on ultrasound.

Congenital vascular abnormalities The portal venous system develops from paired vitelline and umbilical veins which drain the yolk sac and placenta, respectively. These veins intercommunicate around the embryonic duodenum and supply the developing hepatic sinusoids. There is also a constant venous anastomosis between the left portal vein and the hepatic veins known as the ductus venosus, which allows placental blood from the left umbilical vein to bypass the hepatic sinusoids and empty directly into the right heart. Selective atrophy of these embryonic veins leaves the final arrangement as a single postduodenal portal vein and an umbilical vein which eventually atrophies to become the ligamentum teres, but which retains its connection with the left branch of the portal vein (Joyce & Howard 1988). Minor changes in the embryology of the portal venous system can result in major anatomical abnormalities of the portal vein, which include: • a preduodenal position • cavernous transformation • duplication • congenital portosystemic communications. The formation of the inferior vena cava (IVC) is also a

Chapter 18: Surgical Disorders very complex process and is the end result of the coalescence of several venous channels. Anatomical abnormalities, for example absence of the IVC, may be associated with abnormalities of the portal venous system. Congenital portocaval shunts These manifest as abnormal communications between the portal and systemic venous systems. They include extrahepatic congenital portocaval shunts, which have been classified into type 1, when portal venous blood is completely diverted from the liver into the vena cava, and type 2, when there is only partial portal blood flow into the cava (Howard & Davenport 1997). At an early stage in the normal development of the portal venous system, blood flows from the left umbilical vein into the ductus venosus, which acts as a bypass to the retrohepatic portion of the IVC. This arrangement allows the shunting of oxygenated placental blood directly into the heart via the IVC. Approximately 40–50% of umbilical blood traverses the ductus venosus, the remainder flowing through the liver sinusoids (Meyer & Lind 1966). Closure of the ductus venosus and total flow of portal blood through the liver sinusoids are a consequence of the cessation of flow in the umbilical vein on the first day of life; the process is completed within 15–20 days of birth. Acongenital portocaval shunt and absence of the portal venous supply to the liver was first described by John Abernethy in 1793 in a 13-year-old girl with multiple malformations. Since then at least 12 type 1 cases have been described (Joyce & Howard 1988; Howard & Davenport 1997; Howard 2002b). Type 1 cases occur commonly in girls and are usually associated with other anomalies (e.g. polysplenia, biliary atresia and liver tumours). The shunt itself is compatible with normal liver function, although in later life it may predispose to hepatic encephalopathy and liver tumours. Type 2 portocaval (side-to-side) shunts are less common, with only six cases in the literature (Howard & Davenport 1997). Initial reports (Raskin et al. 1984; Barsky et al. 1989) suggested that they presented in adult life with encephalopathy; however, the widespread use of abdominal ultrasound has led to their increased recognition at all ages. A familial incidence of type 2 shunts was reported in three brothers, two of whom presented at 3 and 5 years of age with encephalopathy. Symptoms and biochemical abnormalities were reversed successfully in two of the children who underwent surgical shunt closure (Uchino et al. 1996). There are four published cases presenting in infancy, three of them with jaundice. The portosystemic communication in all cases was a short side-to-side venous channel between the intrahepatic vena cava and the confluence of the portal vein. Doppler imaging demon-

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strated two-way flow in the intrahepatic portal vein depending on caval pressure. Evidence of hepatic arterialization was also observed at laparotomy. The treatment of these shunts requires precise imaging and intraoperative measurement of portal vein pressures. Type 1 shunts are not treatable by conventional means, although transplantation has been performed for the associated liver anomaly. Type 2 shunts should be closed to prevent later encephalopathy, although it is important to ensure that the liver can tolerate the increase in portal venous flow without excessive rises in portal pressure (Howard 1999). Hepatoportal arteriovenous communications Abnormal communications between the hepatic arterial system and the portal venous system have been described within the liver. Such fistulae may be isolated congenital abnormalities and may present with severe portal hypertension, gastrointestinal bleeding and failure to thrive (see Plate 73, Atlas: p. 465). Occasionally they may form part of a vascular syndrome such as the Osler–Weber–Rendu syndrome (hereditary haemorrhagic telangiectasia) (Zentler-Munroe et al. 1989). Fistulae may also arise after blunt liver trauma or penetrating injury including liver biopsy and surgery (Davenport et al. 1999). Heaton et al. (1995) described two children with congenital hepatoportal arteriovenous fistulae who presented during infancy with failure to thrive, splenomegaly and gastrointestinal upset with watery diarrhoea and bleeding. Ultrasound and Doppler flow studies of the portal vein proved crucial to the correct diagnosis and characteristically showed pulsatile portal venous flow with reversal during diastole. The diagnosis was confirmed by mesenteric arteriography, which showed the site and degree of the aberrant communication. Fistulae confined to one segment of the liver are amenable to treatment with hepatic resection. Multiple or bilobar fistulae may be controlled in the short term with arterial embolization or operative hepatic arterial ligation. However, excessive embolization may cause significant ischaemia of the liver and gut and should be undertaken only by experts. Collateral vessels may develop with a recurrence of symptoms, which may be severe enough to warrant liver transplantation (Stringer et al. 1996b).

Portal hypertension Portal hypertension may be caused by a wide variety of conditions, each with a different natural history. It frequently presents with bleeding from oesophageal varices, which is the commonest cause of serious gastrointestinal haemorrhage in children. Precise diagnosis,

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a sound understanding of the therapeutic options, and a multidisciplinary approach are essential for successful management. Definition and pathophysiology The portal vein carries blood to the liver from the gastrointestinal tract and spleen contributing two-thirds of the liver blood supply. The right and left portal veins undergo several divisions to supply each of the liver segments. Terminal portal tract branches supply the hepatic sinusoids. Portal venous pressure is the product of: • blood flow — increased in cirrhosis due to splanchnic vasodilatation • vascular resistance — within the liver this includes both fixed (fibrosis and architectural distortion) and dynamic (sinusoidal vascular tone) components. A rise in portal pressure leads to splenomegaly and the development of portosystemic collaterals at various sites: the distal oesophagus (oesophageal and gastric varices); the anal canal (anorectal varices); the falciform ligament (umbilical varices); and varices in the abdominal wall and retroperitoneum. The junction between mucosal and submucosal varices in the lower 2–5 cm of the oesophagus is the usual site of rupture leading to variceal bleeding (Arakawa et al. 2002). Portal hypertension is defined by an increased hepatic venous pressure gradient (> 5 mmHg), which is the difference between wedged hepatic venous pressure (an indicator of portal venous pressure) and free hepatic venous pressure. A gradient of more than 12 mmHg is necessary for the development of oesophageal varices (Garcia-Tsao et al. 1985). Although the relationship is not linear, the risk of variceal bleeding is increased in larger varices and in those with a higher internal pressure and wall tension (Lebrec et al. 1980). In established cirrhosis, the risk of variceal bleeding is related to the severity of the liver disease. Classification, aetiology and clinical features Portal hypertension in children may be due to: • Primary venous obstruction at a prehepatic (e.g. portal vein obstruction), intrahepatic (e.g. hepatoportal sclerosis), or posthepatic (e.g. Budd–Chiari syndrome) level. Rarely, an arterio-portal venous fistula causes portal hypertension in an unobstructed system. • Intrinsic liver disease (e.g. cirrhosis, fibrosis, nodular hyperplasia). Chronic liver disease is the commonest overall cause of portal hypertension but portal vein occlusion (PVO) is the most frequent cause of extrahepatic portal hypertension. Occasionally, the picture is mixed as in cirrhosis complicated by portal vein thrombosis. Presentation is typically

with acute gastrointestinal haemorrhage (haematemesis and/or melaena) and/or splenomegaly or as part of the manifestation of chronic liver disease. Children with PVO typically present with variceal bleeding at a younger mean age (5 years) than those with cirrhosis (8 years), but onset of haemorrhage may occur at any age (Howard et al. 1988). The risk of bleeding in PVO may decrease with advancing age, concomitant with the spontaneous development of portosystemic collaterals (Webb & Sherlock 1979). A small proportion of children with PVO have small varices, which do not bleed (Lykavieris et al. 2000). An upper respiratory tract infection and, historically, aspirin therapy may be a precipitant. Anecdotal reports suggest that air transport is an additional trigger. Splenomegaly may be associated with evidence of hypersplenism. However, unlike cirrhotics, humoral immunity is preserved in those with PVO. Ascites usually denotes the presence of chronic liver disease but may occur transiently after a major variceal bleed in those with extrahepatic portal hypertension. Encephalopathy may complicate an episode of bleeding in cirrhotics but is rarely detectable in children with PVO. Portal hypertension may cause mucosal oedema in the small intestine leading to malabsorption, protein loss, and failure to thrive. Growth failure is common in cirrhosis and may also be found in children with PVO (Sarin et al. 1992; Mehrotra et al. 1997). In established portal hypertension dilated cutaneous collateral veins carry blood away from the umbilicus towards the tributaries of the vena cava (caput medusae). In long-standing disease, varices around the common bile duct may cause obstructive jaundice. Rarely, pulmonary hypertension may coexist with portal hypertension, more often in children with cirrhosis than those with PVO (Silver et al. 1992; Schuijtvlot et al. 1995). Prehepatic Portal vein occlusion PVO accounts for approximately 30% of all children with bleeding oesophageal varices (Howard et al. 1988; Maksoud et al. 1991). Many aetiological factors have been implicated (Table 18.5). Umbilical vein catheterization in the newborn, with or without infusion of irritant solutions, and umbilical sepsis are recognized precipitants in up to 30% of patients (Webb & Sherlock 1979). However, small prospective studies indicate that this is a rare complication of umbilical catheters (Yadav et al. 1993). Thrombophilic disorders may predispose to portal vein thrombosis but results of investigations must be interpreted cautiously. Circulating levels of natural anticoagulant proteins (Protein C, Protein S, and antithrombin III) are commonly decreased as a result of PVO (Dubuisson et al. 1997; Fisher et al. 2000). Currently, the minority of cases of PVO with a true in-

Chapter 18: Surgical Disorders Table 18.5 Causes of portal vein occlusion (Stringer 2002c). General factors Developmental malformations Septicaemia Thrombophilia Myeloproliferative disorders Paroxysmal nocturnal haemoglobinuria Protein C deficiency Protein S deficiency Antithrombin III deficiency Factor V Leiden mutation Anti-phospholipid antibodies (includes lupus anticoagulant and anticardiolipin) Factor II (prothrombin) gene mutation (G20210A) Homocysteinemia Local factors Umbilical sepsis, catheterization, infusion of irritant solutions Intra-abdominal sepsis and portal pyaemia Abdominal trauma (including surgical) Structural lesions, e.g. portal vein web Cholangitis/choledochal cyst Pancreatitis Malignant disease/lymphadenopathy Splenectomy

herited thrombophilia can usually only be established by investigation of family members. The pattern of portomesenteric venous obstruction may provide a clue to aetiology (Stringer et al. 1994). In myeloproliferative disorders and severe thrombophilia, extensive thrombosis involving portal, mesenteric, splenic, hepatic and deep veins may be present. Intraabdominal sepsis (local inflammation and/or portal pyaemia) and trauma may cause portal vein obstruction, with or without involvement of the superior mesenteric vein. Rarely, isolated splenic vein obstruction is found (Lenthall et al. 1999). In the majority of children with isolated portal vein obstruction the aetiology is unknown. The portal vein is typically replaced by multiple venous collaterals, the so-called portal vein cavernoma. Associated anomalies are uncommon but include congenital heart disease, anomalous IVC, choledochal cyst, intestinal malrotation, duodenal atresia and craniofacial dysostosis (Odievre et al. 1977; Stringer et al. 1994). Intrahepatic The intrahepatic causes of portal hypertension are diverse. Some conditions predominantly affect the venous circulation through the liver (e.g. hepatoportal sclerosis, schistosomiasis, and veno-occlusive disease), but the majority are intrinsic diseases of the liver (e.g. cirrhosis, fibrosis, nodular hyperplasia).

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Hepatoportal sclerosis In a small proportion of children with portal hypertension the portal vein is patent but there is presinusoidal venous obstruction from subendothelial thickening of intrahepatic portal venous radicles (Mikkelsen et al. 1965; Carson et al. 1981). There are striking similarities to idiopathic portal hypertension in Japan and non-cirrhotic portal fibrosis in India (Okudaira et al. 2002). Biochemical liver function is normal. Initially, liver histology is relatively normal but portal tract fibrosis subsequently develops. Angiography confirms intrahepatic portal vein obstruction. The aetiology of this condition is unknown. Most cases are not progressive and respond well to treatment of symptomatic oesophageal varices. Veno-occlusive disease In this form of hepatic venous obstruction, there is a toxic injury to the sinusoidal endothelium leading to occlusion of centrilobular veins and hepatic venules, sinusoidal congestion and hepatocyte necrosis. In the West Indies, South Africa, India and the Middle East the condition is associated with ingestion of toxins found in food or herbal teas. In western countries, veno-occlusive disease is seen after irradiation and/or cytotoxic drug-induced injury to the liver (Kullendorff & Bekassy 1996; DeLeve et al. 2002). A high incidence has been recorded in bone marrow transplant recipients. Clinical features are similar to the Budd–Chiari syndrome with rapid onset of painful hepatomegaly and ascites. If the child survives the acute stage, cirrhosis and portal hypertension may develop. After bone marrow transplantation, onset is usually manifest by jaundice, abdominal pain, ascites and weight gain within 1 month of grafting, but one-third of patients are asymptomatic (Shulman & Hinterberger 1992) (Chapter 15). Treatment is largely supportive and includes the administration of diuretics and N-acetylcysteine. Thrombolytic therapy is of limited benefit, but defibrotide, a drug with antithrombotic and thrombolytic properties, has shown promise in uncontrolled studies (Chopra et al. 2000). Lowdose heparin and ursodeoxycholic acid may have prophylactic roles (Attal et al. 1992; DeLeve et al. 2002). Cirrhosis and congenital hepatic fibrosis (see Chapters 9 and 14) Biliary atresia is the commonest cause of portal hypertension in this category, but there are many other conditions including cystic fibrosis, autoimmune hepatitis, a1-antitrypsin deficiency, and congenital hepatic fibrosis. Posthepatic Budd–Chiari syndrome This is due to hepatic venous thrombosis, typically secondary to an underlying myeloproliferative disorder or thrombophilic state (Valla 2002). Most patients are young adults and the condition is rarely

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seen in children (Gentil-Kocher et al. 1988). In adolescent girls, the oral contraceptive pill may precipitate onset. Similar clinical features develop after hepatic vein occlusion from trauma, malignancy or surgery and with retrohepatic IVC obstruction. Clinical features include hepatomegaly, intractable ascites, symptoms and signs of portal hypertension, and progressive cachexia. Jaundice is variable. The caudate lobe is frequently spared because of its independent venous drainage directly into the IVC. Caudate lobe hypertrophy may compress the cava causing lower limb oedema (see Plate 74, Atlas: p. 466). Onset may be acute (when symptoms of abdominal pain, distension and diarrhoea may be severe), but is more often chronic. Chronic constrictive pericarditis Chronic constrictive pericarditis may cause liver damage similar to that seen in chronic Budd–Chiari syndrome. Echocardiography should help to confirm the diagnosis. Treatment, which may include pericardectomy, leads to progressive resolution of the hepatic changes. Investigation Haematology A full blood count may show anaemia, leucopenia and/or thrombocytopenia from hypersplenism. The prothrombin time is commonly prolonged in patients with intrinsic liver disease or Budd–Chiari syndrome. In PVO, the prothrombin time is often slightly prolonged in association with a reduced factor VII concentration. The presence of reduced procoagulant and anticoagulant protein concentrations in PVO is probably due to reduced portal blood flow and/or portosystemic shunting (Fisher et al. 2000). In patients with Budd–Chiari syndrome, an underlying myeloproliferative disorder or thrombophilic state should be excluded by bone marrow aspirate, and estimation of Protein C, S, factor V Lieden and lupus anticoagulant. Biochemical liver function tests In PVO, plasma albumin may be reduced following a variceal bleed but biochemical liver function is essentially normal. Intrahepatic diseases usually cause abnormal liver function but routine biochemistry can be normal in well-compensated cirrhosis. In Budd–Chiari syndrome, both liver and renal function may be disturbed. Abdominal ultrasound scan This confirms non-specific features of portal hypertension such as large collateral veins and splenomegaly. Hepatic echotexture may indicate the presence of chronic

liver disease. Colour Doppler flow studies provide information on the direction and velocity of flow in the portal vein, hepatic veins and vena cava. Gastrointestinal endoscopy Endoscopy can be used to evaluate gastro-oesophageal and anorectal varices and mucosal features of portal hypertension at all ages. Oesophageal varices are graded according to severity. Large varices may show ‘red signs’ of recent or impending variceal haemorrhage; these stigmata include ‘cherry-red spots’ and ‘varices on varices’ (see Plate 48b , Atlas: p. 457). Portal gastropathy is characterized by mucosal hyperaemia and dilated submucosal veins. CT and magnetic resonance imaging Both modalities are useful in evaluating focal liver lesions associated with portal hypertension and in Budd–Chiari syndrome. In the latter, the findings depend on the duration and degree of venous obstruction; in chronic cases, there is splenomegaly and ascites and the liver parenchyma shows patchy contrast enhancement and caudate lobe hypertrophy. In PVO a variable degree of liver atrophy may be seen. Angiography Magnetic resonance angiography is being increasingly used as a non-invasive alternative to conventional angiography. It confirms the diagnosis of PVO and assesses the patency and calibre of veins throughout the portomesenteric system. Angiography is particularly important when considering portosystemic shunt surgery and when assessing patients with a thrombosed or abnormal portal vein before liver transplantation. Conventional angiography can be performed by several routes but the commonest is by indirect portography. A fine catheter is inserted percutaneously via the femoral artery and the coeliac axis and superior mesenteric arteries are injected with contrast; the portal venous system is imaged by digital subtraction. Direct splenoportography after percutaneous needle puncture of the spleen also enables the measurement of splenic pulp pressure (an index of portal hypertension) but achieves less reliable imaging of the portomesenteric veins and carries a risk of splenic complications. Percutaneous transhepatic portography is occasionally used. Hepatic venography shows a typical ‘spider web’ pattern of venous collaterals around hepatic vein thrombosis in Budd–Chiari syndrome. Inferior vena cavography or magnetic resonance venography may be necessary to determine patency of the IVC.

Chapter 18: Surgical Disorders Percutaneous liver biopsy If there are no contraindications a biopsy is usually undertaken to diagnose any underlying liver disease. In extrahepatic PVO, the liver architecture is normal but mild periportal fibrosis may be seen. In hepatic vein obstruction, liver biopsy typically shows marked venous congestion around central venules with hepatocyte necrosis; in chronic cases, there is progression to hepatic fibrosis and cirrhosis. Management If portal vein thrombosis develops acutely and is diagnosed promptly, treatment may restore normal patency. Rehan et al. (1994) reported a neonate with acute portal vein thrombosis secondary to umbilical vein catheterization which was successfully treated with a regional streptokinase infusion. Parker et al. (2002) described two neonates with idiopathic portal vein thrombosis that responded well to anticoagulation. In established portal hypertension treatment includes the emergency management of active bleeding and the prevention of recurrent bleeding after a first episode (secondary prophylaxis). Primary prophylaxis should be considered in patients who have never bled. In children with good liver function and bleeding varices (e.g. PVO or congenital hepatic fibrosis) treatment is focused on portal hypertension, whereas in cirrhotic patients management is heavily influenced by the severity of their liver disease.

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Table 18.6 A guide to the emergency management of bleeding oesophageal varices. Resuscitation • Airway (must be secure) • Breathing (give oxygen if shocked) • Circulation: insert two intravenous cannulae (22 G or larger) and commence intravenous fluids (5% dextrose if well perfused, colloid if poorly perfused) Investigation • Full blood count, clotting, urea, creatinine, electrolytes, liver function tests • Blood cultures and cross-match (at least 2 units of packed red cells) • Monitor and maintain blood glucose • Accurate monitoring of (a) fluid balance and (b) cardiorespiratory status • Watch for encephalopathy Treatment • Nil by mouth • Ranitidine 1 mg/kg i.v. t.d.s. and oral Sucralfate • I.v. antibiotics if evidence of sepsis • Ensure appropriate sized paediatric Sengstaken tube available • Transfuse packed red cells slowly aiming for Hb approximately 10 g/dl (avoid overtransfusion) • Give vitamin K 1–10 mg slowly i.v. • Correct coagulopathy with fresh frozen plasma and platelets • Octreotide infusion: bolus dose of 1 mg/kg i.v. (maximum 50 mg) over 5 min followed by infusion @ 1–3 mg/kg/h (maximum 50 mg/h) via dedicated line. Continue infusion until 24 h after bleeding ceases and wean off slowly over 24 h • Consider prophylaxis against encephalopathy if poor liver function • Urgent upper GI endoscopy within 24 h to confirm source of bleeding and to treat varices by banding or sclerotherapy

Emergency management of variceal bleeding (Table 18.6 and Chapter 14; Fig. 14.4) Bleeding from oesophageal varices is life threatening and requires hospital admission. Mortality is closely related to the severity of any underlying liver disease. Somatostatin reduces splanchnic blood flow and portal pressure with minimal short-term side-effects, but its plasma half-life is less than 3 min. Octreotide, a longacting analogue of somatostatin, has a plasma half-life of more than 1 h and has largely superseded vasopressin and terlipressin, which have side-effects from systemic vasoconstriction. Most, but not all, studies in adults have shown that octreotide is effective in controlling acute variceal bleeding, particularly when used in combination with endoscopic therapy (Abraldes & Bosch 2002). Balloon tamponade is rarely required to control active variceal bleeding. ASengstaken-type tube can be inserted by an experienced clinician after securing the airway by endotracheal intubation. Only the gastric balloon is inflated and correct positioning must be verified by X-ray. Moderate traction is applied by taping the tube to the side of the face; excessive traction may cause mucosal ulcera-

tion or catastrophic balloon displacement. The balloon is deflated after 12–24 h at the time of endoscopy. Endoscopic treatment of oesophageal varices Injection sclerotherapy Introduced by Crafoord and Frenckner in 1939, endoscopic injection sclerotherapy (EIS) is now a standard technique for inducing variceal thrombosis. With modern fibreoptic endoscopes, EIS is applicable to all age groups and is best performed under general anaesthesia with an endotracheal tube in place. A variety of injection techniques and sclerosants have been used (Stringer 1998). The author prefers a predominantly intravariceal injection using 5% ethanolamine oleate. Between 1 and 3 ml of sclerosant are injected into each of the major variceal columns just above the gastrooesophageal junction (Howard et al. 1988; Stringer 2002c) (Fig. 18.4a). In small children, care must be taken not to over-distend the stomach with air. Varices are initially injected every 1–2 weeks and then

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Fibreoptic endoscope

Needle sheath

Oesophago-gastric variceal columns (a)

Fig. 18.4 (a) Endoscopic injection sclerotherapy. (b) Endoscopic variceal ligation (see text for explanation).

at monthly intervals until sclerosis is complete. Patients are given oral Sucralfate for 48 h and Ranitidine for 2 weeks after each injection session to reduce complications from ulceration (Kumar et al. 1993). Endoscopic review is undertaken after 6 months and then annually, but only large recurrent varices require treatment. Tissue adhesives such as cyanoacrylate have been used as an alternative sclerosant in adults. This liquid preparation transforms into a solid after injection into a varix, thereby achieving haemostasis. It may be advantageous in treating gastric varices and endoscopically accessible ectopic varices. The possibility of post-injection venous embolization of cyanoacrylate is a potential concern in children (Roesch & Rexroth 1998). Efficacy, safety and late sequelae. EIS is a highly effective treatment for oesphageal varices. In one series of 108 children who presented with variceal bleeding, complete sclerosis was achieved in all 36 patients with PVO and in more than 90% of those with chronic liver disease who did not require transplantation (Howard et al. 1988). A mean of five to six injection sessions was required. Long-term efficacy was assessed in 32 of the children with PVO at a mean follow up of 9 years after complete sclerosis

(b)

(Stringer & Howard 1994). Recurrent variceal bleeding developed in 10 (31%), half of whom were effectively controlled by further sclerotherapy. Gastric variceal bleeding was managed by portosystemic shunt surgery in four (13%). Two patients required a splenectomy for symptomatic hypersplenism. EIS alone was effective in more than 80% of cases. Others have reported similar favourable long-term outcomes (Paquet & Lazar 1994). Complications. Transient retrosternal discomfort and fever are common after EIS and usually resolve within 48 h. Children with a pyrexia > 38°C should be treated with intravenous antibiotics pending the results of blood cultures because they may have transient bacteraemia (Sauerbruch et al. 1985). Antibiotic prophylaxis is given to patients at risk of bacterial endocarditis, those with cirrhosis and ascites, and those who are immunosuppressed. Major complications of sclerotherapy include oesophageal stricturing (which responds to dilatation), recurrent oesophageal varices, and interim bleeding (Howard et al. 1988). The latter is usually due to a nonthrombosed varix or an injection ulcer. Complication rates have fallen in recent years, probably as a result of injecting smaller volumes of sclerosant. Some children experience intermittent dysphagia and heartburn secondary to oesophageal dysmotility and gastrooesophageal reflux (Greenholz et al. 1988). Dissemination of the injected sclerosant causing distant complications

Chapter 18: Surgical Disorders Table 18.7 Reported complications of endoscopic injection sclerotherapy for oesophageal varices (Stringer 1998). Variceal haemorrhage (uncontrolled or recurrent varices) Oesophageal ulceration and stricture Oesophageal perforation and mediastinitis Oesophageal dysmotility and gastro-oesophageal reflux Broncho-oesophageal fistula Pleural effusion/chylothorax Respiratory distress syndrome Pulmonary collapse/consolidation Pericardial effusion/tamponade Portal, splenic or mesenteric vein thrombosis Paraplegia Cerebral abscess Digital gangrene Bacteraemia/septicaemia Anaphylaxis Renal failure

has been rarely reported (Table 18.7). The potential longterm risk of neoplasia is a concern but there are very few reports of this potential association (Kokudo et al. 1990) and systematic studies have failed to support a link (Dina et al. 1992).

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varices at each session; the treatment is repeated after 1–2 weeks and then monthly until the varices have been obliterated. Multi-band devices allow the application of several bands with one pass of the endoscope (McKiernan et al. 2002). In adults, EVL is regarded as the method of choice for treating active variceal bleeding and for preventing rebleeding from oesphageal varices. Whilst EVLand EIS are similarly effective, EVL offers more rapid eradication with fewer treatment sessions and lower complication rates. Oesophageal ulcers caused by banding are more superficial and resolve quicker than those induced by sclerotherapy (Young et al. 1993), and the incidence of oesophageal stricture and systemic complications is less (Helmy & Hayes 2001). Several small studies have confirmed the safety and efficacy of EVL in children (Fox et al. 1995; Price et al. 1996; McKiernan et al. 2002). Variceal eradication is achieved after a median of two to four sessions. Reported complications have included interim bleeding, oesophageal perforation, and recurrent varices. Currently, technical difficulties render the technique more hazardous in small children (< 10 kg) and if there is brisk bleeding. EVL and EIS are not mutually exclusive and a combination of both can be particularly useful in some children. Gastric varices

Ectopic varices The development of varices at sites other than the oesophagus or stomach (‘ectopic’ varices) poses a small risk of bleeding in the long term. This risk is greatest in PVO (Lebrec & Benhamou 1985; Heaton & Howard 1993). Ectopic varices are more common in the duodenum, at sites of previous intestinal anastomoses and around stomas. Bleeding from ectopic varices needs investigation by endoscopy and angiography. After local resection, recurrence is common and portosystemic shunting or liver transplantation, depending on the underlying pathology, are often required to control persistent bleeding. In contrast, significant bleeding from anorectal varices and haemorrhoids, which are found in up to onethird of children with portal hypertension (Heaton et al. 1993), is uncommon and can often be controlled by local measures such as injection sclerotherapy or banding. Variceal ligation (banding) In this technique, the varix is aspirated into a transparent cylinder fitted to the end of a flexible endoscope and an elastic band is released by a trip wire passing through the biopsy channel (Fig. 18.4b). Introduced by Stiegmann and Goff in 1988, endoscopic variceal ligation (EVL) causes strangulation of the varix which then thromboses and sloughs. Treatment begins with ligation of the most distal varix in the oesophagus just above the cardia. Up to four bands are applied to the

Many gastric varices are fundal and directly contiguous with lower oesphageal varices. Most are present at the initial endoscopy and are eradicated during the treatment of oesophageal varices. However, 5–10% of patients develop significant gastric varices after treatment of oesophageal varices by EIS. Bleeding from gastric varices may respond to EIS, but this is much less likely if the gastric varices are isolated and not contiguous with oesophageal varices (Sarin 1997). Alternative sclerosants, such as bovine thrombin and cyanoacrylate, have been used successfully in adults (Binmoeller & Borsatto 2000) but have not been evaluated in children. Banding of gastric varices is associated with a high rebleeding rate. If sclerotherapy is ineffective or inappropriate, then surgical shunting or a local devascularization procedure should be considered in those with satisfactory liver function (Heaton & Howard 1993). Surgery for portal hypertension Surgical shunts Shunt surgery and endoscopic therapy are complementary procedures in the management of portal hypertension. Indications for surgery are: • uncontrolled bleeding from oesophageal varices (not responding to at least two sessions of banding or sclerotherapy) in children with PVO or those with chronic liver disease and reasonable liver function

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Section 9: Surgical Management of Liver Disease

Spleen

Kidney 1. (a) Distal splenorenal (Warren)

(c) Side-to-side splenorenal

2. Mesoportal (Rex)

(b) Proximal splenorenal

(d) Mesocaval

3. TIPSS

• bleeding gastric or ectopic varices that cannot be controlled endoscopically • massive splenomegaly causing severe hypersplenism or abdominal pain • lack of access to expert endoscopy. In a small proportion of children, venous anatomy or occlusion may preclude shunt surgery (Bismuth et al. 1980; Prasad et al. 1994; de Ville de Goyet et al. 1998). Many types of portosystemic shunt have been described but mesocaval and spleno-renal shunts have been used most often in children (Fig. 18.5.1). The distal spleno-renal (Warren) shunt is considered to be a selective shunt in that it achieves gastrosplenic variceal decompression whilst maintaining portal perfusion (Warren et al. 1974). Many

Fig. 18.5 Shunt procedures for portal hypertension. 1. Portosystemic shunts. (a) Distal splenorenal. (b) Proximal splenorenal. (c) Side-to-side splenorenal. (d) Mesocaval. 2. Mesenterico-left portal (Rex) shunt. 3. Transjugular intrahepatic portosystemic stent shunt (TIPSS).

reports describe children with diverse causes of portal hypertension undergoing different types of shunt procedures over long time periods. Table 18.8 compares recent results from larger series of children with PVO. The results of the mesocaval interposition shunt using a segment of autologous jugular vein have been generally good. Growth velocity frequently improves after successful portosystemic shunting (Kato et al. 2000). Shunt thrombosis is a major complication and frequently manifests as recurrent variceal bleeding. It is more likely in children under 5 years (Valayer & Branchereau 1998). Shunt patency may be assessed directly by: • colour Doppler ultrasound imaging of the shunt

Chapter 18: Surgical Disorders

349

Table 18.8 Recent results of surgical shunting in children with portal vein occlusion (PVO).

Type of shunt

Author

n

Operative mortality

Rebleeding/ shunt failure

Mesocaval shunt (using autologous vein)

Gauthier et al. (1989)*

54

2%

7% @ mean 3 years

Requires interposition graft (preferably autologous vein). Avoids ‘transplant field’. May be complicated by chylous leak.

Distal splenorenal shunt

Maksoud et al. (1991)

49

0%

12% @ 1–18 years

Avoids ‘transplant field’ and preserves spleen

Bismuth et al. (1980) Alvarez et al. (1983) Orloff et al. (1994)† Prasad et al. (1994)

52 32 34 160

0% 0% 0% 2%

6% @ mean 4 years 6% @ mean 3–4 years 12% @ 0–35 years 12% @ 1–15 years

(b) Side-to-side without splenectomy

Orloff et al. (1994)† Mitra et al. (1993)

75 104

0% 1%

0% @ 0–35 years 13% @ mean 4.5 years

Mesenterico-left portal (Rex) shunt

Gehrke et al. (2002)

51

0%

16% @ median 2 years‡ but only 3% with venous autograft

Central splenorenal shunt (a) End-to-side with splenectomy

Comment

Long-term hazards of splenectomy

Requires patent intrahepatic left portal vein and an interposition graft (preferably autologous vein)

*PVO in 70% cases. †53% of series were children. ‡Patency rate with venous autograft >·97%. N.B. The mesenterico-left portal shunt is a portal vein bypass and not a portosystemic shunt.

• magnetic resonance angiography • conventional angiography or indirectly by: • ultrasound examination of flow patterns in portomesenteric and systemic veins, and assessment of spleen size • improvement in hypersplenism as evidenced by an increase in platelet counts and a reduction in splenomegaly • endoscopic regression of oesophageal varices. Encephalopathy is a well-recognized complication of portosystemic shunt surgery in cirrhotics. Detailed long-term studies have demonstrated that the risk is extremely small in those with PVO (Prasad et al. 1994; Valayer & Branchereau 1998). Alagille et al. (1986) investigated a cohort of patients with PVO up to 24 years after portosystemic shunt surgery using a battery of clinical, psychometric, and encephalographic tests and found no instance of encephalopathy. Rarely, progressive pulmonary hypertension may develop in children with PVO after portosystemic shunt surgery (Levine et al. 1973). This may be a consequence of vasoactive substances bypassing the liver. The introduction of the mesenterico-left portal (Rex) shunt has significantly broadened the indications for shunt surgery in PVO (de Ville de Goyet et al. 1998). In this shunt, a vein graft is interposed between the superior mesenteric vein and the (intrahepatic) left portal vein which is located in the Rex recessus adjacent to the falciform ligament (Fig. 18.5.2). The portal vein occlusion is bypassed, hepatic portal blood flow is restored and portal hypertension is corrected. The operation demands the presence of an adequate calibre, patent intrahepatic left

portal vein and patent splenic and mesenteric veins; this must be established preoperatively by magnetic resonance angiography, ultrasound and/or retrograde hepatic venography. This shunt is a valuable option for selected children with PVO since it restores normal physiology. However, it is not feasible in all cases. Shunt failure is a potential problem but medium-term follow-up studies indicate that excellent results can be achieved with autologous vein grafts (Table 18.8) (Bambini et al. 2000; Gehrke et al. 2002). Non-shunt surgery Other surgical techniques to control variceal bleeding have been disappointing in the long term because of a high rate of rebleeding. Splenectomy alone, suture ligation of varices, and oesophagogastric transection have generally only yielded short-term success, except in gastric variceal bleeding from isolated splenic vein thrombosis when splenectomy may be curative. Radical devascularization procedures have been more successful (Uchiyama et al. 1994) but these often include splenectomy which renders the child susceptible to life-threatening infection. Splenectomy may be necessary for massive splenomegaly causing severe hypersplenism or abdominal pain, but shunt surgery should also be considered in such cases. Splenic embolization is an alternative but its effects may be temporary and the procedure is not without morbidity (Brandt et al. 1989). In cystic fibrosis-related portal hypertension, some authors have recommended partial splenectomy for hypersplenism (Thalhammer et al. 2003) but the validity of their procedure is unproven (Kelly & de Ville de Goyet 2003).

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Section 9: Surgical Management of Liver Disease

Liver transplantation Liver transplantation is the treatment of choice for most children with variceal bleeding complicating end-stage chronic liver disease. Endoscopic treatment of oesophageal varices provides effective control of haemorrhage in children with biliary atresia awaiting transplant (Stringer et al. 1989). However, sclerotherapy is best avoided immediately prior to transplantation (Vickers et al. 1989). In children with variceal bleeding from cystic fibrosis liver disease, endoscopic therapy and/or surgical portosystemic shunting are potential options if liver and lung function are well preserved (Stringer et al. 1993; Debray et al. 1999), but others are best managed by transplantation. Previous portosystemic shunting does not compromise survival after liver transplantation, although operative morbidity is less likely in those who have had a distal spleno-renal or mesocaval shunt, both of which avoid surgery around the porta hepatis (Mazzaferro et al. 1990). Surgery for Budd–Chiari syndrome Rarely, posthepatic portal hypertension has a radiologically or surgically treatable cause such as a caval web. Many children with hepatic vein thrombosis are successfully managed by medical therapy directed at controlling ascites and preventing progressive venous thrombosis (Valla 2002) (see Plate 74, Atlas: p. 466). Portal decompression is necessary for variceal bleeding, deteriorating liver function associated with zonal necrosis on liver biopsy, and intractable ascites. Portosystemic shunting converts the portal vein into a venous outflow tract. Occasionally, more complex shunts are needed in those with IVC obstruction (Stringer et al. 1989b). These procedures are potentially hazardous (Gentil-Kocher et al. 1988) and TIPSS is a less invasive alternative. Liver transplantation is indicated for fulminant liver failure or cirrhosis, but recurrence of Budd– Chiari syndrome in the graft is a risk and patients with thrombophilia usually require longterm anticoagulation (Srinivasan et al. 2002). Primary prophylaxis of variceal bleeding Beta-blockers Propranolol reduces portal pressure by causing splanchnic vasoconstriction and reducing cardiac output. Randomized controlled trials have shown it to be effective in preventing the first variceal bleed and rebleeding in adults with cirrhosis (Hayes et al. 1990; Binmoeller & Borsatto 2000). Uncontrolled studies in children suggest a possible benefit with few side-effects (Shashidhar et al. 1999) but there are no controlled data. If there are no contraindications to b-blockade (e.g. asthma), primary prophylaxis may be worthwhile in children with PVO or cirrhosis and large varices. Therapy should aim to reduce the resting pulse rate by 25%. Endoscopic therapy Prophylactic injection sclerotherapy is controversial. A small proportion of patients with PVO

never bleed. The single prospective, randomized controlled trial in children (predominantly with intrahepatic disease) showed no survival advantage for prophylactic sclerotherapy of oesophageal varices and suggested that treatment might promote bleeding from portal gastropathy or gastric varices which are less amenable to endoscopic treatment (Goncalves et al. 2000). Trials of prophylactic sclerotherapy in adults with cirrhosis have yielded conflicting results (Binmoeller & Borsatto 2000), whilst those with banding have shown a benefit compared with no active treatment (Lay et al. 1997). However, a definite advantage of banding over b-blocker therapy has not been established and variceal recurrence after band ligation is a concern. At present, primary endoscopic prophylaxis cannot be recommended except in situations where a child may be returning to an environment where treatment is limited. Transjugular intrahepatic portosystemic stent shunt (TIPSS) This procedure involves the percutaneous insertion of a guide wire via the jugular vein into a hepatic vein. Under radiological guidance, a needle is then advanced over the wire from the hepatic vein into the right or left portal vein. A balloon catheter is used to dilate this intrahepatic tract and an expandable metal stent is deployed between the hepatic and portal veins (Fig. 18.5.3) (see Plate 48c, Atlas: p. 457). The indications for TIPSS in children include refractory acute variceal bleeding and recurrent variceal bleeding in those awaiting liver transplantation (a ‘bridge to transplantation’) (Heyman & LaBerge 1999). Selected patients with Budd–Chiari syndrome or intractable ascites may also benefit. Portal vein occlusion and uncorrected coagulopathy are contraindications. In adults, the technique is effective and associated with low procedural complication rates, but major risks include stent occlusion and hepatic encephalopathy (Jalan et al. 2000). The incidence of stent occlusion increases with time. Prophylactic stent dilatation may help to maintain long-term patency. These and other complications and the technical demands of the procedure have limited its role in children. Nevertheless, TIPSS has been successfully performed in children as young as 3 years and as small as 13 kg (Heyman & LaBerge 1999). Long-term patency rates in children are not yet known.

Liver trauma After the spleen the liver is the most commonly injured solid abdominal organ. Damage may result from blunt, penetrating or iatrogenic trauma and mortality rates are related to the type of insult. Additional injuries to the head, thorax, and limbs are not uncommon in cases of blunt hepatic trauma, which is associated with a consid-

Chapter 18: Surgical Disorders erable amount of force. Road traffic crashes account for the majority of blunt liver injuries in children, followed by recreational accidents and damage secondary to child abuse. Diagnostic procedures such as needle biopsy may occasionally result in significant haemorrhage from the liver parenchyma. In many series of patients with severe abdominal trauma the liver, which is damaged in approximately 30% of cases, is the most commonly injured organ (Stone & Ansley 1977). The damage may result from blunt or penetrating trauma (Table 18.9); the latter is unusual in children and accounted for only 4% of 328 injuries (Gross et al. 1999). It is noteworthy that more than half of the penetrating injuries reported in North American series are the result of gunshot wounds. Mortality rates are greater after blunt than after penetrating trauma. There is little protection from flexible ribs and major disruption of the organ may occur without any associated rib fractures. The right lobe is injured four times more frequently than the left lobe, the posterior segments being the most vulnerable. Mikeskey et al. (1956) estimated that up to 40% of young children with major liver injuries died before, or soon after, reaching hospital. The risk to the liver of seat-belt compression during rapid deceleration of motor vehicles has been reported in recent years. The mechanism of injury includes compression of the thorax and abdomen, hyperflexion of the trunk and shearing of the peritoneal attachments of the liver. The children may present in the emergency department with evidence of intraperitoneal haemorrhage and a ‘seat-belt sign’ of bruising across the chest and abdomen.The severity of the injury is related to the impact speed of the vehicle and may occur with all types of restraint such as lap belts, lap-and-shoulder belts, and even child car seats (Tso et al. 1993). It should be emphasized, however, that all these restraints minimize the frequency of head injuries. Tso et al. (1993) reviewed 42 injured children aged between 2 months and 15 years who had been restrained automobile passengers. Twenty-six (62%) had sustained significant intra-abdominal injuries even though they were wearing seat belts. Nineteen (45%) had visible belt-related bruising of the abdominal

Table 18.9 Causes of liver injury in 328 children admitted to a North American regional trauma centre in a period of 13 years (Gross et al. 1999). Cause Pedestrians struck by vehicles Vehicle passengers Falls or blows to abdomen Bicycle injuries Child abuse Penetrating injuries

Percentage of all injuries 39 34 13 5 5 4

351

wall and visceral injuries included spleen, bowel, kidney, stomach and pancreas. Five had sustained liver injuries. Recreational injuries are an important cause of trauma in children. Clarnette and Beasley (1997) reviewed 32 cases of bicycle injury seen over a 5-year period. Liver trauma was identified in nine cases. The authors pointed out that subcutaneous bruising was a poor indicator of underlying organ damage. They suggested that the small cross-sectional area of the handlebar results in a powerful impact to a small area of the abdominal wall, which is enough to cause organ rupture. Parenchymal liver damage is well recognized as a possible sequel of child abuse. There may be no obvious external signs of trauma on the abdominal wall and the clinical history is commonly unclear or misleading. There is a high mortality rate associated with this type of injury and many of the victims die before they reach hospital (Gornall et al. 1972). Cooper et al. (1987) pointed out that although there were only 22 cases of child abuse in a review of 8000 cases of paediatric trauma, the mortality in the group, which included six cases of liver trauma, was 45%. Subcapsular hepatic haematomas may present in the newborn period and were identified in 118 (15%) of 783 neonatal autopsies by French and Waldstein (1982). The aetiology is probably a combination of abdominothoracic compression during delivery and decreased clotting function. In 31 cases the lesions were > 3 cm in diameter and in one baby there was intraperitoneal haemorrhage from rupture of the liver capsule. The haematomas are recognized 2–5 days after birth from the association of hepatic enlargement and anaemia. Occasionally an affected infant may become shocked and the intraperitoneal blood may cause discoloration of the periumbilical region and/or the scrotum. The diagnosis is confirmed with ultrasound and CT scanning (Iino et al. 1981). If surgery is required, perihepatic packing is the treatment of choice, with removal of the packs after 48 h. Presentation and investigation Trauma to the liver may be suspected from: • signs of bruising over the upper abdomen or right chest wall, and • peritonism and/or shock may be present • seat-belt marks may be observed and it is important to suspect intra-abdominal or thoracic injury • signs of child abuse such as multiple bruises, poor nutrition and unexplained fractures (Cooper et al. 1987). Investigations: • Plain X-rays are of limited value except in detecting foreign bodies such as bullets after penetrating trauma. • Ultrasonography is quick, portable, and does not expose the child to ionizing radiation but it is operator dependent. It can accurately detect free intraperitoneal fluid. However, solid organ injuries may be overlooked in

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Section 9: Surgical Management of Liver Disease

as many as one-third of patients (Coley et al. 2000). Ultrasound is useful in the subsequent monitoring of children with blunt liver injury managed non-operatively. Other investigation include CT, peritoneal lavage, radionuclide scanning, and angiography, and only a minority of very unstable patients cannot undergo at least one of these tests. Appropriate tests are essential, as the initial clinical evaluation of a child with abdominal trauma may be incorrect in approximately 25% of cases (Meyer & Crass 1982). • An abdominal CT scan is the investigation of choice after major blunt abdominal trauma in the haemodynamically stable child (Advanced Paediatric Life Support 2001). Although there is debate about the value of oral contrast (Shankar et al. 1999), intravenous contrast is invaluable. CT allows the visualization of parenchymal tears (see Plate 75, Atlas: p. 467), disruption of major blood vessels, and an assessment of the volume of any free intraperitoneal blood. Non-perfused liver segments may also be detected (Vock et al. 1986). As well as providing an assessment of liver damage, CT may allow the identification of injuries to other organs, including the diaphragm. It also assists in the detection of late complications such as bile leaks and abscess formation. • Diagnostic peritoneal lavage is potentially misleading in children because the presence of intraperitoneal blood is not by itself an indication for laparotomy (Advanced Paediatric Life Support 2001). However, in centres without ready access to CT scanning, it remains a sensitive method of detecting free blood in the abdomen and may be helpful in selected cases of blunt abdominal injury. • Laparoscopy may have a role in selected patients, but its accuracy is limited and it should not be used to supplant well-validated, non-invasive imaging techniques (Elliott et al. 1998). • Liver scintiscanning is particularly valuable in the diagnosis and management of biliary tract injuries after blunt abdominal trauma (Sharif et al. 2002). • Angiography is useful for the assessment of complex hepatic trauma, but its most valuable role lies in the mangement of severe bleeding and the complication of haemobilia with arterial embolization. A suspicion of liver injury may be raised by a rapid rise in blood transaminase levels, and Hennes et al. (1990) reported that the sensitivity and specificity of elevated enzymes were 100% and 92.3%, respectively. Management (Fig. 18.6) In recent years it has become clear that the majority of liver injuries in children can be managed either nonoperatively or with the aid of relatively simple surgical procedures. In contrast, the small number of cases with severe parenchymal disruption require a high degree of radiological and surgical expertise, and the mortality

rates in these children may be greater than 30%. The trend towards conservative management was highlighted in an early report by Richie and Fonkalsrud in (1972), in which they described four cases of subcapsular haematoma that had resolved without surgery. Stone and Ansley (1977) also reported that bleeding had ceased spontaneously before laparotomy in 67.5% of 203 liver injuries. In the latter series resection of liver tissue was necessary in only 8% and simple packing of the liver wounds with omentum was all that was required to achieve haemostasis in the remainder. The results of treatment were clearly related to the cause of trauma: mortality rates for shotgun injuries were 25%, for blunt trauma 19% and for stab wounds 1%. Non-operative treatment Non-operative treatment of blunt liver injury is now the accepted policy of management provided haemodynamic stability is maintained after initial resuscitation. Careful observation, frequent monitoring and precise fluid management are essential. Additional requirements are nasogastric decompression, antibiotics, bed rest, transfusion, and ready access to an operating theatre. Children with evidence of continuing intra-abdominal bleeding require urgent laparotomy, as do those with bowel perforation or deep penetrating trauma. Recent guidelines suggest that a transfusion requirement of > 25 ml/kg in the first 2 h after injury has a predictive accuracy of 88% and 95% for operative intervention and for major hepatic disruption (Gross et al. 1999). Using this strategy 87% of 328 patients were managed conservatively with a mortality rate of 17%. Associated severe injuries and sepsis caused most of the deaths and only three were related to the liver trauma. A further review of 140 cases of nonoperative management revealed a 14% complication rate which included haematoma rupture, infection, bile leaks and three (2.1%) deaths (MacGillivray & Valentine 1989) (Table 18.10). After major liver injuries, observation usually continues in hospital for 7–10 days. Evidence-based guidelines (Stylianos 2000) suggest that children with uncomplicated isolated liver injuries can be discharged home sooner (after 5 days), but activity should be restricted for 3–6 weeks and contact sports avoided for 2–3 months. Usually the damaged parenchyma and surrounding haematoma is absorbed to form localized collections of fluid within weeks, and these resolve over the following 3–4 months. Surgical treatment Although non-operative management is successful in the majority of children with blunt liver trauma, a small proportion require urgent operative intervention for persistent bleeding. The need for emergency surgical

Chapter 18: Surgical Disorders

353

Stabilization and crystalloid resuscitation 20 ml/kg

Unstable

Haemodynamically stable

20 ml/kg

Unstable

10 ml/kg PRBCs (repeat prn)

Unstable

Fig. 18.6 An algorithm of the management of liver trauma incorporating conservative and surgical treatment. (PRBCs, packed red blood cells.) The haemodynamically unstable child who becomes stable after volume replacement can undergo computed tomography scan. Resuscitation volumes may need to be adjusted in the presence of additional blood loss in polytrauma.

Penetrating injury Peritonitis

Free air

Unexplained deterioration with a significant amount of abdominal fluid

Table 18.10 Nineteen (13.6%) complications encountered during the conservative management of 140 children with liver trauma (MacGillivray & Valentine 1989). Bile leak Ruptured haematoma Haemobilia Pneumonia Abscess Septicaemia Surgical intervention

>40 ml/kg PRBCs in 24 hours

Stable

5 3 2 2 1 1 5 (bile duct injury, infected haematoma, avulsed renal pedicle)

intervention is related more to the volume of intraperitoneal blood loss than to the extent of parenchymal disruption observed on a CT examination (Moulton et al. 1993; Reuss et al. 1995). In isolated blunt liver trauma, surgery should be seriously considered once volume replacement exceeds 40 ml/kg. Prompt arrest of major bleeding is critical to prevent prolonged hypotension, an abdominal compartment

Laparotomy

CT scan

Negative findings

Observation

syndrome with renal failure, and the secondary complications of coagulopathy, acidosis and hypothermia, all of which exacerbate haemorrhage. Intraoperative use of a cell saver, rapid infusers and blood warmers is helpful. Rapid exposure of the abdominal cavity is achieved by a mid-line incision (or a broad transverse incision in a small child). Confirmation of the nature of the liver injury is followed by compression of the hepatic artery and portal vein in the porta hepatis (the Pringle manoeuvre), together with local packing to reduce bleeding from the torn parenchyma. This is followed by a rapid search for major injuries to other organs in the abdomen. Continued severe bleeding after the Pringle manoeuvre suggests the possibility of a tear in the IVC or hepatic veins (retro- or suprahepatic). Improved access to the liver can be obtained by subcostal extensions of the midline incision. Thoracotomy incisions are not necessary unless there is evidence of a major intrathoracic injury. Surgical resection of severely damaged liver requires wide exposure but is rarely required now that the efficacy of intraoperative perihepatic packing has been proven. A

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Section 9: Surgical Management of Liver Disease

key paper suggesting the value of the technique was published in 1981 by Feliciano et al. and reported the survival of nine out of 10 patients who had been treated with packing after other methods of obtaining vascular control had failed. Increasing application of the technique has established the value of emergency packing in arresting haemorrhage, reducing operating time, and reducing the incidence of complications from prolonged hypotension. Beal (1990) showed that 85% of liver injuries can be treated successfully and that mortality rates have declined to between 10 and 15%. Hepatic resection was necessary in only 10% of 683 patients, 50% of whom died. In contrast, packing was used in 29% of cases with severe injuries, including damage to the hepatic veins, vena cava and both lobes of the liver, with a mortality rate of only 14%. Interventional radiology Arterial embolization is widely used for the control of arterial bleeding in many organs and selective hepatic arterial occlusion has been used both as an adjunct to conservative management or as a preliminary manoeuvre to reduce haemorrhage before surgical exploration of the liver (Pain et al. 1991). Gorich et al. (1999) included embolization as part of their non-operative management of 26 patients with arterial bleeding whose ages ranged from 10 days to 77 years. Bleeding was controlled in 92% of cases. Pseudoaneurysms and arteriovenous fistulas, both rare complications of liver trauma, can frequently be managed by embolization techniques. Bile leaks are typically managed by percutaneous drainage with or without ERCP and temporary internal stenting of the bile ducts. In summary, most cases of blunt liver trauma in children can be successfully managed non-operatively. Interventional radiology plays a significant role in some patients. In the small proportion of cases who require surgical intervention, perihepatic packing should be the procedure of choice with removal of the packs after 24–48 h at a second laparotomy. Hepatic resection is now reserved for the occasional patient in whom bleeding is not controlled by packing. Acknowledgements The authors would like to acknowledge the contribution made to this chapter in the first edition of the book (1999), by Mr Mark Davenport, Consultant Paediatric Surgeon, King’s College Hospital, London.

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Tso, E.L., Bonnie, L. & Haller, J.A. (1993) Abdominal injuries in restrained pediatric passengers. Journal of Pediatric Surgery 28, 915–919. Tsuchida, Y., Honna, T. & Kawarasaki, H. (1994) Cystic dilatation of the intrahepatic biliary system in biliary atresia after hepatic portoenterostomy. Journal of Pediatric Surgery 29, 630–634. Uchino, T., Endo, F., Ikeda, S., Shiraki, K. & Sera, Y. (1996) Three brothers with progressive hepatic dysfunction and severe steatosis due to patent ductus venosus. Gatroenterology 110, 1964–1968. Uchiyama, M., Iwafuchi, M., Ohsawa, Y et·al. (1994) Long-term results after nonshunt operations for esophageal varices in children. Journal of Pediatric Surgery 29, 1429–1433. Urushihara, N., Todani, T., Watanabe, Y. et·al. (1995) Does hyperamylasemia in choledochal cyst indicate true pancreatitis? An experimental study. European Journal of Pediatric Surgery 5, 139–142. Valayer, J. (1996) Conventional treatment of biliary atresia: long-term results. Journal of Pediatric Surgery 31, 1546–1551. Valayer, J. & Branchereau, S. (1998) Portal hypertension: portosystemic shunts. In: Pediatric Surgery and Urology: Long Term Outcomes (eds M.D. Stringer, K.T. Oldham, P.D.E. Mouriquand & E.R. Howard), pp. 439–446. W.B. Saunders, London. Valla, D.C. (2002) Hepatic vein thrombosis (Budd–Chiari syndrome). Seminars in Liver Disease 22, 5–14. Verbeek, P.C.M., van Leeuwen, D.J., de Wit, L.T. et·al. (1992) Benign fibrosing disease of the hepatic confluence mimicking Klatskin tumours. Surgery 112, 866–871. Vessey, M. & Painter, R. (1994) Oral contraceptive use and benign gallbladder disease; revisited. Contraception 50, 167–173. Vickers, C.R., O’Connor, H.J., Quintero, G.A., Aerts, R.J., Elias, E. & Neuberger, J.M. (1989) Delayed perforation of the esophagus after variceal sclerotherapy and hepatic transplantation. Gastrointestinal Endoscopy 35, 459–461. De Ville de Goyet, J., Alberti, D., Clapuyt, P. et·al. (1998) Direct bypassing of extrahepatic portal venous obstruction in children: a new technique for combined hepatic portal revascularization and treatment of extrahepatic portal hypertension. Journal of Pediatric Surgery 33, 597–601. Vock, P., Kehrer, B. & Tschaeppeler, H. (1986) Blunt liver trauma in children: the role of computed tomography in diagnosis and treatment. Journal of Pediatric Surgery 21, 413–418. Voyles, C.R., Smadja, W.C., Shands, W.C. & Blumgart, L.H. (1983) Carcinoma in choledochal cysts. Age related incidence. Archives of Surgery 118, 986–988. Waldhausen, J.H.T. & Benjamin, D.R. (1999) Cholecystectomy is becoming an increasingly common operation in children. American Journal of Surgery 177, 364–367. Ware, R., Filston, H.C., Schultz, W.H. & Kinney, T.R. (1988) Elective cholecystectomy in children with sickle hemoglobinopathies: successful outcome using a preoperative transfusion regimen. Annals of Surgery 208, 17–22. Warren, D., Salam, A.A., Hutson, D. & Zeppa, R. (1974) Selective distal spleno-renal shunt. Archives of Surgery 108, 306–314. Watanabe, Y., Toki, A. & Todani, T. (1999) Bile duct cancer

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Chapter 19: Primary Hepatic Tumours BRUCE MORLAND AND JEAN DE VILLE DE GOYET

Epidemiology, 363 Aetiology, 363 Pathology, 365 Malignant tumours, 365 Benign tumours, 366 Malignant tumours, 367

Clinical features, 367 Diagnostic investigations, 367 Clinical staging, 369 Treatment, 369 Prognosis, 373 Benign tumours, 373

Liver tumours are relatively rare in childhood, but may be associated with a range of diagnostic, genetic, therapeutic and surgical problems sufficient to tax even the most experienced clinician. This chapter will outline the epidemiology, aetiology, pathology, initial work-up, and management of liver tumours, concentrating on the commoner malignant tumours, hepatoblastoma and hepatocellular carcinoma. Advice on the diagnosis and management of some of the benign tumours seen in children is included, with general guidelines on selection of patients for surgery or liver transplantation.

Epidemiology Table 19.1 indicates the nature and frequency of hepatic tumours seen in children (Weinberg & Finegold 1986). The incidence of hepatic tumours in childhood is consistently quoted from many series to be in the region of 0.5–2.5 per million population (Dimmick et al. 1994). Data collected from the West Midlands Regional Children’s Tumour Registry (Mann et al. 1990) have reported the incidence to be 1.2 per million person years. The incidence of hepatoblastoma (the commonest malignant tumour) was 0.77 and for hepatocellular carcinoma (HCC) it was 0.09, somewhat lower than other published series. Thus, on average in the UK, approximately 10–15 children with hepatoblastoma and one to two children with HCC are diagnosed each year. There is a male preponderance of 1.8 : 1 for all malignant tumours, consistent with other series. Hepatoblastoma presents in a younger age group, being an uncommon diagnosis over the age of 4 years. HCC has its peak onset in early adolescence, although the range is wide. The older age at onset for HCC may well reflect its close association with other underlying disease processes.

Haemangiomas and haemangioendotheliomas, 373 Mesenchymal hamartoma, 374 Adenomata, 374 Focal nodular hyperplasia, 374

Aetiology Many aetiological factors have been linked with the development of malignant hepatic tumours in childhood (Table 19.2). Broadly speaking, genetic influences are particularly important in the development of hepatoblastoma, whereas environmental factors and coexisting liver disease are strongly associated with HCC. The link between hepatoblastoma and congenital abnormalities, including Beckwith–Wiedemann syndrome and hemihypertrophy, is well described (Fraumeni et al. 1968; Geiser et al. 1970; Sotelo-Avila et al. 1980). Molecular interest has focused on the short arm of chromosome 11, and common genetic links with other embryonal tumours such as Wilms’ tumour and rhabdomyosarcoma. The WAGR (Wilms’ tumour, aniridia, genital anomalies and mental retardation) locus at 11p13 (Koufos et al. 1984) and a second Wilms’ tumour locus at 11p15.5 (Koufos et al. 1989) have been the stimuli for much of the research efforts. Loss of heterozygosity for a recessive allele at 11p15.5 in two patients with hepatoblastoma mapping to an area in the region of IGF-2 (insulin-like growth factor-2) has been demonstrated (Koufos et al. 1985). The loss of heterozygosity for 11p15.5 in a patient with Beckwith–Wiedemann syndrome and hepatoblastoma has also been reported (Little et al. 1988). This same locus has been linked with the development of rhabdomyosarcoma (Scrable et al. 1987). The likely mechanism for tumorigenesis is the loss of a tumour suppressor gene from this region. Other investigators have been able to demonstrate that as well as loss of heterozygosity, loss of genomic imprinting can result in hepatoblastoma (Rainier et al. 1995; Simms et al. 1995). There appears therefore compelling evidence to suggest a common genetic link between the pathogenesis of hepatoblastoma, rhabdomyosarcoma and some cases of Wilms’ tumour,

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Table 19.1 The incidence of hepatic tumours in childhood (after Weinberg & Finegold 1983). Type of tumour

Number

Percentage

Malignant Hepatoblastoma Hepatocellular carcinoma Sarcoma

532 284 79

43 23 6

166

13

75 22 22

6 2 2

57

5

Benign Haemangioma/ haemangioendothelioma Mesenchymal hamartoma Adenoma Focal nodular hyperplasia Other

Table 19.2 Conditions associated with hepatoblastoma and hepatocellular carcinoma. Hepatoblastoma

Hepatocellular carcinoma

Beckwith–Wiedemann syndrome Hemihypertrophy Familial adenomatous polyposis

Hepatitis B Hepatitis C Hereditary tyrosinaemia a1-Antitrypsin deficiency Cirrhosis secondary to biliary atresia Glycogen storage disease type 1 Neurofibromatosis

Gardner’s syndrome Glycogen storage disease type 1 Trisomy 18 Fetal alcohol syndrome Prematurity and low birth weight Maternal exposure to: oral contraceptives gonadotropins metals petroleum products paints and pigments Paternal exposure to: metals Meckel’s diverticulum

Familial adenomatous polyposis Drug/toxin exposure: androgens oral contraceptives methotrexate aflatoxins Fanconi’s anaemia

11p15.5 and the Beckwith–Wiedemann syndrome. The position, however, is far from clear and still requires further investigation. The fact that loss of heterozygosity can occur at several, separate 11p loci and that IGF-2 is not implicated in all tumours are examples of why confusion still reigns (Byrne et al. 1993). Other genes have now been implicated in the development of some cases of hepatoblastoma, particularly in cases associated with familial adenomatous polyposis coli (FAP) and Gardner syndrome, now mapped to chromosome 5q (Scrable et al. 1987; Little et al. 1988). It has

been suggested that as many as 5% of cases of hepatoblastoma may be associated with FAP (Scrable et al. 1987). There are important health implications for survivors of childhood hepatoblastoma with a family history of FAP. These children may have up to 50% incidence of adenomatous polyps in later life and it is important they receive appropriate screening. Other commonly observed genetic abnormalities seen in hepatoblastoma are trisomies of chromosomes 20, 2 and 8 (Stocker 1994), but due to the relative rarity of these tumours the frequency of genetic abnormalities has been difficult to determine. With newer, more sensitive techniques such as fluorescent in situ hybridization (FISH) it appears that such genetic abnormalities may occur in up to 50% of cases of hepatoblastoma (Surace et al. 2002). There is a strong link with HCC and infection with the hepatitis B virus (HBV). The incidence of HCC in chronic HBV carriers is approximately 100-fold greater than in the HBV-negative population (Hall et al. 1985) and is commoner in areas with high endemic HBV infection rates. Chen et al. (1988) reported 100% positivity for HBV infection in Taiwan, and Chan et al. (2002) 64% positivity in Hong-Kong from children with HCC, both areas with very high endemic levels of HBV infection. Although integration of the HBV genome into the HCC genome can be demonstrated at a molecular level (Brechot et al. 1980), this event in itself is not necessarily oncogenic and a secondary, as yet unidentified promoter, is probably necessary for the development of tumour. It has been postulated that such environmental influences may be the reason why the incidence of HCC varies geographically and may not simply be a reflection of the prevalence of endemic HBV infection (Perilongo et al. 1990). Recent evidence from the haemophiliac population (Darby et al. 1997) suggests that patients infected with the hepatitis C virus also have an increased cumulative risk of developing liver cancer and that this risk may be significantly increased with coinfection from HIV-1. The relationship between the development of HCC and cirrhosis is unclear. In general, although the histological features of HCC are similar to those seen in adults, in only about a third of paediatric cases is there underlying cirrhosis (Jones 1960; Czauderna 2002). This is in contrast to adult HCC, where 70–90% of tumours are associated with cirrhosis. In cases associated with tyrosinaemia type I, cirrhosis is an invariable finding (Weinberg et al. 1976). In cases associated with biliary atresia (Fraumeni et al. 1968; Kohno et al. 1995) the development of HCC is not universally associated with cirrhosis, and in cases of cholestasis which may not be associated with cirrhosis (e.g. arteriohepatic dysplasia) there appears to be no predisposition to malignant transformation. Thus, whilst the development of cirrhosis clearly has a part to play in oncogenesis, the exact relationship remains unclear. The finding of giant-cell hepatitis was at one stage thought to be the pre-

Chapter 19: Primary Hepatic Tumours malignant transformation important in the development of HCC, since this is commonly associated with a variety of hepatic pathologies (a1-antitrypsin deficiency, familial cholestasis, etc.). However, the lack of data supporting the onset of HCC in idiopathic giant-cell hepatitis sheds doubt on the exact mechanisms underlying malignant transformation.

Pathology Malignant tumours

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tiation (e.g. muscle fibres in rhabdomyosarcoma) and immunohistochemical techniques can help to distinguish between these tumours and undifferentiated hepatoblastoma. It appears that histology may be an important, independent prognostic factor and that patients with exclusively fetal pathology have improved survival (Finegold et al. 1994; von Schweinitz et al. 1994). On the other hand, unfavourable outcome may be associated with small cell undifferentiated histology (Haas et al. 2001) and variant hepatoblastoma with ‘cholangioblastic features’ (Zimmerman 2002 and personal observation).

Hepatoblastoma Historically, a number of classification systems have been used to define the pathological features of hepatoblastoma. Following the formation of the CELTIC group (Childhood Epithelial Liver Tumours — International Criteria) in 1990, international agreement has been sought on a number of issues, including histopathological classification of hepatocellular tumours, staging of tumours and definitions of response (MacKinlay & Pritchard 1992). The pathology working party of the CELTIC group has agreed on the classification of hepatoblastoma into four groups, based on the work of Weinberg and Finegold (1986). These are: fetal; embryonal; macrotrabecular; and small-cell undifferentiated (see Plate 77b, Atlas: p. 468). The pure epithelial tumours contain fetal cells, embryonal cells or admixtures of the two. Fetal cells are characterized by being smaller than normal hepatocytes with a low nucleo–cytoplasmic ratio and small nucleoli. Mitotic figures are usually uncommon and the cells form into canaliculi, which may contain bile. Some areas may contain abundant intracytoplasmic glycogen producing a lobulated appearance alongside the acidophilic cytoplasm of other areas of tumour cells. Embryonic cells are smaller and less well differentiated, have higher mitotic activity, scanty cytoplasm and little glycogen. The cells frequently form tubular structures and may resemble the early ducts of the embryonic liver. In many tumours a neoplastic mesenchymal component may accompany the epithelial cells. This usually takes the form of small immature spindle cells, but fibrous or osteoid stroma mimicking osteosarcoma can sometimes be seen. Tumours consisting entirely of malignant sarcomatous elements should be classified as hepatic sarcomas (see below). Macrotrabecular tumours commonly contain characteristic fetal cells separated by a macrotrabecular network, which can be indistinguishable from HCC. Undifferentiated tumours are characterized by small cells with scanty cytoplasm. These cells can be similar in appearance to other ‘small blue cell’ tumours of childhood such as neuroblastoma, rhabdomyosarcoma and lymphoma. Morphological features suggesting differen-

Hepatocellular carcinoma Macroscopically these tumours are usually multifocal and invasive, commonly involving both lobes and frequently associated with vascular invasion, extrahepatic extension or both at the time of diagnosis (see Plate 76, Atlas: p. 467). Areas of haemorrhage and necrosis are common and the lesions themselves vary in consistency from soft to firm. This significantly reduces the resectability rate. Czauderna et al. 2002) report only a 36% complete tumour resection rate in a series of 39 children collected by the International Society of Paediatric Oncology in a 4-year time period. The microscopic features distinguishing HCC from hepatoblastoma are the presence of tumour cells larger than normal hepatocytes, broad cellular trabeculae, considerable nuclear pleomorphism, nucleolar predominance, frequent tumour giant cells and absence of haematopoiesis (Weinberg & Finegold 1986; Haas et al. 1989). The fibrolamellar variant of HCC is probably a separate clinical entity. It arises in older children and young adults almost invariably in the absence of underlying cirrhosis. The prognosis for these tumours is more favourable than the normal variant of HCC. Histologically the tumour cells are plump with deeply eosinophilic cytoplasm and a marked fibrous stroma separating epithelial cells into trabeculae (Craig et al. 1980). Other malignant tumours Sarcoma The commonest malignant tumour apart from hepatoblastoma and HCC in childhood is the undifferentiated (embryonal) sarcoma, sometimes referred to as malignant mesenchymoma (Stocker & Ishak 1978). The lesions are usually large and single and may resemble benign mesenchymal hamartomatous lesions (see Plate 76e, Atlas: p. 467). The presence of extensive haemorrhage and necrosis usually indicates the malignant nature of these tumours. Although macroscopically the tumour may appear well demarcated from adjacent normal liver, there is usually extensive microscopic invasion. Micro-

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scopically the cells are spindle-shaped with elongated and irregular nuclei and an underlying myxoid stroma. Lack of rhabdomyoblastic differentiation may help in distinguishing from rhabdomyosarcoma, but it may be difficult to differentiate from other mesenchymal malignancies such as liposarcoma and chondrosarcoma. The exact relationship between undifferentiated sarcoma of the liver and benign mesenchymal hamartoma remains unclear. Anecdotal reports mention ‘malignant transformation’ of mesenchymal hamartoma or associated diseases (De Chadarevian et al. 1994; Lauwer et al. 1997; Ramanujam et al. 1999; Begueret et al. 2001). The exact position remains unclear, but the presence of common histological features at the periphery of malignant lesions (Stocker & Ishak 1983), presence of aneuploidy (Otal et al. 1994) and the recent finding that similar cytogenetic alterations may be found in both tumour types (Sawyer et al. 1989; Speleman et al. 1989; Mascarello & Krous 1992; Bove et al. 1998) hint at this possible relationship. Apossible histogenetic link (common origin of benign and malignant tumours from undifferentiated mesenchymal cells) has also been postulated (Stocker & Ishak 1983; Weinberg & Finegold 1986; Parham et al. 1991). Rare tumours Rhabdomyosarcoma of both the biliary tree and liver parenchyma (Ruymann et al. 1985; Horowitz et al. 1987), primary rhabdoid tumour of the liver (Parham et al. 1988), primary non-Hodgkin’s lymphoma of the liver (Miller et al. 1983), hepatic liposarcoma (Soares et al. 1989) and germ cell tumours of the liver (Mann et al. 1989) have all been described in children but are extremely rare findings (see also Chapter 18).

Benign tumours Vascular tumours The commonest benign tumours of the liver are vascular in origin. The lesions may be solitary or multiple. Histologically they may be divided into two groups (Dehner & Ishak 1971; Weiss & Enzinger 1982; Ishak et al. 1984), being haemangioma and haemangioendothelioma. Haemangioendotheliomas are divided into infantile or type I lesions, and epithelioid or type II lesions. Cavernous haemangiomas have no malignant potential and may be entirely asymptomatic, sometimes found routinely at autopsy in adults as well as children. The lesions usually comprise large, thin-walled channels lined with flat endothelium. Areas of calcification, thrombosis and fibrosis are commonly seen (Chapter 9). Infantile haemangioendothelioma (type I) is seen mostly in neonates and infants and can grow rapidly with various related clinical symptoms (hepatomegaly, congestive heart failure, Kasabach–Meritt syndrome, failure to thrive, jaundice or spontaneous rupture) (see Plate 34,

Atlas: p. 451). It consists of channels of varying size lined by often plump endothelial cells. Epithelioid haemangioendothelioma (type II) lesions appear more aggressive, demonstrating variability in endothelial cell size and shape with ill-formed vascular spaces, although mitoses are infrequent. There is a degree of overlap between types I and II, and both may show areas of fibrosis and calcification, but type II lesions are positive for factor VIIIrelated antigen. The latter helps in diagnosing type II tumours that are rare in children but appear as low-grade malignancies in the adult population and may have an even more aggressive behaviour in children (personal observations). The lack of vascular invasion and absence of mitotic activity usually make the differentiation between malignant angiosarcoma and haemangioendothelioma relatively easy. Mesenchymal hamartoma These lesions are usually found in children under the age of 2 years and commonly present with abdominal distension. The lesions, often very large in size, are not encapsulated and bulge into the adjacent parenchyma. Both solid and cystic areas are seen and there is a lack of haemorrhage and necrosis (see Plate 76e, Atlas: p. 467). Histologically there is an irregular, bland mesenchyme with variable vascularization. Biliary structures, often cystic, can be identified although there are no portal tracts present. The gelatinous stroma contains serous or viscous fluid and pseudolymphatic spaces can be identified. The lesions have been considered with no malignant potential (Srouji et al. 1978) (Chapter 9), but recent observations suggest a possible relation with sarcomas (see above). Focal nodular hyperplasia These rare benign tumours of childhood may be single or multiple. They are not encapsulated and are usually within the substance of the liver, although some have been reported to be pedunculated. The typical appearances are of a stellate fibrosis, the septae containing blood vessels and bile ducts with surrounding inflammatory infiltration. The hepatic parenchyma between the septae may be hyperplastic and may be confused with nodular regenerative hyperplasia (Stocker & Ishak 1981) (see Plate 78, Atlas: p. 468). Adenoma Hepatic adenoma in children shares the same features as in adults. They may occur at any age from birth, and have also been reported in the fetus in utero (Lack & Ornvold 1986). Whereas there is a strong correlation between oral contraceptive use and adult-onset hepatic adenoma, there appears to be no link between maternal use of

Chapter 19: Primary Hepatic Tumours contraceptives and childhood adenoma (Dehner et al. 1979). Adenomas have been reported in patients receiving anabolic steroids, in glycogen storage disease type I, familial diabetes mellitus, transfusion-related haemosiderosis, and galactosaemia. Histologically the lesions may be partially encapsulated and consist of thick cords of benign hepatocytes lacking portal structures and bile ducts. It may be difficult to distinguish between adenoma and well-differentiated HCC.

Malignant tumours Clinical features

367

toblastoma (Table 19.3). HCC tends to present at a slightly older age than hepatoblastoma and is very rare in infancy. Jaundice, whilst uncommon, occurs slightly more often in HCC than hepatoblastoma. Sexual precocity and osteoporosis are not features of HCC. Signs of underlying liver cirrhosis (splenomegaly from portal hypertension, spider naevi, etc.) should be sought as a possible clue to underlying aetiological factors. The rare fibrolamellar type of HCC is seen in an older age group (median age 26.4 years) (Craig et al. 1980) and occurs in non-cirrhotic livers. Abdominal mass is the commonest presentation and systemic symptoms are unusual. These tumours have a more favourable prognosis and are less likely to undergo early metastatic spread.

Hepatoblastoma Hepatoblastoma is most commonly seen in children under the age of 18 months and is rare after the age of 3 years. There is a male predominance of 3 : 2. The commonest presenting feature is of a palpable abdominal mass with abdominal distension, but other features including anorexia, weight loss, pain, vomiting and jaundice have been reported (Table 19.3) (Exelby et al. 1975; Mann et al. 1990). One of the more unusual presenting features of hepatoblastoma is its association with sexual precocity due to the release of human chorionic gonadotropic hormone (b-HCG) by the tumour. Osteoporosis is said to occur in up to 20% of cases and when severe can lead to bone fractures and vertebral compression (Teng et al. 1961). The tumour may rupture spontaneously producing an acute abdomen and haemoperitoneum. Physical examination should also focus on possible syndromes that may be associated with hepatoblastoma (Beckwith–Wiedemann, hemihypertrophy, etc.; see Table 19.2). History-taking should enquire about familial associations such as hereditary polyposis coli, drug and toxin exposure, etc. Hepatocellular carcinoma Clinical features are very similar to those seen with hepaTable 19.3 Signs and symptoms (%) of liver tumours in children.

Abdominal mass Weight loss Anorexia Pain Vomiting Jaundice

Hepatoblastoma (%)

Hepatocellular carcinoma (%)

71 24 22 18 13

58 21 22 16 10

7

10

Other malignant tumours Malignant mesenchymal tumours of the liver make up approximately 10% of the primary malignant tumours of childhood. The commonest of these is the undifferentiated (embryonal) sarcoma. Malignant mesenchymal tumours tend to present in a similar fashion with abdominal pain, mass and fever. The a-fetoprotein (AFP) is normal, there are no abnormalities of the full blood count and liver enzymes, and the serum bilirubin is rarely elevated. Epithelioid haemangioendothelioma is a rare and unique neoplasm, now considered a separate entity from haemangioma and angiosarcoma (Awan et al. 1996), and has a low-to-intermediate malignancy grade. It is mostly seen in young adults but can be observed in teenagers and children, in whom it seems to have a more aggressive behaviour with rapid growth and trend for extrahepatic spread (personal observations). Coincidental diagnosis is possible but most cases are diagnosed late with symptoms that relate to tumour growth: abdominal pain, Budd–Chiari phenomens, portal hypertension or liver failure. Since this tumour tends to be multifocal and widespread in the liver at diagnosis (Ishak et al. 1984; Makhlouf et al. 1999; Van Beers et al. 1992), only a limited number of cases can be considered for surgery. Diagnostic investigations Laboratory tests Full blood count Anaemia (usually normocytic, normochromic) is seen in at least 50% of children with hepatoblastoma (Lack et al. 1982; Mann et al. 1990). The platelet count is also often abnormal, with up to one-third of patients demonstrating thrombocytosis (often in excess of 1000 ¥ 109/l) (Shafford & Pritchard 1993), and fewer patients having thrombocytopenia. Thrombocytosis is thought to be related to increased levels of circulating thrombopoietin (Nickerson et al. 1980). Thrombocytosis

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is less common in HCC patients, but polycythaemia is sometimes seen. Liver function tests These are commonly normal in hepatoblastoma, but are more frequently abnormal in HCC, presumably due to the greater incidence of underlying cirrhosis or hepatitis (Exelby et al. 1975; Lack et al. 1982). a-Fetoprotein AFP is a useful diagnostic and prognostic marker and can be helpful in monitoring disease progress and response to therapy. The developing fetus from 28 days’ gestation produces AFP, reaching maximum levels around 14 weeks. There is a steady decline to term, this fall continuing over the first year of life when normal adult levels are usually reached. AFP levels may be higher in premature infants. The vast majority of hepatoblastoma patients (Pritchard et al. 1982; Mann et al. 1990; Stringer et al. 1995) and over two-thirds of HCC patients (Chen et al. 1988) have elevated levels of AFP at presentation. Levels tend to be higher in patients with more bulky disease and metastases and therefore have prognostic significance. Return of AFP levels to normal following treatment indicates remission, while persistently abnormal results should alert the clinician to the possibility of residual tumour or relapse. Malignant yolk sac tumours may rarely present as a primary hepatic tumour. These tumours also secrete AFP and therefore the presence of elevated serum AFP is not specific for hepatoblastoma/HCC. b-HCG, if elevated at diagnosis may, like AFP, be used to monitor the response of hepatic tumours to therapy. Other markers The fibrolamellar variant of HCC is usually associated with normal values of AFP, but elevation of vitamin B12 binding proteins, especially transcobalamin I (Paradinas et al. 1982), makes them useful markers which may also be used to monitor disease response and progression (Wheeler et al. 1986). Other markers, including elevated urinary cystathionine, elevated serum cholesterol, insulin-like growth factor-2, ferritin, carcinoembryonic antigen and gprothrombin, have all been reported in malignant liver tumours, but are non-specific and of limited benefit in diagnosis and follow-up. Radiological imaging The radiological assessment of any childhood liver tumour will aim to determine the site and characteristics of the lesion, and establish the presence of any metastases, whilst also giving some indication of the suitability for surgical resection. Abdominal X-ray A plain X-ray of the abdomen will often show a mass effect from the hepatic lesion itself and in ad-

dition the presence of any calcification. This investigation provides very little diagnostic information alone, and since the majority of children will probably have an ultrasound or computed tomography (CT) scan as the firstline imaging method of choice, there is no requirement for it to be mandatory in all patients. Ultrasonography This will often confirm the lesion to be rising from the liver and help to distinguish between other common paediatric abdominal tumours presenting with a palpable mass (e.g. Wilms’ tumour and neuroblastoma). The size of the tumour can be defined and measured and information obtained on the presence of cystic features, which may be suggestive of a benign lesion. Vascular structures can be identified (hepatic arteries, hepatic veins, portal veins and inferior vena cava) and Doppler studies performed to confirm flow rates and patency. Ultrasonography may be particularly helpful in differentiating benign hepatic haemangiomas or haemangioendotheliomas by defining the vascular features of these tumours. However, the use of magnetic resonance imaging (MRI) scanning is now the preferred imaging technique for vascular tumours. Although some authors report a reasonable predictive accuracy for extent and resectability of liver tumours (de Campo & de Campo 1988) using ultrasound, the additional information gleaned from CT and/or MRI makes them additional mandatory explorations in the investigation of liver tumours. CT scan CT scanning gives detailed information on the anatomical limits of liver tumours. Intravenous contrast medium should always be used in order to define vascular landmarks and assess patency of vessels (see Plate 76a,b, Atlas: p. 467). Typically, malignant tumours are of low attenuation and demonstrate patchy enhancement with contrast. Vascular lesions may be hard to define without contrast but show dense peripheral enhancement with gradual filling of the central areas following intravenous contrast. CT scanning will also define the presence of para-aortic lymph node metastases, although these tend to be uncommon. MRI scanning This is now increasingly available, enabling comparisons to be made with CT scanning. MRI scanning gives good definition of tumour and surrounding infiltration, enabling accurate assessment of segmental involvement. This has important implications for clinical staging and any proposed surgical interventions. The vascular anatomy can also be demonstrated and may avoid the need for hepatic angiography. Hepatic angiography This may be required prior to surgery if the vascular anatomy has not been clearly demonstrated on MRI scanning.

Chapter 19: Primary Hepatic Tumours Chest X-ray A chest X-ray should be performed to exclude pulmonary metastases. If normal, a CT scan of the chest should be undertaken prior to commencement of therapy, since up to 50% of metastases may not be visible on chest X-ray alone (Stringer et al. 1995).

369

risk of ‘seeding’ malignant cells along the biopsy track, although the risk is greatest in hepatocellular tumours, which are less responsive to subsequent chemotherapy than hepatoblastomas. Clinical staging

Biopsy

The International Society of Paediatric Oncology (SIOP) has introduced a staging system based on preoperative assessment (Fig. 19.1) and the location of the tumour. The liver is divided into four sectors: the lateral and medial sectors of the left lobe, and the anterior and posterior sectors of the right lobe. The staging system divides patients into four groups depending on the sector(s) involved and also allows for vascular involvement of the portal veins and/or inferior vena cava (IVC), extrahepatic extension and distant metastases to be documented (Vos 1990).

Although clinical and laboratory clues can lead to a presumptive diagnosis in the majority of children with liver tumours, caution must be exercised at all times. For example, although a 2-year-old child with grossly elevated AFP and liver mass is most likely to have a hepatoblastoma, it is important to exclude other diagnoses such as malignant germ-cell tumour or HCC. This is particularly relevant when chemotherapy is being contemplated prior to definitive surgery. In the majority of cases therefore it is mandatory to take an initial biopsy. Due to the multifocal nature of many liver tumours a ‘blind’ biopsy may not yield samples containing tumour. It is therefore best to perform a percutaneous biopsy of the liver mass using a Tru-cut or Menghini needle under CT guidance. In addition, the use of imaging may alert the operator to bleeding from the biopsy site. Fine-needle aspiration may be unsatisfactory, as only minimal amounts of tissue may be obtained, which can be notoriously difficult to interpret with any degree of certainty. Caution must be exercised in attempting biopsies in lesions which are highly vascular and which clinically may be difficult to distinguish from a benign vascular anomaly and a highly vascular malignant tumour. In these circumstances, the safest approach is to undertake an open biopsy through a mini-laparotomy in order to be able to visualize the liver and treat any bleeding at the time of surgery. There is a

I

Fig. 19.1 The International Society of Paediatric Oncology pretreatment staging system. Groups I–IV indicate the number of liver sectors (1–4, respectively) involved by tumour. Additional information relating to venous infiltration, extrahepatic and metastatic spread is also provided.

Treatment Modern management of malignant hepatic tumours consists of a combination of chemotherapy and surgical resection, with the highest cure rates being associated with complete surgical resection. Chemotherapy Hepatoblastoma The 3-year overall survival rates of children with hepatoblastoma have improved from 25% to around 80% over the past 20 years as a result of progress in the evaluation of chemotherapy regimens (Exelby et al. 1975; Evans et al. 1982; Plaschkes et al. 1994). Whilst appreciating that surgical resection is essential for long-term cure, the emphasis of each therapeutic modality has

A1

A2

B1

B2

Three adjoining sectors FREE

A2

III

One sector or two non-adjoining sectors FREE

Two adjacent sectors FREE

IV

No FREE sectors

A1

B II

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Section 9: Surgical Management of Liver Disease High risk hepatoblastoma Diagnostic and staging procedures

CCDP alone x 1

Randomisation

Low risk hepatoblastoma

CCDP alone x 1

Super PLADO pre-operative phase

PLADO pre-operative phase

CDDP alone as in pre-operative phase

D E L A Y E D S U R G E R Y

Super PLADO post-operative phase

PLADO post-operative phase

CDDP alone as in post-operative phase

Fig. 19.2 Treatment plan for the SIOPEL-3 study chemotherapy: CDDP, cisplatin 80 mg/m2 every 14 days (four cycles preoperatively, two cycles postoperatively); PLADO, cisplatin 80 mg/m2; doxorubicin 60 mg/m2 every 21 days (three cycles + 1 CDDP alone preoperatively, two cycles

postoperatively); Super PLADO, (day 1), cisplatin 80 mg/m2, (day 15) carboplatin 500 mg/m2 and doxorubicin 60 mg/m2 (every 28 days); four courses CDDP, three courses Carbo/Dox preoperatively, two courses Carbo/Dox, one course CDDP postoperatively.

changed over time. Evans et al. (1982) noted that the use of postoperative adjuvant chemotherapy conveyed a survival advantage to children with completely resected hepatoblastoma and HCC, whereas the preoperative use of similar chemotherapy regimens in unresectable tumours was disappointing. Combinations of cyclophosphamide and vincristine (VCR) with other agents including Adriamycin, actinomycin-D and 5-fluorouracil (5-FU), demonstrated that despite initial response, only 12% of children were disease free at 2 years (Haas et al. 1989). The introduction of cisplatin in the early 1980s led to a consequent improvement in response rate in patients treated either with cisplatin alone or in combination with VCR/5-FU and in those who had proved resistant to previous chemotherapy (Douglass et al. 1985; Douglass et·al.1993). As Adriamycin (doxorubicin) had also been shown to be effective as a single agent (Weinblatt et al. 1982), chemotherapy regimens containing both cisplatin and doxorubicin (PLADO) were a logical step forwards (Ortega et al. 1991; Plaschkes et al. 1995). In the First International Society of Pediatric Oncology Liver Trial (SIOPEL-1), PLADO chemotherapy was tested in a multinational setting for the preoperative management of malignant liver tumours. The 5 years event-free and overall survival figures were 66% and 75%, respectively (Pritchard et al. 2000). In a large, randomized study from the Children’s Cancer Group and Pediatric Oncology Group (Ortega et al. 2000), PLADO chemotherapy was compared with cisplatin, 5-FU and VCR. No significant differences in overall or event-free survival (EFS) were seen between the two chemotherapy schedules, although PLADO consistently outperformed cisplatin/5-FU/VCR (5 years’ EFS 69% vs. 57%, P·= 0.09). More toxicity was observed in the PLADO arm, including two cardiac deaths from cumulative doses of 640 mg/m2

of doxorubicin, dose levels we today would never consider appropriate in these young children. On the basis of the improved results with PLADO chemotherapy the next large-scale study, SIOPEL-3, was planned to investigate a number of new questions and opened in 1998 (Fig. 19.2). Patients are stratified into lowrisk (PRETEXT I, II and III tumours without vascular invasion, extrahepatic disease or metastases) and highrisk tumours (all PRETEXT IV tumours and PTETEXT I, II or III with vascular invasion, extrahepatic disease and/or metastases). Low-risk tumours are randomized to PLADO vs. cisplatin alone whereas high-risk tumours are treated with ‘super PLADO’ which includes carboplatin in addition to cisplatin/doxorubicin. The results of the pilot study for this study (SIOPEL-2) have recently been published in abstract form (Pritchard et al. 2002; Zsiros et al. 2002). They suggest that cisplatin alone for a low-risk group of tumours is effective, with a response rate to chemotherapy of 90% and a 3-year overall survival of 91%. Conversely with the high-risk group of patients, super PLADO is delivering a response rate of 76% with a 3-year overall survival of 52%, suggesting this regimen is no more effective than the results of PLADO alone in SIOPEL-1 where the 5-year overall survival rates for PRETEXT 4 and metastatic patients were 57%. Clearly more effective chemotherapy regimens for this high-risk group are needed. PLADO chemotherapy has a number of problematic side-effects, and regular toxicity monitoring throughout treatment is essential. Doxorubicin is cardiotoxic in a cumulative, dose-dependent manner. Prolonged infusion of at least 48 h duration may reduce the cardiotoxic effects (Legha et al. 1982), and improve cytotoxicity by increasing drug exposure to tumour cells (Rich et al. 1979). Patients should have an echocardiogram before treatment, after

Chapter 19: Primary Hepatic Tumours alternate cycles of PLADO to a cumulative dose of 300 mg/m2, and then prior to each cycle of chemotherapy. This is particularly important if the child is subsequently considered for liver transplantation (see below). Current chemotherapy protocols try and restrict the cumulative doses of anthracyclines to 300 mg/m2. Cisplatin is both ototoxic and nephrotoxic. Regular monitoring of renal function by radioisotope clearance methods (chromium ethylenediamine tetraacetic acid) and serum electrolytes (e.g. hypomagnesaemia) is important. Audiograms are necessary to detect the onset of high-frequency hearing loss characteristic of cisplatin toxicity, which may produce profound speech and language delay in young children (Brock et al. 1988). Hepatocellular carcinoma Although traditionally HCC has been managed in a similar fashion to hepatoblastoma, the impact of chemotherapy is probably less well defined. There is no doubt that responses to PLADO chemotherapy may be achieved, with response rates in the order of 50% (Ortega et al. 1991; Plaschkes et al. 1995). Subsequent complete surgical resection, however, is only possible with a smaller percentage of HCC tumours than with hepatoblastoma. It is possible that the addition of carboplatin to PLADO and the emphasis on the importance of primary surgery planned in the present SIOP study may improve outcome (Shafford & Pritchard 1997). The fibrolamellar variant of HCC is usually a slowgrowing tumour, which metastasizes late and can be treated surgically without the need for adjuvant chemotherapy. The outlook for patients with this disease is generally good. Other tumours Other malignant tumours of the liver are relatively rare and historically have a poor prognosis. Treatment should be dictated by the histological diagnosis. Thus, sarcomatous lesions tend to be managed with combined surgical and multiagent chemotherapy regimens. Adjuvant radiotherapy treatment may have an additional role. Response to therapy The response to therapy may be monitored by serial measurement of: • Radiology. Repeat CT scans or ultrasonography will document shrinkage of the hepatic tumour (Plate 76b, Atlas: p. 467), while chest X-ray or chest CT scans will monitor progress of pulmonary metastases. • AFP levels in those tumours secreting AFP. Patients with a good response to chemotherapy have a rapid fall in serum AFP levels (Pritchard et al. 1982), whereas a failure to return to normal limits in the absence of radiological disease is highly suspicious of minimal residual disease. An increase in AFP after initiation of chemotherapy is usually a sensitive marker of relapse or treatment failure.

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• Transcobalamin levels in fibrolamellar HCC may be a guide to response. Eighty-six per cent of hepatoblastomas respond to PLADO chemotherapy, while the response rate in HCC is only 43% (Plaschkes et al. 1995). Surgery Selection for surgery It is clear that complete cure depends on effective resection of the tumour after chemotherapy. Careful assessment of post-chemotherapy imaging with CT scans, MRI or hepatic angiography is essential to establish that the main portal vein is patent and that there will be sufficient liver remaining after resection. In the majority of cases the tumour will be localized to one half of the liver and compensatory hypertrophy of the contralateral side occurs so that liver insufficiency after surgery is unusual. Tumours that remain multifocal, central in situation, or involving the portal vein after chemotherapy are not resectable and these patients should be considered for liver replacement unless there is extrahepatic disease that has not responded to chemotherapy. Surgical techniques Conventional resection techniques are based on the segmental anatomy of the liver (Couinard 1957). In the majority of cases resection of the hemi-liver (left or right) or extended resections of one side plus additional segments from the opposite side is required. In children, the use of special techniques like ex-vivo surgery followed by autotransplantation of the liver remnant, or prolonged vascular exclusion with cold perfusion of the liver are rarely used, partly because indications are limited and partly because of the increased technical risk associated with the small vessels. Surgery is carried out through a wide upper transverse incision. Standard techniques include isolation and suture ligation of the hepatic artery and portal vein branches to the portion of the liver being resected, followed by division of the liver parenchyma in the line of demarcation that has been produced. Most liver surgeons employ special instrumentation such as an ultrasonic scalpel or a water jet for dividing the liver. These techniques divide liver parenchyma but leave the vascular and biliary structures intact for subsequent coagulation with diathermy for small structures or suture ligation. The hepatic veins draining the area may be suture ligated early on in the procedure, but if access is difficult this step may be delayed until after complete division of the liver. Clamping of the vascular supply (portal vein and hepatic artery) or vascular exclusion (vascular inflow and vena cava) may reduce blood loss during difficult hepatectomies. Although it hastens the procedure and limits the blood loss, it may cause hepatic ischaemia and increase the risk of postoperative liver dysfunction, especially if the residual liver is small. Most liver surgeons now prefer

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a meticulous division of the liver, steadily achieving haemostasis and avoiding vascular clamping. Whereas the operative time may be prolonged, it is associated with more rapid hepatic recovery and patient discharge. Haemostasis at the cut surface is aided by the use of bipolar diathermy for dividing the liver and of argon diathermy for final haemostasis of the cut surface. Application of a layer of fibrin glue lessens the postoperative risk of leakage of blood or bile. Hepatoblastoma Hepatoblastoma is the most frequently resected tumour. The timing of surgery varies between different international groups. In SIOPEL-1, an international (predominantly European) study, 13/154 patients had primary resections and most patients had delayed surgery after preoperative chemotherapy. In contrast, 50/173 patients in the USA study (INT-0098) had a primary resection (stage I and II tumours) (Ortega et al. 2000; Pritchard et al. 2000; Schnater et al. 2002). Once chemotherapy had been given, a complete resection rate of 77% was achieved in SIOPEL-1 compared with 62% in INT-0098. Given the importance of surgical resection in liver tumours, this suggests that the SIOPEL strategy is best, but there are other issues. Localized tumours, and those with favourable histology, may need minimal chemotherapy and the INT-0098 study demonstrated 100% survival in this group with primary surgical resection followed by four cycles of doxorubicin (240 mg/m2 cumulative dose). Treating these patients with preoperative PLADO chemotherapy might be unjustified. The difficulty with the diagnosis of hepatoblastoma in infants and neonates is well recognized, with an error rate of 23% in those cases without primary resection (von Schweinitz et al. 1995). In addition, it is possible that unfavourable, chemotherapy-resistant tumours (Haas et al. 2001) may be missed if reliance is placed on small initial biopsies, supporting the role of primary resection. The debate still rages and recent articles continue to promote primary resection as best practice where feasible (Finegold 2002). Although some patients present with resectable disease, most patients do not and all such patients should undergo chemotherapy prior to surgery. As chemotherapy produces a shrunken and sclerotic tumour mass, the resection line may pass close to this without fear of incomplete resection as long as the margin itself is clear of tumour. This differs from other malignant tumours where a clear margin of at least 1 cm is recommended. Histological examination of hepatoblastomas resected after chemotherapy reveals that much of the residual tumour mass is in fact sterilized disease with smaller nests of persistent tumour within tumours. Liver transplantation for hepatoblastoma. Liver transplantation is an important option in the surgical manage-

ment of hepatoblastoma. Liver transplantation should be considered in all children with stage IV disease, or unresectable tumours without extrahepatic metastases (Chapter 20) (see Plate 77, Atlas: p. 468). Patient selection is crucial for transplantation, but it is a viable option in suitably selected candidates. The most significant predictor of a good outcome after liver transplantation is the chemosensitivity of the tumour. In Birmingham we have demonstrated that there was 100% survival in children who responded well to chemotherapy, compared with 60% survival in poor chemotherapy responders (Achilleos et al. 1996; Al-Qabandi et al. 1999; Pimpalwar et al. 2002), as has been suggested in other series (Molmenti et al. 2002). The presence of lung metastases at diagnosis is not a contraindication for transplantation if the metastases respond to chemotherapy. Liver transplantation is a poor option for patients with recurrent disease or in those with incomplete excision (Otte et al. 1996; Pimpalwar et al. 2002). It is important to plan liver transplantation early in order to deliver chemotherapy effectively and reduce the potential nephrotoxicity associated with both cisplatin and immunosuppressive drugs (Arora et al. 2002) and cardiotoxicity with doxorubicin. Currently, an active split liver transplant programme allows the allocation of a liver graft around the time of conventional surgery and avoids additional chemotherapy (Pimpalwar et al. 2002). Alternatively, using a graft from a live related donor allows this elective operation to be planned within the chemotherapy schedule (Chardot et al. 2002). If liver transplantation is undertaken early, it may be necessary to consider the administration of postoperative chemotherapy. Serious postoperative chemotherapy-related problems are avoided by close scrutiny of immunosuppressive drug dosage and trough levels. Hepatocellular carcinoma and other malignant tumours Resection of HCC in children with cirrhotic livers secondary to an underlying metabolic disease is unlikely to achieve a cure as these tumours are multifocal. Liver transplantation should be considered for unresectable HCC, but only for those who have HCC nodes < 5 cm diameter and absence of vascular invasion or thrombosis. HCC and sarcomas in the non-cirrhotic liver should be considered for resection based on the imaging as described above. Techniques as outlined above are used, but it should be stressed that a clear resection margin of at least 1 cm should be sought to maximize cure rates. Epithelioid haemangioendothelioma is often diffuse or mulitfocal in the liver at diagnosis and thus unresectable in most cases. In contrast, in adults this tumour is considered a low-grade malignancy with very slow growth, and thus liver transplantation is justified for quality of life. This tumour seems much more aggressive in children and

Chapter 19: Primary Hepatic Tumours transplantation should be considered only for slowly growing tumours. Non-resectable cases of HCC and other rarer malignant tumours have been subjected to varying treatments, including embolization and hepatic artery ligation, but without any real evidence of benefit. Current research includes chemoembolization using agents injected into the hepatic artery at angiography, and results are awaited.

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pression has not had a major influence on recurrence rates. Unfortunately the long-term survival of patients with HCC remains poor, which is related to the increased proportion of patients with metastatic (31%) and extrahepatic extension of tumour (39%). Despite partial responses of 49% to PLADO chemotherapy, overall survival for HCC patients in the SIOPEL-1 study was only 28% at 5 years (Czauderna 2002). There is a need to develop more effective therapeutic regimens/agents for these tumours.

Radiotherapy It is difficult to define the role of radiotherapy in the management of hepatoblastoma because traditionally patients have been managed with combinations of surgery and chemotherapy and have not received radiotherapy in isolation (Habrand et al. 1992). Current studies do not recommend the use of radiotherapy to either the primary tumour or lung metastases. The use of radiotherapy is presently restricted to palliation of recurrent disease, or treatment of residual disease following surgery. Prognosis Studies performed in the 1970s and early 1980s highlighted the need to achieve a complete surgical resection of hepatoblastoma and HCC to effect cure. More recently, the change in clinical practice to preoperative chemotherapy has resulted in more tumours being amenable to effective surgery. In the survey of hepatoblastoma patients by Exelby et al. (1975) a complete resection rate of 60% was achieved with survival of 58% in these patients and an overall survival of 35%. In the recent SIOPEL-1 trial (Pritchard et al. 2000) there was a 77% resection rate, EFS at 5 years was 81% in resected patients. For the whole study EFS was 66% and overall survival was 75% at 5 years . Other factors may also be important in the improved survival. In hepatoblastoma, the histological subtype may influence outcome. Haas et al. (1989) suggested that patients with a pure fetal type had improved survival which was not related to presentation with lower stage disease. In contrast, those patients with anaplastic histological features appear to have a worse outcome (Kasai & Watanabe 1970). Data from the SIOPEL-1 study (Plaschkes et al. 1995) suggest that extensive disease at presentation involving all four liver sectors and the presence of metastases confer poor prognosis, which may be related to the difficulty in achieving complete resection of the tumour. In those patients with unresectable hepatic tumours liver transplantation is a viable option (see above and Chapter 20), with encouraging results for 5-year survival (Koneru et al. 1991; Tagge et al. 1992; Pimpalwar et al. 2002). Gratifyingly, the need for long-term immunosup-

Benign tumours Haemangiomas and haemangioendotheliomas The commonest benign tumours are haemangiomas and infantile haemangioendothelioma (Table 19.1). The natural history for these lesions is gradually to progress and enlarge during the first 6 months of life. There may be other cutaneous haemangiomatous lesions which suggest the diagnosis, but most children will present with progressive abdominal distension, a minority of whom have spontaneous haemorrhage. Cardiac failure is a common presentation in haemangioendothelioma due to the enormous vascular load of these tumours. Neonates presenting with cardiac failure often have features of congenital heart disease, which may cause a delay in diagnosis. Other presentations include bruising/petechiae from thrombocytopenia (the Kasabach–Merritt syndrome) (Skopec & Lakatua 1989) or intravascular consumptive coagulopathy. The diagnosis is obtained by radiological imaging including ultrasound, CT scanning or MRI. Biopsy is rarely required and may be dangerous (Chapter 9). Anumber of therapeutic options are available. However, since spontaneous resolution may occur, a ‘watch and wait’ policy may be adopted in asymptomatic children. If treatment is necessary, this should be tailored to individual cases. Surgical resection, ligation of hepatic arteries or embolization may be possible with isolated lesions (Davenport et al. 1995) (Chapters 9 and 18). These techniques carry significant mortality, ranging from 18% to 50%. Medical treatment options include steroid therapy, radiotherapy and chemotherapy with cyclophosphamide. Most clinicians tend to adopt an approach to therapy initially with steroids progressing to chemotherapy if no response is seen. However, patients who present with spontaneous haemorrhage require immediate surgery, which may involve hepatic artery ligation and/or resection of the lesion. Radiotherapy tends to be reserved for resistant cases in view of the potential for second malignancy within the radiation site (Cornelius et al. 1989). Epithelioid haemangioendotheliomas (type II) are rare tumours in children. They are more commonly seen in

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young women and are considered low-grade malignancies with very slow growth and prolonged survival without treatment (Ishak et al. 1984; Lauffer et al. 1996; Makhlouf et al. 1999; Uchimura et al. 2001). However they may be more locally aggressive in children and unsuitable for partial resection (see above). Although adult patients have been considered acceptable for liver transplantation because of the slow growth and low metastatic potential of the tumour, this may not be so in children. These tumours can metastasize, and the general outcome has been poor with rapid recurrence, but patients can have a long survival before recurrence following transplantation (Calder et al. 1996; Kelleher et al. 1989). Mesenchymal hamartoma Mesenchymal hamartoma is a rare tumour seen typically in children under 2 years of age. The majority of children present with abdominal distension, and physical examination reveals a large, smooth, non-tender mass. The tumours are usually well demarcated and resection by lobectomy (extended or not) is the treatment of choice (Lack 1986). Adenomata Adenomata are extremely rare in the paediatric age group but can occur at any age. In children there is an association with glycogen storage disease type I and galactosaemia, while in adults and adolescents there is a well-recognized link with oral contraceptive use — in these cases cessation of the pill may allow resolution. The adenomata are usually diagnosed by ultrasound and confirmed by CT scan or radioisotope imaging using technetium-99m sulphur colloid as adenomata do not take up the isotope. Persistent cases in adults require resection because of the risks of malignancy and rupture with intraperitoneal bleeding. Whilst adenomata are not thought to be premalignant in children, the distinction from a welldifferentiated HCC can be difficult and if there is any doubt resection should be undertaken. Focal nodular hyperplasia Focal nodular hyperplasia (FNH) is also rare in the paediatric age group and occurs more commonly in girls than boys. The vast majority are asymptomatic, though some will present with an abdominal mass or pain. Histologically they have features of a well-localized area of liver cell hyperplasia around a fibrous central scar which shows up clearly on CT or MRI scans. Colloid scans are usually positive as there are sufficient reticuloendothelial cells within the mass to take up the isotope. Surgical resection is only required for symptomatic patients as there is no risk of malignancy.

Acknowledgement We would like to acknowledge the authorship of Mr J. Buckels for the first edition of this chapter.

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Chapter 20: Liver Transplantation DEIRDRE A. KELLY AND DAVID MAYER

Indications for liver transplantation, 378 Chronic liver disease, 378 Acute liver failure, 381 Inborn errors of metabolism, 382 Liver tumours, 383 Pretransplant evaluation, 383 Pretransplant assessment of severity of liver disease, 383 Contraindications for transplantation, 385 Preparation for transplantation, 385 Immunization, 385 Management of hepatic complications, 385 Nutritional support, 386 Psychological preparation, 386 On the waiting list, 386

Liver transplant surgery, 386 The role of the transplant co-ordinator, 387 The liver graft, 387 The donor operation, 387 The back table operation, liver reduction and liver splitting, 387 The recipient operation, 388 Living related liver transplantation, 389 Auxiliary liver transplantation, 389 Postoperative management, 390 Ventilation, 390 Fluid management, 390 Immunosuppression, 390 Prophylactic antibiotics, 391 Other medications, 391

The successful development of paediatric liver transplantation has dramatically changed the prognosis for many babies and children dying of end-stage liver failure and is now accepted therapy for this condition. The most important elements in improving survival post-liver transplantation have been: 1 Better preoperative management of hepatic complications and nutritional support. 2 Innovative surgical techniques to expand the donor pool. 3 Improvements in postoperative immunosuppression. The consequent improvement in survival rate has extended the range of indications for liver transplantation in children to include semi-elective liver replacement, transplantation for metabolic liver disease and unresectable hepatic tumours. Increasing experience has also refined the precise indications for liver transplantation. As shortterm survival has improved, interest has focused on quality of life and long-term survival.

Indications for liver transplantation Liver transplantation is standard therapy for acute or chronic liver failure (Table 20.1).

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Postoperative complications, 391 Early postoperative complications, 391 Complications after the first postoperative week, 392 Late complications post-liver transplant, 393 Survival following liver transplantation, 394 Factors affecting survival, 394 Quality of life post transplant, 395 Growth post transplant, 395 Psychosocial development, 396 Endocrine development, 396 Family functioning, 396 Out-patient monitoring, 397

Chronic liver disease Neonatal liver disease Biliary atresia remains the commonest indication for liver transplantation in children, accounting for 74% of children undergoing transplant below the age of 2 years (European Liver Transplant Registry 2002). Despite the professional emphasis on early diagnosis and management of this condition, in practice many children are still referred too late to benefit from a palliative Kasai portoenterostomy (Chapters 4 and 18). Urgent transplantation is required for those children who have an unsuccessful Kasai portoenterostomy or who develop nutritional or hepatic complications (Beath et al. 1993a). Cholestatic liver disease The outcome of cholestatic liver disease in infancy, such as Alagille’s syndrome, non-syndromic biliary hypoplasia, familial intrahepatic cholestasis, is variable. Liver transplantation is indicated for the development of cirrhosis and portal hypertension, development of malnutrition or growth failure unresponsive to nutritional support, or intractable pruritus which is resistant to maximum medical therapy or biliary diversion (Whitington et al. 1994).

Chapter 20: Liver Transplantation Table 20.1 Indications for liver transplantation. Chronic liver failure Neonatal liver disease Biliary atresia Idiopathic neonatal hepatitis Cholestatic liver disease Alagille’s syndrome Familial intrahepatic cholestasis (FIC) Non-syndromic biliary hypoplasia Inherited metabolic liver disease a1-Antitrypsin deficiency Cystic fibrosis Glycogen storage type IV Tyrosinaemia type I Wilson’s disease Chronic hepatitis Autoimmune Idiopathic Postviral (hepatitis B, C, other) Other Cryptogenic cirrhosis Fibropolycystic liver disease +/– Caroli syndrome Acute liver failure Fulminant hepatitis Autoimmune Halothane exposure Paracetamol poisoning Viral hepatitis (A, B, C, E, or NA-G) Metabolic liver disease Fatty acid oxidation defects Neonatal haemochromatosis Tyrosinaemia type I Wilson’s disease Inborn errors of metabolism Crigler–Najjar type I Familial hypercholesterolaemia Primary oxalosis Organic acidaemia Urea cycle defects Liver tumours Benign tumours Unresectable malignant tumours

Inherited metabolic liver disease a1-Antitrypsin deficiency is the commonest form of inherited metabolic liver disease presenting in childhood in Europe. Although 50–70% of children may develop persistent liver disease progressing to cirrhosis, only 20–30% require transplantation in childhood (Filipponi et al. 1994; Francavilla et al. 2000). The management of tyrosinaemia type I has changed dramatically since the introduction of NTBC [2-(2-nitro4-trifluoromethylbenzoyl)-1,3-cyclohexenedione], which prevents the formation of toxic metabolites and produces rapid clinical improvement. Use of this drug

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has altered the natural history of the disease and the indications for transplantation (Burdelski et al. 1991; Lindstedt et al. 1992; Mohan et al. 1999). Prior to the introduction of NTBC, liver transplantation was indicated for acute or chronic liver failure, the development of hepatic dysplasia or hepatocellular carcinoma (HCC). Liver transplantation is now only indicated for those children who have a poor quality of life, do not respond to NTBC, or in whom hepatic malignancy is thought to have developed (Dionsi-Vici et al. 1997) (Chapter 5). Routine monitoring of children with tyrosinaemia type I being treated with NTBC includes ultrasound, computed tomography (CT) scan or magnetic resonance imaging (MRI) to detect the development of nodules and/or early HCC in association with regular a-fetoprotein levels. Apersistent or sustained rise of a-fetoprotein may indicate the early development of HCC, which should be confirmed by the detection of hepatic dysplasia on liver biopsy (Macvicar et al. 1990; Manowski et al. 1990). Wilson’s disease is a rare indication for liver transplantation in childhood (Chapter 13) but is indicated for those children who present with advanced liver disease (Wilson score > 6), fulminant liver failure or who have progressive hepatic disease despite penicillamine therapy (Nazer et al. 1986; Rela et al. 1993). As long-term survival improves in children with cystic fibrosis (CF), liver transplantation has become a viable alternative and is now the commonest indication in adolescents in some centres. Hepatic decompensation is a late feature of CF liver disease, but portal hypertension is common and bleeding from oesophageal varices may be a serious recurrent problem. Selection for liver transplantation is indicated only for those children with hepatic decompensation (falling serum albumin, prolonged coagulation unresponsive to vitamin K), severe malnutrition or complications of portal hypertension unresponsive to medical management — ascites or uncontrolled variceal bleeding (Debray et al. 1999). Careful assessment of pulmonary function is required as severe lung disease (< 50% of lung function) may indicate the necessity for a heart, lung and liver transplant (Couetil et al. 1997). Thus, early liver transplantation is indicated for those children with moderate lung disease prior to the development of significant irreversible lung disease (Milkiewicz et al. 2002). Preoperative management of respiratory disease is important and should include vigorous physiotherapy, intravenous antibiotics and DNase. Postoperative antibiotics should be based on known bacterial colonization and antibiotic sensitivity. The majority of children with glycogen storage disease type I should respond to appropriate medical and nutritional management. Transplantation is indicated only for those children who develop multiple hepatic adenomata or in whom metabolic control has a significant effect on quality of life. Glycogen storage disease types III and IV

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Section 10: Transplantation Acute hepatic failure: 153 (10%)

Cirrhosis: 51 (3%)

Acute hepatic failure: 333 (14%)

Metabolic diseases: 140 (9%)

Cirrhosis: 228 (9%)

Cancers: 38 (2%)

0–2 years (1589 children)

Cholestat diseases: 1170 (74%)

Metabolic diseases: 579 (24%)

Fig. 20.1 Primary indication for liver transplatation in paediatric patients 1988–2001 (European Liver Transplant Registry).

may progress to cirrhosis and this may be an indication for transplantation because of hepatic dysfunction (Sokal et al. 1992). Chronic hepatitis Autoimmune liver disease types I and II The majority of children with autoimmune liver disease types I or II respond to immunosuppression with prednisolone or azathioprine (Chapter 8). Liver transplantation is indicated for those children who have advanced portal hypertension or do not respond to immunosuppression despite the use of second-line drugs such as cyclosporin A, tacrolimus and mycophenalate mofetil, or those who present with fulminant hepatic failure (Gregorio et al. 1997). Children with autoimmune hepatitis type II are more likely to present in fulminant hepatic failure and have an increased requirement for liver transplantation (Chapters 8 & 20). Most children with chronic hepatitis B or C will be asymptomatic carriers in whom the development of cirrhosis, portal hypertension and/or HCC may evolve over 20–30 years. Although the main indication for transplantation is the development of chronic liver failure, recurrence with hepatitis B or C post-transplantation is likely in 90% of patients without prophylactic therapy, such as lamivudine or hepatitis B immunoglobulin (Bain et al. 1996).

Cholestatic diseases: 1081 (45%) Cancers: 98 (4%)

2–15 years (2409 children)

Fibropolycystic liver disease Fibropolycystic liver disease is a rare indication for liver transplantation in childhood, as liver function usually remains normal for many years in these children even if they develop severe portal hypertension. Liver replacement is only indicated if hepatic decompensation occurs in association with portal hypertension or hepatic enlargement interferes with quality of life. The disease may be associated with infantile polycystic kidney disease and thus, in some instances, both liver and kidney replacement will be required (Chapter 9). Primary immunodeficiency As bone marrow transplantation for primary immunodeficiency has become successful, it is clear that many children with these diseases have associated liver disease. The most common immunodeficiency is CD40 ligand deficiency (hyper IgM syndrome), in which recurrent cryptosporidial infection of the gut and biliary tree lead to sclerosing cholangitis. In this group of children it is important to carry out bone marrow transplantation before the development of significant liver disease or to consider combined liver and bone marrow transplantation if necessary (Hadzic 1999). Timing of transplantation for children with chronic liver failure As many children with cirrhosis and portal hypertension have well-compensated liver function, the timing of liver transplantation may be difficult to predict. Biochemical

Chapter 20: Liver Transplantation decompensation can be predicted by studying the lidocaine metabolite monoethyl glycinexylide (MEGX) (Oellerich et al. 1990), as serial estimates of MEGX formation and excretion over time may be useful predictors in individual patients. In practice, the need for liver transplantation is indicated by a persistent rise in total bilirubin > 150 mmol/l, prolongation of prothrombin ratio (INR > 1.4) and a fall in serum albumin < 35 g/l (Malatack et al. 1987). These parameters have recently been evaluated in order to develop a Pediatric End-Stage Liver Disease Score (PELD) to predict death and have confirmed their accuracy. The PELD score was strengthened by the addition of growth failure and age (< 1 year) to the above values (McDiarmid et·al. 2002). As protein-energy malnutrition is a known complication of chronic liver disease in the developing child, serial evaluation of nutritional parameters may be an alternative guide to early hepatic decompensation. Progressive reduction of fat stores (triceps skin fold) or protein stores (mid-arm muscle area) despite nutritional support usually predict hepatic decompensation (Beath et al. 1993b). Children with complex hepatic complications such as chronic hepatic encephalopathy, refractory ascites, intractable pruritus or recurrent variceal bleeding despite optimum management require prompt referral for transplantation. Variceal haemorrhage which is not controlled by variceal banding or endoscopic sclerotherapy may be temporarily managed by the insertion of a transjugular intrahepatic portosystemic shunt (Chapters 3, 14 and 18). This technique reduces portal vein pressure and prevents variceal haemorrhage, allowing sufficient time for preoperative nutritional support and the search for an appropriate donor. A particularly important aspect in the timing of liver transplantation is consideration of psychosocial development. Children with chronic liver disease have a significant reduction of developmental motor skills, which may be reversed following liver transplantation if performed early enough (Beath et al. 1993a, 1995). Thus, any significant delay in developmental parameters is an indication for referral for liver transplantation. It is essential that children with chronic liver disease should be referred for transplantation before the complications of their liver disease adversely impair the quality of their lives and before growth and development are retarded. Acute liver failure The indications for liver transplantation for acute liver failure vary depending on whether the disease process is due to fulminant hepatitis or secondary to an inborn error of metabolism (Chapters 5 and 7). In general, children with acute liver failure should be referred early to a specialist unit with facilities for transplantation in order to

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provide time for stabilization and to find an appropriate donor organ. Fulminant hepatitis There are four main aims in the management of children with fulminant hepatitis requiring transplantation: 1 To assess prognosis for recovery or liver transplantation. 2 Prevent or treat hepatic complications while awaiting a donor organ/regeneration of native liver. 3 Provide hepatic support. 4 Provide psychosocial support and information for parents. The current information on prognosis of children with fulminant hepatitis is based on previous experience in the pretransplant era, information from adult studies, and more recently information from paediatric studies (O’Grady et al. 1989; Friedman et al. 1994; Lee et al. 2001). Poor prognostic factors for children with fulminant hepatitis requiring listing for liver transplantation are as follows: • non-A to G hepatitis • rapid onset of coma with progression to grade III or IV hepatic coma • diminishing liver size • falling transaminases • increasing bilirubin (> 300 mmol/l) • persistent coagulopathy (> 50 s/control; INR > 4). Unlike adults, children with fulminant hepatitis may have severe coagulopathy but mild encephalopathy and therefore both are not required prior to listing for liver transplantation (Bonatti et al. 1997). All children with grade III hepatic coma, or those who have a persistent coagulopathy (prothrombin ratio INR > 4) and have no evidence of irreversible brain damage from cerebral oedema or hypoglycaemia should be listed for transplantation. As current medical management for cerebral oedema is unsatisfactory and methods of determining irreversible brain damage unreliable, this may be a difficult decision. Cerebral CT scans may detect gross cerebral oedema, haemorrhage or infarction; they may alter selection for transplantation but are not usually helpful in the early stages. Monitoring of cerebral oedema by measurement of intracranial pressure has improved the selection of recipients but not overall survival. Assessment of cerebral blood flow is not helpful as this may be reduced in hepatic failure, but assessment of cerebral perfusion pressure may be more sensitive (Chapter 7). Electroencephalography (EEG) may demonstrate a reduction in electrical activity and ultimately brain death, although these results must be interpreted cautiously in ventilated patients or those treated with thiopentone as

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the EEG tracing is affected by sedation and anaesthetic drugs. Paracetamol poisoning Selection of patients with paracetamol poisoning may be particularly difficult. Children and adolescents have a lower incidence of liver failure with paracetamol overdose than adults, possibly because of the effect of hepatic maturation and glutathione production (Lauterberg et al. 1980). Transplantation is more likely if the overdose was taken with another drug (e.g. LSD, Ecstasy) or with alcohol (Mahadevan et al. 1999). Children should be considered for liver transplantation if there is a persistent coagulopathy (INR > 4), metabolic acidosis (pH < 7.3), an elevated creatinine (> 300 mmol/l) or rapid progression to hepatic coma grade III. In some children cerebral oedema may persist despite evidence of hepatic regeneration and recovery, and influence their postoperative recovery.

Severe extrahepatic disease In these diseases (Table 20.1) the liver functions normally but the missing hepatic enzyme leads to severe extrahepatic disease such as kernicterus in Crigler–Najjar type I, coronary artery disease in familial hypercholesterolaemia, and systemic oxalosis in primary oxaluria. Selection for transplantation is difficult. It is important to evaluate the quality of life of the child on medical management and to consider the potential mortality and morbidity of the primary disease in comparison with the risks, complications and outcome following liver transplantation (Burdelski et al. 1991). The timing of transplantation in these disorders depends on: 1 The rate of progression of the disease. 2 Quality of life of the affected child. 3 The development of severe irreversible extrahepatic disease. Crigler–Najjar type I

Metabolic liver disease Acute liver failure may be the presenting feature of inherited metabolic liver disease such as Wilson’s disease and tyrosinaemia type I (Chapters 5 and 13). The clinical presentation is more likely to be subacute and liver failure occurs in the presence of underlying cirrhosis. Selection for liver transplantation is on the basis of non-response to medication or severe coagulopathy as jaundice and encephalopathy may not be obvious (Nazer et al. 1986). Diminishing liver size does not occur because of the underlying cirrhosis. Infants with neonatal haemochromatosis who present within days or weeks of birth with severe coagulopathy and encephalopathy may be candidates for liver transplantation if medical management using the ‘antioxidant cocktail’ has failed (Chapter 5) (Shamieh et al. 1993; Muiesan et al. 1995; Flynn et al. 2003). Inborn errors of metabolism Certain inborn errors of metabolism are secondary to hepatic enzyme deficiencies (Chapters 5 and 12). Liver transplantation is indicated for these conditions if the hepatic enzyme deficiency leads to: • irreversible liver disease/liver failure and/or hepatoma • severe extrahepatic disease. Those diseases in which the inborn error of metabolism leads to liver failure (tyrosinaemia type I, Wilson’s disease, or a1-antitrypsin deficiency; see above) are managed as acute or chronic liver failure.

The timing of transplantation for this inherited disorder of unconjugated hyperbilirubinaemia depends on: 1 The quality of the child’s life, i.e. how many hours of phototherapy per day are required to control the unconjugated bilirubin levels. 2 The potential development of irreversible structural brain damage secondary to kernicterus. In general it is appropriate to transplant these children between the ages of 3 and 5 years in order to reduce disruption to their education. The most appropriate transplant operation for these children is now auxiliary liver transplantation (see below) (Rela et al. 1997). Organic acidaemia Children with propionic acidaemia or methylmalonic acidaemia are at lifelong risk of recurrent metabolic acidosis and long term brain damage. Liver replacement is considered palliative treatment for these conditions as the enzyme deficiency affects all body tissue. It should be considered early for children who have a particularly severe phenotype or family history (Chapter 5). Very careful preoperative management, including preoperative dialysis and perioperative haemofiltration to control acidosis, is essential to ensure good operative control. Until recently, orthotopic liver replacement has been considered necessary to provide adequate enzyme supplementation. It is possible that auxiliary liver transplantation may be sufficient for mildly affected patients (Rela et al. 1997).

Chapter 20: Liver Transplantation Familial hypercholesterolaemia Children who are homozygous are prone to premature development of coronary artery disease and thus should be transplanted before coronary artery disease is irreversible. In view of recent progress with gene therapy for this condition, auxiliary liver transplantation or gene therapy may be more appropriate treatment strategies (Raper et al. 1996). Primary oxalosis Ideally liver replacement in this condition should be prior to the development of severe irreversible renal failure. As this is often not possible, liver and kidney replacement may be required simultaneously (Ellis et al. 2001). As deficiency of the enzyme alanine glycoxylate aminotransferase results in an overproduction of oxalate, these children are not suitable for auxiliary liver transplantation. Liver tumours Potential indications for liver tumours include unresectable benign tumours causing hepatic dysfunction, and unresectable malignant tumours (hepatoblastoma or HCC) which are refractory to chemotherapy without evidence of extrahepatic metastases (Chapter 19). The preoperative evaluation should include a meticulous search for extrahepatic metastases, with CT scanning of chest and abdomen and regular monitoring of serum a-fetoprotein to detect relapse or recurrence outside the liver; and careful assessment of cardiac function because of the cardiotoxic effects of drugs such as daunorubicin. The timing of transplantation is crucial and is best planned electively during the course of chemotherapy or at completion (Pimpalwar et al. 2002). Bone marrow suppression at the time of transplantation is supported with administration of granulocytestimulating factors. Children with rhabdomyosarcomas are usually unsuitable for transplantation because of the extent of the tumour and presence of extrahepatic metastases (Chapter 19).

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Table 20.2 Pretransplant assessment. Nutritional status Height, weight, triceps skinfold, mid-arm muscle area Identification of hepatic complications Ascites, hepatosplenomegaly, varices on endoscopy Cardiac assessment ECG, echo, chest X-ray (cardiac catheterization if required) Respiratory function Oxygen saturation*, ventilation perfusion scan*, lung function tests† Neurological and developmental assessment EEG, Bayley developmental scales, Stanford–Binet intelligence scales Renal function Urea, creatinine, electrolytes Urinary protein/creatinine ratio Cr EDTA (if available) Dental assessment Radiology Ultrasound of liver and spleen for vascular anatomy Wrist X-ray for bone age and rickets MRI/angiography‡ Serology Cytomegalovirus Epstein–Barr virus Varicella zoster Herpes simplex Hepatitis A, B, C HIV Measles Haematology Full blood count, platelets, blood group

*If cyanosed. †In cystic fibrosis. ‡If portal vein anatomy equivocal. ECG, Electrocardiogram; EDTA, ethylenediamine tetraacetic acid; EEG, electroencephalogram; HIV, human immunodeficiency virus; MRI, magnetic resonance imaging.

5 Establish whether the transplant operation is appropriate for the child and family. 6 Prepare the child and family psychologically.

Pretransplant evaluation (Table·20.2) Evaluation of the patient before transplantation should: 1 Assess the severity of the liver disease and the presence or absence of hepatic complications. 2 Establish the urgency for transplantation. 3 Assess whether the operation is technically feasible. 4 Consider any significant contraindications to successful transplantation.

Pretransplant assessment of severity of liver disease The indications for transplantation should be critically evaluated, the diagnosis should be reviewed, the prognosis should be considered and alternative medical or surgical therapy should be evaluated. It is essential to evaluate whether liver transplantation will improve the quality of life for both child and family.

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Hepatic function The histological diagnosis should be reviewed and if necessary liver histology should be obtained. The decision to list for transplantation is usually based on serial deterioration in hepatic function as indicated by: • albumin (< 35 g/l) • coagulation time (INR > 1.4) • a rising bilirubin (> 150 mmol/l). The extent of portal hypertension may be estimated by establishing the size of the portal vein on ultrasound, and by visualizing oesophageal and gastric varices by gastrointestinal endoscopy, which also establishes the presence of gastritis and/or peptic ulceration.

Children with congenital liver disease, such as biliary atresia, may have an increased incidence of abnormal vasculature. The hypovascular syndrome consists of an absent inferior vena cava, preduodenal or absent portal vein, azygous drainage from the liver and the polysplenia syndrome. It may be associated with situs inversus, dextrocardia or left atrial isomerism (Lilly & Starzl 1974). Angiography is advised to determine the position and size of these abnormal vessels. Liver transplantation causes important haemodynamic changes during the operative and anhepatic phases. It is essential therefore to have baseline information on cardiac and respiration function. Most of the information required will be obvious from an ECG, echocardiogram or oxygen saturation.

Renal function The main abnormalities of renal function in children with either acute or chronic liver failure include renal tubular acidosis, glomerulonephritis, acute tubular necrosis and hepatorenal syndrome. Careful assessment of renal function is necessary in order to plan modification for the potentially nephrotoxic effects of post-transplant immunosuppression and to assess the necessity of perioperative renal support. Haematology Full blood count, platelets, coagulation indices and blood group are obtained. HLA matching is not required.

Cardiac assessment Particular attention should be paid to children who have congenital cardiac disease, for example atrial and ventricular septal defects which are associated with biliary atresia. Peripheral pulmonary stenosis is a known feature of Alagille’s syndrome. Cardiomyopathy may develop secondary to tyrosinaema type I and the organic acidaemias or as a result of chemotherapy of malignant tumours. Cardiac catheterization may be necessary to determine whether: (i) cardiac function is adequate to withstand the haemodynamic changes during the operation; (ii) corrective surgery is required preoperatively; or (iii) the cardiac defect is inoperable and liver transplantation is contraindicated.

Serology It is important to establish immunity to previous infection (Table 20.2). As donor grafts are matched for cytomegalovirus (CMV) status if possible, assessment of previous infection with CMV is important. Children who are Epstein–Barr virus (EBV)-negative are more likely to develop a primary infection post transplant and have a higher risk of developing post-transplant lymphoproliferative disease. Radiology The most important technical information required is the vascular anatomy and patency of the hepatic vessels. Most of the necessary information is obtained by colour flow Doppler ultrasound examination of the liver and spleen. MRI or conventional angiography may be required to visualize abnormal anatomy such as the hypovascular syndrome or to determine the extent of portal vein thrombosis. Evidence of retrograde flow and/or a small portal vein (< 4 mm at the porta hepatis) suggests severe portal hypertension and increases the urgency for liver transplantation.

Respiratory assessment A minority of children with end-stage liver disease develop intrapulmonary shunts (hepatopulmonary syndrome). This potentially reversible complication of liver disease needs early consideration for liver transplantation. The clinical signs of cyanosis and digital clubbing indicate the need for pulmonary function studies, ventilation-perfusion scans, bubble echocardiography and/or cardiac catheterization (Hobeika et al. 1994; Uemoto et al. 1996). Neurodevelopmental assessment The aim of liver transplantation is to improve quality of life post transplant. Thus, it is necessary to identify any existing neurological or psychological defects which may not be reversible post transplantation. The psychological and developmental assessment of children with clinical liver disease may be performed using standard tests such as: the Griffiths developmental scale (for children under the age of 5 years) or the Bayley developmental scales or Stanford–Binet intelligence scales (children of all ages) (Wayman et al. 1997).

Chapter 20: Liver Transplantation Dental assessment Chronic liver disease has an adverse effect on the growth and development of young children, including their dentition. Clinical problems pretransplant include hypoplasia with staining of the teeth and gingival hyperplasia related to poor hygiene. As gingival hyperplasia may be a significant problem post transplant secondary to cyclosporin immunosuppression, it is important to establish good methods of dental hygiene prior to transplantation (Hosey et al. 1995) (Chapter 17).

Contraindications for transplantation As surgical skills have improved there are fewer contraindications to liver transplantation based on technical restrictions. Portal vein thrombosis, age and size are no longer contraindications for transplantation (Beath et al. 1993a). However, experience has shown that certain medical conditions are not curable by transplantation. The contraindications for liver transplantation include: 1 The presence of severe systemic sepsis, particularly fungal sepsis, at the time of operation. 2 Malignant hepatic tumours with extrahepatic spread, because of rapid recurrence. 3 Severe extrahepatic disease which is not reversible following liver transplantation, e.g. severe cardiopulmonary disease for which corrective surgery is not possible, or severe structural brain damage. 4 Severe systemic oxalosis with cardiac involvement, as these children develop significant hypotension and do not withstand the haemodynamic disturbances post transplant. 5 Mitochondrial cytopathies with multisystem involvement (Thomson et al. 1998). 6 Alper’s disease and valproate toxicity because of the progression of neurodegeneration. 7 Giant-cell hepatitis with autoimmune haemolytic syndrome because of disease recurrence. Initially, human immunodeficiency virus (HIV) positivity was a contradiction to transplantation, but with current effective treatment regimes, HIV-positive children can now be considered if necessary. Although hepatitis B and C recur post transplant, postoperative therapy is possible and thus transplantation is acceptable. (Grellier et al. 1996; Araya et al. 1997). Children with a higher risk at surgery include those with: • previous surgery, because of technical difficulties with adhesions and potential small bowel perforation • portal vein thrombosis, because vein grafts may be required.

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Preparation for transplantation Immunization Live vaccines are usually contraindicated in the immunosuppressed child, and so it is important to ensure that routine immunizations are complete, for example diphtheria, pertussis, tetanus and polio, pneumovax for protection from streptococcal pneumonia, and Hib for protection against Haemophilus influenzae. In children older than 6 months, measles, mumps, rubella and varicella vaccination should be offered. Ideally hepatitis A and B vaccination should be prescribed pretransplant. Recent studies suggest that some live vaccines can be safely given post transplantation (Whitington et·al. 1994). Management of hepatic complications The treatment of specific hepatic complications is an important part of preoperative management. Variceal bleeding should be managed as described elsewhere (see Chapters 14 and 18) with oesophageal banding or sclerotherapy, vasopressin or octreotide infusion. Oesophageal banding is preferred to injection sclerotherapy for children on the active liver transplant list as the inevitable development of post-sclerotherapy variceal ulcers may be adversely affected by posttransplant immunosuppression (Reinoso et al. 1997). In children with uncontrolled variceal bleeding, the insertion of TIPSS (transjugular intrahepatic portosystemic stent-shunt) has proved an effective management strategy in older children (Chapters 14 and 18) (Johnson et al. 1996; Heyman & LaBerge 1999). Sepsis, particularly ascending cholangitis and spontaneous bacterial peritonitis, requires effective treatment with appropriate broad-spectrum antibiotics. Cefuroxime (20 mg/kg/dose t.d.s.); amoxil (25 mg/kg/dose t.d.s.) and metronidazole (8 mg/kg/dose t.d.s.) are useful first-line drugs until bacterial cultures are positive. In children with acute liver failure, prophylactic antifungal therapy with either fluconazole or liposomal amphotericin is essential. Children should be suspended from the transplant list during episodes of significant sepsis. Salt and water retention leading to ascites and cardiac failure should be effectively managed with diuretics and salt and water restriction. It is essential to consider intervention with haemodialysis and/or haemofiltration if acute renal failure or hepatorenal failure develop. Haemodialysis is rarely required in chronic liver failure unless there is acute decompensation, but haemodiafiltration may be necessary in acute liver failure to control cerebral oedema and/or coagulopathy. Preoperative haemodialysis and perioperative haemofiltration are

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Table 20.3 Nutritional support in infants and children undergoing liver transplantation.* Nutrient

Preoperative

Postoperative

Carbohydrate (g/kg/day) Protein (g/kg/day) Fat (g/kg/day) Energy intake (EAR)

Glucose polymer (15–20) Low salt protein (3–4) 50–70% MCT (8) 120–150%

Glucose polymer (6–8) Whole protein (2.5–3) 80–90% LCT (5–6) 120%

*Best provided as a modular feed in infants and as calorie supplements in older children. MCT, Medium-chain triglyceride; LCT, long-chain triglyceride; EAR, estimated average requirement.

essential for children undergoing transplantation for organic acidaemia. Recent trials in adults have evaluated a modified dialysis method using a molecular absorbent recirculating system (MARS), which may improve short-term survival in end-stage liver failure. Trials have not yet been performed in children (Mitzner et al. 2000). Nutritional support A number of important advances in the understanding of the pathophysiology of malnutrition in liver disease have led to improved nutritional strategies and improved outcome post transplant. The aim of nutritional therapy is to maintain or improve nutritional status and thus improve morbidity and mortality post transplant. A highcalorie-protein feed, 150–200% of the recommended energy intake (EAR), is required (Table 20.3). It may be difficult to provide this high-energy intake with standard feeds, particularly in fluid-restricted children, thus a modular feed may be appropriate for young babies. It is usually necessary to provide these feeds by nocturnal nasogastric enteral feeding or continuous feeding. If enteral feeding is not tolerated, due to ascites, variceal bleeding or recurrent hepatic complications, parenteral nutrition in normal amounts is required. Although there may be reluctance to use amino acid and lipid solutions in this situation, the calorific value of these essential nutrients overcomes the potential problems of encephalopathy and lipid catabolism (Beath et al. 1993b).

novative play therapy and toys and books suitable for children (Chapter 1). Particularly careful counselling is necessary for parents of children who are being considered for liver transplantation because of an inborn error of metabolism. As their children are not dying from liver disease, these parents may find it more difficult to accept the risks and complications of the operation, the potential mortality and the necessity for long-term immunosuppression. Parents of children who require transplantation for acute liver failure may be too distressed fully to appreciate the significance and implications of liver transplantation and will require ongoing counselling and education postoperatively. Children who survive the liver transplant operation for acute liver failure should have postoperative counselling and play therapy to help them come to terms with their transplant. On the waiting list Many families find the waiting time pretransplant very stressful, and continued support from the multidisciplinary team is required. Mortality on the waiting list used to be as high as 25% prior to the development of reduction hepatectomy, which has dramatically reduced deaths on the waiting list to 5%. Although there are continual problems with donor shortages, particularly for small children, the development of living related liver transplantation and the split liver graft programme has alleviated this problem (De Ville de Goyet et al. 1993; Mirza et al. 1998; Millis et al. 2000).

Psychological preparation The most important aspect of the transplant assessment is the psychological counselling and preparation of the child and family. A skilled multidisciplinary team, including play therapist and psychologist, is essential to the success of this preparation. Parents and appropriate relatives must be fully informed of the necessity for liver transplantation in their child and of the risks, complications and the long-term implications of the operation. Psychological preparation in children older than 2 years is essential and may be successfully achieved through in-

Liver transplant surgery Liver transplantation involves three operations — the donor operation, the back table operation, and the recipient operation. The logistics of co-ordinating these operations together with transplantation of other organs from the same multiorgan donor are complex, and the surgeon relies heavily upon the services of the transplant coordinators. The majority of liver grafts are retrieved from heart-beating cadavers, but can be obtained from live donors (see below).

Chapter 20: Liver Transplantation The role of the transplant co-ordinator Potential cadaveric organs are notified to the procurement co-ordinator, who is responsible for establishing their suitability for transplantation, co-ordinating the multidisciplinary procurement team and making arrangements at the donor hospital. Other duties include promotion of organ donation, education of health service professionals, and donor family support. The recipient co-ordinator is responsible for organizing the recipient operation, including travel arrangements for the patient, organization of theatres, anaesthesia, blood bank and intensive care, care of the recipient’s family during the operation and postoperative follow-up. The liver graft The recipient is selected on the basis of a compatible blood group, size matching, medical urgency and time on the waiting list. Occasionally, blood group O may be given to blood groups A or B, if medically necessary. When possible, grafts from CMV-positive donors are not given to CMV-negative recipients, but medical urgency may dictate otherwise. Unlike the kidney, there is no benefit from HLA matching, and hyperacute rejection is exceptionally rare in liver transplantation even in the presence of a positive cytotoxic crossmatch. Cadaver livers are retrieved from heart-beating donors that have fulfilled the criteria of brainstem death. Proper care of the donor is essential to maintain good-quality donor organs. Brainstem death results in loss of central regulatory mechanisms that control the cardiovascular, respiratory and endocrine systems. Donor resuscitation is directed at optimizing tissue perfusion and oxygenation, maintaining normal blood glucose and body temperature, and controlling sepsis. With the increasing demands for cadaver organs, previous constraints on donor suitability have been relaxed. There is no absolute age limit, although younger donors are preferable for paediatric recipients. Malignancy (except brain tumours) and uncontrolled bacterial sepsis or viral infections such as HIV remain absolute contraindications. Abnormal liver function tests may be misleading and thus the macroscopic appearance of the liver during organ retrieval is an important factor in selection. A hard fibrotic or frankly cirrhotic liver is clearly unusable, as is a grossly fatty liver. When in doubt, histological examination of a frozen section of the liver is essential. The donor operation The liver is retrieved from a cadaver donor as part of an integrated multiorgan operation in which the kidneys, heart and lungs and, on occasion, the pancreas, small bowel, corneas, skin and bone are also removed for trans-

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plantation. The donor is maintained on a ventilator in the operating theatre until the moment of circulatory arrest. Paralysing agents are given to prevent spinal reflexes and broad-spectrum antibiotics to prevent infection. The organs are removed through a full-length midline incision. The liver is inspected with particular care to identify anomalous arterial anatomy. The porta hepatis is dissected, dividing the common bile duct close to the duodenum, and the common hepatic artery is traced to its origin from the aorta. The superior mesenteric vein is identified in the root of the mesentery and prepared for cannulation. The cardiothoracic organs are then mobilized and heparin administered to achieve full anticoagulation. At this stage ventilation is discontinued, the abdominal organs are perfused with ice-cold preservation solution, and the abdomen is packed with ice-slush to achieve rapid cooling. Once the cardiothoracic organs have been removed the liver dissection is completed. The hepatic artery is taken in continuity with a patch of aorta at the origin of the coeliac trunk. The portal vein is divided at its confluence with the superior mesenteric and splenic veins, the infrahepatic vena cava is divided just above the origins of the renal veins, and the suprahepatic vena cava is divided at its junction with the right atrium. After removal of the liver, the hepatic artery and portal vein are flushed again with preservation solution and the bile duct is rinsed free of bile. The liver, immersed in cold preservation solution, is hermetically sealed in plastic bags, and transported in a freezer box packed with ice. Iliac, splenic and superior mesenteric vessels are also removed since they may be required for vascular conduits in the recipient, especially if the liver is split (see below). The back table operation, liver reduction and liver splitting The back table operation is performed at the recipient hospital and is synchronized with the recipient operation. For a whole-liver graft, the back table operation is relatively straightforward; extraneous tissue is cleared from the graft and vascular pedicles checked for tributaries which require ligation. However, the majority of paediatric liver transplants require a liver reduction operation to be performed, to generate either a single reduced-size graft or a pair of split liver grafts. The principles of liver reduction are based upon the work of Couinaud, who described the segmental anatomy of the liver (Couinaud 1957). The liver is composed of eight segments including the caudate lobe (segment I), three segments (II–IV) of the anatomical left lobe and four segments (V–VIII) of the right lobe (Bismuth 1982) (see Plate 79, Atlas: p. 469). It is possible to use a single-segment liver graft but in practice the liver is usually divided along the plane of the falciform ligament to provide a left lateral segmental graft (segments II and III) drained by

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the left hepatic vein. In the reduced graft, the common bile duct, portal vein and hepatic artery are all preserved with the left lateral segment. In contrast, when the liver is split we usually preserve the main trunks of these structures, together with the inferior vena cava, with the right graft. At implantation, microvascular techniques and biliary reconstruction using a Roux loop of jejunum are required for the left split graft. Liver reduction was first used by Bismuth in Paris and proposed as a potential solution to the severe shortage of small paediatric livers (Bismuth & Houssain 1984). Although initial results were poor, the introduction of University of Wisconsin liver preservation solution (Kalayoglu et al. 1988), and technical modifications improved graft survival to match, or even surpass, results with whole livers in small children and infants (Broelsch et al. 1990; Busuttil & Goss 1999). In particular, reduced grafts have a lower incidence of hepatic artery thrombosis compared with equivalent-sized whole liver grafts in young children. The technique of liver reduction was modified to enable split-liver grafting, so that a single liver could be used for two recipients (Pichlmayr et al. 1988). Liver reduction/splitting is performed either in situ as part of the donor operation or ex situ on the back table. Insitu liver reduction or splitting has the advantage that the surgery is performed on a well-perfused functioning liver without the risk of warm ischaemia during back table surgery. It also enables meticulous haemostasis at the cut surface However, in-situ division adds about 2 h to the operating time at the donor hospital with the attendant risk of donor instability and, perhaps, compromise to other donor organs. Because of concerns about primary graft dysfunction due to prolonged cold ischaemia, ex-situ splitting is usually restricted to livers from stable young donors whereas in-situ split grafts may have wider applications (Noujaim et al. 2000). The recipient operation In the early days of liver transplantation, the operation was frequently complicated by extensive bleeding from raw surfaces, particularly in patients with adhesions from previous upper abdominal surgery. Patients with advanced liver disease have portal hypertension, thrombocytopenia and deranged coagulation. During a long operation in a patient with poor liver function, hypothermia exacerbates the coagulopathy. A better understanding of coagulation disorders, improved monitoring, and more sophisticated haemostatic techniques have greatly reduced transfusion requirements. Anaesthetic monitoring includes serial measurements of blood gases, electrolytes, haemoglobin and platelet count together with coagulation indices including thromboelastography. The thromboelastograph gives a pictorial representation of blood clotting and its interpretation

allows the anaesthetist to determine whether there is a defect in clotting factors or platelets, or whether antifibrinolytic drugs such as aprotinin are indicated. In adults and larger children, the use of venovenous bypass, in which blood is diverted from the portal and infrahepatic caval circulation to the superior vena cava, not only reduces portal hypertension and intestinal congestion when the portal vein is clamped, but also improves venous return and renal perfusion when the vena cava is clamped during hepatectomy. The recipient liver transplant operation is carried out through a bilateral subcostal incision, often with an upper midline extension. The operation can be divided into two phases: total hepatectomy, in which the old liver is dissected and removed; and liver graft implantation. Total hepatectomy In the virgin abdomen, hepatectomy is usually straightforward. However, if there has been previous upper abdominal surgery with bleeding, bile leakage or local sepsis, then the dissection may be much more difficult (this is commonly the case following a previous Kasai portoenterostomy for biliary atresia). The liver is mobilized by division of adhesions to surrounding structures. The porta hepatis is dissected and the bile duct (or Kasai porto-enterostomy), hepatic artery and portal vein divided. The liver is then removed by dividing the hepatic veins which drain into the inferior vena cava. Alternatively, the old liver can be removed in continuity with the retrohepatic vena cava. The latter technique is commonly used in cases of liver cancer such as hepatoblastoma in order to ensure complete excision of the tumour. Graft implantation Once the liver graft is removed from the cold preservation fluid it starts to warm; the smaller the liver the more rapid the warming. Thus the vascular anastomoses are performed expeditiously in order to minimize warm ischaemic injury. For a whole graft the vena cava, and portal vein are anastomosed to the equivalent recipient vessels, taking care not to constrict the anastomoses when tying the sutures. For a left lateral segment graft, a triangular incision is made on the anterior aspect of the recipient vena cava for anastomosis of the graft left hepatic vein. Following completion of the venous anastomoses the liver is flushed with a warm rinsing solution to remove cold preservation fluid, and the venous clamps removed. Following reperfusion of the liver from the portal vein, the arterial anastomosis is carried out. The site depends upon the anatomy and relative calibres of the donor and recipient arteries. Most commonly the donor coeliac artery is anastomosed to the bifurcation of the recipient hepatic and gastroduodenal or splenic arteries.

Chapter 20: Liver Transplantation In small children and those with aberrant vessels we often employ vascular conduits. A hypoplastic portal vein (commonly associated with biliary atresia) can be replaced with donor iliac vein. Similarly, a donor arterial graft may be needed to act as a conduit from the recipient aorta to the donor hepatic artery. The final anastomosis is to the graft bile duct. In adults and larger children without previous biliary pathology the donor and recipient common bile ducts are joined together. Children with biliary atresia and those weighing less than 40 kg require a choledochojejunostomy using a Roux-en-Y loop of recipient jejunum. Biliary complications are more common in small children (Chardot et al. 1995), partly due to the small calibre of the donor bile duct and partly due to the more tenuous blood supply to the bile duct of a reduced-size liver. Once the anastomoses have been completed, the operative field is checked for haemostasis and coagulopathy corrected. Bleeding at this stage may originate from raw areas following the hepatectomy, from the surgical suture lines, or from the graft itself. During the first hour after reperfusion there is usually evidence that the liver is working with spontaneous correction of acidosis and clotting factors, and production of bile. In a proportion of cases (up to 25% of small children) the liver graft may be too large to permit abdominal closure without compromising hepatic venous outflow and also ventilation. In such circumstances we usually insert a temporary patch of prosthetic material into the abdominal wall before closing the skin. Alarge graft will rapidly shrink and the patch can usually be removed after a few days (De Ville de Goyet et al. 1998). Living related liver transplantation The shortage of suitable donors for small children prompted Broelsch and colleagues (Broelsch et al. 1991) to adapt the techniques of split cadaveric liver transplantation to obtain partial liver grafts from living donors. There are several potential advantages of living related transplantation. First, it improves the supply of liver grafts for small children who might otherwise die whilst waiting for a suitable cadaveric organ. Second, live donation allows optimal timing of the transplant as an elective procedure, and reduces the stress of waiting for a suitable organ. Third, the graft is obtained from a healthy individual with minimal preservation time. Against the benefits to the recipient, however, must be set the potential risks to the donor. Partial hepatectomy, even in a healthy individual, is associated with an appreciable morbidity. There have been reports of several donor deaths; risk of donor mortality is estimated at between 1 : 100 and 1 : 250 depending upon whether a larger right liver graft or a smaller left graft is taken (Fujita et al. 2000). Donor complications include bile leaks and haem-

389

orrhage from the cut surface, wound pain, infection and incisional hernia, and a surprisingly high incidence of gastritis and peptic ulceration. Potential donors require careful assessment to ensure that they can provide a graft of suitable size, quality and blood group to the recipient without excessive risk to the donor. Donation must be altruistic without coercion by other family members. All donors should have a formal psychological assessment and be counselled about the perioperative risks and possible long-term complications of the procedure. Preoperative investigations include liver function tests, serology and imaging to assess the size of the intended segmental graft as well as details of its vascular and biliary anatomy. Imaging may indicate abnormal graft parenchyma, in particular fatty change. If in doubt a liver biopsy may be necessary. For a child, the graft from a live donor is usually a left lateral graft (liver segments II + III). During the donor operation the left branches of the hepatic artery, portal vein and bile duct and the left hepatic vein are identified and the liver parenchyma divided along the line of the falciform ligament. The vascular and biliary structures are then divided and the graft flushed with cold preservation fluid. Implantation is similar to that employed for left lateral segmental cadaver grafts (see above). Microsurgical techniques are required for the arterial anastomosis to reduce the risk of thrombosis. Following the introduction of this technique, excellent results were reported from Japan where there is a severe shortage of cadaver donors (Tanaka et al. 1993). In the USA approximately one-third of paediatric liver transplants are now performed from living donors. In the UK an active policy on split liver transplantation has largely obviated the need for live donor transplantation. Clearly, parents considering live donation must be fully informed of the risks of the procedure and the prospects of finding a cadaver graft before making a decision. Auxiliary liver transplantation Auxiliary liver transplantation involves transplantation of a donor liver graft without removal of the entire native liver. Its purpose is to retain the native liver in case of spontaneous recovery or for future gene therapy. It is of value in those metabolic liver diseases in which there is a functionally normal liver but transplantation is indicated for severe extrahepatic disease (e.g. Crigler– Najjar type I). In this situation only a small amount of normal liver is needed to compensate for the metabolic defect, and it usually is sufficient to replace the left lateral segments (II and III) with an equivalent donor graft. Reports suggest that this is successful in reducing the levels of unconjugated bilirubin in Crigler–Najjar type I (Rela et al. 1997). This operation is not indicated for metabolic liver disease such as primary oxalosis in which the

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enzyme deficiency contributes to an excess of oxalate production, or in metabolic diseases such as Wilson’s disease or tyrosinaemia in which there is a risk of malignancy in the retained liver. Auxiliary liver transplantation may also be considered for patients with fulminant or subfulminant hepatic failure when there is potential for the original liver to recover (Boudjema 2002). This requires a large auxiliary graft, usually replacing a right or an extended right lobe. Survival rates may be less than with conventional transplantation (Sudan et al. 1997). It is contraindicated when the liver disease is irreversible (e.g. seronegative hepatitis) but may have a role in reversible toxic injuries such as paracetamol poisoning. Once the native liver has recovered, immunosuppression is gradually withdrawn and the liver graft atrophies due to chronic rejection.

Postoperative management Ventilation Although it is possible to extubate some patients in the operating room, it is generally advisable to stabilize the patient in the intensive care unit (ICU) to ensure that liver function is satisfactory with good hepatic artery and portal vein flow on Doppler ultrasound before discontinuing ventilation. Moreover, large upper abdominal incisions are notoriously painful in the early postoperative period, necessitating epidural analgesia, intravenous morphine (according to body weight) or alfentanil (0.5 mg/kg/ min), which may depress respiration. Young infants with severe malnutrition due to chronic liver disease or patients in hepatic coma due to fulminant liver failure may spend a prolonged period in ICU, but the majority of patients return to the ward within 24–48 h postoperatively. Fluid management The principles of fluid management are to maintain circulating volume by providing two-thirds of maintenance fluids with crystalloid, while half-replacing wound drain losses with 4.5% albumin as long as urine output is in excess of 1 ml/kg/h and central venous pressure is satisfactory (> 5–6 mmHg). Patients are often vasoconstricted and relatively hypovolaemic on return from theatres due to fluid losses, especially if there has been preoperative ascites, hypothermia and the use of intraoperative inotropes. Extra colloid fluid replacement with 4.5% albumin and inotropes, such as dopamine (2–5 mg/kg/min) may be necessary. Haemoglobin should be maintained between 8 and 10 g/l. Excessive blood transfusion is contraindicated as a postoperative haemoglobin of < 10 g/l reduces the risk of hepatic artery thrombosis (Buckels et al. 1989). Venesection is recommended for any patient with a haemoglobin > 11 g/l during the first 2 postoperative weeks.

Immunosuppression There have been many recent advances in immunosuppressive drugs, but current protocols consist of the calcineurin inhibitors: (i) cyclosporin microemulsion (Neoral), prednisolone and azathioprine; (ii) tacrolimus combined with prednisolone (Table 20.4). Steroids are reduced over the first 2 weeks and withdrawn or reduced to alternate day therapy after 3 months to improve growth. Azathioprine is usually discontinued after 1 year. Cyclosporin or tacrolimus are continued for life. Although most immunosuppressant drug monitoring is with trough levels, it is possible that peak Table 20.4 Postoperative management of liver transplantation. Fluid management Maintain: CVP > 6 cmH2O Urine output > 1 ml/kg/h with 4.5 or 20% albumin or 5–10% dextrose Hb < 11 g/l Prophylactic antibiotics 1 Cefuroxime 20 mg/kg/dose t.d.s. for 48 h 2 Amoxil 25 mg/kg/dose t.d.s. for 48 h 3 Metronidazole 8 mg/kg/dose t.d.s. over 1 h for 48 h (or rectally) 4 Nystatin: 50 000 units orally q.d.s. if < 10 kg 100 000 units orally q.d.s. if > 10 kg 5. Amphotericin 1 ml/day orally 6. If CMV positive donor, acyclovir 500 mg/m2/i.v. dose t.d.s. over 1 h 7. Co-trimoxazole < 5 years 240 mg od po; > 5 years 480 mg od po, for 6 months Antiplatelet therapy 1 Aspirin 3 mg/kg/day PR or NG (maximum 75 mg) 2 Dipyridamole: if < 10 kg, 25 mg t.d.s. orally for 3 months if > 10 kg, 50 mg t.d.s. orally Anticoagulation (if necessary) Heparin (60–120 units/kg/day) to maintain PT 20–30 s Antacids Ranitidine 3 mg/kg/dose t.d.s. If gastric pH < 5, omeprazole 10–20 mg i.v. b.d. Antihypertensives Acute: 1 Labetalol 1–3 mg/kg/h 2 Nifedipine 5–10 mg/dose s.l. p.r.n. Chronic: 1 Nifedipine 5–10 mg t.i.d. 2 Atenolol 25–50 mg/day Immunosuppression Cyclosporin A (ME) 5 mg/kg b.d. or Trough levels: 0–1 month 200–250 ng/l 1–3 months 180–200 ng/l 3–12 months 150–200 ng/l > 12 months 70–100 ng/l Prednisolone 2 mg/kg (Ø) 3 months Azathioprine 1–2 mg/kg 12 months

Tacrolimus 0.075 mg/kg b.d. 8–12 5–8 3–8 3–5 Prednisolone 2 mg/kg (Ø) 3 months

Chapter 20: Liver Transplantation cyclosporin levels (C2 levels) may be more effective in preventing rejection and reducing side-effects (Keown et al. 1998). A recent European multicentre study, which directly compared tacrolimus with neoral post transplant, demonstrated a significant reduction in the incidence of acute and steroid-resistant rejection in the tacrolimus group compared with the cyclosporin group without significant difference in adverse side-effects (Kelly et al. 2002), although long-term outcome is still being evaluated. Mycophenolate mofetil (MMF) 10–40 mg/kg has recently been developed as an adjuvant immunosuppressive agent. It is an antiproliferative agent which is similar in action to azathioprine and may depress the bone marrow. The long-term safety and efficacy is undetermined but it has no cosmetic side-effects, is renal sparing and does not require drug monitoring. It was initially used as rescue therapy and was found to be effective and safe but with significant gastrointestinal and haematological side-effects in adults. More recently MMF has been used with neoral and prednisolone as primary immunosuppression (Renz et al. 1999; Chardot et al. 2001). Anti-interleukin-2 receptor antibodies (IL-2 antibodies) are monoclonal antibodies, which selectively target the IL-2 receptors on activated T-cells, which is a key step in the development of cell-mediated immunity. Two antibodies are available, Basiliximab and Daclizumab, both of which are renal sparing and provide effective induction immunosuppression post transplant in combination with a calcineurin inhibitor in adults. To date there is little experience with children (Ganschow et al. 2001; Kelly 2001). Sirolimus is a macrocyclic triene antibiotic which prevents T-cell proliferation by inhibiting cytokine production and does not inhibit calcinueurin. In adults, sirolimus has been evaluated as both primary and rescue immunosuppression for liver transplant recipients and has the advantage of being both renal sparing and reducing the need for high-dose steroids (McAlister et al. 2001). Significant side-effects include delayed wound healing, hyperlipidaemia and an increase in the rate of hepatic artery thrombosis, and it should not be used immediately post transplant but may be useful for chronic rejection. There are few studies of sirolimus in paediatric liver transplantation, although conversion to sirolimus was effective in children who developed hypertrophic obstructive cardiomyopathy on tacrolimus (Pappas et al. 2000). Prophylactic antibiotics Broad-spectrum antibiotics are prescribed for 48 h unless there is continuing infection (Table 20.4). Systemic antifungals, fluconazole or liposomal amphotericin, should

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be continued for 14 days in children with acute liver failure or those undergoing a second laparotomy for complications (Tollemar et al. 1995). Whilst patients are on steroids it is advisable to give low-dose cotrimoxazole or trimethoprim as prophylaxis against Pneumocystis carinii infection. Oral nystatin and amphotericin to prevent oral and oesophageal candidiasis may be continued for 6–12 months. Prophylaxis for CMV infection is required for CMVnegative recipients of a CMV-positive donor. Acyclovir (1500 mg/m2/day i.v. or 200–400 mg/dose q.d.s. orally) or ganciclovir (5 mg/kg) prevents infection in the short term when immunosuppression is intense (Davison et al. 1993). There is no satisfactory prophylaxis for EBV, although some units use acyclovir or ganciclovir. Other medications The incidence of stress ulcers and excess gastric secretion is high in children recovering from liver transplantation, particularly those on high doses of steroids (Dimand et al. 1989; Kelly 1994a). Therefore, it is important to prevent steroid-induced peptic ulceration with ranitidine, which, unlike cimetidine, does not interact with cyclosporin sucralfate (2–4 g q.d.s.) and/or omeprazole (10–20 mg i.v. b.d.). Antiplatelet drugs, aspirin and dipyridamole are prescribed to prevent vascular thrombosis and discontinued at 3 months. Intravenous heparin and/or warfarin may be indicated for children with a high risk of thrombosis. Antihypertensive medication is usually required because of the effects of the immunosuppressive therapy. Nifedipine (5–10 mg/dose) and/or atenolol (25–50 mg/dose) are usually adequate.

Postoperative complications Early postoperative complications Complications in the early postoperative period may be due to: • the preoperative condition of the recipient (e.g. malnutrition, sepsis, renal failure) • the quality of the graft (e.g. primary non-function, acidosis, coagulopathy) • surgical complications (e.g. intra-abdominal haemorrhage, vascular thrombosis, venous outflow obstruction) • side-effects from drugs (e.g. cyclosporin-induced renal failure; hyperglycaemia from either tacrolimus or cyclosporin). A number of factors may predispose to postoperative renal failure. Some patients have impaired renal function preoperatively which may have been aggravated by intraoperative cardiovascular instability requiring inotrope support. In such patients early administration of

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nephrotoxic immunosuppression, such as cyclosporin or tacrolimus, should be delayed as rejection is not usually a problem in the first 2–3 days post transplant. Alternatively, renal sparing drugs such as MMF, sirolimus or IL-2 antibodies should be considered. Oliguria is common and should be managed by ensuring adequate fluid replacement or frusemide challenge (1–2 mg/kg i.v., or infusion 0.25 mg/kg/h). Anuria with a rising urea, creatinine or potassium requires renal haemodialysis or filtration. The main causes of graft loss in the first week include: • primary non-function (PNF) secondary to hyperacute rejection which occurs on day 4–5 • hepatic artery or portal vein thrombosis • systemic sepsis. Primary non-function is a serious complication which requires immediate retransplantation. It may be suspected if there is persistent coagulopathy, acidosis, a high potassium and transaminases > 10 000 IU/l. If secondary to hyperacute rejection, the diagnosis can only be made by liver biopsy (which may be impractical) or by identification of raised immunoglobulins (Adams et al. 1990). Treatment consists of retransplantation or an increase in immunosuppression. Hepatic artery thrombosis occurs in 10% of children. The incidence has fallen following the introduction of reduction hepatectomy and split liver grafts with the use of larger donor blood vessels (Rela et al. 1996; Mirza et al. 1998). Medical prevention of hepatic artery thrombosis is by maintaining a low haematocrit (< 10 g/haemoglobin) and the use of antiplatelet agents such as aspirin (3 mg/kg/day) and dipyridamole (25–50 mg t.d.s.) (Buckels et al. 1989). Portal vein thrombosis is less common. The diagnosis of hepatic artery or portal vein thrombosis is made by Doppler ultrasound and confirmed by angiography (see Plate 80, Atlas: p. 469). Treatment includes: • immediate laparotomy with thrombectomy and use of anticoagulants • retransplantation. Retransplantation is not always required as collateral blood vessels may develop. Late complications of hepatic artery thrombosis include biliary leaks and strictures or hepatic abscesses (Chardot et al. 1995). Systemic sepsis is treated as indicated with broadspectrum antibiotics and antifungals. Retransplantation is not indicated if sepsis leads to multiorgan failure and graft non-function. Haemorrhage from the cut surface of the liver is a rare complication and is managed conservatively unless there is confirmed bleeding or haemodynamic instability. Abdominal tamponade may decrease renal blood flow causing renal failure.

Complications after the first postoperative week Complications arising after the first postoperative week include: • acute rejection • biliary leaks/strictures • persistent wound drainage • sepsis. Acute rejection is less common in infants (20%) but increases to 50–60% in older children (Murphy et al. 1996). The clinical signs and symptoms include fever, irritability and abdominal discomfort. The diagnosis is confirmed by detecting a rise in bilirubin, alkaline phosphatase, aspartate and alanine transaminases, and g-glutamyl transpeptidase (GGT). It is always necessary to have histological confirmation. Acute rejection is indicated by a mixed inflammatory infiltrate in portal tracts with subendothelial lymphoid infiltration (endothelialitis) and inflammatory infiltration of bile ducts (Hubscher 1996) (see Plate 81, Atlas: p. 469). Treatment is with pulse methylprednisolone (20–40 mg/kg/day) intravenously over 2 or 3 days. If there is inadequate histological or biochemical response, treatment with methylprednisolone may be repeated but conversion to a more potent immunosuppressive drug such as tacrolimus may be required (Reyes et al. 2000). Chronic rejection occurs in < 10% of children at any time post transplant (Murphy et al. 1996). The diagnosis is suggested by the gradual onset of jaundice, pruritus and pale stools which indicate biliary obstruction. Biochemical changes include a higher rise in bilirubin, alkaline phosphatase and GGT than in transaminases. Histology may demonstrate extensive damage and loss of bile ducts (vanishing bile duct syndrome) with arterial obliteration and fibrosis (see Plate 82, Atlas: p. 469). Most children respond to an increase in immunosuppression, such as the addition of MMF or conversion to tacrolimus or sirolimus, but some require retransplantation. The incidence of biliary complications has increased with the use of reduction hepatectomies and split liver grafts (Chardot et al. 1995; Mirza et al. 1998). Biliary strictures may be secondary to an anastomotic stricture, oedema of the bile ducts or hepatic artery ischaemia. Biliary leaks may be secondary to leakage from the cut surface of the liver or from hepatic artery ischaemia. Most biliary leaks will settle with conservative management. Large leaks causing biliary peritonitis, biliary abscesses or sepsis will require surgical drainage and reconstruction. The majority of intrahepatic biliary strictures are now managed medically with ursodeoxycholic acid or radiologically using percutaneous transhepatic cholangiography. The dilated biliary tree is cannulated and external biliary drainage established (see Plate 83a,b, Atlas: p. 470). Biliary dilatation may be performed using balloons and biliary stents. Surgical reconstruction is now only required

Chapter 20: Liver Transplantation for the management of extrahepatic biliary strictures or if interventional radiology fails. Persistent drain losses may be due to preoperative ascites or secondary to rejection, sepsis, hepatic vein obstruction or peritonitis. It may lead to acidosis and coagulopathy due to loss of bicarbonate and coagulation factors. Treatment is of the primary cause, fluid restriction and diuretics. Sepsis is still the commonest complication following liver transplantation (60–70%) (Beath et al. 1993a). The majority of infections are bacterial infections related to central line insertion (Streptococcus faecalis and S. viridans, Pseudomonas aeruginosa and Staphylococcus aureus). Fungal infections with Candida albicans and Aspergillus spp. are documented in approximately 20% of patients and are particularly common in patients with fulminant hepatitis with acute hepatic necrosis pretransplant. Vancomycinresistant enterococcus (VRE) is a common gut pathogen, but systemic infection requires treatment with Synercid (Gray et al. 2000). Late complications post-liver transplant Late complications (after 3 weeks) may occur at any time post transplant. They include: • side-effects of immunosuppression • CMV or EBV infection • post-transplant lymphoproliferative disease (PTLD) • late biliary stricture • late hepatic artery or portal vein thrombosis. There are numerous side-effects of immunosuppressive therapy (Table 20.5). Some are short term, such as stunting and hypertension secondary to steroids, while nephrotoxicity and increased risk of viral infection are lifelong. Hirsutism and gingival hyperplasia are sideeffects of cyclosporin which, although cosmetic, have an

Table 20.5 Immunosuppressive complications post transplantation. Drug

Complications

Steroids

Stunting Hypertension Cushingoid facies

Cyclosporin A

Hirsutism Gingival hyperplasia Hyperlipidaemia

CYA/Tacrolimus

Nephritis Hypertension Neurotoxicity Hyperglycemia ?Lymphoproliferative disease

Tacrolimus

?Cardiomyopathy

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important effect on quality of life. With careful monitoring of immunosuppression to ensure adequate trough levels, nephrotoxicity should be minimized (Ellis et al. 1986; Bartosh et al. 1997). CMV infection occurs 5–6 weeks post transplant despite prophylaxis with acyclovir or ganciclovir (Davison et al. 1993; Mellon et al. 1993; Gane et al. 1997). It is more common in children than adults, reflecting the number of CMV-negative children undergoing liver transplantation. The risk of CMV disease as opposed to CMV infection is indirectly related to receiving a transplant from a CMV-positive donor, but is usually treated effectively with high-dose ganciclovir 5 mg/kg and hyperimmune CMV globulin dose. The development of primary EBV is a significant longterm problem. Approximately 65% of children undergoing liver transplantation will be EBV-negative pretransplant and 75% of this group will have a primary EBV infection within 6 months of transplantation (Davison et al. 1993). It is important to diagnose primary EBV infection and reduce immunosuppression, if possible, in order to prevent further progression to lymphoproliferative disease (Newell et al. 1996). There is a close relationship between primary EBV infection and the development of lymphoproliferative disease (Ho et al. 1988). The spectrum of B-lymphocyte proliferation ranges from benign hyperplasia to malignant lymphoma. The clinical features may represent infectious mononucleosis, isolated lymphoid involvement or malignant lymphoma EBV. Polymerase chain reaction (PCR) is usually positive, but is not diagnostic of PLTD. The diagnosis is based on identifying the characteristic histology from the affected tissue, which may demonstrate polymorphic B-cell proliferation or lymphomatous features of nuclear atypia and necrosis. EBER staining for EBV is positive. Immunofluorescent staining of heavychain and light-chain immunoglobulins may differentiate monoclonal from polyclonal infiltrates. Almost any organ in the body may be affected, although the liver and gut are most commonly involved. Although initially it was felt that the incidence was higher with tacrolimus than with cyclosporin, this may be due to the initial use of inappropriately high levels of tacrolimus (Cox & Freese 1996; Furlan et al. 2000). Treatment includes: • reduction of immunosuppression • intravenous acyclovir (3 mg/m2) or ganciclovir (6–10 mg/kg) may be effective (McDiarmid et al. 2002) • infusion of autologous T-cells directed against EBV cells (Haque et al. 2002) is a research technique which may have future potential • chemotherapy which is tailored to the type of lymphoma is necessary if the lymphoproliferative disease becomes overtly malignant, chemotherapy is required if the PTLD becomes overtly malignant

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Graft

(%)

(%)

100

100 82

79

80 79

p log rank = NS

77

76

75

75

74

73

73

60

80 60

70

66

69

p log rank = 0.059 40

63

61

60

65

59

40 - 1) have slower catchup growth but will eventually achieve normal height (McKiernan et al. 1992; Sarna et al. 1995). The growth-suppressant effects of corticosteroids in liver transplantation have been documented by many units. Catch-up growth will be observed either when alternate-day steroids are instituted or steroids are discontinued post transplant as is routine in some units (Andrews et al. 1994; Dunn et al. 1994). Failure to thrive and stunting are intrinsic features of certain genetic disorders such as Alagille’s syndrome. Linear growth may improve post transplantation for Alagille’s syndrome, but approximately half these children do not achieve normal height (Cardona et al. 1995).

feeding regimen. In the minority of patients, however, nocturnal enteral feeding may be required for 1–2 years to maintain normal growth (Kelly 1997). Psychosocial development There is an initial deterioration in psychosocial development post transplant as noted by deterioration in social skills, language development, and eye/hand coordination for up to 1 year post transplant (Beath et al. 1995; Wayman et al. 1997). However, the majority of children will achieve normal psychosocial development post transplant but the rate of improvement is related to the age of onset of liver disease and age at the time of transplant (Stewart et al. 1989). Children who do not have a transplant until significant motor or psychological developmental delay has taken place are unlikely adequately to catch up post transplant and achieve normal developmental scores. In contrast, children who have undergone transplant earlier have been shown to have complete nutritional and developmental catch-up within 1–4 years post transplant and be capable of attending normal school (Beath et al. 1995; Stone et al. 1997; van Mourik et al. 2000) (see also Chapter 1). It is clear, therefore, that referral for transplantation before children develop irreversible psychosocial developmental delay is mandatory. Non-compliance with therapy Non-compliance with immunosuppressive therapy is less common in liver transplant recipients than in renal transplant recipients (Molmenti et al. 1999; Watson 2000). This may be because the median age at renal transplantation is 14.3 years, compared with 2.5 years for liver transplantation. It is possible that children who were grafted at a young age are more likely to accept medication through their adolescence (see also Chapter 1).

Behavioural feeding problems Children with end-stage liver disease have associated anorexia and vomiting. They are often fed unpalatable feeds, sometimes by nasogastric tube. Many of these infants may never have fed normally prior to their transplant and thus will have missed their developmental milestones for chewing, swallowing and normal feeding behaviour. The perioperative emphasis on nutritional support often creates parental anxiety about feeding which further exacerbates these difficult behavioural problems. Review of data in Birmingham from our unit shows that up to 60% of patients who were tube-fed prior to liver transplantation develop significant feeding problems postoperatively. The management of these disorders includes a multidisciplinary approach with a dietician, food psychologist and a strict behavioural

Endocrine development Long-term studies from France have shown that children surviving liver transplantation will enter puberty normally, girls will develop menarche and both boys and girls will have pubertal growth spurts (Codoner-Franch et al. 1994). Successful pregnancies have been reported (Laifer & Guido 1995; Jain et al. 1997). Family functioning Few data are available on family functioning but a number of early studies have indicated that the extreme stress experienced by families may lead to marital breakup and dysfunctional family behaviour (Rodrigue et al. 1996).

Chapter 20: Liver Transplantation Out-patient monitoring Initial post-transplant management includes frequent follow-up by the transplant centre, usually at weekly intervals, extending with time to monthly, 3-monthly, and then 6-monthly intervals. Monitoring should include: 1 Assessment of nutritional status by measuring height, weight, triceps skin fold, mid-arm circumference and mid-arm muscle area. 2 Detection of potential complications (e.g. rejection, hepatic artery thrombosis, biliary complications) by performing regular liver function tests and 6-monthly or annual abdominal ultrasound examinations. 3 Monitoring of immunosuppression to maintain adequate peak or trough levels of cyclosporin and trough levels of tacrolimus to prevent rejection and reduce toxicity (Table 20.4). 4 Monitoring for PTLD by EBV PCR 3–6 monthly; and measuring serum albumin as a falling albumin may be an early sign of gut PTLD. 5 Protocol liver biopsies. Although annual liver biopsies produce little additional information unless other investigations are abnormal (Rosenthal et al. 1997), 5- and 10year biopsies may detect chronic hepatitis and fibrosis in 25–50% of children which is not related to hepatitis C or G, but may be autoimmune in origin (Davison et al. 1998; Evans et al. 2001). It is essential to encourage both child and family to return to a normal life by reducing outpatient visits and encouraging return to school, nursery and playgroup, and discouraging the parents from continuing to maintain their child in a sick role. Many families may find the transition from intensive management in specialist units to the more relaxed outpatient follow-up difficult to cope with, and need additional support and encouragement to regain a normal life. Promising lines of research For the moment, liver transplantation is here to stay, although the rapid development of techniques to improve hepatocyte transplantation for acute liver failure or metabolic liver disease is encouraging (Vons 2001; Boudjema et al. 2002). The continued advance in targeted immunosuppressive drugs can only improve the outcome for children undergoing liver transplantation (Vincenti 2002).

References Achilleos, Q.A., Buist, L.J., Kelly, D.A., McMaster, P., Mayer, A.D. & Buckels, J.A.C. (1996) Unresectable hepatic tumours in childhood and the role of liver transplantation. Journal of Pediatric Surgery 11, 1563–1567. Adams, D.H., Hubscher, S.G., Burnett, D. & Elias, E. (1990) Immunoglobulins in liver allograft rejection: evidence for

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follow-up of auxiliary liver transplantation for fulminant hepatic failure. Transplantation Proceedings 29, 485– 486. Sudan, D.L., Shaw, B.W. Jr & Langnas, A.N. (1998) Causes of late mortality in pediatric liver transplant recipients. Annals of Surgery 227, 289–295. Tanaka, K., Uemoto, S., Tokunaga, Y. et·al. (1993) Liver transplantation in children from living-related donors. Transplantation Proceedings 25, 1084–1086. Thomson, M., McKiernan, P., Buckels, J., Mayer, D. & Kelly, D. (1998) Generalised mitochondrial cytopathy is an absolute contraindication to orthotopic liver transplantation in childhood. Journal of Pediatric Gastroenterology and Nutrition 26, 478–481. Tollemar, J., Hockerstedt, K., Ericzon, B., Jalanko, H. & Ringden, O. (1995) Liposomal amphotericin B prevents invasive fungal infections in liver transplant recipients. Transplantation 59, 45–50. Uemoto, S., Vinomarta, Y., Tanarka, A. et·al. (1996) Living related liver transplantation in children with hypoxaemia related to intrapulmonary shunting. Transplantation International 9 (Suppl. 1), S157–S159. Van Mourik, I.D.M., Beath, D. & Kelly, D. (2000) Long term nutrition and neurodevelopmental outcome of liver transplantation in infants aged less than 12 months. Journal of Pediatric Gastroenterology and Nutrition 30, 269–276. Vincentil, F. (2002) What’s in the pipeline? New immunosuppressive drugs in transplantation. American Journal of Transplantation 2, 898–903. Viner, R.M., Forton, J.T.M., Cole, T.J., Clark, I.H., NobelJamieson, G. & Barnes, N.D. (1999) Growth of long term survivors of liver transplantation. Archives of Disease in Childhood 80, 235–240. Vons, C. (2001) Transplantation of isolated hepatocytes, is it an alternative for total liver transplantation? On the treatment of hereditary hepatic metabolic disease. Journal de Chirurgie 138, 342–346. Watson, A.R. (2000) Non-compliance and transfer from paediatric to adult transplant unit. Pediatric Neprhology 14, 469–472. Wayman, K.I., Cox, K.L. & Esquivel, C.O. (1997) Neurodevelopmental outcome of young children with extrahepatic biliary atresia 1 year after liver transplantation. Journal of Pediatrics 131, 894–898. Whitington, P.F., Freese, D.K., Alonso, E.M., Schwarzenberg, S.J. & Sharp, H.L. (1994) Clinical and biochemical findings in progressive familial intrahepatic fibrosis. Journal of Pediatric Gastroenterology and Nutrition 18, 134–141. Yandza, T., Gauthier, F. & Valayer, J. (1994) Lessons from the first 100 liver transplantations in children at Bicetre Hospital. Journal of Pediatric Surgery 29, 905–911. Zitelli, B.J., Gartner, B., Malatack, J.J. et·al. (1987) Pediatric liver transplantation: patient evaluation and selection, infectious complications, and life-style after transplantation. Transplantation Proceedings 19, 3309–3316.

Chapter 21: Small Bowel Transplantation in Children JORGE REYES AND KAREEM ABU-ELMAGD

Introduction, 402 Indications, 402 Indications for intestinal transplantation, 403 Evaluation for transplantation, 405 Intestinal assessment, 405 Preoperative management, 407 The transplant procedure, 407 Selection of donors, 407 Donor operation, 408

Graft preservation, 409 Recipient operations, 409 Postoperative management, 410 Immunosuppression, 411 Prevention of infection, 411 Management of fluid balance, 411 Nutrition, 412 Assessment of the graft, 412 Complications post transplant, 413

Introduction Organ transplantation in children has been routinely successful and clinically applicable for over 20 years in organs such as the liver, kidney and heart. Successful transplantation of the intestine, however, remained difficult because of the need to provide sufficient immunosuppression to prevent rejection without creating untreatable clinical circumstances such as overwhelming infection and disabling drug toxicity. The intestinal allograft did not fit the paradigm that had been defined for other organs and experimentally tested in dogs by Lillehei in 1959 and Starzl in 1960. Though these studies served as technical centrepieces for intra-abdominal transplant procedures that involved more than one organ, the predicted cellular events of rejection and also potentially graft-vs.-host disease (GVHD) were poorly understood. Early experience with cyclosporin immunosuppression was largely unsuccessful (Grant 1989; Starzl et al. 1989a; Grant et al. 1990; Margreiter et al. 1992; McAlister et al. 1992), though it was notable that transplantation of the intestine in combination with a liver allograft appeared to reduce rejection (Calne et al. 1969; Kamada et al. 1983; Grant 1989). Until 1990 only the isolated intestine recipient of Goulet, and a living related donor intestinal segment transplanted by Deltz had survived (Deltz et al. 1989; Goulet et al. 1992). The introduction of the immunosuppressant tacrolimus (previously FK506) into clinical transplantation has significantly improved survival (Todo et al. 1992), though the postoperative course remains complex and the long-term outcomes are still unravelling (see Fig. 21.1). Advances in clinical surgery and immunosuppressive

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Clinical/surgical factors, 413 Rejection, 413 Infections, 414 Chimerism and GVHD, 415 Causes of graft loss, 415 Survival, 415 Nutritional status and longterm rehabilitation, 416 Present and future status, 416

management over the last 12 years have made human intestinal transplantation a clinical reality. In this chapter we will examine the basis of successful clinical paediatric intestinal and liver transplantation that are a result of advances in the following principles: • indications for transplantation • surgical technique • appropriate immunosuppression • induction of donor-specific non-reactivity.

Indications The advent of successful intestinal transplantation identified a range of diseases affecting children that place them at risk of total parenteral nutrition (TPN)-induced complications. Table 21.1 summarizes the diagnoses by cause that fortuitously distribute patients by age, risk for early or late mortality, and outcome post transplant. A multidisciplinary approach to intestinal failure in the setting of an intestinal transplant programme can facilitate the identification and management of serious medical and surgical problems that allows for the appropriate selection of candidates and the optimum transplant procedure. Most large paediatric gastrointestinal (GI) units which manage 10–15 home PN patients per year can expect that up to five patients will develop a serious complication meriting assessment for small bowel transplantation, one or two of whom may then be listed for small bowel transplantation (Beath et al. 1997). Optimization of TPN and enteral management may stabilize patients’ clinical syndromes while awaiting organ donation, and in some patients lead to resolution of cholestasis and independence from TPN, thus avoiding transplantation.

Chapter 21: Small Bowel Transplantation

403

1.0 .9 .8 P = 0.003

Fig. 21.1 Kaplan–Meir survival curve according to histopathology on liver biopsies from 161 patients referred for intestinal transplant evaluation. Bridging fibrosis (n = 37) and cirrhosis (n = 48) had similar clinical behaviour and warrant liver replacement in the face of persistent jaundice and coagulopathy. (Reproduced with permission from Bueno et al., 1999).

Patient survival

.7 .6

Portal fibrosis

.5

Cholestasis

.4 .3 .2

Bridging fibrosis Cirrhosis

.1 0.0 0

Table 21.1 Causes of intestinal failure requiring intestinal transplantation in children. Surgical short gut (as a consequence to): Congenital malformations Necrotizing enterocolitis (NEC) Trauma Volvulus Intestinal atresia Gastroschisis* Intestinal dysmotility: Intestinal pseudo-obstruction Intestinal aganglionosis (Hirschsprung’s disease) Enterocyte absorptive impairment: Microvillus inclusion disease Autoimmune or idiopathic enteropathy Tumours: Familial polyposis Inflammatory pseudotumour

*Gastroschisis may be associated with intestinal atresia, volvulus, NEC or vascular occlusion.

Indications for intestinal transplantation Intestinal transplantation, either alone or as a composite graft with other intra-abdominal organs, is indicated for children with irreversible intestinal failure who develop life-threatening complications related to direct toxicity of TPN or the catheters needed to infuse them. Causes of intestinal failure (Table 21.1) Intestinal failure is defined as GI disease that leads to failure to maintain sufficient fluid, electrolyte and nutritional status for more than a month that leads to dependency on TPN.

12

24

36

48

60

72

84

Time after evaluation (months)

Surgical causes The commonest cause of intestinal failure in childhood is the short bowel syndrome due to surgical correction of congenital defects such as gastroschisis, mid-gut volvulus, intestinal atresia or surgery for necrotizing enterocolitis (Table 21.1). Patients with gastroschisis may have intestinal dysmotility in association with their abdominal wall defect. The introduction of TPN in 1969 dramatically improved outcome for children with short bowel syndrome (Wilmore et al. 1969), but longterm outcome is related to the rate of intestinal adaptation and the development of TPN complications. The capacity for intestinal adaptation is influenced by the length and type of residual small bowel (whether it is ileum or jejunum), the site of intestinal resection, the presence or absence of the ileocaecal valve, the length of remaining colon, and the age of the patient. In clinical practice, the minimum length of intestine necessary for adaptation is difficult to establish because of inadequacies in assessing bowel length following resection and the subsequent development of dysmotility, inflammation, and shortening of the remaining bowel. The presence of an ileocaecal valve is crucial for adaptation as it may reduce bacterial overgrowth and improve function (Wilmore 1972; Grosfeld et al. 1986). In general, ileum adapts better than jejunum. Adaptation may be improved by enteral supplementation, utilization of oral glutamine (Windmueller & Spaeth 1978; O’Dwyer et al. 1989; Wilmore et al. 1988; Vanderhoof et al. 1992) and growth hormone (Byrne et al. 1995). Functional causes Functional causes for intestinal failure include disorders of motility, e.g. chronic intestinal pseudo-obstruction (CIP), Hirschsprung’s disease and aganglionosis; or mucosal disorders such as microvillous inclusion disease and protracted diarrhoea of unknown cause.

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In CIP, patients present at birth or in the first year of life with signs and symptoms of intestinal obstruction without an anatomical cause. The disorder may be secondary to neuropathic or myopathic dysfunction (Hyman & DiLorenzo 1993). Abdominal distension and constipation are common symptoms. Many patients with the neuropathic form have severe abdominal pain and become narcotic dependent. Patients with the myopathic form are at risk of spontaneous intestinal perforation, megacystis/megaureter with consequent repeated urinary tract infections and eventual renal dysfunction. Microvillus inclusion disease is an autosomal recessive disorder characterized by the combination of hypoplastic villous atrophy in which the apical surface enterocytes contain vesicles with microvilli and secretory granules (Davidson et al. 1978). Eighty percent of children die in infancy from malabsorption and malnutrition without TPN. Long-term survivors are dependent on TPN. Intestinal tumours Unlike adult practice, malignancy is an unusual cause of intestinal failure. Diffuse intestinal polyposis requiring extensive surgery is occasionally encountered. Complications of TPN Parenteral nutrition permits children with intestinal failure to survive for many years but is associated with a number of life-threatening complications. These include catheter sepsis, metabolic disorders, loss of venous access from extensive venous thrombosis (see Plate 86, Atlas: p. 471), pulmonary embolism and the development of TPN-induced liver dysfunction (Steiger & Srp 1983; Ricour et al. 1990; Pollard et al. 1994). By far the most severe complication induced by TPN is cholestatic liver disease. This complication is more common in children than in adults on TPN, especially in neonates who have suffered extensive loss of their intestine due to necrotizing enterocolitis (NEC) or intestinal atresias. Many studies have noted that TPN liver disease is more common in premature or low birth weight infants, which may be related to the immaturity of the neonatal liver (Beale et al. 1979). There is both diminished hepatic uptake and synthesis of bile salts and a reduced enterohepatic circulation (Tzakis et al. 1992). Inability to establish enteral feeding is common in children requiring parenteral nutrition, and TPN liver disease is more likely to develop in those children who are unable to tolerate any enteral feeding (Colomb et al. 1992). Prolonged fasting leads to reduction in secretion of gastric inhibitory polypeptide (GIP) and vasoactive intestinal polypeptide (VIP), which when combined with reduced gastrin catabolism results in increased serum gastrin and gastric hypersecretion, leading to intestinal stasis, reduction in gall-bladder contractility and decreased exocrine

pancreatic secretion (Rombeau & Rolandelli 1987). Intestinal stasis may lead to bacterial overgrowth, bacterial translocation and sepsis. The reduction in cholecystokinin release may influence gall-bladder size and contractility and cause the development of biliary sludge and gallstones (Barbier et al. 1992). TPN liver disease is more common in neonates with recurrent episodes of sepsis, which may be related to either central line infections or bacterial translocation with release of endotoxin into the portal vein circulation (Balisteri & Bove 1990). It is possible that hepatotoxicity may be related to the components of TPN, and a variety of precipitating factors have been suggested, such as the excessive provision of protein and carbohydrates, glycine, alanine, tryptophan, and flavinoids, associated with relative deficiencies in selenium, tocopherol and taurine (Manginello & Javitt 1981; Das et al. 1993). Recently, hypermagnesaemia was reported in children with TPN cholestasis related to excessive manganese supplementation (Fell et al. 1996), suggesting that manganese toxicity exacerbates cholestasis in children with established liver disease. Histology The early histological changes are related to centrilobular cholestasis without inflammation, necrosis or fatty infiltration. Steatosis is relatively uncommon in infants, but is secondary to hepatic accumulation of lipid or glycogen. More advanced liver disease includes portal fibrosis, pericellular fibrosis and bile ductular proliferation. Patients with more severe pathological damage to the liver will have a higher mortality rate (see Plate 87, Atlas: p. 471) (Bueno et al. 1999). Clinical features of TPN liver disease Clinical jaundice is a sensitive indicator of ongoing liver damage, although bilirubin may improve with treatment of sepsis or intestinal adaptation. Persistently elevated bilirubin (> 100 mmol/1) carries a high 1-year mortality and is an indication for transplantation (Beath et al. 1995). Splenomegaly may develop early and is helpful in staging hepatic fibrosis. Clinical evidence of portal hypertension (history of bleeding oesophageal varices, hepatosplenomegaly and ascites) suggests irreversible liver disease. Management of TPN and liver disease The loss of different sections of the GI tract leads to differing clinical syndromes and management problems. Malabsorption of minerals and folic acid is common with duodenal resections, while protein and carbohydrate malabsorption are major problems with jejunal resections. Disruption of the enterohepatic circulation of bile salts with malabsorption of vitamin B12 occurs with ileal resection. The reduction in intestinal transit time, in association with malabsorption of carbohydrate, may precipitate fermentation and small bowel bacterial overgrowth syndrome (Gorgstrom

Chapter 21: Small Bowel Transplantation et al. 1957; Dudrick et al. 1991; Edes et al. 1990; Ricotta et al. 1981; Bond et al. 1980) and may cause steatorrhoea with saponification of luminal ionized calcium and excessive free oxalate absorption by the colon, leading to hyperoxaluria and the development of oxalate urolithiasis. TPN liver disease is potentially reversible if TPN is discontinued before the development of severe fibrosis of cirrhosis (Dahms & Halpin 1981), although this is not an option for children with irreversible intestinal failure, from mucosal causes (e.g. microvillous atrophy) or functional causes (e.g. pseudo-obstruction). In children with a short gut from neonatal surgery, the aim is to reduce cholestasis by encouraging intestinal adaptation, thus achieving independence from TPN and avoiding transplantation. Hepatic dysfunction may be reduced by the introduction of enteral feeding, which may encourage normal biliary dynamics, improve bile flow and reduce intestinal stasis and bacterial overgrowth. The use of modular feeds given continuously initially, in increasing volumes, is useful for bowel adaptation in patients with the short bowel syndrome, and may be used in association with codeine and/or loperamide to increase transit times. Bile flow and the formation of biliary sludge may be improved using oral ursodeoxycholic acid (10–20 mg/kg) (Linco and Burnes 1991). It is important to prevent sepsis, in particular, catheter sepsis and bacterial overgrowth using oral decontamination therapy (Spaeth et al. 1990). The addition of glutamine to TPN solutions may improve gut immunity and intestinal adaptation. Other strategies utilized include cycling of TPN, selective bowel decontamination (Kubota et al. 1990), and most recently the use of intravenous cholecystokinin (Teitelbaum et al. 1995). Innovative bowel tapering and lengthening surgery has successfully improved the motility of previously dilated segments of bowel. This improvement in function together with an increase in the surface area of the intestine may allow sufficient adaptation to discontinue TPN (Hassan et al. 2002; Kumar et al. 2002). In children with an adequate length of small bowel and/or an ileocaecal valve, in whom there is potential for further intestinal adaptation, an isolated liver transplant may be preferred to a combined liver and intestinal transplant (Gupte et al. 2002; Kumar et al. 2002). Vascular access Vascular access and infectious problems are the next TPN-induced complications, and are a consequence of the need for ‘lifelong’ venous catheterization. In practical terms ‘venous accessibility’ is limited to six sites: the pairs of internal jugular, subclavian, and iliac veins. The loss of 50% of these sites warrants consideration for intestinal transplantation. Likewise, patients presenting life-threatening catheter sepsis with metastatic infections, unusual pathogens, or multisystem organ fail-

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Table 21.2 Evaluation of paediatric small bowel transplantation candidates. Intestinal assessment Anatomy of remaining bowel Upper and lower gastrointestinal barium studies Motility studies Histology of bowel Hepatic assessment Bilirubin, alkaline phosphatase, aspartate aminotransferase (AST) Albumin a-Fetoprotein Prothrombin time, partial thromboplastin time Liver ultrasound for hepatic vessels Liver histology (when indicated) Vascular access Doppler ultrasound for patency of central veins Nutritional evaluation Weight, height, triceps, skinfold, mid-arm circumference Transferrin, albumin, prealbumin, serum amino acid analysis Vitamins A, D, E, B12 , thiamine Triglycerides General Full blood count Blood type (ABO), tissue typing, cross-matching Blood urea nitrogen (BUN), serum creatinine Chest X-ray Echocardiogram, electrocardiogram Ventilation/perfusion scan (if indicated) Investigations for infection Blood, urine, throat, faeces, ascites culture: bacterial, fungal, viral, hepatitis screen, CMV, EBV Quantitative stool cultures

ure should be referred for intestinal transplantation (Kaufman et al. 2001).

Evaluation for transplantation (Table·21. 2) Children referred for intestinal transplantation generally have complex medical, surgical, and social histories. A thorough multidisciplinary evaluation is required including: • confirmation of the cause and extent of intestinal failure • potential for intestinal adaptation and medical or surgical intervention • identification of other organ dysfunction such as cardiac, pulmonary, or central nervous system. Intestinal assessment Confirmation of diagnosis It is essential to confirm the diagnosis in patients with

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motility disorders or mucosal lesions by reviewing previous history, radiology and histology. There may be considerable variation in the extent of GI tract involvement and manometric findings in patients with CIP. Thus, functional assessment of the entire GI tract (including the oesophagus) is critical in the selection of the appropriate intestinal graft (Sigurdsson et al. 1998). Patients with extensive ‘long-segment’ Hirschsprung’s disease require thorough review of all pathological material prior to transplant to establish the extent of the disease with further examination of intra-operative ‘frozen-section’ of residual intestine at the time of transplantation. Intestinal tract anatomy is assessed by barium studies to ascertain continuity, deformities, or gross functional abnormalities. The length of bowel in patients with short bowel syndrome is estimated as far as possible, identifying the length of ileum and jejunum, the presence or absence of the ileocaecal valve, and any evidence of dysmotility. Intestinal function The best test of intestinal function is tolerance to enteral feeds, thus it is important to obtain a good feeding history in order to establish whether there is any potential for adaptation or medical therapy. Assessment of motility may be performed by: • carmine red marker transit time (normal > 6 h) • technetium-labelled gastric emptying (normal < 4 h) • intestinal manometry • in patients with dysmotility syndromes, it may be useful to measure the response to pro-kinetic drugs such as domperidone, metoclopromide, cisapride or erythromycin. Absorption studies that include xylose absorption are rarely performed, but measurement of stool electrolytes, reducing substances and steatocrit may be helpful in assessing severity of mucosal disease. It is essential to assess the potential for adaptation in patients with short gut syndrome by: • Encouraging either continuous or bolus enteral feeds. • Treating bacterial overgrowth with antibiotics (amoxycillen and metronidazole). • Addition of glutamine to TPN or enteral feeds (Vanderhoof et al. 1992). • Consideration of growth hormone therapy (Byrne et al. 1995). • Consideration of corrective surgery in children with short gut, such as re-establishing continuity of bowel, or bowel lengthening may improve intestinal function. Patients with ‘extreme short gut’ defined as resection of more than 80% of the small bowel including the ileocaecal valve are unlikely to adapt and should be considered early for transplantation.

Hepatic function Most children who are referred for intestinal transplantation will have some hepatic dysfunction. The assessment of hepatic function is critical in establishing whether the patient requires an isolated intestinal transplant or a combined liver/intestinal transplant, as well as determining pre- and postoperative morbidity. Persistently elevated bilirubin (> 100 mmol/l) carries a high 1-year mortality and is an indication for transplantation if persistent (Beath et al. 1995). Splenomegaly may develop early and is helpful in staging hepatic fibrosis. Clinical evidence of portal hypertension (history of bleeding oesophageal varices, hepatosplenomegaly, and ascites) suggests irreversible liver disease and the need for liver transplantation with or without intestinal transplantation. The assessment should include: • biochemical liver function tests • coagulation profile • serum albumin • liver histology is used to establish the severity and extent of hepatic fibrosis or cirrhosis and also to exclude other potential liver diseases such as viral hepatitis • upper GI endoscopy to establish presence of varices or portal gastropathy • Doppler ultrasound studies of splanchnic venous anatomy which include portal vein, splenic vein, hepatic veins, and inferior vena cava are performed routinely since the patency of these vessels may modify the operative procedure • the presence of gallstones and common duct stones may be established by ultrasound, magnetic resonance cholangiography (MRC) or endoscopic retrograde cholangiography. Vascular access Vascular access should be assessed by ultrasound to confirm patency of internal jugular, subclavian, and iliac veins with venography as required (see Plate 86, Atlas: p. 471). General assessment Nutritional and developmental status is established as for liver transplantation (Chapter 20). All patients are screened for active bacterial or fungal infection and previous exposure to cytomegalovirus (CMV) and Epstein–Barr virus (EBV). Immunological deficiencies are assessed when clinically indicated. Cardiac assessment includes electrocardiograph and echocardiograph to exclude cardiomyopathy or evidence of previous pulmonary embolism. A ventilation/perfusion scan is occasionally required.

Chapter 21: Small Bowel Transplantation Psychological assessment Small bowel transplantation remains a relatively new procedure with an unknown long-term prognosis and it is important that both child and family are appraised of the risks and complications of this procedure in order to make an informed decision. Psychological preparation of the child is paramount and should include preparation for a stoma and ileostomy. On completion of the assessment, the decision will be made whether the child requires an isolated small bowel transplant or combined liver and small bowel transplantation, or in rare case an isolated liver transplant only. The indications for isolated small bowel transplantation include: • irreversible intestinal failure with expected long-term dependence on parenteral nutrition • loss of vascular access with normal liver function and histology • mild to moderate hepatic fibrosis (grade 1–3) with normal hepatic synthesis • intractable GI fluid loss. The current indications for combined small bowel liver transplantation are: • irreversible liver disease secondary to TPN • loss of vascular access with evidence of significant hepatic disease • inborn errors of liver metabolism leading to small bowel failure (e.g. protein C or S deficiency). Liver only transplantation in children with intestinal failure is only indicated in children with surgical short gut who are considered to have the potential for intestinal adaptation, but have irreversible liver failure. Contraindications for small bowel transplantation. Current contraindications include: • uncontrolled sepsis or malignancy elsewhere in the body • HIV infection and severe cerebral, cardiac or respiratory disease. There are no age or size limitations, although in practice infants weighing < 5 kg are rarely transplanted because of the lack of similar sized small donors.

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reduced grafts, have significantly reduced the waiting time and the mortality (from 60% to 14%) (Deville et al. 2000). Children with surgical short gut syndrome and those with a high plasma bilirubin at the time of evaluation have the shortest duration of survival (Beath et al. 1997; Bueno et al. 1999).

Preoperative management Management of patients awaiting small bowel transplantation requires careful attention to prevention of sepsis, maintenance of nutrition and prevention and management of vascular and hepatic complications. Sepsis rates may be reduced by aseptic catheter techniques and by the use of selective bowel contamination (polymixin B, gentamicin and amphotericin administered orally). TPN protocols may need modification to ensure adequate nutrition for growth and to overcome hepatic catabolism. Tolerance to oral intake is crucial since this can affect post-transplant nutritional management. Children should be stimulated to eat before transplant, even if no nutritional benefit is gained, as this encourages developmental progress for eating and swallowing. Prevention of vascular thrombosis is difficult and use of anti-coagulation is not universally accepted. Liver failure in the setting of intestinal failure has an ominous prognosis, and a significant 1-year mortality secondary to infection, bleeding and encephalopathy (Bueno et al. 1999). Because such children have a high mortality it is essential that intestinal failure patients be referred for assessment once identified. Hepatic complications should be managed as described in Chapters 14, 18 and 20. Cholestatic patients should be treated with ursodeoxycholic acid (10–20 mg/kg) and supplemented with adequate fatsoluble vitamins parenterally. Bleeding oesophageal varices are treated with sclerotherapy or banding, but the majority of these patients will bleed from ‘portal gastropathy’ which can be controlled with continuous infusion of somatostatin (octreotide) (see Chapters 14 and 18). The use of transjugular intrahepatic portosystemic shunts (TIPS) are rarely indicated. Hypersplenism with severe thrombocytopenia may have a transient response to splenic artery embolization.

Timing of transplantation As quality of life may be acceptable for many children maintained on parenteral nutrition, the timing of this operation may be difficult. Furthermore, the difficulty in obtaining suitable age- and size-matched donors for small children means a lengthy wait for a suitable organ, and between 37% and 50% of patients died while awaiting small bowel transplantation (Reyes et al. 1994; Beath et al. 1997), although newer techniques, such as the use of

The transplant procedure Selection of donors Grafts for intestinal transplantation are obtained for ABO-identical brain-dead donors from neonates to age 55 years. Donors with a history of prolonged cardiopulmonary arrest or significant inotrope requirement should be avoided as this may result in significant bowel

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ischaemia. Donors with malignancy are excluded but those with systemic viral or bacterial infection in the absence of an identifiable thoracic or abdominal source are acceptable. Matching with human leucocyte antigen (HLA) is unnecessary. CMV-positive donors are only considered for transplantation into CMV-positive recipients unless the patient is dying from liver failure. CMVnegative patients awaiting isolated intestinal grafts should only receive organs from CMV-negative donors. Graft pretreatment to deplete the lymphoid population of the intestinal allograft with either irradiation or a monoclonal antibody (such as OKT3 or ATG) as prophylaxis for GVHD is performed in some centres (Langnas et al. 1996). Ideally, donors should be of similar size to the recipient. However, reductions of intestinal and liver/intestine allografts may be necessary because of the prolonged wait for age- and size-matched donors.

Donor operation The procurement of abdominal visceral organs, either en bloc or as separate components, is similar to a large cluster of grapes with a double central stem consisting of the coeliac axis and superior mesenteric arteries (Starzl et al. 1991) (Fig. 21.2). The separate grape clusters represent the different abdominal organs, which include the liver, stomach, duodenum, pancreas, small intestine and colon. These can be removed or retained according to the clinical needs of the recipient, with preservation of the double arterial stem structures in the larger composite grafts which include the complete multivisceral, modified multivisceral, liver/small bowel and modified liver/small bowel allografts. In the isolated small bowel allograft only the superior mesenteric artery stem is retained. The procurement technique focuses on simple isolation and cooling of the organs to be transplanted, with preser-

CA SMA

Variable amounts of jejunum retained

SMA

SMV

Fig. 21.2 Modified ‘cluster graft’ used to replace resected viscera after upper abdominal exenteration. The conceptual flexibility with this technique allows for variable retention or removal of different portions of the gastrointestinal tract. In this figure of the donor operation a canula has been placed in the infrarenal aorta and a clamp has been placed in the supracoeliac

aorta. The entire ‘cluster graft’ is removed with the coeliac artery and superior mesenteric artery joined in a single aortic patch (Carrel patch). CA, Celiac artery; SMA, superior mesenteric artery; SMV, superior mesenteric vein. (Reproduced with permission from Starzl et al., Surgery, Gynecology and Obstetrics, 172, 335–344, 1991.)

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Fig. 21.3 The composite liver-small bowel allograft with preservation of the duodenum in continuity with the graft jejunum and heptic biliary system is a practical variation of the original ‘cluster graft’. The pancreas is transected to the right of the portal vein, however, in patients suffering total parenteral nutrition-induced pancreatic disease (with endocrine or exocrine deficiencies) it may be preserved. The aortic patch

containing the coeliac trunk and superior mesenteric arteries is anastomosed to a conduit of donor thoracic aorta. This technique allows reductions of the liver and/or intestinal components of the allograft, thus permitting the use of larger donor organs for smaller recipients. (Reproduced with permission from Bueno et al., Journal Pediatric Surgery 35, 291–295, 2000.)

vation of the vascular and parenchymal anatomy (Starzl et al. 1984). This procedure has been simplified using a limited hilar dissection by preserving the duodenal loop and pancreas with the liver/small bowel allograft, thus avoiding transection of the common bile duct. Procurement is limited then to simple isolation of the stomach and division at the pylorus, and transection of the ileum at the ileocaecal valve with mobilization of the colon (Abu-Elmagd et al. 1998). The pancreas, when it is not required, is removed as a back table dissection to the right of the superior mesenteric vein. These grafts are ideally suited to very small donors (neonates), thus avoiding manipulation of the hepatic hilus and larger donors where graft reduction is necessary (Fig. 21.3). Both situations have allowed for increased donor utilization (Bueno et al. 2000; Deville et al. 2000; Sudan et al. 2001). The isolated small bowel graft can be procured as a composite graft with the other organs and then separated as a back table procedure into separate intestine, pancreas and liver allografts. The entire multivisceral procurement will take 3–4 h (Abu-Elmagd et al. 2000). These composite grafts are removed with minimal contamination since the hollow viscera are sealed off by stapling and transection. The succus entericus is left undisturbed and transplanted with the graft.

cross-clamped. In-situ perfusion using cold University of Wisconsin (UW) solution, with venous bed decompression via a venotomy in the intrapericardial suprahepatic vena cava (Kalayoglu et al. 1988; Todo et al. 1989) is performed. Separation of organs is performed on the back table, and the graft is stored in ice for transport. Preservation time can vary from 2.8 to 14.8 h, with a mean of 07.83 h without significant evidence of preservation injury.

Graft preservation After completion of the donor dissection, systemic heparinization is performed and the proximal aorta is

Recipient operations Most children who need an intestinal or multiorgan transplant have had multiple previous abdominal explorations for intestinal resection, lengthening procedures, or treatment of complications. The combination of severe adhesions and portal hypertension presents a significant surgical challenge. The volume contraction of the abdominal cavity resulting from previous resections has required the use of silastic silos, closure using only skin and subcutaneous tissue, and recently, graft reductions of the intestinal and liver allograft by extended right hepatic resection or left lateral segmentectomy (Fig. 21.3) (Bueno et al. 2000). Once the donor organs are found to be satisfactory then the recipient operation begins in order to avoid prolonged cold ischaemia times. The recipient operation involves removal of the failed organs with exposure of the vascular anatomy for arterialization and venous drainage, identification of proximal and distal recipient bowel remnants, and finally allograft implantation.

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Section 10: Liver Transplantation

Composite grafts Composite grafts include multivisceral, and liver/small bowel. For these composite procedures the native liver is removed with preservation of the recipient inferior vena cava. It is necessary to ensure that the axial stem of the portal vein between the donor organs remains intact. In recipients of a liver/small bowel graft, the portal vein of the remaining foregut is attached to the intact portal stem of the donor. Arterialization of these grafts is accomplished with the double arterial stem of the coeliac and superior mesenteric arteries (as a Carrel patch) anastomosed to the infrarenal or supra-coeliac aorta, with an interposed aortic conduit or iliac artery homograft. The composite graft is connected first to a common conduit of recipient hepatic veins (‘piggy-back’ to the skeletonized recipient vena cava), and then to the arterio-aortic anastomosis. In the multivisceral operation the recipient’s portal vein and GI tract, pancreas and liver are removed with the enterectomy and replaced with the donor portal vein in continuity via the liver, which prevents the need for a portal vein anastomosis. In the modified multivisceral operation the liver is excluded and only the gastro-pancreas-intestinal tract is transplanted. In this operation the portal venous return is directed into the recipient’s portal vein. Restoration of intestinal continuity requires an anastomosis with native proximal gut (oesophago-gastric anastomosis in the multivisceral procedure) and distal native gut, usually a colo-enteric anastomosis with the distal ileum allograft. Because the ‘duodenal preserving’ composite liver/intestine allograft leaves the hepatic hilus undisturbed, biliary anastomosis is not necessary (Fig. 21.3). A ‘chimney’ or ‘loop’ allograft ileostomy is performed for routine surveillance of the intestinal allograft. This ileostomy can be taken down after several months when a stable immunosuppressive regimen has been achieved, and there has been freedom from rejection without the need for frequent endoscopic surveillance. Isolated intestinal grafts Many patients with functional intestinal failure will not have had abdominal operations or resections. In patients with Crohn’s disease with multiple abdominal fistulae, enterectomy may be performed before the transplant procedure in order to have a well-healed abdominal cavity. In patients with surgical short gut, the proximal and distal remnants of the intestine are identified. Arterialization of the graft will be from the donor superior mesenteric artery to the infrarenal aorta. Venous drainage through the superior mesenteric vein may be to the recipient portal vein, superior mesenteric vein, splenic vein, or inferior

vena cava. An interposition donor venous graft can be applied to any of the aforementioned native veins in order to avoid a difficult surgical exposure and tension on the vascular anastomosis. Intestinal continuity is provided with anastomoses to previously identified native proximal and distal bowel, with a ‘chimney’ ileostomy for endoscopic surveillance. The time between procurement and implantation of the allograft (cold ischaemia time) ranges from 2 to 17 h, while the warm ischaemia time (time that it takes to sew the graft in) is approximately 30 min. Both these intervals are important determinants of preservation injury to the intestine. In order to reduce postoperative fluid loss, a segment of large intestine was included in 32 patients (Todo et al. 1995), but led to an increased rate of infection and graft failure. In order to improve postoperative motility, donor coeliac ganglia preservation of the intestinal allograft was also studied, but with no apparent benefit.

Postoperative management The key to successful postoperative management is effective teamwork between anaesthetists, surgeons, paediatricians, nursing and paramedical staff. Recipients of composite grafts (multivisceral, liver small bowel, or cluster grafts) suffer from end-stage liver/disease and may require a longer intensive care stay to manage pulmonary, cardiac and hepatic function. Recipients of isolated small bowel transplants are less likely to require intensive care, but still present similar infectious risks and the potential to develop hepatic or pancreatic complications. Recipients of isolated intestinal transplants have a median intensive care unit and hospital stay of 5 days and 9 weeks, respectively, vs. 17 days and 12.4 weeks, respectively, for larger composite grafts (Reyes et al. 1998). Recipients of isolated liver transplant in the context of intestinal failure have a prolonged postoperative course, because of the need to encourage intestinal adaptation. The prolonged intensive care stay is related to the potential for graft malfunction, infection and preoperative liver failure, and difficulties with early extubation, which may be exacerbated by the significantly longer operative times for the composite grafts (median time 13 h) vs. the isolated small bowel transplants (median time 9 h). Discrepancies in donor/recipient size may prevent initial closure of the abdominal wall at the time of transplant, requiring the use of silastic silos until appropriate fluid and electrolyte management can permit definitive closure. The increase in intra-abdominal volume with compression of the thoracic cavity may be an additional factor responsible for respiratory impairment. Unusually severe rejection of an isolated small intestine allograft with systemic venous drainage into the inferior vena

Chapter 21: Small Bowel Transplantation cava can produce respiratory insufficiency and an ARDS (acute respiratory distress syndrome) picture. The main principles of postoperative management are: • immunosuppression and prevention of rejection • prevention and treatment of infection • fluid balance and maintenance of nutritional status • assessment of graft function • long-term rehabilitation. Immunosuppression The same postoperative immunosuppression is used in both isolated or composite intestinal allograft recipients. This is based on a combination of tacrolimus (previously FK506) and steroids. Some units begin immunosuppression in the operating room and others immediately afterwards. Initial intravenous methylprednisolone (10 mg/kg) is followed by a steroid taper of methylprednisolone (5 mg/kg/day), reduced over 5 days to 1 mg/kg/day. Tacrolimus (0.1 mg/kg/day) is given by continuous intravenous infusion and maintained at a steadystate whole blood level of 20–25 ng/ml (microparticle enzyme immunoassay; MEIA). Oral tacrolimus is started (0.15 mg/kg/day) once GI motility is observed, although some units start oral tacrolimus immediately postoperatively. Trough levels should be 20–25 ng/ml initially, reducing to 8–12 ng/ml after 6–12 months. Prostaglandin (Prostin) is administered at a dose of 0.003–0.009 mg/kg/day, for the first 5 postoperative days because its beneficial vasodilatatory effects on renal and splanchnic vasculature may prevent microvascular thromboses, related to acute cellular rejection and ischaemic damage (Takaya et al. 1991). This combination required persistently high levels of drug therapy in order to prevent rejection, thus facilitating opportunistic infections. Consequently, the addition of ‘third agents’ to the maintenance regimen began after 1995, using aziathioprine, cyclophosphamide, mycophenolate mofetil (MMF) and most recently rapamycin. There was no benefit to the use of cyclophosphamide or MMF so their use was abandoned. The use of rapamycin has allowed for good graft function and freedom of rejection under lower levels of tacrolimus (Pinna et al. 2000; Sindhi et al. 2001). Induction therapy using a humanized IgG1 monoclonal antibody directed at the a subunit of the human interleukin-2 receptor (Daclizumab) has significantly increased rejection-free survival. Protocols are presently under study using ‘pretreatment’ (prior to allograft implantation) and induction protocols with other antilymphocyte antibodies such as Thymoglobulin and Campath (Abu-Elmagd et al. 2002a; Tzakis et al. 2002). These strategies alter the lymphocyte population of donor and recipient, and have been used principally to

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avoid GVHD (Starzl et al. 1989a; Langnas et al. 1996). The paradigm of donor and recipient lymphocyte populations forming ‘genetic composites’ (Murase et al. 1991) is known as ‘micro-chimerism.’ It is believed that the engagement of these two immunocyte populations leads to mutually cancelling immune reactions, with the eventual development of varying disease of non-reactivity (Starzl et al. 1993) (Fig. 21.4). Interestingly, however, the augmentation of micro-chimerism using the infusion of donor bone marrow cells recovered from donor vertebral bodies at the time of intestinal allograft procurement has not resulted in enhanced intestinal allograft acceptance (Reyes et al. 2002). Prevention of infection Prophylactic antibiotics are given for 14 days post transplant. They include Ciprofloxacin 5 mg/kg/dose b.d.; Amoxyl 25 mg/kg/dose t.d.s.; or Vancomycin if the patient has been colonized with methicillin-resistant Staphylococcus aureus or resistant faecal streptococci; Metronidazole 8 mg/kg/dose t.d.s. Co-trimoxazole (240 mg orally if less than 5 years; 480 mg orally over 5 years) is used as prophylaxis against Pneumocystis carinii. Oral non-absorbable selective bacterial and fungal decontamination (Table 21.3) is given every 6 h for 2 weeks (Green et al. 1994). Surveillance stool cultures are performed weekly. Quantitative cultures with colonies of > 108 organisms are considered significant only in the presence of systemic sepsis or ongoing acute cellular rejection of the intestinal allograft, and are treated appropriately. It is important to note that bacterial translocation can occur with intestinal allograft rejection or other opportunistic infections such as EBV enteritis. It is necessary to treat both the disease causing the immunological damage of the mucosal barrier and the infection (Sigurdsson et al. 1995). Antiviral prophylactic strategy is directed towards prevention of infection with CMV and EBV, and includes: • 2-week course of intravenous ganciclovir (10 mg/kg/ day) with concomitant CMV-specific hyperimmune globulin (cytogam\super R) (Bueno et al. 1997) • oral acyclovir (200 mg q.d.s. < 5 years; 500 mg q.d.s. > 5 years) or oral gancyclovir may be continued for 3 or 6 months. Management of fluid balance Fluid balance in this group of patients may be difficult to manage because of previous liver disease and the requirement for intra-operative coagulation or colloid support. In the first 2–3 days post transplant, the fluid shifts between graft, lungs, and peripheral tissues can result in overall fluid retention, but intravascular volume depletion. This is exacerbated by high-dose steroids,

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Section 10: Liver Transplantation

Fig. 21.4 The one-way paradigm of both solid organ and bone marrow transplantation assumed a defenceless organ or recipient being attacked by a ‘single army’ of immunocytes. The two-way paradigm envisages ‘two armies’ of immunocytes (of recipient and donor origin) which under immunosuppression

will produce varying degrees of non-reactivity (‘chimerism’). The ‘chimerism’ phenomenon is known to occur with transplantation of all solid organs, but its role in enhancing clinical alloreactivity or acceptance of transplanted organs is still being elucidated.

tacrolimus, nephrotoxic antibiotics and antifungals. Fluid balance must take into account fluid losses from abdominal drains, nasogastric and stoma output and urine output. Fluids should be restricted to two-thirds maintenance and provided as dextrose/saline with colloid as required to maintain central venous pressure (6–10 cmH2O), urine output 0.5–1.5 ml/kg/h.

will not voluntarily eat after transplantation as this may be the first time many of them will have experienced normal feeding. Management requires a multidisciplinary approach involving psychological support. Enteral supplementation may be required long term. Independence from TPN is achieved in all functioning grafts within 4–6 weeks (Janes et al. 1997).

Nutrition

Assessment of the graft

Total parenteral nutrition is provided with standard TPN formulas and tapered gradually as oral or enteral nutrition is advanced. Enteral feeds by continuous infusion may start as soon as bowel sounds are obvious. In general it is best to start with simple feeds such as isotonic dipeptide formulas containing medium-chain triglycerides, glutamine and glucose polymers. This is later converted to a lactose- and gluten-free diet that contains dietary fibre such as pectin to promote normalization of intestinal motility and function. Long-chain triglyceride is added later when lymphatics are established. Many children

Monitoring of liver and pancreatic components of composite intestinal allografts is performed as for isolated transplantation of these solid organs. Regular assessment of liver function tests, amylase, and insulin requirements is routine; abdominal ultrasound and biopsies from transplanted organs are performed as required. Intestinal grafts Assessment of anatomical and functional viability of an intestinal allograft begins in the operating room imme-

Chapter 21: Small Bowel Transplantation diately after graft reperfusion. Venous outflow disturbances may result in congestion and ecchymosis, which must be differentiated from hyperacute rejection and ischaemic damage. Similar changes may be seen in the ileal stoma postoperatively. As intestinal allografts may be composed of varying lengths of the GI tract with functionally and anatomically differing segments (stomach, duodenum, small intestine, colon), the assessment of these grafts must be flexible, aggressive and multidisciplinary. There are no good functional or biochemical markers to assess injury or rejection of intestinal allografts. Radiological evaluation using barium usually reveals a normal mucosal pattern with intestinal transit times of 2–4 h. Serum nutritional markers (transferrin, albumin, retinoic acid) and absorption studies (D-xylose, tacrolimus, quantification of fat in the stool) provide long term measures of function in a stable graft but little useful information about clinical disease. The most effective means of assessment of graft status and diagnosis of rejection are: • Assessment of stomal output for volume, consistency, reducing substances and bacterial overgrowth. An increase in stomal output suggests either infection or rejection, but does not differentiate between the two. The presence of blood in the stool is always an ominous sign requiring an urgent endoscopy, since this may be due to rejection or infection. • Routine enteroscopic surveillance performed twice a week through the allograft ileostomy provides adequate information in the majority of cases. Occasionally, upper GI endoscopy with visualization and biopsy of the proximal allograft is necessary. • The use of ‘zoom endoscopy’ (Kato et al. 2000) has enhanced clinical assessment, although histopathology remains the gold standard. • Formal motility testing is occasionally required for long term functional assessment (Mousa et al. 1998).

Complications post transplant Clinical/surgical factors Complications related to the surgical procedure or the post-operative clinical management of the recipient are common (47%). The major technical complications are biliary or intestinal anastomotic leaks, intestinal perforation, and thrombosis of the hepatic artery in the larger composite grafts which may be complicated by severe intra-abdominal infections with polymicrobial and fungal organisms. The most serious clinical management issues are rejection, infection, fluid and electrolyte disturbances, renal dysfunction and hypertension, which are exacerbated by high levels of tacrolimus and steroids (Mousa et al. 1998).

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Rejection Historically, the incidence of intestinal allograft rejection has been reported to be as high as 90%, and is more frequent and severe in recipients of isolated intestinal grafts, compared with liver/small bowel, or multivisceral allografts. Most episodes occur within the first 90 days. The use of OKT3 for the treatment of severe steroid-resistant rejection is also more common in isolated small bowel transplantation. Rejection of the liver when it is part of a composite graft is 43%, suggesting that the liver graft may protect the intestinal component. In composite grafts that included other organs the occurrence of rejection was as follows: colon 34%, stomach 12%, and pancreas 12% (Abu-Elmagd et al. 1998). Acute intestinal rejection presents with non-specific symptoms such as: • fever, abdominal pain and distension • nausea, vomiting • increase in stomal output • the stoma may become oedematous, erythematous and friable • GI bleeding can occur in severe rejection, with ulceration and sloughing of the intestinal mucosa. Sepsis due to bacterial or fungal translocation occurs as a result of disruption of the intestinal mucosal barrier from rejection. Paradoxically, such severe infections can only be treated by stabilizing the allograft mucosal barrier with augmented immunosuppression. Endoscopically, the transplanted intestinal mucosa loses its velvety appearance and becomes hyperaemic or dusky, as well as hypoperistaltic. Erythema may be focal or diffuse; the mucosa becomes friable, and diffuse ulceration appears (Sigurdsson et al. 1998) (see Plate 88, Atlas: p. 472). Histologically, there is variable presence of lamina propria, oedema and villous blunting. The diagnosis rests on the presence of a mononuclear cell infiltrate, cryptitis with apoptosis, and regeneration. Neutrophils, eosinophils and macrophages may be seen traversing the muscularis mucosa (White et al. 1995; Lee et al. 1996; Sudan et al. 2000a). The degree of epithelial and crypt cell damage varies. It is unclear whether, in the most severe form of rejection, the progressively worsening apoptosis or a vascular response to rejection leading to ischaemia results in the severe mucosal sloughing and crypt destruction. The mucosal surface becomes replaced by inflammatory pseudomembranes and granulation tissue, which precipitate continuous blood loss as well as intermittent septic episodes from bacterial and fungal translocation (see Plate 88, Atlas: p. 472). Chronic rejection has been observed in patients with persistent intractable rejection episodes. These patients present with:

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Section 10: Liver Transplantation

• Progressive weight loss, chronic diarrhoea, intermittent fever and astrointestinal bleeding. • Endoscopic mucosal biopsies reveal a scant cellular infiltrate, with villous blunting, focal ulceration, and epithelial metaplasia. Full-thickness intestinal biopsies may reveal obliterative arteriopathy, which is uncommon in children. • Radiographically it may present areas of strictures and dilatations, with areas of arteriopathy on angiography. The most important factor responsible for improvement in clinical outcomes has been a decrease in frequency and severity of rejection. This has been achieved by increasing centre experience, use of triple-drug immunosuppression, and the early diagnosis of opportunistic infections (Reyes et al. 2002). Therapy Graft rejection is treated with high doses of intravenous methylprednisolone (10 mg/kg) as bolus therapy in cases of mild rejection, and with a taper in cases of moderate to severe rejection. The tacrolimus trough levels in whole blood are increased to 20–25 ng/ml by either the oral or intravenous routes. OKT3 or thymoglobulin is reserved for steroid-resistant rejection, or in cases of severe mucosal injury and crypt damage (Reyes et al. 2002). There was a higher incidence of rejection in patients treated with cyclophosphamide/mycophenolate mofetil induction therapy, so this induction protocol is no longer used (Reyes et al. 1998). Infections Infectious complications are frequent because of several predisposing factors; these include: • the severity of preoperative liver failure • the presence of intra-abdominal, pulmonary or catheter sepsis prior to transplantation • the higher level of immunosuppression required to prevent rejection in intestinal grafts. There is a higher incidence of infectious complications in recipients of large composite intestinal allografts, perhaps because of the technically challenging transplant procedures, with increased operative time, transfusion requirements, and intestinal cold ischaemia times. Bacterial pathogens include staphylococci (intravenous line induced), enterococci and Gram-negative rods. Recently, the hospital-acquired vancomycinresistant enterococcus (VRE) has been a problem in the UK (Gray et al. 2000). Enteric organisms are usually associated with abdominal wound infections, deep abdominal abscesses, peritonitis, pneumonia and bacterial translocation from grafts damaged by rejection. Multiple sources of infection can occur simultaneously, or there may be mixed infections from the same source. The multi-

ple antibiotic regimens required to treat these infections may precipitate the development of resistant organisms such as the nascent strain of panresistant enterococci, and fungal infections. Fungal infections are usually the result of intravenous line contamination, translocation due to rejection, massive antibiotic usage, and intestinal leaks. Aggressive medical and surgical therapy is required in patients with this complication. It is not usually wise to reduce immunosuppression as the coexistence of cellular rejection warrants maintaining an intact mucosal barrier by appropriate augmentation of immunosuppression. Complete withdrawal of immunosuppression is impossible in this recipient population due to a high incidence of rebound rejection. CMV infection develops in 22% of paediatric intestinal graft recipients and often involves the allograft intestine (91%). Children have comparable morbidity to adults, but a lower mortality. CMV disease is highest in CMVnegative recipients of CMV-positive grafts (Bueno et al. 1997; Green et al. 1999); these recipients have more aggressive disease manifested by a higher incidence of recurrence, persistence of disease, involvement of native intestine, hepatitis, central nervous disease, and retinal involvement. Diagnosis is usually made after nonspecific symptoms have prompted measurement of CMV RNA (Hebert et al. 1996), CMV antigenaemia in the peripheral blood and/or an endoscopy (see Plate 89, Atlas: p. 472). Endoscopy images usually reveal superficial ulcers in a background of normal mucosa. Histopathology shows typical CMV inclusion bodies, although care must be taken not to associate occasional crypt epithelium apoptosis with rejection. Successful clinical management has been accomplished in over 95% of episodes using ganciclovir alone or in combination with CMV-specific hyperimmunoglobulin. It is essential to avoid rejection by maintaining immunosuppression at baseline and reducing it only in the face of deteriorating clinical disease (Sigurdsson et al. 1995). EBV-associated post-transplant lymphoproliferative disease (PTLD) has occurred in 31% of children, which puts them at a significantly higher risk than adult intestinal recipients (11%). Recipients of multivisceral grafts have a higher incidence of infection (50%) vs. recipients of isolated small bowel (29%) or liver/small bowel (27%). Clinical presentation includes non-specific intestinal and systemic symptoms, bleeding, lymphadenopathy and tumours found on physical examination or endoscopy (see Plate 90, Atlas: p. 473). Risk factors include recipient age, history of previous splenectomy, and the use of OKT3 (Fig. 21.5). Therapy includes the reduction and withdrawal of immunosuppression, antivirals (ganciclovir, acyclovir, hyperimmunoglobulin), cytokines (interferon-alpha) and chemotherapy. More recently Rituximab (a monoclonal antibody) and infusion of HLA-

Chapter 21: Small Bowel Transplantation 100

415

PTLD Risk By Splenectomy

Fig. 21.5 Risk of developing post-transplant lymphoproliferative disease (PTLD) in paediatric intestinal transplant recipients based on their having had a splenectomy (n = 14) or not (n = 17). Splenectomy has been seen to increase the risk of developing PTLD at all time points.

Cummulative PTLD Free Survival(%)

90 80 70 60 50 40

No Splenectomy Splenectomy

30 20 10 0

matched T-cells have had some success in treating this difficult disorder (Haque et al. 2001; Pinkerton et al. 2002).The disease may be fatal in up to 45% of patients, in whom rebound rejection was a significant contributor to mortality (Reyes et al. 1996). It is important to develop strategies for prevention and early diagnosis of PTLD using in-situ hybridization staining for EBV early RNA in all suspicious histology, and establishing ‘viraemia’ by EBV-PCR (Green et al. 1996). This strategy of pre-emptive antiviral therapy using ganciclovir and CMV-IVIG (and when possible reduction of immunosuppression) was utilized when increasing viral loads were detected in the peripheral blood of recipients, and has resulted in decreased incidence of PTLD, as well as improved outcomes (Green et al. 2001). Although viral infections are less common, respiratory syncytial virus, adenovirus and parainfluenza virus lead to significant morbidity and severe mortality in this population. Chimerism and GVHD The phenomenon of donor and recipient cell migration observed in all solid organ recipients has been described as ‘chimerism’. This hypothesis forms the basis of the two-way paradigm of transplantation immunology, where donor and recipient cell populations interact with mutually cancelling effects producing eventual allograft acceptance (Starzl et al. 1993). Using bone marrow augmentation with adjuvant donor bone marrow cells the presence of donor cell chimerism was documented in 100% of the study population and 80% of the control patients (Abu-Elmagd et al. 1998). GVHD is unusual in this population, and may be asymptomatic or associated with rejection. Skin changes consistent with GVHD were diagnosed by histopatholog-

0

1

2

3 4 5 6 7 8 Time After Transplantation (Years)

9

10

ical criteria in only seven children (8%), and in only two patients who had received adjunct bone marrow, with onset ranging from 6 days to 8 years following transplant. Histological criteria of GVHD include keratinocyte necrosis, epithelial apoptosis of native GI tract, or epithelial cell necrosis of oral mucosa. Spontaneous resolution occurred in all but one patient, who had hereditary IgG and IgM deficiency and died from septicaemia. GVHD was diagnosed 4 days after stopping immunosuppression and was confirmed by immunohistochemical studies visualizing donor cell infiltration into the lesions (Reyes et al. 1997).

Causes of graft loss The main cause of intestinal graft loss is infection, which may be associated with rejection or PTLD in 48% of grafts lost. Twenty-eight percent of grafts are lost due to surgical technical/clinical complications. The decision for graft enterectomy should be based on significant intestinal graft dysfunction and the need to withdraw immunosuppression, prior to the development of infectious complications, which may persist after removal of the graft. Retransplantation of the intestine is required for acute and chronic rejection and hepatic artery thrombosis, and has a high failure rate due to the precarious clinical status of the patient when the retransplant is performed. Retransplantation should be restricted to highly selected cases such as early vascular thrombosis or primary nonfunction of the graft prior to significant manifestations of other organ failure (Reyes et al. 1998).

Survival Survival has improved with the use of tacrolimus, and international experience has confirmed the feasibility and

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Section 10: Liver Transplantation

life-saving potential of this therapeutic modality (Grant 1996; Langnas et al. 1996; Reyes et al. 2002). Currently, at the University of Pittsburgh, 84 patients have received 89 intestinal transplants between June 1990 and January 2002 (Table 21.3). Twenty-six received isolated intestine, 54 combined liver/intestine, and four multivisceral. There were 45 boys and 39 girls with a mean age of 3.2 years (range 0.5–18 years). Forty-five (54%) patients were still alive in January 2002. The actuarial survival rates for this patient population at 1, 3 and 5 years were 74%, 59%, and 56%, respectively. The estimated actuarial survival for all types of grafts was 67%, 53%, and 47% at 1, 3 and 5 years, respectively. The isolated intestinal grafts had the best patient and graft survival, when compared with the larger composite grafts (liver/small bowel or multivisceral). These data reflect the improved survival rates reported world-wide (Grant 1999). The inclusion of allograft colon did not affect survival, but increased patient and graft loss from infection in the recipients of this intestinal segment. There was no benefit in weaning TPN or intravenous fluids when compared with patients who did not receive allograft colon. Thus, the only indication for inclusion of allograft colon should be as a reconstructive segment in selected cases of Hirschsprung’s disease or CIP where a pull-through procedure through the rectum may be functionally beneficial (Tzakis et al. 1995). Use of bone marrow augmentation did not improve actuarial patient or graft survival, although there was no morbidity associated with the infusions. Indeed, when analysing survival statistics after intestinal transplantation, the 1-year survival figures reflect on surgical experience, and appropriate perioperative clinical management; which should result in approximately 70% patient survival. However, because of the high inci-

Table 21.3 Types of intestinal grafts.

dence of rejection, and need for higher long-term immunosuppression, survival continues to decrease, with a 3-year patient survival of 55%. Most of the deaths are from opportunistic infections such as CMV and PTLDassociated EBV infection, which may be prevented by early diagnosis and pre-emptive therapy. Further improvement in survival, however, rests on decreasing the incidence of rejection and providing long-term rehabilitation and graft acceptance without the need for high baseline immunosuppression. Nutritional status and longterm rehabilitation Independence from TPN has been accomplished in 39 of 45 surviving children (87%) in Pittsburgh, usually within the first 4–6 weeks. Although all children are tolerating a regular oral diet, 87% of these receive their complete nutritional requirements solely from this route. The remainder (17%) have required enteral supplementation because of behavioural feeding problems or inadequate calorie intake. Food allergies to lactose and gluten have been common (Strohm et al. 1999). Linear growth occurs to a greater degree in older children than in recipients 1–5 years of age, and progresses after weaning from TPN as calories are provided via oral and/or enteral routes. Deficiencies in red blood cell folate, zinc and copper levels have been documented postoperatively in some patients. The intensity of home medical services, however, decreases over a 1- to 3-year period post transplant as the patient recovers and is reintegrated into the home and school environment. Children are able to make physical and developmental progress. All school-aged children participate in a school programme. Older children and adolescents are often upset about the alterations to their bodies with protruding lines, tubes and an ileostomy. Thus removal of medical appliances may be psychologically and developmentally beneficial, helping the child adapt more easily to life after intestinal transplant (Kosmach 1998; Sudan et al. 2000b).

Children (n = 89)

Present and future status

Intestine Primary Retransplant Total

23 1 24 (27%)

Liver/intestine Primary Retransplant Total

51 3 54 (61%)

Multivisceral Primary Retransplant Total

10* 1 11 (12%)

*Modified multivisceral (without liver) (n·=·2).

Rapidly accumulating international experience has allowed the development of clinical and surgical strategies demonstrating the feasibility, reliability and life-saving potential of intestinal transplant procedures (Grant et al. 1996; Langnas et al. 1996; Grant 1999; Reyes et al. 2002). This reserved optimism must be weighed against the poor outlook for patients with intestinal failure, many of whom will die without transplantation. The most significant preoperative risk factors reflect liver failure and include: clinical jaundice, coagulopathy, fibrosis/cirrhosis on liver biopsy, and hypersplenism (Bueno et al. 1999). Thus early referral for management of intestinal failure

Chapter 21: Small Bowel Transplantation and consideration for intestinal transplantation should occur prior to the development of significant liver dysfunction, particularly in infants with short gut syndrome. The improved survival of both patient and graft with the isolated intestinal transplant vs. the composite grafts is mainly due to the absence of these critical risk factors and a simpler surgical and clinical post-transplant management. But, it also reflects the ability effectively to remove a failed intestinal graft and resume TPN if the clinical circumstances permit. This advantage is such that it is not justified to remove a normal liver as part of the transplant procedure, nor to allow a patient to develop liver failure prior to consideration for intestinal transplantation. From these data, it is evident that the balance between the need for high levels of immunosuppression to prevent rejection, and the incidence of opportunistic infection as a consequence of immunosuppression remains the major obstacle to the further development of intestinal transplantation. The improvements in technical and clinical skills, such as the early diagnosis and prevention of infection with the use of pp65 CMV antigenaemia, EBVPCR in peripheral blood, and Epstein–Barr early RNA (EBER) in tissue sampling, have enhanced our ability to reduce post-transplant complications and improve survival. However, strategies aimed at decreasing the immunogenicity of the intestinal allograft, thereby reducing the incidence and intensity of rejection and the need for augmentation of immunosuppression, are required to make survival rates for intestinal transplantation comparable to other forms of solid organ transplantation. It is possible that the development of an immunomodulation strategy that changes the immunogenicity of the intestinal allograft while permitting the phenomenon of bidirectional cell migration and chimerism could reduce the incidence and severity of rejection. The concept of graft cytoablation, for example with relatively low doses of ex vivo irradiation, may accomplish this by reducing mature T-cells and B-cells and sparing stem and precursor cells (Williams et al. 1989). Ex vivo irradiation of intestinal allografts combined with systemic donor bone marrow infusion is presently being performed in a GVHD-prone rat intestinal transplant model (N. Murase, personal communication). These studies may eventually facilitate a strategy which combines graft cytoablation and adjunct donor bone marrow infusion for use in clinical trials, leading to improved survival in intestinal transplantation (Abu-Elmagd et al. 2002b).

References Abu-Elmagd, K., Reyes, J., Todo, S. et·al. (1998) Clinical intestinal transplantation: new perspectives and immunologic considerations. Journal of the American College of Surgery 186, 512–527.

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Abu-Elmagd K., Fung J., Bueno J. et·al. (2000) Logistics and technique for procurement of intestinal, pancreatic, and hepatic grafts from the same donor. Annals of Surgery 323, 680–697. Abu-Elmagd, K.M., Bond, G.J., Murase N. et·al. (2002a) Tolerance for human intestinal transplantation. Transplantation 74, 38. Abu-Elmagd, K.M. (2002b) Intestinal and multivisceral transplantation: long-term results and future prospects. Transplantation 74, 247. Balisteri, W.F., Bove, K.E. (1990) Hepatobiliary consequences of parenteral alimentation. Progressive Liver Disease 9, 567–601. Barbier, J., Gineste, D., Kraimps, J.L. et·al. (1992) Hepatobiliary complications of total parenteral nutrition. Chirurgie 118, 47. Beale, E.F., Nelson, R.M., Bucciarelli, R.L. et·al. (1979) Intrahepatic cholestasis associated with parenteral nutrition in premature infants. Paediatrics 64, 342. Beath, S.V., Booth, I.W. & Murphy, M.S. (1995) Nutritional care in candidates for small bowel transplantation. Archives of Disease in Childhood 73, 348. Beath, S.V., Needham, S.J., Kelly, D.A. et·al. (1997) Clinical features and prognosis of children assessed for isolated small bowel (ISBTx) or combined small bowel and liver transplantation (CSBLTx). Journal of Paediatric Surgery 32, 459–461. Bond, J.H., Currier, B.E., Buchwals, H. et al. (1980) Colonic conservation of malabsorbed carbohydrates. Gastroenterology 78, 444–447. Bueno, J., Green, M., Kocoshis, S. et·al. (1997) Cytomegalovirus infection after intestinal transplantation in children. Clinical Infectious Diseases 25, 1078–1083. Bueno, J., Ohwada, S., Kochosis, S. et·al. (1999) Factors impacting on the survival of children with intestinal failure referred for intestinal transplantation. Journal of Pediatric Surgery 34, 27–33. Bueno, J., Abu-Elmagd, K., Mazariegos, G. et·al. (2000) Composite liver-small bowel allografts with preservation of donor duodenum and hepatic biliary system in children. Journal of Pediatric Surgery 35, 291–295. Byrne, T.A., Morrissey, T.B., Nattakom, T.V., Ziegler, T.R. & Wilmore, D.W. (1995) Growth hormone, glutamine, and a modified diet enhance nutrient absorption in patients with severe short bowel syndrome. Journal of Parenteral and Enteral Nutrition 19, 296–302 Calne, R.Y., Sells, R.A., Pena, J.R. et·al. (1969) Introduction of immunologic tolerance by porcine liver allograft. Nature 223, 472–474. Colomb, B.V., Goulet, O., Rambau, D.C. et·al. (1992) Long term parenteral nutrition in children; liver and gall bladder disease. Transplantation Proceedings 24, 1054. Dahma, B.B. & Halpin, T.C. (1981) Serial liver biopsies in parenteral nutrition associated cholestasis in early infancy. Gastroenterology 81, 136. Das, J.B., Cosentino, C.M., Levy, M.F. et·al. (1993) Early hepatobiliary dysfunction during total parenteral nutrition: an experimental study. Journal of Pediatric Surgery 28, 14–18. Davidson, G.P., Cutz, E., Hamilton, J.R. & Gall, D.G. (1978). Familial enteropathy: a syndrome of protracted diarrhea from birth, failure to thrive, and hypoplastic villous atrophy. Gastroenterology 75, 783–790.

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Deltz, E., Schroeder, P.H. et·al. (1989) Successful clinical small bowel transplantation: report of a case. Clinical Transplantation 3, 89–91. Deville, D., Goyet, J., Mitchell, A. et·al. (2000) En block combined reduced liver and small bowel transplants: from large donors to small children. Transplantation 69, 555–559. Dudrick, S.J., Latifi, R. & Fosnocht, D.E. (1991) Management of the short-bowel syndrome. Surgical Clinics of North America 71, 625–643. Edes, T.E. (1990) Clinical management of short-bowel syndrome: Enhancing the patient’s quality of life. Short-Bowel Syndrome 88, 91–95. Fell, J.M.E., Reynolds, A.P., Meadows, N. et·al. (1996) Manganese toxicity in children receiving long-term parenteral nutrition. Lancet 345, 1218. Goulet, O., Revillon, Y., Brousse, N. et·al. (1992) Successful small bowel transplantation in an infant. Transplantation 53, 940. Gorgstrom, B., Dahlquist, A., Lundh, G., et al. (1957) Studies of intestinal digestion and absorption in the human. Journal of Clinical Investigations 36, 1521–1536. Grant, D. (1989) Intestinal transplantation: current status. Transplantation Proceedings 21, 2869–2871. Grant, D. (1996) Current results of intestinal transplantation. International Transplant Registry. Lancet 347, 1801–1803. Grant, D. (1999) Intestinal transplantation: 1997 report of the international registry. Intestinal Transplant Registry. Transplantation 67, 1061–1064. Grant, D., Wall, W., Mimeault, R. et·al. (1990) Successful smallbowel/liver transplantation. Lancet 335, 181–184. Gray, J., Darbyshire, P.J., Beath, S.V., Kelly, D. & Mann, J.R. (2000) Experience with quinupristin/dalfopristin in treatment of infections with vancomycin-resistant Enterococcus faecum in children. Pediatric Infectious Disease Journal 19, 234–8. Green, M., Bueno, J., Sigurdsson, L. et·al. (1999) Unique aspects of the infectious complications of intestinal transplantation. Current Opinions in Organ Transplantation 4, 361–367. Green, M., Reyes, J., Jabbour, N. et·al. (1996) Use of quantitative PCR to predict onset of Epstein–Barr viral infection and posttransplant lymphoproliferative disease after intestinal transplantation in children. Transplantation Proceedings 28, 2759–2760. Green, M., Reyes, J., Webber, S. & Rowe, D. (2001) The role of antiviral and immunoglobulin therapy in the prevention of Epstein–Barr virus infection and post-transplant lymphoproliferative disease following solid organ transplantation. Transplantation and Infectious Disease 3, 97–103. Grosfeld, J.L., Rescorla, F.J. & West, K.W. (1986) Short bowel syndrome in infancy and childhood: analysis of survival of 60 patients. American Journal of Surgery 151, 41–46. Gupte, G.L., Kumar, N., Kelly, D.A. et·al. (2002). 11 years experience of evaluating children with intestinal failure (if) referred for possible intestinal transplantation. Journal of Paediatric Gastroenterology and Nutrition 34, 449. Haque, T., Taylor, C. & Wilkie, G.M. (2001) Complete regression of posttransplant lymphoproliferative disease using partially HLA-matched Epstein–Barr virus-specific cytotoxic T cells. Transplantation 72, 1399–1402. Hassan, K.O., Beath, S.V. & McKiernan, P.J. (2002) Difficult management choices for infants with short bowel syndrome and liver failure. Journal of Pediatric Gastroenterology and Nutrition 35, 216–219.

Hebert, H., Muller, C., Loffler, J., John, G. & Einsele, A. (1996) Monitoring of CMV infection: a comparison of PCR from whole blood, plasma-PCR, pp65-antigenaemia and virus culture in patients after bone marrow transplantation. Bone Marrow Transplantation 17, 861–868. Hyman, P.A. & DiLorenzo, C. (1993). Chronic intestinal pseudoobstruction. In: Pediatric Gastrointestinal Disease (eds R. Willie, J.S. Hyams), pp. 641–651. W.B. Saunders, Philadelphia. Janes, S., Beath, S.V., Jones, R., MacDonald, A. & Kelly, D.A. (1997) Enteral feeding after intestinal transplantation: the Birmingham experience. Transplantation Proceedings 29, 1855–1856. Kalayoglu, M., Sollinger, W.H., Stratta, R.J. et·al. (1988) Extended preservation of the liver for clinical transplantation. Lancet i, 617–619. Kamada, N., Davies, H.S., Wight, D. et·al. (1983) Liver transplantation in the rat: biochemical and histological evidence of complete tolerance induction in nonrejector strains. Transplantation 35, 304–311. Kato, T., O’Brien, C.B., Berho, M. et·al. (2000) Improved rejection surveillance in intestinal transplant recipients with frequent use of zoom video endoscopy. Transplantation Proceedings 32, 1200. Kaufman, S.S., Atkinson, J.B., Bianchi, A. et·al. (2001) Indications for pediatric intestinal transplantation. Pediatric Transplantation 5, 80–87. Kosmach, B. (1998) Care routines following pediatric intestinal transplantation. Program and Abstracts from the 5th International Symposium on Intestinal Transplantation, Cambridge, UK Poster 66. Kubota, A., Okada, A., Imura, K. et·al. (1990) The effect of metronidazole on TPN-associated liver dysfunction in neonates. Journal of Pediatric Surgery 25, 618–621. Kumar, N., Beath, S., van Mourik, I., McKiernan, P., Kelly, D. & de Ville de Goyet, J. (2002). New strategies to improve outcome of children awaiting small bowel transplantation. American Journal of Transplantation 2 (Suppl. 3), 374 (Abstract only). American Journal of Transplantation 2, 939. Langnas, A.N., Shaw, B.W., Antonson, D.L. et·al. (1996) Preliminary experience with intestinal transplantation in infants and children. Pediatrics 97, 443–448. Lee, R.G., Nakamura, K., Tsamauda, A.C.M. et·al. (1996) Pathology of human intestinal transplantation. Gastroenterology 110, 1820–1834. Lillehei, R.C., Goott, B. & Miller, F.A. (1959) The physiological response of the small bowel of the dog to ischemia including prolonged in vitro preservation of the bowel with successful replacement and survival. Annals of Surgery 150, 543–560. Linco, P.D. & Burnes, J. (1991) Ursodeoxycholic acid for the treatment of home parenteral nutrition-associated cholestasis. A case report. Gastroenterology 101, 250. Manginello, F.P. & Javitt, N.B. (1981) Parenteral nutrition and neonatal cholestasis. Journal of Pediatrics 99, 445–449. Margreiter, R., Konigsrainer, A. & Schmidt, T. et·al. (1992) Successful multivisceral transplantation. Transplantation Proceedings 24, 1226–1227. McAlister, V., Wall, W., Ghent, C., Zhong, R., Duff, J. & Grant, D. (1992) Successful small intestine transplantation. Transplantation Proceedings 24, 1236–1237. Mousa, H., Bueno, J., Griffiths, J. et·al. (1998) Intestinal motility after small bowel transplantation. Transplantation Proceedings 30, 2519–2520.

Chapter 21: Small Bowel Transplantation Murase, N., Demetris, A.J., Metasuaki, T. et·al. (1991) Long survival in rats after multivisceral versus isolated small bowel allotransplantation under FK506. Surgery 110, 87–88. O’Dwyer, S.T., Smith, R.J., Hwang, T.L. & Wilmore, D.W. (1989). Maintenance of small bowel mucosa with glutamineenriched parenteral nutrition. Journal of Parenteral and Enteral Nutrition 13, 579–585. Pinkerton, C.R.. Hann, I., Weston, C.L. et al. (2002) Immunodeficiency-related lymphoproliferative disorders: prospective data from the United Kingdom Children’s Cancer Study Group Registry. British Journal of Haematology 118, 456–461. Pinna, A.D., Weppler, D., Nery, J.R. et·al. (2000) Induction therapy for clinical intestinal transplantation: comparison of four different regimens. Transplantation Proceedings 32, 1193. Pollard, A.J., Sreeram, N., Wright, J.G., Beath, S.V., Booth, I.W. & Kelly, D.A. (1994). Pulmonary embolism in children/endlash another hazard of parenteral feeding. Gut 35, S33. Reyes, J., Bueno, J., Kocoshis, S. et·al. (1998) Current status of intestinal transplantation in children. Journal of Pediatric Surgery 33, 243–254. Reyes, J., Green, M., Bueno, J. et·al. (1996) Epstein–Barr virus associated posttransplant lymphoproliferative disease after intestinal transplantation. Transplantation Proceedings 28, 2768–2769. Reyes, J., McGhee, W., Mazariegos, G. et·al. (2002) Thymoglobulin in the management of steroid resistant acute cellular rejection in children. Transplantation 74, 419. Reyes, J., Todo, S., Green, M. et·al. (1997) Graft-versus-host disease after liver and small bowel transplantation in a child. Clinical Transplantation 11, 345–348. Reyes, J., Tzakis, A., Todo, S. et·al. (1994) Candidates for small bowel transplantation and possible indicators of outcome. Transplantation Proceedings 26, 1445. Ricotta, J., Zuidema, F.D., Gadacz, R.T. et al. (1981) Construction of an ileocecal valve and its role in massive resection of the small intestine. Surgery Gynecology and Obstetrics 152, 310–314. Ricour, C., Gorski, A.M., Goulet, O. et·al. (1990). Home parenteral nutrition in children. Eight years experience with 112 patients. Clinical Nutrition 9, 65–71. Rombeau, J.L. & Rolandelli, R.H. (1987) Enteral and parenteral nutrition in patients with enteric fistulas and short bowel syndrome. Surgical Clinics of North America 67, 551–571. Sigurdsson, L., Green, M., Putnam, P. et·al. (1995) Bacteremia frequently accompanies rejection following pediatric small bowel transplantation. Journal of Pediatric Gastroenterology and Nutrition 21, 356. Sigurdsson, L., Reyes, J., Putnam, P.E. et·al. (1998) Endoscopies in pediatric small intestinal transplant recipients; five years experience. American Journal of Gastroenterology 93, 207–211. Sindhi, R., Webber, S., Vekataramanan, R. et·al. (2001) Sirolimus for rescue and primary immunosuppression in transplanted children receiving tacrolimus. Transplantation 72, 851–855. Spaeth, G., Berg, R.D., Specian, R.D. & Deitch, E.A. (1990). Food without fiber promotes bacterial translocation from the gut. Surgery 108, 240–246. Spagnuolo, M.I., Iorio, R., Vegnente, A. & Guarino, A. (1996) Ursodeoxycholic acid for treatment of cholestasis in children

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on long-term total parenteral nutrition: a pilot study. Gastroenterology 111, 716–719. Starzl, T.E., Demetris, A.J., Trucco, M. et·al. (1993) Cell migration and chimerism after whole-organ transplantation: the basis of graft acceptance. Hepatology 17, 1127–1156. Starzl, T.E., Hakala, T.R., Shaw, B.W. Jr et·al. (1984) A flexible procedure for multiple cadaveric organ procurement. Surgery in Gynecology and Obstetrics 158, 223–230. Starzl, T.E. & Kaupp, H.A. Jr (1960) Mass homotransplantation of abdominal organs in dogs. Surgery Forum 11, 28–30. Starzl, T.E., Rowe, M.I., Todo, S. et·al. (1989a) Transplantation of multiple abdominal viscera. Journal of the American Medical Association 261, 1449–1457. Starzl, T.E., Todo, S., Tzakis, A. et·al. (1989b) Abdominal organ cluster transplantation for the treatment of upper abdominal malignancies. Annals of Surgery 210, 374–386. Starzl, T.E., Todo, S., Tzakis, A. et·al. (1991) The many faces of multivisceral transplantation. Surgery in Gynecology and Obstetrics 172, 335–344. Steiger, E. & Srp, F. (1983). Morbidity and mortality related to home parenteral nutrition in patients with gut failure. American Journal of Surgery 145, 102–105. Strohm, S., Koehler, A. & Reyes, J. (1999) Management in pediatric small bowel transplant. Nutrition in Clinical Practice 14, 58–63. Sudan, D.L., Iverson, A., Weseman, R.A. et·al. (2000b) Assessment of function, growth and development and longterm quality of life after small bowel transplantation. Transplantation Proceedings 32, 1211–1212. Sudan, D.L., Iyer, K.R., Deroover, A. et·al. (2001) A new technique for combined liver-small intestinal transplantation. Transplantation 72, 1846–1848. Sudan, D.L., Kauffman, S.S., Shaw, B.W. et·al. (2000a) Isolated intestinal transplantation for intestinal failure. American Journal Gastroenterology 95, 1506. Takaya, S., Iwaki, Y. & Starzl, T.E. (1991) Liver transplantation in positive cytotoxic crossmatch cases using FK506, high dose steroids, and prostaglandin E/super 1. Transplantation 54, 927–933. Teitelbaum, D.H., Han-Markey, T. & Schumacher, R.E. (1995) Treatment of parenteral nutrition-associated cholestasis with cholecystokinin-octapeptide. Journal of Pediatric Surgery 30, 1082–1085. Todo, S., Nery, J., Yanaga, K. et·al. (1989) Extended preservation of human liver grafts with UW solution. Journal of the American Medical Association 261, 711–714. Todo, S., Reyes, J., Furukawa, H. et·al. (1995) Outcome analysis of 71 clinical intestinal transplantations. Annals of Surgery 333, 270–282. Todo, S., Tzakis, A.G., Abu-Elmagd, K. et·al. (1992) Cadaveric small bowel and small bowel-liver transplantation in humans. Transplantation 53, 369–367. Tzakis, A., Nour, B., Reyes, J. et·al. (1995) Endorectal pullthrough of transplanted colon as part of intestinal transplantation. Surgery 117, 451–453. Tzakis, A.G., Kato, T., Nishida, S. et·al. (2002) Preliminary experience with campath (C1H) in intestinal and liver transplantation. Transplantation 74, 33. Tzakis, A.J., Todo, S. & Reyes, J. (1992) Clinical intestinal transplantation; focus on complications. Transplantation Proceedings 24, 1238–1240. Vanderhoof, J.A., Blackwood, D.J., Mohammadpour, H. & Park, J.H. (1992). Effects of oral supplementation of

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glutamine on small intestinal mucosal mass following resection. Journal of the American College of Nutrition 11, 223–227. White, F.V., Reyes, J., Jaffe, R. et·al. (1995) Pathology of intestinal transplantation in children. American Journal of Surgical Pathology 19, 687–698. Williams, J.W., Sankary, H.N., Foster, P.F et·al. (1989) Splanchnic transplantation: an approach to the infant dependent on parenteral nutrition who develops irreversible liver disease. Journal of the American Medical Association 261, 1458–1462. Wilmore, D.W. (1972). Factors correlating with a successful outcome following extensive intestinal resection in newborn infants. Journal of Pediatrics 80, 88–95.

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Chapter 22: Liver Disease in the Developing World SENG-HOEK QUAK, ANUPAM SIBAL AND MEI-HWEI CHANG

Neonatal liver disease, 421 Aetiology, 421 Diagnosis, 422 Treatment and outcome, 422 Chronic liver disease, 422 Metabolic liver disease, 423 Indian childhood cirrhosis, 423 Infectious diseases, 424 Typhoid, 424 Dengue fever, 424 Malaria, 425

Hepatic tuberculosis, 425 Hepatotoxicity associated with anti-TB therapy, 426 Hepatobiliary and pancreatic ascariasis, 427 Portal hypertension, 427 Extrahepatic portal hypertension, 427 Hepatoportal sclerosis, 427 Liver disease, 427 Viral hepatitis, 428 Hepatitis A virus infection, 428

Liver disease in children is a common problem in the developing world. The most important aetiology is infection, which includes viral hepatitis, dengue fever, typhoid, malaria and tuberculosis. As a result of improved environmental sanitation and socio-economic conditions, there has been a change in the pattern of disease in the developing world. International programmes such as the universal hepatitis B vaccination programme in hyperendemic areas have changed the natural history of hepatitis B and have implications for the control of infectious liver diseases in other parts of the world. As modern medicine and sanitation control and reduce the incidence of infectious diseases, it has become apparent that both genetic and metabolic liver diseases are as important a cause of liver disease in children in the developing world as in developed countries. Unfortunately, lack of resources, training and specialized laboratory support makes the diagnosis and management of those rare diseases a problem in many areas. The success of liver transplantation internationally has led to its development in many countries. As the organization of an effective cadaver donor programme is difficult for many reasons, the most effective programmes rely on living related donation, mostly for end-stage liver disease. Much needs to be done to improve child health in many developing countries. It is important to continue to control the remaining infectious causes of liver diseases, and to develop better ways to diagnose and treat genetic and metabolic liver diseases.

Hepatitis B virus infection, 429 Hepatitis C virus infection, 432 Other causes of viral hepatitis, 432 Orthotopic liver transplantation, 432 Organization of liver transplant programme, 433 Donor issues, 433 Living related organ donation, 434 Pretransplant issues, 434 Indications for transplantation, 435 Post-transplant outcomes, 436

Neonatal liver disease Neonatal liver disease includes many clinical conditions. Although these have already been addressed in detail (see Chapter 4), the spectrum of neonatal liver disease and cholestasis in developing countries differs significantly from that in developed nations, both with respect to aetiology and management (Table 22.1). Aetiology Neonatal cholestasis (NC) constitutes around a third of hepatobiliary disorders in India, Malaysia and Taiwan. In Delhi, NC constituted 26% (211/817) of all paediatric hepatobiliary cases. Biliary atresia was responsible for about a quarter of these (47/211). Idiopathic giant cell hepatitis (36%) and cholestasis due to multiple factors (16%) were the other major causes. The relative incidence of conditions leading to NC, as reported from a countrywide analysis in India, is shown in Table 22.1 (Consensus report on neonatal cholestasis 2000). Metabolic conditions constituted only 4%, which reflects the lack of diagnostic facilities in India. In a series of 50 consecutive cases of obstructive jaundice seen at a tertiary centre in Singapore, 66% were due to idiopathic hepatitis, 28% to biliary atresia, 4% to choledochal cyst and 2% to galactosaemia (Ramzan & Quak 1992). In Taiwan, about 49% of the neonatal hepatitis was due to cytomegalovirus (CMV) infection (Chang et al. 1987). Neither a1-antitrypsin deficiency nor cystic fibrosis were documented in either the Singapore

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Table 22.1 Spectrum of neonatal cholestasis syndrome in India (n = 1008). Hepatocellular Neonatal hepatitis Idiopathic giant cell hepatitis TORCH infections Sepsis Others (malaria, UTI, etc.) Metabolic Galactosaemia a1-Antitrypsin deficiency Total parenteral nutrition-related Others Others

533 468

53%

64% 22% 8% 6% 43 35% 33% 19% 13%

89% 11%

Ductal paucity Non-syndromic Syndromic

83% 17%

Aetiology

Category I centres (n = 6)

Category II centres (n = 5)

Total patients Viral hepatitis Autoimmune Metabolic Others* Unknown

809 147 (18.20%) 49 (6.00%) 170 (21.00%) 83 (10.30%) 360 (44.50%)

175 32 (18.3%) 3 (1.7%) 24 (13.7%) 65 (37.1%) 51 (29.1%)

*Others: galactosaemia, hereditary fructose intolerance, glycogen storage disease, tyrosinaemia type 1, Niemann–Pick disease, Gaucher’s disease.

22

Obstructive Biliary atresia Choledocal cyst

Idiopathic

Table 22.2 Aetiological profile of chronic liver disease in India.

385

38%

29

3%

61

6%

UTI, urinary tract infection.

or Taiwan series. Metabolic diseases such as abnormal bile salt metabolism were not excluded because of lack of laboratory support. Over 50% of children with NC are referred to hospital later than in the developed countries. This may be because the parents delay seeking medical advice due to the complex social set-up (with decisions being made by the extended family) or because alternative medicine systems are consulted prior to seeking appropriate medical attention. The average age at presentation to a specialized centre with NC is usually 3.5 months. Diagnosis Diagnosis is as described in Chapter 4, but many of the specialized investigations are not available in developing countries, and accurate diagnosis depends on collaboration with specialized units in the developed world. Treatment and outcome The final outcome in a significant proportion of cases is dependent on the age at diagnosis and the availability of appropriate management. The delay in diagnosis and referral is reflected by the reported prevalence of cirrhosis in 75–100% of cases undergoing laparotomy for NC. Of 44 children who underwent the Kasai procedure only 20% became jaundice free in India (Narasimhan & Chowdhary 2001), which could be attributed to advanced age at presentation (> 90 days) in 60% of cases. In Singapore, where biliary atretic patients are regularly operated on, 37% of

the patients had successful portoenterostomy as defined by clearance of jaundice (Marret et al. 1994). Many of the children are referred too late with advanced liver disease and cannot benefit from the Kasai portoenterostomy (Chapters 4 and 18), leaving transplantation as the only option. However, the high cost and the lack of available donor organs make this an unrealistic option for many children. Of 84 children considered for liver transplantation in Delhi, 59% had NC (biliary atresia constituted 40% of these). Thirty children were found to be unfit for transplantation, of whom 18 had NC. All 18 had severe malnutrition and 11 had intercurrent sepsis reflecting improper medical management and late referral for transplantation. As specific commercial liver feeds are not available in many developing countries, most units rely on modular feeds incorporating medium-chain triglycerides. A greater awareness regarding diagnosis and referral of these patients, a uniform approach to investigation and treatment and strengthening/improvement of laboratory and surgical facilities at referral centres will hopefully improve the outcome of these infants in developing countries in the near future.

Chronic liver disease Most chronic liver disease is due to chronic viral hepatitis (Table 22.2). The accuracy of the diagnosis depends on the local expertise and the degree of specialization of laboratory support. The aetiological profile of chronic liver disease (CLD) as determined in a nationwide survey of teaching medical institutions in India from 1988 to 1997 in shown in Table 22.2. Category I centres are those with specialist paediatric gastroenterology and hepatology units and Category II are without such units. It is likely that metabolic and autoimmune liver disease is underrepresented because of lack of diagnostic facilities. While treatment for each of these conditions is no different from the West, lack of specialized metabolic feeds and high cost of drugs such as interferon are serious limitations.

Chapter 22: Liver Disease in the Developing World

423

Metabolic liver disease

Indian childhood cirrhosis (see also Chapter 13)

In the developing world, the diagnosis and management of metabolic liver disease pose several challenges. As the clinical presentation may be non-specific, accurate diagnosis requires specific and reliable diagnostic facilities that only exist in a few centres in developing countries. Even in centres where these facilities exist, social, cultural and economic factors may reduce the number of families willing to allow their child to undergo invasive tests or to consider prenatal testing. In a nationwide survey involving 11 teaching medical institutions in India (six with specialized paediatric gastroenterology and hepatology services and five without such services), metabolic liver diseases (MLD) constituted up to 46% (8–43% in specialized centres) of the reported CLD over a period of 1–9 years. Wilson’s disease was the most frequently diagnosed MLD and Indian childhood cirrhosis (ICC) was infrequently reported (Pediatric liver study Group of India 1999). Others frequently diagnosed MLD were a1-antitrypsin deficiency, galactosaemia, hereditary fructose intolerance, glycogen storage diseases, tyrosinaemia type I, Neimann–Pick disease and Gaucher’s disease. Most metabolic defects were diagnosed on the basis of clinical features and liver histology, as specific enzyme assays were rarely available. Isolated metabolic diseases such as tyrosinaemia have been reported from Singapore (Goh et al. 1993). Treatment of metabolic liver disease is a challenge in developing countries, as therapeutic options are limited. Dietary management involves unpalatable diets and the use of nasogastric feeding, which is difficult to support in the community without the appropriate infrastructure. Specialized feeding formulas are not freely available. Although many nutritional companies have agents in developing countries, the process of importing the required formula is slow, expensive and may be impossible (Table 22.3). Liver transplantation is limited to a few centres and is rarely an option (see below).

ICC was one of the commonest causes of chronic liver disease in children in India and responsible for a large number of childhood deaths, but has now become practically non-existent. In the 1980s, the incidence was 1 : 4000 rural live births, but recently it accounted for less than 2% of the metabolic liver diseases at large teaching hospitals (Arora et al. 1999).

Table 22.3 Specialized formulas available in Malaysia. Disorders

Formula

Galactosaemia

Soy formula — Isomil, Prosobee, Formula-S, Nursoy, Alsoy MSUD diet powder* Low phe/tyr diet powder† Neocate Generade*

Maple syrup urine disease Tyrosinaemia Nutritional supplement for end-stage liver disease

*Medd-Johnson; †SHS.

Aetiology The aetiology of ICC was thought to be related to copper toxicosis (Tanner et al. 1979) from ingestion of animal milk, which had been contaminated by copper in brass cooking pots (Tanner et al. 1983; Bhave et al. 1987). Clinical features The mean age at presentation was 18 months (range 6 months to 5 years). It was commoner in males than in females (3 : 1) and had an insidious onset with abdominal distension, malaise with rapid progression to liver failure and death. Physical features included hepatomegaly, ascites and portal hypertension. The diagnosis was based on liver histology, which included: hepatocyte necrosis with ballooning and Mallory’s hyaline; pericellular interlobular fibrosis; inflammatory infiltration, and grossly elevated liver copper (> 250 mg/g dry weight). Treatment and prognosis Although untreated ICC has a high mortality (86% within 6 months of hospital attendance), treatment early in the course of the disease (preicteric stage) has recently been shown to allow long term disease-free survival. All 29 patients treated with D-penicillamine were found to be growing well with normal liver function tests 5–12 years after diagnosis. Only four had residual hepatosplenomegaly, which showed inactive micronodular cirrhosis on biopsy. No major side-effects from penicillamine therapy were reported (Bavdekar et al. 1996). The disappearance of ICC remains enigmatic, but may have been related to a change in feeding practices and a reduction in use of brass cookware (Bhave et al. 1992) (Chapter 13). Sporadic cases of an ICC-like disorder in infants have been reported from other countries (idiopathic copper toxicosis). It is possible that different mechanisms (environmental, genetic or combination of both) may give rise to copper-associated childhood toxicosis. Further developments in the mapping of genes involved in copper metabolism may shed more light on the aetiopathogenesis of this, fortunately now rare, disorder.

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Infectious diseases

Treatment and outcome

For yellow fever, Lassa fever, schistosomiasis, hydatid disease, Marburg and Ebola viruses, see Chapter 6.

In the view of the high proportion of multidrug-resistant strains (50% in China, 50–88.7% in Vietnam, 16–25% in Singapore, 40–92% in India) the treatment of typhoid in developing countries is with third-generation cephalosporins (i.v. ceftriaxone or cefotaxime 100 mg/kg/day, oral cefuroxime 10 mg/kg/day) or quinolones (ciprofloxacin or ofloxacin i.v. 10 mg/kg/day or oral 20 mg/ kg/day). Maintenance of adequate hydration and dietary intake is essential. Treatment is continued for 5 days after fever settles. Hospital admission is required for complications, toxicity and for hydration/nutrition. If hepatitis is associated, other causes of jaundice need to be excluded. Hepatomegaly and jaundice usually resolve within the first 7–10 days with appropriate therapy, whereas the transaminases resolve within 2–3 weeks.

Typhoid Enteric fever is an acute systemic bacterial illness caused by the salmonella group of organisms and is a major health problem in developing countries. Typhoid bacilli are filtered by the liver and Kupffer cells and excreted in the bile. Hepatic enlargement is a common occurrence in enteric fever and has been recognized since 1899 by Osler. Clinical features and diagnosis Between 23% and 90% children with typhoid fever are reported to have mild to moderate hepatomegaly and approximately 1–16% are jaundiced. Moderately elevated hepatic transaminases are common. Hepatic manifestations are more severe in relapses and in infections by multidrug-resistant Salmonella typhi (Jagdish et al. 1994). Salmonella endotoxin may induce consumptive coagulopathy, depletion of complement, arteritis, all of which may damage hepatocytes. Direct invasion of the hepatocyte by the organism may also contribute to the hepatic insult. The differential diagnosis includes: • haemolysis (in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency or thalassaemia) • ascending cholangitis • salmonella liver abscess • cholecystitis • amoebic liver disease • malaria with jaundice • viral hepatitis. An important differentiating clinical feature is that the jaundice associated with typhoid fever tends to occur at the peak of fever, whereas in viral hepatitis, jaundice is usually followed by decrease in fever. Furthermore, an ALT/LDH ratio of < 4 is seen in typhoid hepatitis and > 4 in viral hepatitis (El Newihi et al. 1996). Hepatic encephalopathy has been rarely reported (Olubodun et al. 1994). Acute typhoid cholecystitis is rare.

Dengue fever Dengue infection (dengue fever, dengue haemorrhagic fever (DHF) and dengue shock syndrome), caused by mosquito-borne flavivirus, is endemic in many areas of the tropics and subtropics including South-east Asia, India, the Pacific islands and the Caribbean. DHF is a severe, often fatal, febrile disease caused by dengue viruses and characterized by capillary permeability and abnormalities of haemostasis. Clinical features Dengue fever is characterized by • biphasic fever • myalgia • arthralgia • rash, which may be petechial • leukopenia and lymphadenopathy • hepatomegaly in 79–100% of patients • protein-losing shock syndrome may develop, dengue shock syndrome (DSS) • fulminant hepatitis with encephalopathy and Reye’s syndrome has been reported from Thailand (Nimmannitya et al. 1987) • myocarditis with a congested liver and ascites • pleural effusion.

Liver histology The liver biopsy may demonstrate a mild hepatitis, parenchymatous degeneration, peripheral infiltration by mononuclear cells and central necrosis with characteristic granulomatous collections of mononuclear cells called typhoid/Mallory nodules.

Diagnosis Hepatic transaminases are elevated (AST, ALT) and peak in the second week of illness. They gradually normalize by the 3rd to 4th week of illness. Jaundice is less common (15–62%), except in those with DHF or DSS (Mohan et al. 2000). Hypoxia/ischaemia resulting from the prolonged shock and metabolic acidosis in DHF/DSS may be responsible for the severity of hepatic dysfunction.

Chapter 22: Liver Disease in the Developing World The differential diagnosis includes acute hepatitis while the clinical features of DSS may be confused with patients with acute liver failure in view of the changes in sensorium, bleeding tendency and hepatomegaly. Liver histology demonstrates centrilobular necrosis, fatty change, Kupffer cell hyperplasia, acidophilic bodies and monocyte infiltration of the portal tract. Outcome Treatment is supportive. Hepatic involvement is selflimited although a few patients may develop hepatic failure. Recovery is usual within 48 h except for DHF or DSS. Malaria The liver is intimately related with Plasmodium falciparum and vivax, as it has a key role both in the life cycle of the organism and also in protective immunity against it. Clinical features Jaundice and hepatomegaly are more common in paediatric malarial infections (68%) compared with adult infections (6%). Jaundice is usually unconjugated, but may also be conjugated, which is more common with falciparum malaria than with vivax. Mild elevation of hepatic aminotransferases is common. Severe infection may occur in neonates who present with clinical features suggestive of cholestasis. Liver histology usually reveals fatty change, liver cell necrosis, nuclear vacuolation, Kupffer cell hyperplasia and mononuclear cell infiltration. Kupffer cells contain malarial pigment in the form of dark brown granules, and in acute malaria due to P. falciparum numerous parasitized red blood cells and iron. Immunofluorescence staining in liver biopsy sections reveals intense deposition within the reticuloendothelial elements (Cook 1994). In hyperendemic regions, an aberrant immunological response to plasmodium results in hyperreactive malarial splenomegaly (tropical splenomegaly). This condition is characterized by massive splenomegaly and an elevated malarial antibody (polyclonal IgM). Significant hepatomegaly is a common associated finding, but liver histology demonstrates normal hepatocytes, with numerous lymphocytes in dilated sinusoids and enlarged Kupffer cells. Malarial pigment is usually absent. Sudden massive intravascular haemolysis occurring in a previously infected individual followed by fever and haemoglobinuria is known as Blackwater fever. Now fortunately rare, it is observed in non-immune individuals residing in endemic areas and taking quinine irregularly for prophylaxis or presumptive treatment. It is associated

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with P. falciparum, scanty or absent parasitaemia and carries a poor prognosis. The attack consists of fever with or without rigors, pain in loins, haemoglobinuria, icterus, bilious vomiting, circulatory collapse and acute renal failure. Fulminant hepatic failure has also been reported. Treatment is with antimalarial chemotherapy and measures to maintain circulatory volume. Cholestasis may occur, but hepatotoxicity may also be due to the toxic effects of antimalarial agents such as amodiaquine, pyrimethamine/sulphadoxine. Outcome Jaundice and hepatomegaly usually improve quickly after treatment of malaria within 4–6 days. Treatment varies from region to region based on resistance. Chloroquine, sulphadoxine/pyrimethamine and quinine may be used. Falciparum malaria is more severe in jaundiced patients (Wilairatana et al. 1994) and is associated with higher mortality (Murthy et al. 1998), perhaps because of the increased numbers of parasites causing severe intravascular haemolysis, rather than hepatitis. Treatment aims are to reduce parasitaemia and manage associated complications such as hypoglycaemia and lactic acidosis. In severe and complicated P. falciparum malaria, treatment is quinine salt 10 mg/kg 8 hourly i.v. in 5% dextrose irrespective of the chloroquine resistance status of the area. Quinine therapy should be for a minimum duration of 7 days including both parenteral and oral doses. Alternative treatment includes Artemisinin derivatives such as: Artemisinin, 10 mg/kg once a day i.v. for 5 days, with a double divided dose administered on the first day; Artesunate, 1 mg/kg (two doses) i.m./i.v. at an interval of 4–6 h on the first day followed by 1 mg/kg once daily for 5 days; Artemether, 1.6 mg/kg (two doses) i.m. at an interval of 4–6 h on the first day followed by 1.6 mg/kg once daily for 5 days. In children with G6PD deficiency, certain antimalarials (sulphadoxine/pyrimethamine) may provoke severe intravascular haemolysis. Neither chronic hepatitis nor cirrhosis are reported long term, but there may be residual reticuloendothelial cell changes due to hyperreactive malarial splenomegaly. Hepatic tuberculosis Liver involvement is seen in miliary and congenital tuberculosis (TB), or as a result of hepatotoxicity of antitubercular drugs. Clinical features Primary hepatobiliary TB is associated with fever, abdominal pain and hepatomegaly. Hepatomegaly is found in 60% of children with abdominal or disseminated TB

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(Thapa et al. 1991). Other presentations include (Alvarez & Carpio 1983): • recurrent obstructive jaundice (30%) • hepatic calcification • tuberculous cholangitis • bile duct strictures and lymph nodes at porta hepatis • liver abscess, particularly in endemic areas. Diagnosis and outcome Elevation of hepatic aminotransferases is usual. The diagnosis is based on finding caseating granulomas on liver biopsy with evidence of TB elsewhere in the body. In children with a liver abscess, liver function tests may be normal. A diagnostic tap of the abscess is rarely helpful, but a biopsy from the wall of the abscess may show caseating granulomas or acid-fast bacilli. Alternatively, the diagnosis should be suspected if the diagnostic tap reveals sterile yellowish fluid, the imunodiagnostic tests for amoebiasis are negative and there is no response to combined therapy with antibiotics and antiprotozoal agents. Treatment of hepatic TB requires balancing the hepatotoxic effect of the anti-TB therapy with its beneficial effects. Use of streptomycin may be needed along with ethambutol and ciprofloxacin, which are safe for the liver (Table 22.4). If compliant, treatment is usually successful.

factors predisposing to it are still not clearly defined, advanced age, female sex, poor nutritional status, high alcohol intake, underlying liver disease (hepatitis B and hepatitis C) and HIV have been reported as risk factors for ATT-induced hepatotoxicity in adults. Acetylator status, previously considered a factor in hepatotoxicity, does not appear to be an important determinant of hepatotoxicity due to isoniazid (INH) particularly in children (Seth & Kabra 2001). Risk factors for ATT-induced hepatitis in children are not clear, but are more likely if there is underlying liver disease, severe malnutrition, or extensive TB (tuberculous meningitis or miliary TB). The rate of INH-induced hepatotoxicity in children is 3–10% with serious jaundice in 0.6% of cases. Hepatotoxicity is more likely in adolescents but there is no difference between slow and rapid acetylators. Rifampicin was initially thought to potentiate isoniazid-induced hepatotoxicity (INH), but subsequent studies showed similar rates of hepatotoxicity when INH was used alone or in combination with rifampicin. Only 0.6% of patients on rifampicin may develop jaundice. Pyrazinamide in recommended doses (20–35 mg/kg/day) does not potentiate INH-induced hepatitis, although it may give rise to a rise in transaminases (Seth & Kabra 2001). Hepatitis is more likely with combination therapy. Diagnosis and management

Hepatotoxicity associated with anti-TB therapy (see also Chapter 8) Hepatotoxicity is a significant problem with antitubercular therapy (ATT). The reported rate of hepatotoxicity with ATT is 4.28% in western countries (Steele et al. 1991) and 11.5% in Indian studies (Pande et al. 1996). ATTinduced hepatitis causes a mortality of 6–12% if the drugs are continued after the onset of symptoms. Evidence of hepatitis in a patient on ATT presents a particularly difficult dilemma, as it is necessary to decide whether the hepatotoxicity is part of the disease or a potentially severe hepatotoxic reaction that warrants discontinuation of therapy. Although the mechanism of hepatotoxicity and the risk

Table 22.4 Recommended doses of antitubercular drugs in children. Drug

Dose (mg/kg/day)

Isoniazid Rifampicin Pyrazinamide Ethambutol Streptomycin Ciprofloxacin

5 10 25 20 20 10

Although clear-cut guidelines about monitoring liver function are not agreed, it would seem prudent to measure AST and ALT every 2–3 weeks for the first 8 weeks. The development of jaundice or hepatomegaly would warrant immediate action. ALT or AST more than twice the upper limit of normal, or visible jaundice, or serum bilirubin > 2 mg/dl (> 40 mmol/l) in the presence of ATT indicates hepatotoxicity secondary to ATT. The differential diagnosis should include other causes of infectious hepatitis, such as viral hepatitis (Kumar et al. 1991). Absence of fever, a prodromal illness or tender hepatomegaly are important clues to the presence of drug-induced hepatitis. If jaundice develops or if transaminases rise more than four times normal, INH, rifampicin and pyrazinamide should be stopped and streptomycin (20 mg/kg) and ethambutol (20 mg/kg) should be started. Continuing unmodified ATT in the presence of liver dysfunction can result in liver failure. Weekly transaminase levels should be performed till AST and ALT return to less than twice normal (usually 2–4 weeks) when INH can be restarted at 5 mg/kg. Rifampicin (10 mg/kg) can be restarted 1 week later. Pyrazinamide may be added a further 1 week later if stopped during the intensive phase of therapy (Indian Academy of Pediatrics 1997; Seth & Kabra 2001). Streptomycin and ethambutol may be stopped when two of the drugs have been reintroduced. Weekly monitoring of

Chapter 22: Liver Disease in the Developing World liver enzymes should continue till all hepatotoxic drugs have been reintroduced and continued for 2 weeks. The last drug to be introduced should be stopped if transaminases rise again to more than twice normal. Hepatobiliary and pancreatic ascariasis Ascariasis is caused by the nematode Ascaris lumbricoides, which is the largest and most prevalent of the human helminths. Ascaris infections are usually asymptomatic unless there is a heavy infection. In the Indian subcontinent, ascariasis is highly endemic in Kashmir, central and south-west India and Bangladesh. Hepatobiliary and pancreatic ascariasis (HPA) is a well-described entity in which the helminth enters the ampullary orifice from the duodenum and either blocks the duct or advances into the common bile duct, the hepatic ducts or the cystic duct. Occasionally, the worms enter the gall bladder or the pancreatic duct. Worm invasion of the hepatobiliary tree is less common in children than in adults, possibly due to the smaller size of the ductal system, which makes it difficult for the worms to enter (Khurroo et al. 1990). The clinical spectrum includes acute cholecystitis, pancreatitis, cholangitis or a hepatic abscess. The worms either move from the ducts or die there forming a nidus for bile duct calculi. The diagnosis is suggested by finding adult worms or eggs in stool (Khurroo et al. 1987). The worms may also be detected on a computed tomography (CT) scan of the liver (Rocho et al. 1995). Treatment of biliary ascariasis includes conservative management for cholangitis and pancreatitis and oral anti-helminthics to paralyse the worms, which are then expelled by the peristaltic activity of the intestine. Endoscopic intervention (removal by basket) may be used when patients do not respond to the initial symptomatic treatment or when the worm has not moved out of the ducts within 3 weeks of treatment. Pyrantel pamoate (10 mg/kg, single dose), Mebendazole (100 mg b.d. for 3 days), are all affective against the worm and safe to use. Albendazole (200 mg orally < 2 years; 400 mg orally > 2 years) has the advantage of single dose when used for A. lumbricoides. A second course may be given if the patient is not cured by 3 weeks after treatment.

Portal hypertension (see also Chapter 18) Extrahepatic portal hypertension Portal hypertension (PHT) is an important cause of morbidity and mortality in children with liver diseases. Extrahepatic portal venous obstruction (EHPVO) is responsible for three-quarters of the cases of PHT seen in India (Arora et al. 1999). These patients often have a history of umbilical sepsis and/or umbilical catheterization during the neonatal period (most commonly exchange

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transfusion for neonatal hyperbilirubinaemia). This may be casually related to portal vein thrombosis, although definite evidence from prospective studies is lacking (Yadav et al. 1993). EHPVO is the commonest aetiology of upper gastrointestinal (GI) bleeding in children in India, 86% of upper GI bleeding (91% of those with varices) was due to EHPVO among children in India, compared with about one-third of children with varices in the West (Yaccha et al. 1996). Hepatoportal sclerosis Hepatoportal sclerosis (also known as non-cirrhotic portal fibrosis or idiopathic portal hypertension) is a common cause of PHT among adults in India (Dhiman et al. 2002). Although there are few studies in children, hepatoportal sclerosis was present in 1.7% of 115 paediatric patients with PHT (Arora et al. 1999), and in another study in 3.25% of 338 children with PHT seen over 6.5 years (Poddar et al. 2000). Liver disease PHT secondary to cirrhosis is mostly due to biliary artesia. Most of these children are too old at presentation for a portoenterostomy because of a delay in referral. Clinical features Children may present with asymptomatic splenomegaly, failure to thrive or GI haemorrhage. Ascites is a rare feature. Most paediatric patients with EHPVO in developing countries present later than their counterparts in the West. They are likely to have had two or more previous episodes of variceal haemorrhage, usually have massive splenomegaly and moderate iron-deficiency anaemia. The median age at presentation of children with hepatoportal sclerosis is 11 years (range 5–14 years) and in contrast to adults children rarely present with a variceal bleed. The clinical features of children with liver disease are as described elsewhere (Chapter 14). Differential diagnosis Isolated splenomegaly without upper GI haemorrhage or evidence of hepatic decompensation must be differentiated from other causes of splenomegaly such as lymphoma, leukaemia, Epstein–Barr virus infection, etc. In India, congestive splenomegaly (hyperreactive malarial splenomegaly), sickle cell disease, thalassaemia and kala azar (which may also present with pancytopenia and upper GI haemorrhage) need to be considered and schistosomiasis should be excluded in endemic areas.

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Treatment and outcome

Epidemiology

Treatment options are the same as in the West, and include endoscopic sclerotherapy, variceal banding and shunt surgery (Mitra et al. 1993; Ganguly et al. 1997). Banding is now the preferred treatment option, as it requires fewer sessions, has less side-effects and non-compliance is less. The latter is of particular relevance for patients on low incomes who have long journeys to hospital (Mitra et al. 1993). Patients with PHT due to hepatoportal sclerosis have an excellent prognosis as the histological changes are rarely progressive and the development of spontaneous shunts tends to protect these patients from variceal bleeding. Four of six patients with variceal bleeding were managed with endoscopic sclerotherapy and two with shunt surgery. All were alive and well after a median follow-up of 5.7 months (Poddar et al. 2000). Although liver transplantation is the treatment of choice for those with cirrhotic portal hypertension, it remains unrealistic for most patients due to nonavailability of organs, prohibitive cost and lack of specialized centres.

HAV infection is prevalent in Asia, Southern Europe, Southern America and many other parts of the world. The epidemiological status of hepatitis A is divided into high, intermediate and low endemicity. The prevalence has declined gradually in the past 20 years (Ikematsu et al. 1987; Yap & Guan 1993; Poovorawan 1998) as a result of improved sanitation and socio-economic conditions, and so many developing countries have moved from high to intermediate endemicity. However, even within the same developing country, low and intermediate areas may be mixed with high endemicity areas, with a series of local epidemics. With these changes in epidemiology, there has been a decrease in immunity against hepatitis A (Hadler 1991), increasing the number of children and adolescents who are now susceptible to HAV. The Shanghai hepatitis A epidemic in 1988 demonstrated the impact of a large epidemic in the context of reduced immunity and exposure. More of the population was susceptible to hepatitis A in the Shanghai epidemic because it was a low to intermediate endemic area, while the surrounding areas were of high endemicity. Almost 300 000 people developed clinical hepatitis A, and 47 [15 were hepatitis B surface antigen (HBsAg) carriers] died (Yao 1991).

Viral hepatitis Viral hepatitis is a world-wide health problem, which is most prevalent in children in the developing world. Hepatitis A to E are the main causes of viral hepatitis. Hepatitis A and E viruses are enterally transmitted and do not lead to chronic liver disease, while hepatitis B, C, and D viruses are parenterally transmitted and lead to chronic viral hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Hepatitis D and E are rare in children even in the developing world, thus this section will discuss the relevance of hepatitis A, B and C virus infection to child health in these countries. Hepatitis A virus infection (see also Chapter 6) Hepatitis A virus (HAV) is a non-enveloped, singlestranded RNA virus. It has four genotypes with a single serotype. It belongs to a new genus, Hepatovirus, within the family Picornaviridae. It has been the most common viral hepatitis in the developing world. The main route of transmission is through the faecal–oral route by contaminated food, water, or household contact. Uncooked or partially cooked shellfish is an important source of HAV infection, while transmission from food handlers, and infected children to medical personnel has been reported. Travellers to endemic areas are at high risk and may transmit HAV after infection. After 10–12 days, HAV is detectable in the blood and faeces, but becomes undetectable after the appearance of jaundice.

Clinical features Hepatitis A remains an important cause of morbidity in the developing world. The incubation period ranges from 15 to 50 days. The prodrome is abrupt with general malaise, fever, anorexia, nausea, vomiting, and abdominal pain or discomfort. Jaundice appears within 1 week and lasts for < 2 weeks in the majority of cases. Hepatomegaly and elevation of aminotransferases are usual during the prodromal period. Serum bilirubin and aminotransferases return to normal within 2–3 months. HAV infection is often asymptomatic in young children, in contrast to infection in adults. It is more severe in those with chronic liver diseases, such as chronic hepatitis B or C (Keefe 1995;Vento et al. 1998). The relapsing or cholestatic form of hepatitis A is rare in children. The severity of the hepatitis and the number of symptomatic cases depend on age. The case-fatality rate was reported to be 0.1% in children < 14 years old, 0.4% in adolescents and young adults (15–39 years), and 1.1% in patients ≥ 40 years. Although hepatitis A is mostly a self-limited acute disease, it can lead to fulminant hepatic failure on rare occasions, mainly in South America and South-east Asia. Among 5529 children in Pakistan with symptoms of acute hepatitis, between 1991 and 1998, 2735 children had positive IgM antibody to HAV. Thirty (1%) children showed progressive hepatic dysfunction and liver failure (Shah

Chapter 22: Liver Disease in the Developing World et al. 2000). In children with viral hepatitis A, particularly fulminant hepatitis A, presenting with anaemia and very high bilirubin levels, an association with G6PD should be considered (Sibal, personal communication). Prevention The improvements in sanitation and water supply and the introduction of HAV vaccine are important factors contributing to the control of HAV. Seroepidemiological studies conducted in Taipei city showed intermediate endemicity in 1975–1976 (Hwang et al. 1983). When the study was repeated in 1984, anti-HAV was undetectable in children < 5 years of age, and only 5% in children 5–10 years old (Hsu et al. 1985). When the study was repeated again in the same area in 1989, no children < 10 years were anti-HAV-positive (Tsen et al. 1991). In 2000, hardly any children and young adults < 20 years of age have immunity to HAV (Tseng et al. 2001). In contrast, 50% in the 20–30-year-old age group, are anti-HAV positive, and 90% > 30 years are positive. Before the introduction of hepatitis A vaccine, immune globulin was used to control local epidemics or prevent infection in travellers, but only provided immunity for 3–6 months. The development of effective hepatitis A vaccine has produced long-term immunity. Formalininactivated HAV vaccines are currently in clinical use and are highly immunogenic and safe, with mild side-effects in both children and adults. Live-attenuated vaccines are still under clinical investigation. A recent study in children in Taiwan demonstrated that inactivated HAV vaccine, given in a schedule of 0, 1, 6 months, provided protection for > 5 years and by mathematical calculation for > 25 years (Horng et al. 1993; Fan et al. 1998). The seroprevalence rate of anti-HAV was 95% at 1 month after the first dose of HAV vaccine, and 100% at 6 and 7 months and 1–5 years after the first dose of vaccine. Alarge double-blind, community-based control trial of an inactivated hepatitis A vaccine was conducted in a total of 40 119 children aged 1–16 years in Thailand. During the trial there were 40 cases of hepatitis A, 38 of which were in the control group. The protective efficacy was 94% after two doses of hepatitis A vaccine, suggesting that two doses of HAV vaccine are as effective as three. Two double doses of HAV vaccine are more convenient for those travelling to endemic areas and this is now the recommended schedule. The successful control of hepatitis A endemics in the mountain aboriginal in Taiwan is a good example (data from the Center of Disease Control, R.O.C.). In spite of the low endemicity status of hepatitis Ain Taiwan, hepatitis A outbreaks were common in the mountain areas of Taiwan in aboriginal populations since 1980. Since June 1995, hepatitis A vaccine has been administered to 15-month-old infants in all outbreaks and epi-

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demics in the aboriginal regions. From May 1996, vaccine administration was extended to children aged 12. As a result, the number of reported cases of hepatitis A in the aboriginal regions and villages in Taiwan decreased effectively from 1995 to 1998. A combined hepatitis A and B vaccine (Twinrix) has been successfully developed for children or young adults to prevent hepatitis A and hepatitis B, with good immunogenicity to both viruses (Tsai et al. 2001). The problems with control of hepatitis A are listed in Table 22.5. Hepatitis B virus infection (see also Chapters 6 and 8) Epidemiology Hepatitis B virus (HBV) infection is a world-wide health problem. It is prevalent in Asia, Africa, southern Europe and Latin America, where the HBsAg-seropositive rate ranges from 2% to 20% (Maynard et al. 1998; Chen et al. 2000). In most part of Asia, the HBsAg carrier rate in the general population is approximately 5–20% (Table 22.6) (Chen, personal communication). In highly prevalent areas, primary HBV infections occur mainly during infancy and early childhood. The age of primary infection is an important factor affecting outcome. Infection during infancy and early childhood leads to a high rate of chronicity. Before the implementation of the universal HBV vaccination programme, the HBV infection rate (i.e. the chronicity rate) in Taipei city increased with age, ranging from 5% in infants to 10% in children 2 years of age, and was nearly 50% at age 14 years (Hsu et al. 1986; Tsen et al. 1991). This suggested that most

Table 22.5 Problems with the control of hepatitis A virus (HAV) infection. 1 Frequent, rapid international travel 2 Increasing susceptibility of the population due to improved sanitation 3 High cost of the HAV vaccine 4 Inadequate resources for immunization

Table 22.6 Seroprevalence of hepatitis B surface antigenaemia in the general population in Asian Countries prior to the HBV vaccination programme. Country

HBsAg+ rate

Country

HBsAg+ rate

Japan Korea Malaysia Singapore Thailand Indonesia

~1% 3–15% ~ 5% 5–7% 8–10% ~10%

Philippines Vietnam China Hong Kong Taiwan

~13% ~15% 10–20% ~12% 15–20%

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chronic HBsAg carriers were infected before 2 years of age in this population (Hsu et al. 1986). In parts of Africa, such as rural Senegal, horizontal infection occurs very early. By the age of 2 years, 25% of children were infected, while at age 15 the infection rate was 80% (Feret et al. 1987). Perinatal transmission Perinatal transmission from HBsAg carrier mothers to their infants is a very important route of transmission leading to chronicity in hyperendemic areas. It accounts for the transmission route in 40–50% of HBsAg carriers in Asia. Around 90% of the infants of the hepatitis B e antigen (HBeAg)-seropositive carrier mothers became HBsAg carriers (Stevens et al. 1975) irrespective of a high or low HBsAg and/or HBeAg carrier rate in the population. Horizontal and parenteral transmission Horizontal transmission from highly infectious family members such as elder siblings is common, particularly in Africa. Parenteral transmission from improperly sterilized syringes or other contaminated instruments remains a problem in the developing world (Beasley et al. 1982; Hsu et al. 1993). Other sources of infection include institutionalized children and multiple or large amount of blood transfusions, etc. In Africa, HBV transmission occurs mainly horizontally during early childhood. Clinical features and natural history Acute or fulminant hepatitis B HBV infects all ages. The normal incubation period is 2–6 months and symptoms may occur as early as 2 months of age in infants of HBsAg carrier mothers. Acute hepatitis B usually runs a self-limited course, and recovers with anti-HBs seroconversion. Acute or fulminant hepatitis B occurs mainly in infants of hepatitis B e antibody-seropositive mothers in high prevalence areas (Shiraki et al. 1980; Chang et al. 1987). There is a high mortality rate in children with fulminant hepatitis B, but those who survive do not develop chronic liver disease. The presence of the HBV precore mutant (from G to A at nucleotide 1896) has been described in fulminant hepatitis B in adults (Carman et al. 1991), but was not confirmed by later studies (Feray et al. 1993). A study in children in Taiwan revealed that although 33% (five of 14) children with fulminant hepatitis B had hepatitis B precore stop codon mutant, this was in a similar proportion (30%, three of 10) in children with acute hepatitis B only (Hsu et al. 1995). The remaining nine of the 14 children with fulminant hepatitis had wild-type HBV, suggesting that the precore stop codon mutant did not cause the severe liver damage. Identical precore sequences were obtained from five mothers and their infants, who developed fulminant hepatitis, suggesting a maternal infant transmission.

Chronic hepatitis B Children with chronic HBV infection are usually asymptomatic. Liver histology is mild initially (Chang et al. 1988) but may progress to severe liver damage in later life during the process of acute exacerbation and HBeAg seroconversion. Hepatitis B e antigen is an important marker reflecting active viral replication and infectivity; hence its clearance is used as a marker for seroconversion or the success of antiviral therapy (Nordenfelt & Andren-Sandberg 1976). With age, serum HBeAg gradually clears and HBV replication reduces over a period of 2–7 years (Chang et al. 1995), although the mechanism remains unclear. HBeAg clearance is usually preceded by an acute exacerbation with elevation of aminotransferases and active inflammation of the liver. The peak level of aminotransferases ranges from ALT > 300 IU/l to > 800 IU/l in adolescents and young adults. It is usually accompanied by bridging necrosis on liver histology. Seroconversion takes place in 40% of children within 1 year of an acute exacerbation. After HBeAg clearance, aminotransferase levels gradually return to normal, and anti-HBe develops spontaneously. An acute exacerbation with reactivation of HBV replication and re-elevation of aminotransferases is unusual in children once anti-HBe appears (Chang et al. 1995). Unfortunately, it is likely that permanent liver damage and integration of the genome of HBV has already taken place, despite the disappearance of HBeAg. Complications Development of liver cirrhosis or HCC is rare but occasionally observed during childhood, particularly in hyperendemic areas for HBV infection (Ni et al. 1991). Approximately 80% of children with HCC in Taiwan were anti-Hbe-seropositive (Chang et al. 1989). It is estimated that the risk of HCC during lifetime in HBsAg carriers is around 25% and is higher in those with persistent HBeAg positivity (Yang et al. 2002). Prevention of hepatitis B and related liver diseases Immunoprophylaxis is the most cost-effective way to achieve global control of HBV infection and its related complications (Beasley et al. 1983; Lee et al. 1983). Passive immunization using hepatitis B immunoglobulin (HBIG) provides temporary immunity, but the cost of antenatal screening and HBIG is beyond most developing countries. The most important strategy has been the universal immunization programme to prevent both perinatal and horizontal transmission of HBV infection (Table 22.6), which depends on the local epidemiological conditions, i.e. high or low prevalence rate of HBsAg carriage in children, and the budget of the government. In Taiwan, the first hepatitis B immunization programme was launched in July 1984. In this programme, a combination of passive and active immunization effectively prevents HBV transmission from highly infectious

Chapter 22: Liver Disease in the Developing World mothers (HBeAg-positive mothers). Routine prenatal screening of the pregnant mothers for both HBsAg and HBeAg has been conducted. HBIG is given within 24 h after birth for infants of high-risk mothers with positive HBeAg and HbsAg. To all infants, the first dose of hepatitis B vaccine is given within the first week after birth, and the second and third doses at 1 and 6 months later (Chen et al. 1987). The efficacy of prevention for infants of high-risk mothers is approximately 85% (Hsu et al. 1988). In areas where HBV infection prevalence is low or financial resources are limited, immunization with three doses of HBV vaccine in a 0, 1 and 6-month schedule without antenatal screening of the mothers or administration of HBIG is a reasonable strategy to save cost. Such programmes have been successful in Thailand and many other countries in Asia (Poovorawan et al. 1992). The effect of universal hepatitis B immunization on the control of liver diseases in children Universal hepatitis B vaccination has effectively reduced both perinatal and horizontal transmission of HBV (Tsen et al. 1991) and thus the rate of chronic HBV infection world-wide. The first universal hepatitis B vaccination programme in the world was launched in Taiwan in July 1984 (Chen et al. 1987). The

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seroprevalence rates of HBsAg in Taiwan children before and during the 15 years after the start of the vaccination programme are shown in Table 22.7 (Tsen et al. 1991; Chen et al. 1996; Ni et al. 2001). The HBsAg carrier rate decreased significantly from around 10% before the vaccination programme to < 1% afterwards in children younger than 15 years. In reports from many countries such as Gambia and Korea (Whittle et al. 1995; Choe et al. 1996), universal vaccination programmes have been equally successful. The hepatitis B carrier rate has fallen from 5–10% to < 1%, demonstrating that universal vaccination is more effective than selective immunization for high-risk groups (Table 22.8) (Da et al. 1995). The reduction in HBV infection after the launch of the universal hepatitis B vaccination programme in July 1984 in Taiwan has had a dramatic effect on the incidence of HCC in children. The annual incidence of HCC in children aged 6–14 years was reduced to one-quarter from 0.52 per 100 000 children born before July 1984 to 0.13 per 100 000 children born after July 1984 (Chang et al. 1997). This trend has continued and it is expected that there will be a subsequent decline in the incidence of HCC in adults in the future. Difficulties with therapy for hepatitis B

Table 22.7 Seroprevalence of hepatitis B surface antigen before (1984) and after (1989, 1994, 1999) universal vaccination against hepatitis B virus in Taiwan. HBsAg Seropositive Rate (%) Age (years)

1984

1989

1994

1999

2560).

Budget High High Lower Lower

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Hepatitis C virus infection (see also Chapter 6) Epidemiology The seroprevalence of hepatitis C virus (HCV) infection is around 0.8–3% in the adult population and < 0.2% in children in most parts of the world, except for some hyperendemic areas (Stevens et al. 1990; Chang et al. 1993). HCV infection occurs mainly in high-risk children, such as those who have been exposed to blood products (children with haemophilia, thalassaemia, received blood transfusion, haemodialysis, malignancy, and organ transplantation) or in children of HCV-infected mothers. Perinatal transmission Compared with HBV infection, the level of virus in circulation is much lower (Chang et al. 1996; Ohto et al. 1994) and thus perinatal infection is much lower than that in HBV. Transmission is related to the level of maternal HCV RNA. The rate of maternal transmission in infants of mothers who were HCV RNAseropositive and HIV-seronegative is up to 15%, with a mean rate of 5% (Chang 1996; Nagata et al. 1994). HCV RNA can be detected in the breast milk, but the titre (10 000 copies/mlL) is much lower than that in maternal serum (105–2.5 ¥ 107 copies/ml) (Lin et al. 1995) and breast feeding is considered safe, which is of particular relevance for the developing world. Parenteral exposure to HCV Transfusion and injection using unsterile needles were the most important cause of HCV transmission in the developing world. They remain important routes of HCV transmission in children in those areas of the developing world with limited resources, where mass blood screening for anti-HCV is not universally done even nowadays. The HCV infection rate in thalassaemic children in Taiwan ranged from 43% to 60% (Ni et al. 1996), while approximately 15–20% of the paediatric haemodialysis populations and 3–4% of survivors of childhood malignancy were infected by HCV. Screening of anti-HCV in donated blood has reduced HCV infection to minimal levels in this country, but it remains a source of infection in less developed countries (Ni et al. 1994). Sporadic cases The proportion of cases without identifiable risk factors has consistently ranged from 35% to 40%. Intramuscular injection using unsterile syringes or needles is the most likely route of transmission.

Clinical features After primary infection with HCV, 60–80% of children have a chronic course as in the West. HCV RNA is detectable in serum by 2 weeks after exposure, and anti-HCV is detectable in serum by 4–8 weeks. Most

chronically infected children remain asymptomatic with normal liver function profiles. However, transient or persistent elevation of aminotransferase levels is not uncommon, particularly in vertically infected children. Chang et al. followed up 10 children with new HCV infection; four later lost HCV RNA, while six had a chronic course (Chang et al. 1995). Fujisawa et al. followed up 53 children with chronic HCV infection. Hepatic transaminases remained abnormal for 1.5–13 years, but virological clearance of HCV RNA was only demonstrated in four of the 53 (Fujisawa et al. 1998). Ten children had biochemical remission for more than 3 years, while 39 children remained abnormal biochemically. Prevention Unlike hepatitis B, there is currently no effective vaccine for the prophylaxis of HCV infection. Screening of blood, blood products and using disposable syringes and needles have reduced post-transfusion HCV infection and hepatitis effectively in those countries with sufficient resources and organization in the developing world. In Taiwan, the incidence has declined to zero after HCV screening of blood was instituted in 1992. However, infection through mother–infant transmission, parenteral exposure through invasive instruments, and organ transplantation are still sources of infection and can only be prevented by education of the public to avoid unsterile, invasive procedures such as injections, acupuncture, tattooing, etc. Other causes of viral hepatitis Hepatitis D, hepatitis E, and other non-A–E hepatitis are uncommon cases of viral hepatitis in children. Hepatitis D is particularly rare in children in the developing world. Hepatitis G, TT virus, or SEN viruses can be detected frequently in the serum of children with or without hepatitis, and are not seen as causing viral hepatitis in children. Hepatitis E virus (HEV) infection is endemic in South and central Asia and is enterically transmitted. Outbreaks of acute and fulminant hepatitis E occurred in the Middle East, India, northern and western parts of Africa and Mexico. Unlike hepatitis A in endemic areas, HEV infection rarely occurs in children younger than 10 years. In India, coinfection of hepatitis E and hepatitis A was observed in children with fulminant hepatitis (Sibal et al., personal communication). In children with fulminant hepatitis, non-A–E hepatitis and DHF are important aetiological agents. Treatment is supportive (Chapters 6, 7 and 8).

Orthotopic liver transplantation (see also Chapter 20) Orthotopic liver transplantation (OLT) is accepted treat-

Chapter 22: Liver Disease in the Developing World ment for children with end-stage liver disease. Survivors are able to lead a high-quality normal life. Despite the many complications and the necessity for longterm immunosuppression, the majority of recipients are pleased with the outcome and contribute actively to their family and society. As the 5-year actuarial survival rate is well over 85% for children in many international centres, many developing countries have set up liver transplant programmes in recent years. Despite limited resources and support, many of these programmes have been successfully established by hepatologists and transplant surgeons. This section attempts to discuss the many problems faced by OLT programmes in the developing world and highlight the differences from developed countries. Organization of liver transplant programme In contrast to the rest of the world, many transplant programmes in developing countries are initiated by the medical profession with or without institutional or government support and thus may not have the full range of support to establish a successful programme. This should be discouraged as OLT is a life-long commitment and only well-established institutions can offer a meaningful long term follow-up. Not all developing countries have the resources and expertise to manage the complexities of an organ donation programme, let alone the cultural and legal differences, and so for many countries it is best to begin with a living related donation programme. It is essential to obtain ethical support and approval, prior to establishing a transplant programme, particularly when a living related programme is being considered. There may well be issues related to the sale of donor organs, even in developed countries, and both transplant surgeons and hepatologists in developing countries must be aware of this problem. In general, in developed countries, transplant surgeons and hepatologists lead the transplant programmes. The team includes many people (see Chapter 20) such as anaesthetists, immunologists, pathologists, psychiatrists, intensivists, microbiologists, radiologists, haematologists, pharmacists, dieticians, nurses, transplant coordinators, biochemists. The team must be well organized and have good communication mechanisms with regular meetings such as pretransplant assessment discussions, mortality and morbidity conferences. In many developing countries, not all team members may have equal expertise and this may compromise both the care of the recipient and the success of the programme. Before considering a transplant programme, time and effort should be spent in training the supporting staff and the team to manage all aspects of liver transplantation. Pretransplant care and assessment, immediate post-

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transplant care and long term care are as important as surgical technique (Quak 1991). Liver transplantation is very much a team effort and all the members of the team must be fully committed to the care of the patient. Unfortunately, there are significant problems in utilizing suitably qualified personnel, as it is extremely costly to send the whole team to developed countries for training. Often, only surgeons and hepatologists are trained in the West and initiate the transplant programme in their home countries upon their return. Intensivists play a key role in the successful management of a transplant, particularly in the immediate postoperative period, when haemodynamic instability can adversely affect graft function. In developing countries, there are few well-trained intensivists and many hepatologists may have to function as an intensivist as well. It is also essential to have appropriate support services, especially good laboratory and radiology support. The laboratory must be equipped with up-to-date facilities and able to perform the essential tests over 24 h. These tests include routine liver and kidney function tests, coagulation and blood counts. This is not usually a significant problem in most developing countries, although there may be more difficulty with specialized tests such as drug monitoring (cyclosporin and tacrolimus), viral serology such as hepatitis B DNA, hepatitis C RNA and CMV PCR or antigen detection. Adequate radiological imaging of the vascular and hepatobiliary system is crucial for both pre- and posttransplant assessment (see Chapter 20). Interventional radiologists play an important role postoperatively in the management and treatment of many complications (see Chapter 3). Such expertise may not be available in the developing world, while Doppler ultrasonography, magnetic resonance imaging and CT angiography are expensive. The transplant surgeons in developing countries often have to rely solely on their clinical judgement to manage these problems during the postoperative period. A well-trained liver pathologist, who is familiar with transplantation, is important to help the clinician decide between rejection, ischaemia or infection in the graft. Although there is a shortage of pathologists worldwide, this is particularly true in many developing countries. It is not uncommon for the transplant centres to courier the biopsy specimen to specialized centres in the West for opinion, which is far from ideal as precious time is lost which may adversely affect the outcome for the recipients. Donor issues Cadaveric organ donation is not widely accepted in many countries due to lack of education, religious and cultural reasons, and thus few national donor programmes have been established. In some countries, legislation is neces-

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sary before instigating a successful organ donation campaign. Ethical committees should be established to ensure that organ donation is within the ethical guidelines of the countries, followed by public education and political support to promote organ donation in the developing countries. In those countries with a cadaveric donor programme, the organ donation rate is lower than in the West. In Singapore, where there is a well-established organ donation programme, cadaveric liver donation is only about 10 per million population. This is partly because the medical community is neither aware nor fully convinced of the benefit of OLT, and so patients with brain death are not routinely referred to the transplant co-ordinators, and partly because of public ignorance and objections from family members. In addition, there are few networks for sharing donor organs, as most developing countries function independently and many suitable organs are wasted. Lack of political agreement, poor communication and variable standards of health care are major factors preventing sharing organs in the developing world. Hepatitis B-positive donors In many endemic areas in the developing world, there is a high incidence of anti-HBc antibody-positive donors. The exact incidence varies from country to country. In Singapore, anti-HBc antibody is detected in about 30–40% of healthy adults, and in 53% of organ donors. Due to the shortage of donor organs, it is not possible to reject these anti-HBc antibody-positive donor organs despite the risk of reactivating hepatitis B and infecting the immunosuppressed recipients who have a high risk of fulminant liver failure. In Singapore, of the anti-Hbcpositive grafts that have been transplanted, 18% of the recipients subsequently developed hepatitis B de novo and are on long term antiviral treatment. Fatty liver Many donor grafts are rejected because of severe fatty infiltration in South-east Asia. In Singapore, out of 98 consecutive cadaveric liver donors, 16 (16%) were rejected because of severe fatty change. Of 61 healthy living donors who volunteered for liver donation, nine (15%) were rejected for the same reasons. This may be because of underlying obesity, the dietary pattern of Asians and/or ingestion of native herbal medicine. Further research is necessary to solve this problem, but in the meantime, it is a major limitation for the programme. Living related organ donation In view of the severe shortage of cadaveric donor organs

and the difficulty involved with the brain death laws, living related liver transplantation (LRLT) has become an option for children with end-stage liver disease in most Asian centres, e.g., Hong Kong, Japan, Korea and Taiwan (de Villa et al. 2003). In India, for example, because of shortage of organs, eight of the nine livers transplanted in the largest paediatric series, from Delhi, were from living related donors. LRLT has a number of advantages in the developing world as the transplant can be performed in an elective manner. The transplant team is fully prepared for the operation, both the donor and recipient can be carefully studied before the operation and the transplant surgeons have a full understanding of the anatomy prior to surgery. Theatre staff and theatre time can be planned in such a way that the transplant operation is not performed during the theatre busy hours. LRLT has a shorter ischaemic time than in cadaveric transplantation, which has potential benefits for the recipient with earlier establishment of graft function, less complications related to vascular ischaemia and possibly less rejection. Occasionally, the living related recipient can be weaned off immunosuppressants totally. On the other hand, LRLT has a significant morbidity and potential mortality for the donors, which must be made clear during the assessment and preparation period. All potential living donors must be carefully assessed and counselled before being accepted as a donor.

Pretransplant issues Infections Hepatitis B Hepatitis B infection is endemic in East and South-east Asia and although hepatitis B vaccination has been incorporated into many national vaccination programmes, it is still not universally implemented. In places like Taiwan, Malaysia, Hong Kong and Singapore where hepatitis B vaccination has been implemented since 1980s, chronic hepatitis B carriers are less common in the paediatric age group. However, even with hepatitis B vaccination in infancy, 5% of infants born to HBeAg-positive carriers mothers are chronic carriers. Thus, a number of paediatric patients with end-stage liver disease are chronic hepatitis B carriers. In Singapore, out of 33 paediatric liver recipients, two were hepatitis B carriers. They required oral lamivudine pretransplant, hepatitis B immunoglobulin during the peri-operative period and then long-term oral lamivudine with reduced levels of immunosuppression. An alternative strategy is high-dose hepatitis B revaccination post transplant that has had conflicting results (Sanchez-Fueyo et al. 2000). Tuberculosis TB is endemic in many developing countries and childhood TB is not uncommon. Children with endstage liver disease who are both malnourished and im-

Chapter 22: Liver Disease in the Developing World munodeficient are more likely to be infected. It is well known that bacille Calmette–Guérin vaccination during early childhood does not fully protect against the infection. Thus, it is essential to exclude TB by chest X-ray, sputum culture and Mantoux test during the pretransplant assessment. Family members should be screened, as the child will be at high risk of infection during the immediate postoperative period with a potentially fulminant course. TB may also be transmitted via the donor graft. Prophylactic isoniazid should be considered if there has been any contact with TB. Nutritional status Severe malnutrition at referral for transplantation is common in all parts of the world (see also Chapter 20), but is a particular problem in the developing world because of delayed or late referral for OLT. Late referral may be because the primary health care paediatricians have little knowledge of the clinical course of children with endstage disease, or are unaware of the benefit of OLT, and do not consider referral. Furthermore, there is little understanding of the necessity for proper nutritional care and many patients have protein malnutrition, gross nutritional rickets, iron deficiency anaemia, and coagulopathy at assessment. In the Indian series from Delhi, 18 of 84 children assessed for a liver transplantation were so severely malnourished that they were unsuitable for OLT because of the time required for nutritional rehabilitation. This is particularly tragic, as appropriate management and vitamin supplementation could have avoided many of these nutritional problems. Inadequate nutritional support is more likely in patients with metabolic liver disease, partly because lack of diagnostic expertise hampers early diagnosis and partly because specialized feeding formulas are not widely available in developing countries. Parental attitude Liver transplantation is accepted in developing countries as a treatment option, but many parents in developing countries are unwilling to accept it. Poor education, lack of understanding, fear of long term medications, religious objections and cultural factors contribute to rejection of this treatment option. In India, more than half the families refused OLT, with a clear bias against transplanting girls, and so far only 25% of girls have been transplanted in Delhi. Clearly, much public and professional education is required to highlight the success and benefits of transplantation, the need for adequate management and early referral.

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Biliary atresia Alagille's syndrome Glycogen storage disease Unconfirmed metabolic disease

Fig. 22.1 Indications for liver transplantation in Singapore. Biliary atresia is the commonest indication in Asia and in other countries such as India. Note the high proportion of unconfirmed liver disease, thought to be metabolic liver disease.

Indications for transplantation Chronic liver disease The main indication for transplantation in the developing world is biliary atresia (Fig. 22.1). Many other diseases are undiagnosed and thought to be metabolic liver disease. Liver transplantation for hepatitis B-related cirrhosis is not common in children, but liver transplantation may be indicated for HCC in hepatitis B carrier children if the tumour is localized in the liver. In a series from India, 84 children fulfilled the criteria for transplantation; 70% had biliary atresia, 15% had fulminant liver failure, 7% had cryptogenic cirrhosis, 3% had metabolic disease and 3% had hepatic tumours. Thirtysix percent were considered unsuitable because of late referral, with advanced clinical pathology with gross clinical features, severe ascites, protein calorie malnutrition and multiple vitamin deficiencies. Acute liver failure In children in the developing word, acute liver failure is mainly due to infection or to drugs. Hepatitis A is common in tropical countries, but only a small proportion of children develop fulminant liver failure. The causes of drug-induced liver failure include accidental or nonaccidental paracetamol overdose or the ingestion of native herbal medicines. Although a number of native herbal concoctions are known to cause hepatic injury, the exact mechanism and the hepatotoxic ingredients are not known. Due to the difficulty in finding cadaveric donors, living related liver transplantation is the treatment of choice.

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Post-transplant outcomes The outcome of OLT in developing countries varies. Few patients survive long enough on the cadaveric waiting list to receive a donor, and thus only countries with living related programmes are able to offer a viable procedure. However, in countries with relatively well-established programmes such as South Africa, Hong Kong, India, Singapore and Taiwan, the graft and patient survival rates are acceptable, with actuarial survival ranging from 50–90% (Lee et al. 1998; Chen et al. 2003). Retransplantation is not available in developing countries in view of the unavailability of cadaveric donors. The only option possible in such cases is living related transplantation, but sadly in most cases the child dies. As in the West, cyclosporine and tacrolimus are the two main immunosuppressants used, but other agents such as micophenolate mofetil are becoming available. The main problems with post-transplant immunosuppressants are the cost and the difficulties in providing accurate and affordable therapeutic drug monitoring. Depending on the regime used, and the size of the patient, the cost of immunosuppressant can be as high as US$1000.00 per month, which is beyond the means of the vast majority of patients in the developing world. Long-term survival depends on the availability of immunosuppression and the rate of intercurrent infection. Post-OLT TB is particularly difficult to manage, as a number of the anti-TB medicines are also hepatotoxic. Often, third-line medications and a combination of four or more drugs may be necessary. Though it is always mandatory to exclude active TB in the recipient, latent TB can be activated because of the immunosuppressive therapy. Infection with multidrug-resistant strains is common among many developing countries and the sensitivity of the organism should be obtained.

Acknowledgement Dr D. Mishra’s help in preparing this manuscript is acknowledged.

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transfusion hepatitis C virus infection in children. Journal of Pediatrics 124, 709–113. Ni, Y.H., Chang, M.H., Hsu, H.Y. et·al. (1991) Hepatocellular carcinoma in childhood — the clinical manifestations and prognosis. Cancer 68, 1737–1741. Ni, Y.H., Chang, M.H., Huang, L.M. et·al. (2001) Hepatitis B virus infection in children and adolescents in a hyperendemic area: 15 years after mass hepatitis B vaccination. Annals of Internal Medicine 135, 796–800. Ni, Y.H., Chang, M.H., Lin, K.S. et·al. (1996) Hepatitis C viral infection in thalassemic children: clinical and molecular studies. Pediatric Research 39, 323–328. Nimmannitya, S., Thisyokorn, V. & Hemsrichart, V. (1987) Dengue hemorrhagic fever with unusual manifestations. South East Asian Journal of Tropical Medicine and Public Health 18, 398–406. Nordenfelt, E. & Andren-Sandberg, M. (1976) Dane particleassociated DNA polymerase and e antigen: relation to chronic hepatitis among carriers of hepatitis B surface antigen. Journal of Infection and Disease 134, 85–89. Ohto, H., Terazawa, S., Sasaki, N. et·al. (1994) Transmission of hepatitis C virus from mothers to infants. New England Journal of Medicine 330, 744–750. Olubodun, A., Adefuye, B.C. & Talabi, A.D. (1994) Typhoid fever associated with severe hepatitis. Central African Journal of Medicine 9, 262–264. Pande, J.N., Singh, St. N., Khilnani, G.C., Khilnani, S. & Tandon, R.K. (1996) Risk factors for hepatotoxicity from antituberculosis drugs: a case–control study. Thorax 51, 132–136. Pediatric liver study Group of India. (1999) Metabolic liver disease in childhood: Indian scenario. Indian Journal of Pediatrics 66, S97–S103. Poddar, U., Thapa, B.R., Puri, P. et·al. (2000) Non-cirrhotic portal fibrosis in children. Indian Journal of Gastroenterology 19, 12–13. Poovorawan, Y. (1998) Changing epidemiology and prevention of hepatitis A virus infection. Acta Paediatrica Sinica 39, 139–145. Poovorawan, Y., Sanpavat, S., Pongpunglert, W. et·al. (1992) Long term efficacy of hepatitis B vaccine in infants born to hepatitis B e antigen-positive mothers. Pediatric Infection and Disease Journal 11, 816–821. Quak, S.H. (1991) Pre-liver transplantation management of children. Annals of Academy of Medicine Singapore 20, 534–539. Ramzan, M. & Quak, S.H. (1992) A clinical study of obstructive jaundice among Singapore infants. Journal of Singapore Paediatrics Society 34, 205–208. Rocho, M.S., Costa, N.S.S., Anqelo, M.T. et·al. (1995) CT identification of ascaris in biliary tract. Abdominal Imaging 20, 317–319. Sanchez-Fueyo, A., Rimola, A., Grande, L. et·al. (2000) Hepatitis B immunoglobulin discontinuation followed by hepatitis B virus vaccination: a new strategy in the prophylaxis of hepatitis B virus recurrence after liver transplantation. Hepatology 31, 496–501. Seth, V. & Kabra, S.K., eds. (2001) Essentials of Tuberculosis in Children, 2nd edition. Jaypee Brothers, Medical Publishers (P) Ltd, New Delhi. Shah, U., Habib, Z. & Kleinman, R.E. (2000) Liver failure attributable to hepatitis A virus infection in a developing country. Pediatrics 105, 436–438.

Shiraki, K., Yohihara, N., Sakurai, M., Eto, T. & Kawana, T. (1980) Acute hepatitis B in infants born to carrier mothers with the antibody to hepatitis B e antigen. Journal of Pediatrics 97, 768–770. Steele, M.A., Burk, R.F. & Desprez, R.M. (1991) Toxic hepatitis with isoniazed and riampicin. A Meta-analysis. Chest 19, 465–471. Stevens, C.E., Beasley, R.P., Tsui, J. & Lee, W.C. (1975) Vertical transmission of hepatitis B antigen in Taiwan. New England Journal of Medicine 292, 771–774. Stevens, C.E., Taylor, P.E., Pindyck, J. et·al. (1990) Epidemiology of hepatitis C virus — a preliminary study in volunteer blood donors. Journal of the American Medical Association 263, 49–53. Tanner, M.S., Portmann, B., Mowat, A.P. et al. (1979) Increased hepatic copper concentration in Indian childhood cirrhosis. Lancet 1(8128), 1203–1205. Tanner, M.S., Kantarjian, A.H., Bhave, S.A. & Pandit, A.N. (1983) Early introduction of copper-contaminated animal milk feeds as a possible cause of Indian childhood cirrhosis. Lancet 2, 992–995. Thapa, B.R., Yachha, S.K. & Mehta, S. (1991) Abdominal tuberculosis. Indian Pediatrics 28, 1093–1100. Tsai, I.J., Chang, M.H., Chen, H.L. et·al. (2001) Immunogenicity and reactogenicity of the combined hepatitis A and B vaccine in young adults. Vaccine 19, 437–441. Tsen, Y.J., Chang, M.H., Hsu, H.Y. et·al. (1991) Seroprevalence of hepatitis B virus infection in children in Taipei, 1989: five years after a mass hepatitis B vaccination program. Journal of Medical Virology 34, 96–99. Tseng, H.Y., Lu, C.Y., Lee, C.Y. et·al. (2001) Hepatitis A virus infection in Taipei in 1999. Journal of Formosan Medical Association 100, 604–607. Vento, S., Garofano, T., Renzini, C. et·al. (1998) Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. New England Journal of Medicine 338, 286–290. Whittle, H.C., Maine, N., Pilkington, J. et·al. (1995) Long-term efficacy of continuing hepatitis B vaccination in infancy in two Gambian villages. Lancet 345, 1089–1092. Wilairatana, P., Looareesuwan, S. & Charoenlarp, P. (1994) Liver profile changes and complications in jaundiced patients with falciparum malaria. Tropical Medical Parasitology 45, 298–302. Yaccha, S.K., Khanduri, A., Sharma, B.C. & Kumar, M. (1996) Gastrointestinal bleeding in children. Journal of Gastrointestinal Hepatology 11, 903–907. Yadav, S., Dutta, A.K. & Sarin, S.K. (1993) Do umbilical vein catheterization and sepsis lead to portal vein thrombosis — a prospective, clinical and sonographic evaluation. Journal of Pediatric Gastroenterology and Nutrition 17, 392–396. Yang, H.I., Lu, S.N., Liaw, Y.F. et·al. (2002) Hepatitis B e antigen and the risk of hepatocellular carcinoma. New England Journal of Medicine 347, 168–174. Yao, G. (1991) Clinical spectrum and natural history of viral hepatitis A in a 1988 Shanghai epidemic. In: Viral Hepatitis and Liver Disease (eds Hollinger, F.B., Lemon, S.M. & Margolis, H.), pp. 76–78. Williams & Wilkins, Baltimore. Yap, I. & Guan, R. (1993) Hepatitis A seroepidemiology in Singapore: a changing pattern. Transactions of the Royal Society of Tropical Medicine and Hygiene 87, 22–23.

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Chapter 4 Chapter 4: The Jaundiced Baby

(a)

(b) Plate 1 Infants with the neonatal hepatitis syndrome (NHS) present with prolonged jaundice. They may have intrauterine growth retardation or be small for gestational dates. Abdominal distension due to hepatosplenomegaly may be obvious.

(a)

(c) Plate 3 Tebida scan. Hepatobiliary scanning with Tebida (99m-technetium trimethyl 1 bromo-imminodiacetic acid) will produce good visualization of liver cells, especially after pretreatment with phenobarbitone (5 mg/kg for 5 days). This investigation may differentiate between neonatal hepatitis (a) in which there is patchy uptake of isotope but good excretion in comparison with (b) in which there is no excretion of isotope from the liver, suggesting either extrahepatic biliary atresia or severe intrahepatic cholestasis. Alternatively, radioisotope may be concentrated in a choledochal cyst (c).

(b) Plate 2 Abdominal ultrasound. (a) It is normal to demonstrate a large gall bladder after a 4-h fast. In babies with intrahepatic cholestasis or extrahepatic biliary atresia, the gall bladder may be small or difficult to visualize. (b) Abdominal ultrasound may also indicate choledochal cyst which is an important treatable cause of prolonged nenoatal jaundice.

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Plate 4 Histology. The characteristic features of neonatal or giant cell hepatitis are: conspicuous cholestasis with bile staining of hepatocytes, bile plugs within bile cannuliculae and bile ductules, multi-nucleated giant cell transformation with rosette formation and extramedullary haematopoiesis (a). In contrast, features suggestive of biliary atresia are: bile duct proliferation, bile plugs and portal tract oedema with variable fibrosis. There may be some giant cell transformation but extramedullary haematopoiesis is unusual (b). a1-Antitrypsin deficiency may be differentiated from other causes of neonatal hepatitis by identifying periodic acid–Schiff (PAS)-positive granules of a1-antitrypsin within hepatocytes (c).

Plate 5 Hypopituitarism may present with neonatal hepatitis and prolonged cholestasis. The diagnosis may be suspected by mid-line facial abnormalities, nystagmus or microgenitalia in males.

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Plate 6 Alagille’s syndrome is a genetic disorder with characteristic facies (a), which consists of a broad forehead, deep set eyes, mild hypertelorism, straight nose, a pointed chin. It is associated with skeletal abnormalities, such as butterfly vertebrae (b) and curved distal phalanges (c). The histology demonstrates a paucity of intrahepatic bile ducts (d).

(a)

Plate 7 Zellweger’s syndrome includes profound hypotonia, facial dysmorphism with a high forehead and large fontanelle. Note the hypotonia of the lower jaw.

Plate 8 Niemann–Pick C typically presents with prolonged cholestasis and hepatomegaly. Foamy storage cells may be identified in both Kupffer cells and hepatocytes (a) or in bone-marrow aspirate (b). In time the child will develop supranuclear ophthalmoplegia (paralysis of upward gaze) (c).

(b)

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Chapter 5: The Acutely Ill Baby

Plate 9 Infants with acute liver failure present with coagulopathy, encephalopathy and jaundice. For the main causes in infancy see Plates 10, 11 and 12.

Plate 11 Neonatal haemochromatosis. This rare familial disorder is characterized by an elevated serum iron, ferritin and hypersaturation of iron binding capacity. Histology shows hepatic necrosis with iron deposition in hepatocytes and Kupffer cells.

(a)

Plate 10 Galactosaemia may present with acute liver failure or cholestasis with a giant-cell hepatitis. This 6-week-old baby presented with both, as she developed cholestasis from biliary obstruction due to biliary sludge, note the bile plugs.

Plate 12 Mitochondrial deletions or depletions. These rare inherited defects present with acute liver failure with multisystem involvement. Hepatic histology may demonstrate microvesicular steatosis (a), while muscle biopsy demonstrates ragged red fibres due to a deficiency of the respiratory chain enzymes (b). Gomori’s I step trichrome.

(b)

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(a) Plate 15 Despite treatment with NTBC, there is a risk of hepatocellular carcinoma which is best documented by CT Scan or MRI to detect nodularity.

(b) Plate 13 Tyrosinaemia type I may present with acute or chronic liver failure. Hypertrophic cardiomyopathy (a) and rickets (b) are common.

Plate 16 Familial erythrophagocytic syndrome presents with jaundice, liver failure and pancytopenia. The diagnosis is made by demonstrating haemophagocytosis in liver or bone marrow aspirate.

Plate 14 Tyrosinemia Type 1. Histology is nonspecific with steatosis, fibrosis or cirrhosis, although hepatic dysplasia may lead to hepatocellular carcinoma.

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Chapter 6: Acute Hepatitis

Plate 17 Acute viral hepatitis. Histology is rarely required for diagnosis, but demonstrates inflammation, ballooning of hepatocytes, lobular disarray and reticulin collapse. Haematoxylin and eosin, ¥ 25.

Plate 19 Hepatic abscesses present with fever and abdominal pain. The diagnosis is first suspected on ultrasound, the above demonstrates an abscess.

Plate 20 The diagnosis is confirmed by CT scan that shows a thick-walled right hepatic abscess (a). It is best treated by percutaneous aspiration and drainage through the liver parenchyma to avoid local spillage from the cavity (b).

Plate 18 Histological features of cytomegalovirus infection may be diagnostic, demonstrating hepatocellular enlargement, enlarged nucleus and owl-eye appearance due to intranuclear inclusion bodies.

(a)

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(a) Plate 21 Acute hepatic encephalopathy may be difficult to detect in infants or older children. Electroencephalography demonstrates a slow rhythm and reduced amplitude with characteristic triphasic waves.

(b)

(a),(b) Plate 22 The rapid development of cerebral oedema in acute liver failure is a poor prognostic sign. This is best demonstrated by a CT scan, which shows reduction in the size of the ventricules (a) and reversal of grey/white matter (b).

Plate 23 Liver histology is usually obtained at post mortem or at transplantation. There is usually severe hepatic necrosis with reticulin collapse and biliary proliferation. There may be significant inflammation in viral hepatitis (a), which is absent in paracetamol toxicity (b).

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Chapter 8: Chronic Hepatitis

(a)

(a)

(b) Plate 25 Hepatitis B infection may be suggested by the detection of hepatitis B surface antigen (Orcien stain ¥ 1000). (a) Fatty change with glycogenated nuclei and cytoplasmic eosinophilia is characteristic of hepatitis C (b).

(b)

(c) Plate 24 Chronic hepatitis is characterized histologically by portal inflammation consisting predominantly of lymphocytes and plasma cells; hepatocellular damage manifests by swelling (balloon degeneration) and hepatocellular necrosis, which may be focal or piecemeal (a) or bridging portal tracts (b). Fibrosis may be mild with expansion of portal tracts or moderate with portal or periportal septum (b). Autoimmune hepatitis type I often presents as cirrhosis (c) in which the fibrous tissue links portal tracts giving rise to nodules.

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(c)

(a)

(b)

(d) Plate 26 Primary sclerosing cholangitis affects both intra- and extrahepatic bile ducts and may be associated with autoimmune hepatitis type I in children. It is best diagnosed by endoscopic retrograde cholangiopancreatography, which demonstrates the characteristic features of an enlarged gall

bladder with irregularity of intrahepatic ducts due to septal dilatation and short strictures (a); MRI is less invasive and just as accurate (b). Liver histology demonstrates the characteristic ‘onion skinning’ of the bile ducts (c). It may be associated with an indeterminate colitis with non-specific mucosal inflammation and crypt abscesses, as in this case (d).

Chapter 8

Plate 27 Drug-induced liver disease may resemble autoimmune hepatitis, while Carbamazepine may cause a granulomatous hepatitis, as in this case, or acute liver failure.

Plate 29 Sodium valproate and tetracycline both cause a fatty liver with microvesicular fat within hepatocytes which is associated with hepatocellular dysfunction and may progress to acute fulminant hepatitis.

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Plate 28 Actinomycin and other chemotherapy for malignancy may cause hepatocellular necrosis and acute liver failure. Note the loss of architecture and haemorrhage.

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Chapter 9: Congenital and Structural Abnormalities of the Liver

Plate 30 Abdominal ultrasound showing multiple hepatic cysts characteristic of fibropolycystic disease which includes congenital hepatic fibrosis, Caroli’s disease and polycystic kidneys.

Plate 32 Endoscopic retrograde cholangiography in a patient with Caroli’s disease, congenital hepatic fibrosis and minimal polycystic renal disease. It demonstrates gross abnormalities of the intrahepatic biliary tree which communicates with hepatic cysts.

Plate 31 In congenital hepatic fibrosis hepatic histology demonstrates widened portal tracts which are linked by broad bands of fibrous tissue. Bile ducts are prominent, dilated and abnormal. Recurrent cholangitis may lead to biliary cirrhosis.

Plate 33 Abdominal ultrasound indicating single hepatic cyst. These are often asymptomatic, but can be aspirated under radiological control if symptoms arise.

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(a)

(c)

(b)

(d) Plate 34 Cutaneous haemangiomata are common and usually regress within 6 months (a). They may be associated with multiple haemangiomata leading to high output cardiac failure. (b) This MRI scan in a 3-month-old infant demonstrates a large right hepatic haemangioma. There is a large shunt through the haemangioma into dilated hepatic veins. The aorta is enlarged above the coeliac trunk but is significantly smaller below the coeliac trunk due to shunting. The femoral arteries are small

(approximately 1 mm in diameter) which can make catheterization difficult. Treatment includes cyanoacrylate glue embolization using a pigtail catheter in lower thoracic aorta showing intense hypervascularity of right hepatic haemangioma before (c) and reduction in blood flow following successful embolization (d). Hepatic artery ligation or liver transplantation are alternative treatments.

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Chapter 10 Chapter 10: Non-alcoholic Steatosis

(a) Plate 35 Non-alcoholic fatty liver (NAFLD) or non-alcoholic steato-hepatitis (NASH) are common diseases in adults and are increasingly being recognized in children with obesity, type 2 diabetes mellitus and a number of inherited metabolic conditions. This boy developed hyperphagia, excessive weight gain and fatty liver after hypothalamic surgery.

(b) Plate 36 This liver biopsy demonstrates the severe steatosis (a) common in NASH with hepatitis, and Mallory bodies which sometimes develops into fibrosis (b) and cirrhosis.

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Chapter 11: Hepatobiliary Disease in Cystic Fibrosis

(a)

Plate 37 Cystic fibrosis. The commonest presentation of cystic fibrosis is with malnutrition, abdominal distension and hepatosplenomegaly secondary to cirrhosis and portal hypertension.

(b) Plate 38 Ultrasound examination often demonstrates a coarse liver texture and a micro gallbladder with gall stones (a). Imaging of the biliary tree may show variable dilatation of the ducts (b). Magnetic resonance cholangiopancreatography is less invasive than endoscopic retrograde cholangiography and produces excellent imaging (image lent by Dr Isabelle Durieu, Lyon).

(a)

(b)

Plate 39 Histology may demonstrate steatosis and chemical cholangitis (a), or focal biliary fibrosis (b) with portal inflammation.

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Chapter 12: Metabolic Liver Disease in the Infant and Older Child

Plate 40 Glycogen storage disease type I (a,b,c) are characterized by increased glycogen storage. Hepatocytes are swollen with glycogen and steatosis is prominent. Glycogen6-phosphatase is either deficient or functionally abnormal.

(a),(b) Plate 41 Glycogen storage type IV typically demonstrates cytoplasmic inclusions of the abnormal glycogen (amylopectin) (a) which is completely removed by diastase (b).

Plate 42 Hereditary fructose intolerance is associated with severe steatosis on liver histology. Persistent ingestion of fructose leads to cirrhosis.

Plate 43 Gaucher’s disease affects reticuloendothelial cells in liver, bone marrow and lung. Liver histology shows fibrosis and pale Gaucher’s cell around the portal tract (Masson-Trichrome ¥ 200).

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Chapter 13: Disorders of Copper Metabolism

(a)

(a)

(b) (b) Plate 44 Wilson’s disease may present with fulminant hepatitis (a), haemolysis and low alkaline phosphatase. This young girl, who was successfully transplanted, had Kaiser Fleischer rings on slit-lamp examination (b).

Plate 45 Liver biopsy demonstrated severe hepatitis and underlying cirrhosis (a). Copper storage was demonstrated using Orcein stain (b).

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Chapter 14: Complications and Management of Chronic Liver Disease

(a)

(c)

(b)

Plate 46 Clinical features of biliary cirrhosis in infancy. Jaundice is severe, with wasting, ascites, prominent abdominal veins, clubbing and hepatosplenomegaly. The abdominal scar is from failed portoenterostomy for biliary atresia (a). Both plantar and palmar (b) erythema develop early. In older children facial telangiectasia (c) and spider naevi may be obvious.

Plate 47 Liver histology of biliary cirrhosis with portal inflammation and fibrosis linking portal tracts leading to nodule formation.

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(a) (c)

(b)

Plate 48 (a) Splenoportogram in cirrhosis, illustrating large gastro-oesophageal varices arising in the short gastric and left gastric veins and the azygous and hemiazygous system. Intractable variceal bleeding (b) or ascites may respond to insertion of a transjugular intrahepatic portosystemic shunt (TIPS). This venogram demonstrates the shunt that has been created by placing a stent between the right hepatic and right portal veins, establishing good flow between the portal vein and the hepatic vein and reducing the portal vein pressure (c).

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Chapter 15 Chapter 15: The Liver in Systemic Illness

(a) Plate 49 Sinusoidal dilatation secondary to raised hepatic pressure from constrictive pericarditis due to tuberculosis. The patient improved following pericardectomy and isoniazid.

(b) Plate 51 Thalassaemia. There is marked haemosiderosis involving both hepatocytes and Kupffer cells (a) which has almost disappeared 3 years post-bone marrrow transplantation (b).

Plate 50 Percutaneous transhepatic cholangiogram demonstrating obstructed biliary tree most often due to biliary sludge following cardiac surgery.

Plate 52 Graft vs. host disease is most common after bone marrow transplantation. It may affect skin, intestine and liver. Liver histology demonstrates loss of bile ducts which may be irreversible.

Chapter 15

Plate 53 Veno-occlusive disease occurs in 26% of patients postbone marrow transplantation. Liver histology shows occlusion of the terminal venules, sinusoidal congestion and necrosis of hepatocytes. Fibrosis and cirrhosis may develop.

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Plate 54 Liver biopsy demonstrating hepatic candidiasis in an immunosuppressed patient post-liver transplantation (Grocutt stain ¥ 20).

(b)

(a) Plate 55 This infant with severe combined immunodeficiency (SCID) presented with acute liver failure due to fatal Pneumocystis carinii infection of liver with numerous abscesses (a) and interstitial disease in the lung (b).

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(b)

(a) Plate 56 CD40 ligand deficiency is a rare X-linked immunodeficiency syndrome that is treatable by bone marrow transplantation. Sclerosing cholangitis secondary to cryptosporidia infection in the liver may develop and is demonstrated in this ERCP (a), which demonstrates the

characteristic dilatation and beading of the bile ducts. This boy developed liver failure after bone marrow transplantation, due to graft vs. host disease and cryptosporidial cholangitis with loss of bile ducts (Masson Trichrome ¥ 400) (b).

Chapter 16: Skin Disorders in Liver Disease

Plate 57 Photosensitive porphyria-like skin lesions in a child with Alagille’s syndrome. She had elevated urinary porphyrins which were thought to be secondary to liver dysfunction.

Plate 58 Fat malabsorption is common in liver disease and may lead to a raised pigmented rash secondary to essential fatty acid deficiency.

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Plate 59 Immunosuppression with cyclosporin A commonly causes excessive hirsutism, which resolves on reduction of the drug. Plate 61 Autoimmune hepatitis. The side-effects of steroids are obvious in this young girl, who is cushingoid and has developed facial acne.

Plate 60 Eczema is common in young children, but may become exacerbated post transplant, particularly with cyclosporin A treatment. Plate 62 Warts are common in post-transplant patients. This child on cyclosporin therapy had warts on his hands that spread to his face. They can be treated conservatively with keratolytic paints or destructively by cryotherapy.

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Chapter 16

(a) Plate 63 Tinea corporis (ringworm) is common in children, but may be more severe in immunosuppressed children post-liver transplant.

(b) Plate 65 This papular skin rash (a) was secondary to T-cell infiltration confirmed on skin histology which demonstrates inflammation extending into the epidermis (b). It resolved on reduction of immunosuppression.

Plate 64 Pityosporium folliculitis is a common skin complaint in children on long-term immunosuppression. It may respond to oral or topical anti-fungal agents.

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Chapter 17: Dental Care of Children with Liver Disease

(a) Plate 66 Delayed emergence of upper primary incisors in a 22-month-old child post-liver transplant. The upper central incisors are partially erupted but there is no sign of the lateral incisors.

Plate 67 Severe gingival overgrowth post-liver transplant in a child on both cyclosporin and nifedipine. Note the poor oral hygiene and calculus deposits (a). The teeth are dysplastic and have severe intrinsic green pigmentation (b) from prolonged jaundice.

(b)

Chapter 18: Surgical Disorders of the Liver and Bile Ducts

Plate 69 Endoscopic retrograde cholangiopancreatography (ERCP) in a child who presented with pancreatitis. The X-ray demonstrates dilatation of both common bile ducts and the pancreatic duct which joins the biliary tract at some distance from the ampullae forming a long common pancreaticobiliary channel. Plate 68 Percutaneous cholangiogram in a child who had previously undergone a Kasai portoenterostomy. There is free flow of contrast into the Roux loops. The bile ducts are very abnormal and show typical cloud-like appearance of biliary atresia.

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Plate 71 Percutaneous transhepatic cholangiogram (PTC) in a 6-week-old infant with jaundice from biliary obstruction secondary to spontaneous bile duct perforation. The dilated right and left hepatic ducts have been punctured at PTC with 22-G Chiba needles and contrast injected. Strictures involving the confluence of the right and left ducts are shown with rounded filling defects in both main ducts due to biliary sludge. No contrast is seen in the extrahepatic bile duct and duodenum. Findings were confirmed at laparotomy and a hepaticojejunostomy performed.

(a)

(b) Plate 70 Choledochal cysts may be diagnosed by endoscopic retrograde cholangiopancreatography (ERCP) which demonstrates a congenital cystic dilatation of the common bile duct (type 1 disease ) (a) or fusiform dilatation (type 1F) with pancreaticobiliary malunion (b).

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Plate 72 Endoscopic retrograde cholangiopancreatography (ERCP) in a 4-year-old girl who presented with intermittent jaundice. Treatment includes placement of an endoscopic stent or surgical removal of the isolated biliary stricture.

(a)

(b)

(c)

Plate 73 Catheter aortogram shows an enlarged hepatic artery draining through a congenital arterioportal fistula into a left portal vein varix (a). Superior mesenteric arterioportogram (SMAP) demonstrating that there is no main portal vein flow into the liver due to reversal of portal flow via the fistula. There are a few portal vein collaterals draining portal blood into the caudate lobe, but most of the flow is through portosystemic collaterals in the upper abdomen (b). After embolization of the fistula (seen as two small metallic rings) there is normal portal vein flow into the liver with no collaterals (c). Doppler ultrasound 24 h after embolization demonstrated thrombosis of the left portal vein varix.

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*

(a)

(c)

(b) (d) Plate 74 The Budd–Chiari syndrome is usually due to hepatic vein obstruction which increases the size of the caudate lobe (a). It is best demonstrated by venography using a catheter placed in the internal jugular vein. This right hepatic venogram shows a critical stenosis of the right hepatic vein ostium (b); while the wedged hepatic venogram shows retrograde filling of the

portal vein and filling of varices in the upper abdomen as a result of the portal hypertension (c). After balloon angioplasty and dilatation, the right hepatic vein stenosis has been abolished with improved blood flow, a reduction in the pressure gradient and resolution of the portal hypertension (d).

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Plate 75 CT scan showing haematoma in the liver following blunt liver trauma. Note that the blood has tracked between liver segments. Conservative management may be all that is required.

Chapter 19: Primary Hepatic Tumours

(a),(b) (g),(h)

(c),(d)

(e),(f)

Plate 76 Hepatic tumours are best diagnosed by CT scan. These X-rays demonstrate a large hepatoblastoma before (a) and after intravenous contrast (b). They also help to identify different tumours: hepatoblastoma (c); epithelioid haemangioendothelioma (d); hepatocarcinoma (e) and the cut surface of hepatocarcinoma at surgery (f). Cystic tumours such as mesenchymal hamartoma (g) and sarcoma (h) can also be differentiated from solid tumours.

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(a),(b) (a)

(c),(d) Plate 78 Focal nodular hyperplasia is a benign tumour which may grow in size and become painful. This 11-year-old girl had a large left-sided tumour seen on MRI scanning (a,b). The preoperative angiogram demonstrated the vascularity of the tumour (c ) visualized at surgery (d). LHA, Left hepatic artery; RHA, right hepatic artery. (b) Plate 77 Extensive involvement of all segments of the liver with a multifocal hepatoblastoma as seen on this MRI scan is an indication for transplantation (a). The diagnosis was confirmed histologically (b), which demonstrates invasion by malignant cells, which are smaller than normal hepatocytes with low nuclear–cytoplasmic ratio and small nucleoli. Cells may be foetal, embryonal, macrotrabecular or small cell undifferentiated (haematoxylin and eosin, ¥ 82).

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Chapter 20: Liver Transplantation

IVC

2

7

8 1

3

4

5 6

PV

Plate 79 Schematic diagram of liver demonstrating eight segments. The left lateral segments, 2 and 3, are most commonly used for reduction hepatectomy, split liver, living relation or auxiliary liver transplantation.

Plate 81 Liver histology demonstrating acute rejection. There is a mixed inflammatory infiltrate of the portal tract, with eosinophils, endotheliitis, lymphoid infiltration and inflammation of bile ducts. There is some hepatocyte loss. (Haematoxylin & eosin ¥ 20.)

Plate 82 Liver histology demonstrating chronic rejection. There is an inflammatory infiltrate in the portal tract with loss of bile ducts — ‘vanishing bile duct syndrome’ (haematoxylin and eosin, ¥ 20).

Plate 80 Hepatic angiogram indicating a patent coeliac axis but absent hepatic artery secondary to hepatic artery thrombosis. The patient was retransplanted successfully.

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(a) (a)

(b) Plate 83 Biliary obstruction occurs in 20% of children post-liver transplant due to hepatic artery ischaemia or a biliary anastomotic stricture (a). Following balloon dilatation of the stricture, using a percutaneous transhepatic approach, there is good drainage of contrast from the intrahepatic bile ducts across the biliary anastomosis into the jejunal Roux loop (b).

(b) Plate 84 Percutaneous transhepatic portogram shows a critical stenosis of the portal vein anastomosis post transplant with numerous varices in the upper abdomen. This was successfully treated with balloon dilatation (b) demonstrating no pressure gradient across the portal vein anastomosis and a reduction in variceal filling.

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Plate 85 Chronic graft hepatitis develops 5–10 years post transplant and may be related to chronic rejection or de novo hepatitis (haematoxylin and eosin, ¥ 400).

Chapter 21: Small Bowel and Liver Transplantation in Children

Plate 87 Severe total parenteral nutrition cholestasis is an indication for a liver or combined liver and intestinal transplant. The early histological changes are related to centrilobular cholestasis without inflammation, necrosis or fatty infiltration or fibrosis. Plate 86 Chronic venous occlusion secondary to central venous lines is a common complication of total parental nutrition (TPN). This bilateral arm venogram shows occlusion of the left axillary, left subclavian and left innominate veins with a stenosis of the right subclavian vein. There is a right internal jugular vein tunnelled central line with its tip in the superior vena cava. Lack of venous access for TPN is an indication for small intestinal transplantation.

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(c)

(a)

(b)

Plate 88 Endoscopic and histological appearance of severe intestinal allograft rejection. There has been ‘sloughing’ of the mucosa (a). Histopathology reveals loss of villi and crypts (b) and apoptosis in the crypts (c) (haematoxylin and eosin, ¥ 100 (b) and ¥ 400 (c)).

Plate 89 Typical endoscopic appearance of ‘shallow’ ulcer surrounded by normal mucosa. Histopathology shows typical CMV inclusion bodies. The number of inclusion bodies has been associated with more severe clinical disease, with gradual disappearance as the disease resolves. (From: Sigurdsson, L., Reyes, J., Putnam, PE. et al. (1998) Endoscopies in pediatric small intestinal transplant recipients; five years experience. American Journal of Gastroenterology 93, 207–211.)

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(b) (a)

(c)

Plate 90 Endoscopic appearance of PTLD lesion: raised ‘tumorous’ ulcerated lesion surrounded by normal appearing mucosa (a). Histopathology shows polymorphic infiltrate (b) (haematoxylin and eosin, ¥ 40) which demonstrates ‘transformed’ PTLD lymphocytes staining positive for EBER (c) (in-situ hybridization for Epstein–Barr virus early RNA) (¥ 600).

Index

Page numbers in italics refer to figures; those in bold to tables. Plates appear in the Atlas Section starting on page 439. Index entries are arranged in letterby-letter alphabetical order. Aagenaes syndrome 56 abdominal distension ADPKD 165–6 see also ascites; hepatosplenomegaly abdominal mass, liver tumours 367, 367 abdominal pain acalculous cholecystitis 340 choledochal cysts 333 gallstones 339 abdominal trauma 351 abdominal X-rays 20 liver tumours 368 abetalipoproteinaemia 236–7 ABO incompatibility 290, 338 ABO matching, liver transplantation 387 abscesses drainage 29 liver see liver abscess acaeruloplasminaemia 245–6, 246, 250 acanthocytosis, abetalipoproteinaemia 236 acanthosis nigricans 184–5, 186 acetaminophen see paracetamol acetylator status 154, 426 N-acetylcysteine cystic fibrosis liver disease 200, 204 fulminant hepatic failure 115 hepatorenal syndrome 288 neonatal haemochromatosis 78 non-alcoholic fatty liver disease 191 paracetamol overdose 121, 152 Wilson’s disease 253 N-acetyl-p-benzoquinoneimine (NAPQI) 151 N-acetyltransferase polymorphisms 149, 154 acid–base disturbances, fulminant hepatic failure 112, 119, 120 acne vulgaris 304, Plate 61 actinomycin 293, Plate 28 acute fatty liver of pregnancy, maternal 85, 86, 211 acute hepatitis 92–106 drug-induced 149 infective see acute infective hepatitis Wilson’s disease 248 acute infective hepatitis 92–104 clinical features 92 differential diagnosis 92 fulminant hepatic failure 107–9, 108 investigations 92–3, Plate 17 non-viral causes 93, 101–4 viral see viral hepatitis, acute acute liver failure 107 aetiology 107–9, 108 infantile 77–82 clinical presentation 77–8, Plate 10 investigations 75 mitochondrial energy disorders 79–80 neonatal haemochromatosis 78–9

prognosis 122 tyrosinaemia type I 80–2 liver transplantation 379, 381–2, 435 nutritional support 11–12 see also fulminant hepatic failure acutely ill infants 74–91 age at presentation 74, 75 diagnosis 74, 76 hepatocyte transplantation 88 investigations 74, 75 liver failure see acute liver failure, infantile management approach 74 acute renal failure 119, 277 acute tubular necrosis 119, 278 acyclovir 99, 305 liver graft recipients 390, 391, 393 small bowel graft recipients 411 1-acylglycerol-3-phosphate O-acyltransferase 188 adefovir 135, 395 adenoma, hepatic 366–7, 374 glycogen storage disorders 215, 216 management 374 adenovirus infections 100 fulminant hepatic failure 112 neonatal 43–4, 109 adherence, treatment 5, 396 adolescence 12–14 cholelithiasis 339 definition 12–13 information requirements 14 moving towards independence 13 transition to adult care 14 treatment adherence 5 ADPKD see autosomal dominant polycystic kidney disease adrenal calcification 226 adrenoleukodystrophy, neonatal (NALD) 229 Adriamycin see doxorubicin adult care, transition to 3, 14 adverse drug reactions 148 see also drug-induced liver disease age acutely ill infants 74, 75 drug-induced liver toxicity and 149 liver transplantation and 394 AGPAT2 gene 188 AIDS see HIV infection Alagille’s syndrome 49–50 cardiac disease 49–50, 283 clinical features 49–50, Plate 6 diagnosis 50, Plate 6 liver transplantation 396 photosensitive skin lesions 302, Plate 57 renal disease 50, 287 alanine aminotransferase (ALT) 17, 18 albendazole 103, 427

albumin infusions 267, 278 plasma 17, 18 liver transplantation timing and 381 neonatal hepatitis syndrome 41 sclerosing cholangitis 147 alcoholic liver disease 183 aldolase B deficiency see hereditary fructose intolerance alfacalcidol (1,25-dihydroxy-vitamin D) 62, 62 alkaline phosphatase (ALP) 17, 18 biliary atresia 46 chronic hepatitis 128 cystic fibrosis 202 neonatal hepatitis syndrome 39 sclerosing cholangitis 147 Wilson’s disease 248 Alpers–Huttenlochler syndrome (Alper’s syndrome) 110, 230–1, 385 a1-antitrypsin 19, 51 PI variants 51–2, 199 serum 52 a1-antitrypsin deficiency 51–3, 288 aetiology and genetics 51–2 clinical features 52 diagnosis 19, 52, 213, Plate 4 liver transplantation 53, 379 management 52 non-alcoholic fatty liver disease 185, 186 prognosis 52–3, 264 a-fetoprotein (AFP), serum 19 congenital vascular anomalies 174, 176 fulminant hepatic failure 123 liver tumours 368, 371 tyrosinaemia type I 81, 82, 379 Alström/Bardet–Biedl-like disorders 187 Alström syndrome 185, 187 Amanita phalloides poisoning 113, 121 amino acids, serum 19, 265–6 d-aminolevulinic acid (d-ALA) dehydratase deficiency 234 aminotransferases 17, 18 anti-tuberculosis therapy and 426 biliary atresia 46 chronic hepatitis 128 cystic fibrosis 202 fulminant hepatic failure 111, 112 neonatal hepatitis syndrome 39 non-alcoholic fatty liver disease 186, 189 sclerosing cholangitis 147 ammonia hepatic encephalopathy and 274 plasma 18, 19 fulminant hepatic failure 112 therapeutic reduction 118 ammonium thiomolybdate (tetrathiomolybdate; TM) 251, 252, 253 amoebic liver abscess 103, 104

475

476

Index

amoxycillin dental procedures 318, 319, 319 hepatotoxicity 154 amphotericin 292, 293, 305, 306 post-liver transplant 390, 391 ampicillin 154 amylase, plasma 333, 334 amylo-1,6-glucosidase (debrancher enzyme) deficiency 215–16 anaemia haemolytic see haemolytic anaemia in hepatoblastoma 367 anaesthetic monitoring, liver transplant surgery 388 analgesia, post-transplant 390 anastomotic strictures, after choledochal cyst surgery 335 angiography 21, 25–7 liver trauma 352 magnetic resonance (MR) 25, 344 portal hypertension 344 see also hepatic angiography angiomatosis bacillary (BA) 174 systemic cystic 174 angiomatous naevi 302 angioplasty 26, 31 angiosarcomas, hepatic 174 antacids 390 antenatal diagnosis a1-antitrypsin deficiency 52 biliary atresia 325 CDG syndrome 227 choledochal cysts 333 glycogen storage disorders 214, 215, 216, 217 mitochondrial energy disorders 80, 228 neonatal haemochromatosis 79 Nieman–Pick disease 224, 225 organic acidaemias 88 polycystic kidney disease 166–7, 168 tyrosinaemia type I 82 anthropometry 8, 266 cystic fibrosis 203 antibiotics fulminant hepatic failure 115, 120 hepatic encephalopathy 276 hepatic infections 101, 102 hepatotoxic 153–4, 154 liver abscess 104 pretransplant therapy 385 prophylactic dental procedures 316, 318, 319, 319 post-liver transplant 390, 391 post-small bowel transplant 411 skin conditions 305 spontaneous bacterial peritonitis 278 typhoid 424 anticonvulsants fulminant hepatic failure 119 liver toxicity 155 antifungal agents fulminant hepatic failure 120–1 hepatotoxic 154 post-bone marrow transplant infections 292 prophylactic post-transplant 390, 391, 411 pretransplant 385 skin conditions 305, 306 antihistamines, pruritus in neonates 63 antihypertensive therapy 390 anti-interleukin-2 receptor monoclonal antibodies 391, 411 anti-La antibodies 59 anti-liver-kidney microsomal (LKM) antibodies 142, 143, 144, 286 antimalarial therapy 425 antimicrobials, liver toxicity 153–4, 154

anti-nuclear antibodies (ANA) 142, 143, 144, 148 antioxidants cystic fibrosis 204 neonatal haemochromatosis 78–9 non-alcoholic fatty liver disease 191 antiplatelet therapy 390, 392 antiretroviral drugs 290 anti-Ro antibodies 59 anti-smooth muscle antibodies (SMA) 142, 143, 144, 148 anti-soluble liver antigen (SLA) antibodies 142 antituberculous therapy 426, 426 hepatotoxicity 154–5, 426–7 antiviral agents hepatitis B 134–5 herpesvirus infections 99–100 liver toxicity 154 post-transplant lymphoproliferative disease 393, 414–15 prophylactic, post-transplant 390, 391, 411 skin conditions 305 aplastic anaemia 290–1 fulminant hepatic failure 121 parvovirus B19 infection 97 apolipoprotein B mutations 237 apolipoprotein E 185 apoptosis, hepatocyte 259 appearance, altered physical 5–6 apraxia, constructional 117 arachidonic acid metabolites, cystic fibrosis liver disease 200 arachnoid cysts 166, 167 arginine, in urea cycle disorders 84, 84 arginosuccinate lyase (ASA) deficiency 83–4 arginosuccinic acid synthetase deficiency (citrullaemia) 58, 83–4 aromatic amino acids (AAA), serum 265–6 ARPKD see autosomal recessive polycystic kidney disease Artemisinin derivatives 425 arterial catheterization complications 27 procedure 25–6 arterial spasm 27 arterial thrombosis 27 arteriohepatic dysplasia see Alagille’s syndrome arterioportal fistula (APF) 29–30, 174, 341, Plate 73 arteriovenous communications, hepatoportal 29–30, 341, Plate 73 arteriovenous fistulas, traumatic 354 arteriovenous malformations (AVMs) 29, 174, 177 arthritis autoimmune overlap syndromes 286–7 sarcoidosis 294–5 artificial hepatic support devices 121 Ascaris lumbricoides (ascariasis) 103, 340, 427 ascites 267–9 ADPKD 166, 167 chronic granulomatous disease 295 dietary management 9, 9 fetal/neonatal 76, 76–7 fulminant hepatic failure 119–20 pathophysiology 267–8 pretransplant management 385 refractory 269 spontaneous bacterial peritonitis 268, 278 treatment 268, 268–9 aspartate aminotransferase (AST) 17, 18 aspergillosis, cutaneous 306–7 asphyxia, neonatal 60 aspiration, fluid collections 29 aspirin hepatotoxicity 152 liver graft recipients 390, 392 Reye syndrome and 152–3, 231

asterixis 117 atenolol 273, 273, 390 athlete’s foot 306 atopic dermatitis, post-liver transplant 303–4, Plate 60 Atox1 copper chaperone 243, 244 ATP7A (Menkes’ protein) 243, 245 ATP7B (Wilson’s disease protein; WDP) 243–5, 244, 247 ATP7B gene 243, 245 mutation analysis 251 transfer 254 Augmentin 154 autoantibodies autoimmune hepatitis (AIH) 142, 142–3 drug-induced 143 sclerosing cholangitis 146 virus-induced 143 autoimmune disorders associated with autoimmune hepatitis 143–4 hepatitis C 141 autoimmune haemolytic anaemia 290 with giant-cell hepatitis 59–60, 385, 395 autoimmune hepatitis (AIH) 142–6 arthritis overlap syndromes 286–7 associated disorders 143–4 classification 142, 142–3 clinical features 110, 143 Coombs’-positive 290 de novo, in grafted livers 395 diagnosis 19, 144, 144 histology 129, 144, Plate 24 liver transplantation 146, 380 post-transplant recurrence 395 sclerosing cholangitis overlap syndrome 146, 148 severity 144 treatment 144–6 type 1 142, 143, 145–6, 380 type 2 142, 143, 145–6, 380 type 3 142 autoimmune liver disease 142–8 joint disease overlap syndromes 286–7 autoimmune polyglandular syndrome type 1 (APECED) 144, 289 autoimmune sclerosing cholangitis (ASC) 146, 285 see also sclerosing cholangitis autosomal dominant polycystic kidney disease (ADPKD) 163, 164–7 clinical features 166 diagnosis 166–7, 171 future research 173 management and outcome 167 molecular genetics/pathogenesis 164–5, 165 pathology 165–6 autosomal recessive polycystic kidney disease (ARPKD) 163, 167–8, 287 Caroli’s disease association 163, 167, 170, 287 diagnosis 168, 171, 172 future research 173 azathioprine autoimmune hepatitis 145 hepatotoxicity 156, 293 liver transplant recipients 390, 390 bacillary angiomatosis (BA) 174 bacterial cultures 17 bacterial infections after portoenterostomy 47, 329–30 hepatic 93, 101–2 neonatal jaundice 44 post-liver transplant 393 post-small bowel transplant 414–15 secondary 120–1, 278 skin 307–9 bacterial overgrowth, small bowel 58, 59, 404–5 bacterial toxins, cystic fibrosis liver disease 200

Index bacterial translocation 404, 411 band ligation, varices see endoscopic variceal ligation barbiturate coma, cerebral oedema 119 Bardet–Biedl syndrome 185, 186, 187 Bartonella infection 101–2 Basiliximab 391 B-cell proliferation, post-transplant 393 Beckwith–Wiedemann syndrome 363–4 behavioural feeding difficulties 11, 11 post-liver transplant 396 benzodiazepine antagonists 118, 276 benzodiazepines 118, 274 beta-blockers, portal hypertension 273, 273, 350 b-glucosidase deficiency see Gaucher disease betaine 191 bicycle injuries 351 bifunctional protein deficiency 230 bile diversion, neonatal hepatitis syndrome 62 impaired enterohepatic circulation 339 leaks liver trauma 354 post transplant 32, 392 bile acids cystic fibrosis liver disease 200 synthesis 54 synthesis disorders 213 primary 53, 53–4 Zellweger syndrome 56–7 bile duct(s) carcinoma 334, 337 cystic fibrosis 199–200 liver graft surgery 330 papillomas 337 proliferation, neonatal hepatitis syndrome 41 spontaneous perforation 48, 335–6, Plate 71 surgical disorders 324–40 see also common bile duct; intrahepatic bile ducts bile duct paucity 41, 49–51 cystic fibrosis 53 graft-vs.-host disease 51, 291, Plate 52 isolated non-syndromic 51 non-syndromic 51, 51 syndromic see Alagille’s syndrome bile duct strictures benign 336 cystic fibrosis 201–2, 205 isolated/idiopathic 336, Plate 72 post-liver transplant 31–2, 392–3, 394, Plate 83 sclerosing cholangitis 148 bile duct tumours 336–7, 337 benign 337 malignant 336–7 bile salt export pump (BSEP) 55 biliary atresia (extrahepatic biliary atresia; EHBA) 324–32 aetiology 42, 324–6 cardiac defects 283, 324, 325 classification 326, 326–7 clinical features 46, 327 complications and outcome 47 developing world 421, 422, 427 diagnosis 46, 327, Plate 2, Plate 3, Plate 4, Plate 68 incidence 324 liver transplantation 47, 331–2, 378, 435 management 46–7, 327–32, 329 neonatal hepatitis syndrome 45–7 pathogenesis 326–7 portal hypertension 47, 330, 343 quality of life 331 role of screening 327 surgery see Kasai portoenterostomy vs. Alagille’s syndrome 50

vs. a1-antitrypsin deficiency 52 vs. cytomegalovirus infection 42 biliary atresia splenic malformation (BASM; polysplenia) syndrome 46, 47, 324–5, 325 biliary cirrhosis 47, 263, Plate 47 biliary disease, cystic fibrosis 201–2, 205 biliary fibrosis, focal, cystic fibrosis 203, Plate 39 biliary hypoplasia, extrahepatic 49 biliary obstruction inspissated bile syndrome 336 malignant disease 293 post transplant 31–2, 392–3, Plate 83 spontaneous perforation of bile duct and 335, 336 see also jaundice, obstructive biliary peritonitis after percutaneous transhepatic cholangiography 28 choledochal cyst rupture 334 spontaneous perforation of bile ducts 335 biliary sludge 338 cardiac disease 282, 283, 284, Plate 50 gastrointestinal disease 285 management 339–40 TPN liver disease 339, 404 see also cholelithiasis biliary tree embryology 162–3, 325 invasive cholangiographic techniques 28–9 bilirubin conjugated 17, 18 free, factors affecting 35 inherited disorders of conjugation 63 neurotoxicity (kernicterus) 35–6, 37, 382 serum 301 chronic hepatitis 128 Crigler–Najjar syndrome 37 fulminant hepatic failure 111 Gilbert’s syndrome 38 liver transplantation timing and 381 physiological jaundice 36 sclerosing cholangitis 147 small bowel transplant and 404, 406 see also hyperbilirubinaemia bilirubin uridine diphosphate glucuronosyl transferase (UDPGT) activity in neonates 36 gene (B-UGT) defects 37, 38 biochemical liver function tests see liver function tests biopsy liver see liver biopsy muscle 228, Plate 12 renal 172 skin 23, 310–11 biotin therapy 88 birth trauma 351 Bithionol 103 biting 117–18 black pigment gallstones 338 Blackwater fever 425 bleeding see haemorrhage/bleeding blood cultures 17 blood transfusion, variceal bleeding 271, 272 body mass index (BMI) 185, 187 boils 308 bone marrow aspiration 23 bone marrow failure fulminant hepatic failure 121 non A-E hepatitis 97 bone marrow transplantation (BMT) CD40 ligand deficiency 293, 380 cholelithiasis 338 familial haemophagocytic lymphohistiocytosis 83, 291 liver dysfunction after 291–2

477

Nieman–Pick disease 224, 225 sickle-cell disease 290 bowel decontamination, selective 407 brain damage bilirubin-induced (kernicterus) 35–6, 37, 382 contraindicating liver transplantation 122, 381–2 see also neurological disease brain natriuretic peptide 284 brainstem death 387 branched chain amino acids (BCAA) catabolism 233 disorders of catabolism 232–3, 234 serum 265–6 supplementation 267, 276 brancher enzyme (a1,4-glycan-6glycosyltransferase) deficiency 216–17, Plate 41 breast feeding in cholestasis 10 in hepatitis C 137 in neonatal liver disease 61 breast-milk jaundice 35, 36 British anti-Lewisite (BAL) 252 bromosulphophthalein sodium retention 63 brown pigment gallstones 338 brucellosis 102 bruising spontaneous 262 in trauma 351 BSCL2 gene 188 Budd–Chiari syndrome 343–4, Plate 74 in ADPKD 166 diagnosis 20, 268 investigations 344 management 30, 350 neonatal hepatitis syndrome 60 Byler disease (progressive familial intrahepatic cholestasis; PFIC) 54–6 C27-hydroxylase deficiency 53, 54 caeruloplasmin 244, 244, 245–6 deficiency (acaeruloplasminaemia) 245–6, 246, 250 plasma 246, 246 in Wilson’s disease 246, 246, 250 cancer see malignancy candidiasis 306 cutaneous 306 hepatobiliary 292, 293, Plate 54 oral 306 caput medusae 342 carbamazepine, liver toxicity 155, Plate 27 carbenicillin 305 carbohydrate deficient glycoprotein (CDG) syndrome 213, 227–8 carbohydrate metabolism chronic liver disease 266 inherited disorders 212–20 carboplatin 370, 371 carbymyl phosphate synthetase (CPS) deficiency 83–4 carcinoma, bile duct 334, 337 cardiac disease 282–4, Plate 50 ADPKD 166 Alagille’s syndrome 49–50, 283 hepatic congestion 283 hypoxia 282 investigations 284, 284 low cardiac output 283 management 284, 284 cardiac dysrhythmias, fulminant hepatic failure 120 cardiac failure, congestive see heart failure, congestive cardiac function, pretransplant assessment 384, 406 cardiac–hepatic syndromes 283, 283–4

478

Index

cardiac output low 283 in portal hypertension 284 cardiac transplantation 338, 379 cardiac valve replacement 338 cardiomyopathy 283–4, 384 cardiovascular complications, fulminant hepatic failure 120 carnitine deficiency, cystic fibrosis 53 metabolism 85 supplements fatty acid oxidation defects 85, 86 mitochondrial DNA depletion syndrome 80 organic acidaemias 87 valproic acid therapy and 155 carnitine palmitoyl transferase I deficiency 85–6 Caroli’s disease 47–8, 163, 170 ARPKD association 163, 167, 170, 287 diagnosis 170, 171, Plate 32 Caroli’s syndrome 48, 170 carotenaemia 302 cataracts, neonatal 77 cat-eye syndrome 45 cathartics, hepatic encephalopathy 118 catheter angiography see hepatic angiography caudate lobe hypertrophy 344, Plate 74 CCS copper chaperone 243, 244 CD40 ligand deficiency 293, 380, Plate 56 CDG (carbohydrate deficient glycoprotein) syndrome 213, 227–8 cellulitis 308 CELTIC group 365 central nervous system (CNS) monitoring 115–16 central venous access 31 central venous catheterization, fulminant hepatic failure 114 central venous lines (CVLs), tunnelled 31 cephalosporins 154, 278, 424 cerebral aneurysms, ADPKD 166 cerebral oedema fulminant hepatic failure 112, 118–19, 381, Plate 22 management 118–19 Reye syndrome 232 cerebrotendinous xanthomatosis 53, 54 chemotherapy benign vascular tumours 373 hepatotoxicity 293, Plate 28 liver transplantation and 372 malignant liver tumours 369–71, 370, 372 non-alcoholic fatty liver disease after 187 post-transplant lymphoproliferative disease 393 cherry red macular spot 224 chest X-rays 20, 369 chickenpox (varicella) 98 immunocompromised patients 305 neonatal 42 child abuse, physical 351 Children’s Liver Disease Foundation 2 chimerism, small bowel transplantation 411, 412, 415 chloral hydrate 59 chlorothiazide 268–9 cholangiocarcinoma cystic fibrosis 198 postportoenterostomy 331 cholangiography 28–9 biliary atresia 326, 327, Plate 68 sclerosing cholangitis 147, Plate 26 cholangitis ascending bacterial after choledochal cyst surgery 335 after portoenterostomy 47, 329–30

choledochal cysts 334 pretransplant management 385 congenital hepatic fibrosis 169 cryptosporidial 293, 294, Plate 56 ‘destructive’ 163, 163 sclerosing see sclerosing cholangitis cholecystectomy 340 cholecystitis, acalculous 340 cholecystogram, percutaneous 28–9 cholecystokinin 285 therapy 336, 339 TPN liver disease 404 cholecystostomy 340 choledochal cysts 47, 332–5 aetiology and pathogenesis 333 classification 332, 332 clinical features 47, 333 complications 333–4 investigations 47, 333–4, Plate 2, Plate 3, Plate 70 malignant change 334, 337 pathology 333 results and complications 335 rupture 334 surgical management 334–5 treatment and outcome 47 type 5 (Caroli disease) 47–8 choledocholithiasis 48, 340 cholelithiasis (gallstones) 337–40 aetiological risk factors 338, 338–9 choledochal cysts 334 clinical features 339 cystic fibrosis 201, 205, 338 diabetes mellitus 288 diagnosis 339 drug-induced 59 epidemiology 337 management 339–40 neonatal hepatitis syndrome 48 pathogenesis 338 sickle-cell disease 289, 338 thalassaemia 290, 338 TPN liver disease 59, 404 cholestasis Alagille’s syndrome 49, 50 cardiac disease 284, 284 cholelithiasis 338 clinical presentation 261 cystic fibrosis 199–200, 201 drug-induced 150 hepatitis A 95 liver transplantation 378 metabolic liver disease 211, 212, 213 neonatal see neonatal cholestasis nutritional support 9–11, 12 pathogenesis 259 post-Kasai 330 progressive familial intrahepatic (PFIC) 54–6 prolonged, copper overload 247 pruritus 301 TPN-associated see under parenteral nutrition cholesterol, serum 19 biliary atresia 46 progressive familial intrahepatic cholestasis 55 cholesterol ester storage disease (CESD) 57, 221, 226 cholesterol stones mixed 338 pure 338 cholestyramine, neonatal liver disease 62 cholic acid 53, 54 chondrodysplasia punctata, rhizomelic (RCDP) 229 chromosomal analysis 23 chromosomal disorders, neonatal hepatitis syndrome 45 chronic granulomatous disease 294, 295

chronic hepatitis 127–61 acute onset 128 asymptomatic 127 autoimmune 142–8 classification 127, 128 clinical features 127–8 definition 127 differential diagnosis 128, 128 drug-induced 150 see also drug-induced liver disease histology 129, Plate 24 insidious onset 127–8 investigations 128–9, 129 management 129–30, 380 pathogenesis 127 recurrence in grafted livers 395, Plate 85 viral 130–42 Wilson’s disease 248 chronic intestinal pseudo-obstruction (CIP) 338, 404, 416 chronic liver disease 259–81 causes 259–60, 261 clinical presentation 261–2, Plate 46 compensated 261 complications and their management 261, 264–79, 381 decompensated 261–2 developing world 422, 422–3 diagnostic aspects 260–1 diagnostic dilemmas 263 hepatitis A infection 95 investigations 262, 262 liver pathology 262–3 liver transplantation 263–4, 350, 378–81, 379 developing world 435 timing 380–1 mechanisms 259–60, 260 neuropsychological impairment 5 nutritional support 8–9, 264–7 portal hypertension 269–74, 342, 427–8 prognosis 263–4, 264 skin manifestations 261, 301, 302, Plate 46 see also cirrhosis cidofovir 99–100 cimetidine, hepatotoxicity 156 ciprofloxacin 411, 424 cirrhosis a1-antitrypsin deficiency 53 autoimmune hepatitis 144 biliary 47, 263, Plate 47 cardiomyopathy 284 causes 259–60, 261 cholelithiasis 338 chronic hepatitis 128, 129, Plate 24 complications 261 copper-related see copper-related cirrhosis cystic fibrosis 203, 205 hepatic venous outflow (cardiac) 263 hepatitis B 130, 131, 430 hepatocellular carcinoma risk 260, 364–5 histological classification 263 Indian childhood see Indian childhood cirrhosis macronodular 263 micronodular 262–3 mixed pattern 263 morphological classification 262–3 non-alcoholic fatty liver disease (NAFLD) 186, 191 North American Indian familial 56 pathogenesis 259, 260 portal hypertension 343 post-necrotic 111, 123, 263 pre-existing, fulminant hepatic failure 111 renal dysfunction 287 see also chronic liver disease cisplatin 370, 370, 371

Index citrullinaemia (arginosuccinic acid synthetase deficiency) 58, 83–4 clindamycin 318, 319 clonidine 273 clubbing 201, 261, 277 CMV see cytomegalovirus coagulation tests 17, 18 coagulopathy a1-antitrypsin deficiency 52 biliary atresia 327 chronic liver disease 276, 276 fulminant hepatic failure 107, 112, 116–17 glucose-6-phosphatase deficiency 214 liver transplant surgery 388 management 276 systemic sepsis 295 coenzyme Q 80, 228–9 cognitive impairment, Wilson’s disease 248 cold sores 304 collateral circulation, portosystemic 270, 270, 342 colon, with small bowel grafts 410, 416 coma barbiturate 119 stage IV encephalopathy 117, 118 urea cycle disorders 84 common bile duct spontaneous perforation 48 stones 48, 340 community (local health) team 2, 3 competence, to give consent 3–4 compliance, treatment 5, 396 computed tomography (CT) 20 in ADPKD 166 Caroli’s disease 170 fulminant hepatic failure 115 helical/spiral 20 liver abscess 104, Plate 20 liver trauma 352, Plate 75 liver tumours 368, 371, Plate 76 portal hypertension 344 vascular anomalies 175 condyloma acuminatum 304 congenital and structural abnormalities of liver 162–82 congenital heart disease 283, 324, 325, 384 congenital hepatic fibrosis (CHF) 163, 168–70 associations 168–9 with Caroli’s syndrome 48, 170 clinical features 169 diagnosis 169, 171, 172 management 169 pathology 168, Plate 31 portal hypertension 343 prognosis and outcome 170 vs. cirrhosis 263 congenital infections 40, 41–4 conjugation 148 consent to treatment 3–4 constructional apraxia 117 continuing care 3 convulsions fulminant hepatic failure 119 hypoxic/ischaemic liver damage 155 coping styles, pretransplant assessment 6 copper 243 chaperones 243, 244 deficiency 243 deposition, congenital hepatic fibrosis 169 free serum 246, 250 isotopic 250 liver 246, 249 metabolism 243–6, 244 disorders 246–58 post-Kasai 330 normal biochemical values 246, 246 overload states 247 serum 246, 250

toxicosis idiopathic 423 infantile 247, 254–6 urine 246, 250 copper-chaperone for superoxide dismutase (CCS) 243, 244 copper-related cirrhosis in adults 256 in childhood, non-Wilsonian 254–6 Indian childhood cirrhosis see Indian childhood cirrhosis in older children 256 sporadic 247, 254, 256 Tyrolean childhood cirrhosis 254, 255, 255–6 without excess copper ingestion 256 copper transporter Ctr1 243, 244 coproporphyria, hereditary 234 coproporphyrins, urinary 63 cornstarch, uncooked 214, 218 coronary artery disease, premature 383 coronary bypass surgery 282 corticosteroids (steroids) autoimmune hepatitis 145 cerebral oedema 119 cutaneous side-effects 304, Plate 61 delayed tooth eruption 316 graft-vs.-host disease 292 growth suppression 396 haemangiomas 176, 373 intestinal graft rejection 414 liver graft rejection 392 liver transplant recipients 390, 390–1 priming, interferon therapy 134 side effects 393, 393 small bowel transplantation 411 topical, eczema 303 cortisol, plasma 19 corynebacterial skin infections 308 cotrimoxazole dermatological conditions 305 hepatotoxicity 154 post-transplant 390, 391, 411 Cow+Gate (C+G) 13 Cox17p 243, 244 Coxiella burnetii 109 Coxsackie virus infections 100 neonatal 43–4, 109 creatinine, serum, fulminant hepatic failure 112 Creutzfeldt–Jakob disease (CJD) 246 Crigler–Najjar syndromes 37–8 liver transplantation 37, 382, 389 Crohn’s disease hepatic involvement 285–6, 294, 338–9 small bowel transplantation 410 cryoglobulin 276 cryptococcosis, cutaneous 307 cryptosporidial cholangitis 293, 294, Plate 56 CT see computed tomography Ctr1 copper transporter 243, 244 cuproenzymes 244 cutaneous T-cell lymphoma 309, Plate 65 cyanoacrylate 346 cyanosis 277, 288 cyclophosphamide 370, 411 cyclosporin(e) 393, 393 autoimmune hepatitis 145 cardiotoxicity 283–4 cutaneous side-effects 303, 304, Plate 59 gingival overgrowth see gingival overgrowth graft-vs.-host disease 292 hepatotoxicity 156 liver transplant recipients 390, 390–1 nephrotoxicity 395 neuropsychological effects 5 cystenterostomy 334 cystic disease of liver see fibropolycystic disease, congenital

479

cystic fibrosis (CF) cholelithiasis 201, 205, 338 genetics 197 hepatobiliary disease 197–210, 285 clinical features 201–2, Plate 37 definition 198 diagnosis 19, 201, 202–3 epidemiology 197–8, 198 future research prospects 206 management 203–5 pathogenesis 198–201, 199 pathology 203 prevention 203–4 prognosis and outcome 205–6 steatosis 189, 200, 203, Plate 39 inspissated bile syndrome 48, 203 liver transplantation 205, 379 neonatal hepatitis syndrome 53, 203 cystic fibrosis transmembrane conductance regulator (CFTR) 197, 199 cystic haemangiomas 173 cysts ADPKD 165–6 ARPKD 167 Caroli’s disease 170 choledochal see choledochal cysts congenital hepatic fibrosis 168 hydatid 102 multiple 164, Plate 30 post-enterostomy 330 secondary to infarction 171 solitary 164, Plate 33 traumatic 171 cytochrome c oxidase (Cox) 243, 244, 244 cytochrome P450 enzymes 148, 149 autoantibodies 143 cystic fibrosis 201 cytokeratins, vascular anomalies 176 cytomegalovirus (CMV) infection 98 congenital/early postnatal 41–2, 51 diagnosis 98 drug therapy 99–100 fulminant hepatic failure 109 histology 98, Plate 18 post-bone marrow transplant 292 post-liver transplant 305, 393 post-small bowel transplant 414, Plate 89 pretransplant matching 384, 387, 408 prophylaxis, graft recipients 390, 391, 411 cytotoxic drugs 293 Daclizumab 391, 411 debrancher enzyme deficiency 215–16 decision making, involvement of child 3–4 defibrotide 292, 343 delta virus see hepatitis D virus dengue fever 424–5 dengue haemorrhagic fever (DHF) 100–1, 424–5 dengue shock syndrome (DSS) 424, 425 dental care 313, 315–19 liver disease, guidelines 315–16 liver transplant 317, 319 transplant recipients 316–18 guidelines 318–19 pretransplant 319, 385 dental caries 313–14 hypoplastic teeth 315 management guidelines 315 dental disease 313–15 prevention 314 dental enamel 313 hypoplasia 315, 316 dental pigmentation 314–15, 316, Plate 67 dentine 313 dermatological manifestations see skin manifestations/disorders dermatophytoses 305–6, Plate 63

480

Index

dermis 300 desferrioxamine 79 desmopressin 276 developing world 421–38 chronic liver disease 422, 422–3 infectious diseases 423–7 liver transplantation 432–6 donor issues 433–4 indications 435, 435 organization of programme 433 outcomes 436 pretransplant issues 434–5 neonatal liver disease 421–2, 422 portal hypertension 427–8 viral hepatitis 428–32 development, liver transplantation and 5, 381, 396 developmental assessment 4–5 pretransplant 6, 384 diabetes mellitus hepatic manifestations 288 type 1, non-alcoholic fatty liver disease 187 type 2 185–6 non-alcoholic fatty liver disease 183, 186, 187 dialysis pretransplant 385–6 in urea cycle disorders 84 diarrhoea 10, 55 diclofenac, hepatotoxicity 153 dietary management abetalipoproteinaemia 237 cystic fibrosis 204 developing world 423, 423 fatty acid oxidation defects 85, 86 galactosaemia 77 glycogen storage disorders 214, 216, 217, 218 hepatic encephalopathy 9, 12, 118, 275–6 hepatic enzyme deficiencies 84 hereditary fructose intolerance 219 mitochondrial energy defects 80 neonatal liver disease 62 non-alcoholic fatty liver disease 190–1 organic acidaemias 87, 88 tyrosinaemia type I 82 see also nutritional support dietary supplements see nutritional supplements diethylcarbamazine 103 24,25-dihydroxycholanoic cleavage enzyme deficiency 53, 54 dihydroxy cholestanoic acid (DHCA) 229, 230 dihydroxycholestanoic acidaemia 230 dimercaprol 252 dipyridamole 390, 392 discharge planning 2–3 disseminated intravascular coagulation (DIC) 116, 117 distal intestinal obstruction syndrome (DIOS) 201, 204, 205 diuretics ascites 268, 268–9 fulminant hepatic failure 114, 119 divalent metal transporter (DMT1) 243 DNA analysis 23 docosahexanoic acid (DHA) 230 donors cadaver intestinal grafts 407–8 cadaver livers 387 developing world 433–4 hepatitis B-positive 434 living related 7, 389 dopamine 114, 390 dopamine b-monoxygenase 244 Doppler ultrasound 20 hepatic vascular anomalies 175 pre-small bowel transplant 406 Down syndrome 45, 338

doxorubicin 293, 370, 370–1 drainage, fluid collections and abscesses 29 drowsiness 117 drug-induced liver disease (DILD) 148–56 autoimmune hepatitis 143 clinicopathological spectrum 149–50 developing world 435 diagnosis 113, 150–1 drugs implicated 151–6 fulminant hepatic failure 109, 109–10, 122 histology 110–11, 129, 151, Plate 27 mechanisms 148 natural history 150 neonatal hepatitis syndrome 59 pathogenesis 148–9 prevention 151 risk factors 149 treatment 151 vs. systemic sepsis 295 drugs interactions 149 metabolism by liver 148 self-administration 13 Dubin–Johnson syndrome 63 ductal plate development 162–3 malformation (DPM) 162–3, 163, 168, 170 duct paucity see bile duct paucity ductus venosus 340, 341 duodenal anomalies, congenital 338 duodenal resections 404 dysostosis multiplex 220 dyspnoea 277, 330 dystrophia myotonica 338 Ebola virus 101 Echinococcus granulosus (hydatid disease) 102 Echinococcus multilocularis (alveolar echinococcosis) 102 echovirus infections 100 neonatal 43–4, 109 ecthyma gangrenosum 308 ectopic varices 347 eczema, post-liver transplant 303–4, Plate 60 EEG see electroencephalography Ehlers–Danlos syndrome 174 eicosanoids, cystic fibrosis liver disease 200 electroencephalography (EEG) 23 fulminant hepatic failure 115, 381–2, Plate 21 hepatic encephalopathy 117, 117, 275 electrolytes chronic liver disease 267 fulminant hepatic failure 114, 119 supplements 10 electron transfer flavoprotein (ETF) 85, 86 electron transfer flavoprotein dehydrogenase (ETF-DH) 85, 86 electron transport chain defects see mitochondrial respiratory (electron transport) chain defects embolization, therapeutic 26 gastrointestinal bleeding 30–1 liver trauma 354 malignant liver tumours 373 vascular anomalies 29–30, 176, 177, 341, Plate 34 embryotoxon, posterior 49 emergencies, consent in 4 enamel see dental enamel encephalopathy, hepatic after shunt surgery 349 chronic liver disease 262, 274–6 clinical features 117–18, 274 clinical stages 117 diagnosis 23, 274–5 dietary management 9, 12, 118 fulminant hepatic failure (acute) 107, 111–12, 117–18

as guide to management 114, 115, 381 monitoring progress 115–16 prognosis and 122–3 infants 78, 107 management 118, 275–6 metabolic liver disease 211, 212, 213 pathogenesis 274, 275 precipitating factors 271–2, 274 endocrine development, liver transplant recipients 396 endocrine disorders 44–5, 288–9 endoscopic injection sclerotherapy (EIS) complications 346–7, 347 gastric varices 347 oesophageal varices 272, 273, 345–7, 346 pretransplant 385 prophylactic 350 endoscopic retrograde cholangiopancreatography (ERCP) 20, 28 biliary atresia 327 choledochal cyst 334, Plate 70 choledocholithiasis 340 sclerosing cholangitis 147, Plate 26 endoscopic sphincterotomy 335, 340 endoscopic ultrasound (EUS) 21 endoscopic variceal ligation (banding) 272, 273, 346, 347, 350 pretransplant 385 endoscopy, upper gastrointestinal 23 cystic fibrosis 202 portal hypertension 344 variceal bleeding 272, 345, 345–7 enemas, hepatic encephalopathy 118 energy deficits 265, 265 requirements, neonatal liver disease 61 supplements 8–9, 10, 11 enoylCoA hydratase/hydroxyacylCoA dehydrogenase deficiency 230 Entamoeba histolytica 109 see also amoebic liver abscess enteral feeding 266 inability to establish 404 liver transplant recipients 386 nasogastric tube 11 post-small bowel transplant 412 pre-small bowel transplant 406 TPN-associated cholestasis 405 enteric fever (Salmonella typhi) 102, 424 enteric viral sepsis, neonatal 43–4 enterohepatic circulation of bile, impaired 285, 339 enteroviruses 100 enzyme replacement therapy (ERT) 223, 224 enzymes, hepatic induction, drug-induced 149 inherited deficiencies 83–6 see also specific enzymes epidermal growth factor receptor (EGFR) 173 epidermis 300 Epstein–Barr virus (EBV), antigens 99 Epstein–Barr virus (EBV) infection 98–9 diagnosis 99 fulminant hepatic failure 98, 99, 109, 110, 112 histology 98–9 transplant recipients 292, 384, 393, 414–15 treatment 99 ERCP see endoscopic retrograde cholangiopancreatography erythema infectiosum 97 erythromycin 153–4, 305 erythrophagocytosis see haemophagocytic lymphohistiocytosis Escherichia coli skin infections 307–8 essential fatty acids (EFA) deficiency 302, Plate 58 supplements 9–10

Index ethambutol 426 ethnicity childhood obesity and 185 non-alcoholic fatty liver disease (NAFLD) and 186, 191 exanthem subitum 43, 99 exchange transfusion fulminant hepatic failure 116, 121 neonatal jaundice 36 exercise, non-alcoholic fatty liver disease 191 extracorporeal shock wave lithotripsy 340 extrahepatic biliary atresia (EHBA) see biliary atresia eye abnormalities Alagille’s syndrome 49 Wilson’s disease 248, 249, Plate 44 facies Alagille’s syndrome 49, Plate 6 Zellweger syndrome 56, 229, Plate 7 factor V levels 122 factor VII 116 factor VIII 116, 176 famciclovir, hepatitis B 135 familial adenomatous polyposis (FAP) 364 familial haemophagocytic lymphohistiocytosis (erythrophagocytosis) 122 familial hypercholesterolaemia 383 familial intrahepatic cholestasis, progressive (PFIC) 54–6 family (including parents) attitudes to liver transplantation 435 consent to treatment 3–4 impact on 1 live-related donors 7, 389, 434 post transplant functioning 7, 396 family support 1–16 fulminant hepatic failure 122 liver transplantation 386 neonatal liver disease 63 psychological 4–7 Fanconi–Bickel syndrome 217–18 Fanconi syndrome 249 Farber’s disease 221 Fasciola hepatica 103 fat emulsions 8–9, 10 nutritional deficits 265 fatty acid oxidation defects 84, 84–6, 235 clinical features 85 diagnosis 75, 85, 213 pathophysiology 84–5 treatment and prognosis 85 fatty acids b-oxidation 85 essential see essential fatty acids free, non-alcoholic fatty liver disease 184 metabolism 84–5 short-chain 274 very long-chain (VLCFA) 229, 230, 230 fatty liver see steatosis, hepatic feeding problems, behavioural see behavioural feeding difficulties feed intolerance 9 feed refusal 10, 11 feeds, supplementary see nutritional supplements femoral artery catheterization 21, 25–6 thrombosis 26 fetal ascites 76, 76–7 fibroblast growth factor, basic (bFGF) 176 fibrocystin 167 fibropolycystic disease, congenital 162–73 classification 163, 164 differential diagnosis 171–2, 172 embryology 162–3, 163 future research 173

management 172–3, 380 fibrosis, hepatic see hepatic fibrosis FIC1 gene 55 FK506 see tacrolimus FLJ14728 gene 56 flucloxacillin 154, 305 fluconazole 154, 305 flucytosine 292, 293, 305, 306 fluid collections, aspiration and drainage 29 fluid management cerebral oedema 118 chronic liver disease 267 fulminant hepatic failure 114 post-liver transplant 390, 390 post-small bowel transplant 411–12 variceal bleeding 272 fluid restriction 9, 9, 12, 268 fluid retention, chronic 284 flumazenil 118, 276 fluoride supplements 314 5-fluorouracil (5-FU) 370 focal biliary fibrosis, cystic fibrosis 203, Plate 39 focal nodular hyperplasia (FNH) 173, 366, 374, Plate 78 folinic acid 102 folliculitis 308 foscarnet 100 fresh frozen plasma (FFP) 114, 116, 276 fructose 218 intolerance see hereditary fructose intolerance fructose-1,6-bisphosphatase deficiency 219–20 frusemide ascites 268, 268 fulminant hepatic failure 114, 119 fucosidosis 221 fulminant hepatic failure (FHF) 107–26 aetiology 107–10 chemical biochemistry 111 clinical presentation 112 complications 116–21 definition 107 diagnosis 112, 113 differential diagnosis 112–13 EBV infection 98, 99, 109, 110, 112 hepatitis A 95, 108, 122, 428–9 hepatitis B 108–9, 110, 123, 131–2, 430 liver transplantation 121–2, 123, 381–2, 390 management 113–22, 114, 115 non A-G hepatitis 97, 109, 110, 122 outcome 123 pathogenesis 111–12 pathology 110–11 prognosis 122–3, 381 Wilson’s disease see under Wilson’s disease see also acute liver failure fumaryl acetoacetase (FAA) 80–1 fungal infections diagnosis 310 immunocompromised patients 293, Plate 54 post-bone marrow transplant 292 post-small bowel transplant 414 secondary, fulminant hepatic failure 120–1 skin 305–7 furunculosis 308 galactosaemia 77, 218 clinical presentation 44, 77 diagnosis 77, 213, Plate 9 fulminant hepatic failure 111 management and prognosis 77 neonatal screening 77 galacto-sialidosis 221 gall bladder micro, cystic fibrosis 201, Plate 38 neonatal hepatitis syndrome 41, Plate 2 ultrasound imaging 20 gallstones see cholelithiasis

481

g-aminobutyric acid (GABA) 274 gamma-glutamyl transpeptidase (GGT) 17, 18 amniotic fluid 325 biliary atresia 46 chronic hepatitis 128 cystic fibrosis 202 neonatal hepatitis syndrome 41 progressive familial intrahepatic cholestasis 55 sclerosing cholangitis 147 ganciclovir 100, 305, 393 prophylactic, post-transplant 411 Gardner syndrome 364 gastric inhibitory peptide (GIP) 404 gastric varices 347 gastrin 404 gastrointestinal bleeding congenital hepatic fibrosis 169 fulminant hepatic failure 117 interventional radiology 30–1 see also variceal bleeding gastrointestinal disease 284–6 gastro-oesophageal varices 270, Plate 48 see also oesophageal varices; variceal bleeding gastropathy, portal hypertensive 270 gastroschisis 403 gastroscopy 23 Gaucher cells 220, 223, Plate 43 Gaucher disease 220–3, 221, Plate 43 type 1 220–3 type 2 220, 223 type 3 220, 223 GBV-C 96 Generaid supplements 267 general anaesthesia dental procedures 314, 316 interventional radiology 26 gene therapy cystic fibrosis 205 Wilson’s disease 254 genetics copper intoxication syndromes 256 cystic fibrosis 197 drug-induced liver disease 149 hepatoblastoma 363–4 non-alcoholic fatty liver disease (NAFLD) 185 Wilson’s disease 245, 251 genetic tests 23 gentamicin 305 germ cell tumours, hepatic 366 GGT see gamma-glutamyl transpeptidase Gianotti–Crosti syndrome 302 giant-cell hepatitis autoimmune haemolytic anaemia with 59–60, 385, 395 hepatitis C 140 hepatocellular carcinoma and 364–5 neonatal 41, Plate 4 Gilbert’s syndrome 38 Gillick competence 3 gingival overgrowth 303, 316–18, 393, Plate 67 prevalence 317 prevention 318, 319, 385 glandular fever 98 glomerulonephritis, hepatitis B 132 glucocerebrosidase deficiency see Gaucher disease gluconeogenetic defects 75 glucose, blood 17, 18 fulminant hepatic failure 116 neonatal hepatitis syndrome 41 see also hypoglycaemia glucose-6-phosphatase deficiency 212–15 transporter, defects 215 glucose-6-phosphate dehydrogenase (G6PD) deficiency 425, 429

482

Index

glucose feeds, glucose-6-phosphatase deficiency 214 GLUT2 transporter deficiency 217–18 glutamate 274 glutamine, in TPN solutions 405 glutaric acidaemia type 2 86 glutathione 148, 149 glutathione S-transferase A1, serum 202 gluten-sensitive enteropathy 169 a1,4-glycan-6-glycosyltransferase (brancher enzyme) deficiency 216–17, Plate 41 glycogen 212 glycogen storage diseases (GSD) 212–18, 213 I 212–15, Plate 40 Ia 212–15 I non-a 215 III 215–16 IV 216–17, Plate 41 VI 217 IX 217 XI 217–18 liver transplantation 215, 216, 217, 379–80 glycoprotein storage disorders 221–2 glycosylation, congenital disorders of 227–8 glypressin 272, 273 GM1 gangliosidosis 221 graft rejection intestinal allografts 413–14, Plate 88 liver allografts acute 392, Plate 81 chronic 392, Plate 82 graft-vs.-host disease (GVHD) 291, 291–2 bile duct loss 51, 291, Plate 52 cutaneous 309 post-small bowel transplantation 411, 415 Gram-negative skin infections 307–8 Gram-positive skin infections 308 granular cell tumour, bile duct 337 granulocyte-colony stimulating factor (G-CSF) 215 granulocyte macrophage-colony stimulating factor (G-CSF) 215 granulomatous disorders, chronic 294, 294–5 granulomatous hepatitis, drug-induced 150 griseofulvin 305 growth liver transplant recipients 395–6 small bowel transplant recipients 416 growth hormone (GH) 266 deficiency 288–9 GVHD see graft-vs.-host disease H2 antagonists fulminant hepatic failure 115, 117 hepatotoxicity 156 see also ranitidine haemangioendotheliomas 366, 373–4 epithelioid (type II) 366, 367, 372, 373–4 infantile (type I) 173, 366, 373–4 haemangiomas 162, 173, 366, Plate 34 cavernous 173, 366 diagnosis 175–6 management 176–7 classification 173, 173–4 clinical features 174 cutaneous 174, Plate 34 cystic 173 diagnosis 175–6 giant cavernous 173, 176, 177 management 29–30, 176–7, 373–4 pathology 176 haematological disease 289–92 haematology, pretransplant 384 haematomas, hepatic 351, 352, Plate 75 haemochromatosis, neonatal (NNH) 78–9, 213, 382, Plate 11 haemodialysis, pretransplant 385–6

haemofiltration fulminant hepatic failure 116–17 liver transplant recipients 385–6 haemoglobin, post-liver transplant 390 haemolytic anaemia (and haemolysis) 290 autoimmune see autoimmune haemolytic anaemia cholelithiasis 338 immune related 290 sickle-cell disease 289 Wilson’s disease 249 haemolytic disease of newborn 37 haemolytic uraemic syndrome 338 haemophagocytic lymphohistiocytosis (erythrophagocytosis) 291 familial 82–3, 122, 291, Plate 16 haemophilia A 290 haemorrhage/bleeding after liver biopsy 22 after percutaneous transhepatic cholangiography 28 biliary atresia 46 fulminant hepatic failure 116–17 gastrointestinal see gastrointestinal bleeding liver trauma 352, 353–4 neonatal hepatitis syndrome 38 post-liver transplant 392 haemosiderosis, thalassaemia 290, Plate 51 hair, trichosporonosis 307 hair-like bile duct syndrome 49 halothane 109–10 hamartoma, mesenchymal see mesenchymal hamartoma HAV see hepatitis A virus HBV see hepatitis B virus HCV see hepatitis C virus HE1/NPC2 gene 225 heart disease see cardiac disease heart failure, congestive neonatal hepatitis syndrome 60 pretransplant management 385 vascular anomalies/tumours 174, 176, 177, 373 HELLP syndrome, maternal 85, 211 helminthic infections 102–3 hemihypertrophy 174, 363 heparin 390 hepatectomy cadaver donors 387 partial, living related donors 389 reduction/splitting 387–8, Plate 79 total, liver graft recipients 388 see also resection, liver hepatic angiography (catheter angiography) 25–7 catheterization procedure 25–6 complications 27 diagnostic 21, 25 indications 25 interventional procedures 26–7 liver tumours 368 vascular anomalies 176 see also angiography hepatic artery embolization 21, 26 liver trauma 354 malignant liver tumours 373 vascular anomalies 176 liver graft surgery 329, 330 surgical ligation 176 thrombosis (HAT), post-liver transplant 31, 392, 394, Plate 80 hepatic congestion, in cardiac disease 283, Plate 49 hepatic dysplasia, in tyrosinaemia type I 82 hepatic encephalopathy see encephalopathy, hepatic

hepatic fibrosis chronic hepatitis 129, Plate 24 congenital see congenital hepatic fibrosis drug-induced 150 hepatitis C 141 methotrexate toxicity 156 pathogenesis 259, 260 vs. cirrhosis 262 hepatic infections 92–104 non-viral 93, 101–4 viral see viral hepatitis hepaticoenterostomy 334, 335 hepatic steatosis see steatosis, hepatic hepatic support, fulminant hepatic failure 121 hepatic vasculature acquired disorders, interventional radiology 30 catheter angiography 25–7 congenital anomalies, interventional radiology 29–30 diagnostic imaging 25 hepatic vein obstruction Budd-Chiari syndrome 343–4, Plate 74 in cardiac disease 283 hepatitis acute 92–106 chronic 127–61 neonatal see neonatal hepatitis; neonatal hepatitis syndrome hepatitis A 93–6 clinical features 94, 428–9 developing world 428–9 diagnosis 94, 112 epidemiology 428 extrahepatic manifestations 95 fulminant hepatic failure 95, 108, 122, 428–9 management and outcome 94–5 neonatal 42 prevention 95–6, 429, 429 recurrent 95 risk factors 94 hepatitis A virus (HAV) 93–6, 428 hepatitis B virus combination vaccine 95, 429 IgM and IgG antibodies 94 transmission 94, 428 vaccines 95, 429 virology/pathophysiology 94 hepatitis B acute 131–2, 430 antenatal screening 132 chronic (carriers) 130–6, 430 clinical features 132 hepatitis D infection 136 hepatocellular carcinoma 130, 131, 278, 364, 430 histology 132, Plate 25 management 133, 380 treatment 133–6, 431 clinical presentation 131–2, 430 developing world 429–31 diagnosis 112, 129, 129, 131–2 epidemiology 429, 429–30 extrahepatic manifestations 132 fulminant hepatic failure 108–9, 110, 123, 131–2, 430 Gianotti–Crosti syndrome 302 immunization 132–3, 430–1, 431 at-risk infants 129, 132–3, 431 universal 133, 431, 431 liver transplantation 136, 380, 434 natural history 131, 430 neonatal 42, 43 positive organ donors 434 prevention 132–3, 430–1 recurrence post-liver transplant 395 serological markers 129, 131 vaccine 129, 431 hepatitis A vaccine combination 95, 429

Index hepatitis B immunoglobulin (HBIG) 129, 430, 431 hepatitis B virus (HBV) core antigen antibody (cAb) 129, 131 DNA 129, 130, 131 e antigen (eAg) 129, 131, 133, 430 precore mutant 430 surface antigen (sAg) 129, 131, 133 transmission 130, 430 horizontal 130, 430 perinatal 130, 430 prevention 132–3, 430–1 virology 130–1 X protein 131 hepatitis C 136–42 chronic 137–8, 140–1, 432 management 141, 380 treatment 141–2 clinical features 137–8, 432 developing world 432 epidemiology 136–7, 432 extrahepatic disorders 141 fulminant hepatic failure 109 histology 129, 140, 141, Plate 25 investigations and diagnosis 138, 138–40, 139 liver transplantation 395 natural history 130, 140–1 neonatal 43 pathogenesis 137 prevention 432 screening newborn infant 140 serology 138 hepatitis C virus (HCV) 137 antibodies (anti-HCV Ab) 137, 138, 139, 140 core antigen 139 genotypes 139–40 induced autoantibodies 143 RNA 138–9, 139, 432 newborn infant 140 persistence 140–1 transmission 136–7, 137, 432 hepatitis D virus (HDV; delta virus) infection 136 developing world 428, 432 diagnosis 129, 136 fulminant hepatic failure 109 hepatitis E 96 developing world 428, 432 fulminant hepatic failure 109 hepatitis E virus (HEV) 96 hepatitis F 96 hepatitis G 96, 432 hepatitis G virus (HGV) 96, 109 hepatoblastoma aetiology 363–4, 364 chemotherapy 369–71 clinical features 367, 367 diagnostic investigations 367–9, Plate 76, Plate 77 epidemiology 363, 364 histopathological classification 365, Plate 77 prognosis 373 treatment 372, 373 hepatocellular carcinoma (HCC) 278–9 aetiology 364, 364–5 cirrhosis 260, 364–5 clinical features 367, 367 diagnostic investigations 367–9, Plate 76 epidemiology 363, 364 fibrolamellar variant 365, 367, 368, 371 hepatitis B 130, 131, 278, 364, 430 non-alcoholic fatty liver disease (NAFLD) 191 pathology 365 postportoenterostomy 331 prognosis 373 treatment 371, 372–3 tyrosinaemia type I 81, 82, 278–9, Plate 15

hepatocellular degeneration, fulminant hepatic failure 110–11 hepatocytes apoptosis 259 copper handling 243, 244 ‘ground-glass’ 132 necrosis see necrosis, hepatic hepatocyte transplantation acutely ill neonates 88 fulminant hepatic failure 121 Wilson’s disease 254 hepatolenticular degeneration see Wilson’s disease hepatomegaly a1-antitrypsin deficiency 52 biliary atresia 46 cystic fibrosis liver disease 201 diabetes mellitus 288 fibropolycystic disease 171 inborn errors of metabolism 211 malaria 425 metabolic investigations 213 sickle-cell disease 289 Wilson’s disease 248 hepatoportal sclerosis 343, 427, 428 hepatopulmonary syndrome 276–7, 288 liver transplantation and 384 post-enterostomy 330–1 hepatorenal syndrome 119, 277–8, 287–8 liver transplantation 278 type 1 277–8, 288 type 2 278, 288 hepatosplenomegaly inborn errors of metabolism 211 lysosomal storage disorders 220, 221–2 metabolic investigations 212, 213 Niemann–Pick disease 224, 225 see also hepatomegaly; splenomegaly hepatotoxicity direct 148 TPN components 404 see also drug-induced liver disease; toxinrelated hepatic injury hepatotropic viruses 92, 93, 93 hereditary fructose intolerance (HFI) 218–19 diagnosis 213, 219, Plate 42 fulminant hepatic failure 111 hereditary haemorrhagic telangiectasia 174 hereditary spherocytosis 290, 338, 340 hernias, in ADPKD 166 herpes simplex virus (HSV) types 1 and 2 acute hepatitis 98 autoimmune hepatitis and 143 fulminant hepatic failure 109 immunocompromised patients 304–5 neonatal infection 41, 42, 109 treatment 99 herpesviruses 97–100 fulminant hepatic failure 109 treatment of infections 99–100 see also specific viruses HFE gene 185 Hickman lines 31 Hirschsprung’s disease, small bowel transplantation 403, 406, 416 hirsutism, cyclosporin-induced 303, 393, Plate 59 histiocytosis familial haemophagocytic lymphohistiocytosis 82–3, Plate 16 Langerhans cell 60 histopathology 21–2 histoplasmosis, cutaneous 307 HIV infection 294 congenital 43 haemophilia A 290 liver transplantation 385 maternal, coexisting hepatitis C 137

483

HLA haplotypes, autoimmune hepatitis 142 Hodgkin’s disease 293 HSV see herpes simplex virus human chorionic gonadotrophin (b-HCG) 367, 368 human herpesvirus 6 (HHV-6) 43, 99 human immunodeficiency virus infection see HIV infection human papillomavirus (HPV) infections 304, Plate 62 human parvovirus B19 see parvovirus B19 infection Hunter syndrome 222 Hurler syndrome 222 hyaluronic acid, serum 202 hydatid disease 102 hydrops fetalis (fetal ascites) 76–7 3-hydroxy 3 methyl glutaric aciduria 234 3b-hydroxy-D5-C27-steroid dehydrogenase/isomerase deficiency 53, 54 3-hydroxyisobutyric aciduria 234 11b-hydroxysteroid dehydrogenase 1 gene 185 25-hydroxy vitamin D 266 hyperammonaemia emergency management 83–4, 84 hepatic encephalopathy and 274 organic acidaemias 87 urea cycle disorders 83 hyperamylasaemia 333, 334 hyperbilirubinaemia conjugated benign 63 biliary atresia 46, 327 neonatal 35, 38, 39 recurrent, neonatal sclerosing cholangitis 48 unconjugated breast-milk jaundice 35, 36 inherited disorders 37–8 neonatal 35–8 physiological 35, 36 systemic disease 37 see also jaundice hypercholesterolaemia, familial 383 hyperglycinaemia 87 hyperinsulinaemia non-alcoholic fatty liver disease 184, 184–5, 188 obesity 287 hyperkalaemia, fulminant hepatic failure 119 hyperlacticacidaemia 214 hyperlipidaemia glycogen storage diseases 214, 216 post-liver transplant 395 hypernatraemia, fulminant hepatic failure 119 hyperoxaluria 405 hyperparathyroidism, secondary 266 hyperpigmentation 302 hypertension in ARPKD 168 post-liver transplant 284, 395 hypertrichosis, cyclosporin-induced 303, 393, Plate 59 hypertriglyceridaemia, non-alcoholic fatty liver disease (NAFLD) 184, 186 hyperuricaemia, glucose-6-phosphatase deficiency 214 hyperventilation, fulminant hepatic failure 120 hypobetalipoproteinaemia 237 hypoglycaemia 17 dietary management 9 fructose-1,6-bisphosphatase deficiency 219–20 fulminant hepatic failure 112, 116 glycogen storage diseases 212, 214, 216, 217, 218 hereditary fructose intolerance 218

484

Index

infantile hypoketotic 85 neonatal hepatitis syndrome 38, 41 hypokalaemia, fulminant hepatic failure 119 hyponatraemia, fulminant hepatic failure 119 hypoparathyroidism 289 hypopigmentation 302 hypopituitarism 288–9 investigations 75 neonatal hepatitis syndrome 44–5, Plate 5 hypotension, fulminant hepatic failure 120 hypothalamic surgery, non-alcoholic fatty liver disease after 187, Plate 35 hypothyroidism 289 congenital 37, 44 infantile hepatic haemangiomas 176 non-alcoholic fatty liver disease (NAFLD) 186 hypovascular syndrome 384 hypoxaemia 277 hypoxic liver injury, in cardiac disease 282 ibuprofen, hepatotoxicity 153 ICC see Indian childhood cirrhosis I-cell disease 221 icterus see jaundice IgA deficiency, selective 338 ileal resection/disease 285, 338–9, 403 ileostomy 410 imipenem 154 immune deficits chronic liver disease 278 see also immunocompromised patients immune modulatory therapy, hepatitis B 134 immune response hepatitis B 131 hepatitis C 137 immunization, pretransplant 385 immunocompromised patients 293–4, Plate 54 cutaneous lesions 304–10 cytomegalovirus (CMV) infection 98, 305 Epstein–Barr virus infection 98 hepatitis B 136 malignant disease 293 skin defences 303 immunodeficiency 293–4 inherited (primary) 293, 380, Plate 55 immunoglobulin, hepatitis A immunization 95–6, 429 immunosuppressive therapy adverse effects 393, 393, 395 autoimmune hepatitis 145 cutaneous side-effects 303–4 developing world 436 graft-vs.-host disease 292 hepatotoxicity 156, 287 inflammatory bowel disease 285 intestinal graft rejection 414 liver graft rejection 392 liver transplant recipients 390, 390–1 non-compliance 396 out-patient monitoring 397 small bowel transplantation 402, 411 impetigo 308 inborn errors of metabolism (IEM) fatty acid oxidation defects 84 fulminant hepatic failure 108, 110 hepatocyte transplantation 88 investigations 75, 212, 213 liver transplantation 379, 382–3 mutation detection 88 presenting in infancy/older child 211–42 presenting in neonates 83–8 screening 88 severe extrahepatic disease 382 vs. systemic sepsis 295 see also metabolic liver disease; specific disorders

inclusion bodies, cytomegalovirus (CMV) 98, Plate 18 independence, moving towards 13 Indian childhood cirrhosis (ICC) 254–5, 423 aetiology 254, 256, 423 prevalence 255 Indian childhood cirrhosis (ICC)-like disorders 255–6, 423 indomethacin, hepatotoxicity 153 infant feeding, copper-related childhood cirrhosis and 254, 255–6 infant formula milks cholestatic liver disease 9–10, 11, 61 high-energy 8, 11 lactose-free 62 manufacturers 13 methods of concentrating 8–9, 9 infantile copper toxicosis 247, 254–6 infantile polycystic disease see autosomal recessive polycystic kidney disease infants acutely ill see acutely ill infants gallstones 339 hepatic encephalopathy 78, 107 see also neonates infarction, cysts secondary to 171 infections acute hepatitis see acute infective hepatitis biliary atresia and 325 causing fulminant hepatic failure 107–9, 108 congenital/early postnatal 40, 41–4, 76 immune deficiencies 293, 294, Plate 55 immunocompromised patients 293, Plate 54 liver dysfunction 295 post-bone marrow transplant 292 post-small bowel transplant 411, 414–15 pre-liver transplant 434–5 secondary to fulminant hepatic failure 120–1 skin, post-liver transplant 304–9, 305 see also bacterial infections; fungal infections; sepsis; specific infections infectious diseases, developing world 423–7 infectious mononucleosis (IM) 98–9 sporadic fatal (SFIM) 98, 99 inferior vena cava (IVC) 341 inferior vena cavography 344 inflammatory bowel disease (IBD) 285–6 differential diagnosis 286 glycogen storage disease type I non-a 215 management 285–6 sclerosing cholangitis 146, 146, 285 inflammatory pseudotumors of bile duct 337 influenza-like illness, Reye syndrome and 231 information adolescents and young adults 14 provision 2 sharing, process 4 information leaflets 2 inherited liver disorders, neonatal jaundice 37–8 inspissated bile syndrome (IBS) 48, 336 cardiac disease 284 cystic fibrosis 48, 203 diagnosis and treatment 336 insulin-like growth factor-1 (IGF-1) deficiency 266 insulin resistance 287 drug treatment 191 measurement 189 non-alcoholic fatty liver disease (NAFLD) 184, 187–8 intellectual assessment 4–5 intensive care unit fulminant hepatic failure 114 post-transplant care 390 intensivists, developing world 433 intercellular adhesion molecule (ICAM) 326

interferon-a (IFN-a) adverse effects 134 developing world 431 haemangiomas 176 hepatitis B 134 hepatitis C 142 hepatitis D 136 lamivudine combination therapy 135 pegylated (PEG) 135, 142 ribavirin combination therapy 142 interferon-gamma, chronic granulomatous disease 295 interleukin-2 receptor monoclonal antibodies 391, 411 intermediary metabolism, disorders of 232–6 International Autoimmune Hepatitis Group (IAHG) 144 International Society of Paediatric Oncology (SIOP) chemotherapy trials (SIOPEL) 370, 370, 372, 373 tumour staging system 369, 369 intertrigo 306 interventional radiology 25–34 liver trauma 354 post-liver transplant complications 31–2, 392–3, Plate 83, Plate 84 see also embolization, therapeutic intestinal assessment, for small bowel transplantation 405, 405–6 intestinal atresias 403, 404 intestinal failure 286 causes 403, 403–4 transplant options 407 intestinal lymphangiectasia 169 intestinal obstruction syndrome, distal (DIOS) 201, 204, 205 intestinal pseudo-obstruction, chronic (CIP) 338, 404, 416 intestinal transplantation see small bowel transplantation intestinal tumours 404 intra-arterial line, fulminant hepatic failure 114 intracranial aneurysms, ADPKD 166, 167 intracranial haemorrhage, fulminant hepatic failure 116 intracranial pressure (ICP) monitoring 115–16, 119 raised, management 118–19 intrahepatic bile ducts (IHBDs) classification of diseases 163, 164 cysts communicating 163 congenital hepatic fibrosis 168 post-enterostomy 330 dilatation 162, 163 ARPKD 167, 168 Caroli’s disease 170 embryology 162–3 involution/destructive cholangitis 163, 163 intrapulmonary arteriovenous shunting 276–7, 288, 330–1 intravenous (i.v.) drug users 136, 137 invasive diagnostic imaging 25–34 investigations 17–24, 19 iron deficiency 266 overload, thalassaemia 289 iron storage disease, neonatal 78–9 isoniazid, toxicity 109, 154, 426 isosorbide dinitrate 27 isovaleric acidaemia (IVA) 88, 232–3, 234 itraconazole 154 Ivemark’s familial dysplasia 169 JAG1 gene 49 jaundice 301 ADPKD 166

Index cardiac disease 282, 283 chronic liver disease 262, Plate 46 fulminant hepatic failure 111, 112 malaria 425 neonatal see neonatal jaundice neonatal sclerosing cholangitis 48 obstructive bile duct tumours 336 choledochal cysts 333, 334 cholelithiasis 339, 340 see also biliary obstruction TPN-associated cholestasis 404 typhoid 424 see also hyperbilirubinaemia jejunal resections 403, 404 Jeune syndrome 168–9 joint disease, autoimmune 286–7 juvenile chronic arthritis (JCA) 286–7 Kasabach–Merrit syndrome 174, 177, 373 Kasai portoenterostomy 46–7, 324, 327–32 complications 47, 328–31 developing world 422 liver transplantation after 388 postoperative care 328, 329 preoperative care 329 procedure 327, 328 results 47, 331 revision 328 Kawasaki’s disease 295 Kayser–Fleischer (KF) rings 248, 249–50, Plate 44 keratinocytes 300 kerion 306 kernicterus 35–6, 37, 382 ketoconazole 154, 305 b-ketothiolase deficiency 234 key workers 2–3 kinky hair disease 245 Klebsiella pneumoniae infections 307–8 Klippel–Trenaunay–Weber syndrome 174 kwashiorkor 302 labetalol 390 lactate, plasma 228 lactic acidosis fructose-1,6-bisphosphatase deficiency 219 glucose-6-phosphatase deficiency 214 mitochondrial respiratory chain disorders 79, 228 lactulose 118, 276 lamin A/C 188 lamivudine 395 developing world 431 hepatitis B 135, 136 resistance 135 lamotrigine, hepatotoxicity 155 Langerhans cell histiocytosis 60 Langerhans cells 300 laparoscopy, diagnostic 352 large intestine, with small bowel grafts 410, 416 larva migrans, visceral 103 Lassa fever 101 Lawrence–Moon–Biedl syndrome 169 Legionella pneumophila 102 leptin, hepatic steatosis and 185, 191 leptospirosis 101, 109 lethargy 117 leukaemia, acute 293 leukotrienes, cystic fibrosis liver disease 200 liaison nurse 2–3 life, with liver disease 1 ligamentum teres 340 Linton tube 272 lipid metabolism, chronic liver disease 266 peroxidation, cystic fibrosis 200

lipid storage disorders 221 lipodystrophy/lipoatrophy syndromes 185, 188 lipopolysaccharide, cystic fibrosis liver disease 200 liposarcoma bile duct 337 hepatic 366 listeriosis (Listeria monocytogenes) 102 congenital 44 lithotripsy, extracorporeal shock wave 340 liver drug metabolism 148 functions 18 reduction 387–8, Plate 79 segmental anatomy 387, Plate 79 splitting 387–8, Plate 79 liver abscess 101, 103–4 amoebic 103, 104 bacterial causes 101 chronic granulomatous disease 295 neonatal pyogenic 104 pyogenic 103, 104 radiology 104, Plate 19, Plate 20 tuberculous 426 liver biopsy 21–2 Alagille’s syndrome 50, Plate 6 a1-antitrypsin deficiency 52 aspiration technique 21 biliary atresia 46, 327 chronic hepatitis 129 chronic liver disease 262–3 contraindications 22 cystic fibrosis 203 fulminant hepatic failure 112, 123 hepatic steatosis 189 hepatitis B 133 hepatitis C 138, 141 image-guided 27–8 liver transplant recipients 397 liver tumours 369 neonatal hepatitis syndrome 41, Plate 4 Niemann–Pick C 57, Plate 8 percutaneous 21–2 complications 22, 27 image guidance 27 protocol 22 portal hypertension 345 transjugular 21 image guidance 27–8 Tru-cut 21 vascular anomalies 176 Wilson’s disease 250, Plate 45 liver failure acute see acute liver failure fulminant see fulminant hepatic failure intestinal failure with 407 late-onset 107 metabolic investigations 212, 213 metabolic liver disease 211 subacute 107 liver function, pretransplant assessment 384, 406 liver function tests 17–19, 18 baseline 17 cystic fibrosis 202 liver tumours 368 portal hypertension 344 second-line 17–19, 19 liver-kidney transplantation 167 liver phosphorylase deficiency 217 liver transplantation 378–401 auxiliary 122, 389–90 ‘bridge’ to 30, 121 complications 391–4 after first week 392–3 dermatological 300, 303–10 early postoperative 391–2

485

late 393–4 radiological management 31–2, 392–3, Plate 83, Plate 84 contraindications 385 dental care 316–19, 317, 319, 385 developing world see under developing world disease recurrence after 394–5, Plate 85 donors 387 future research 397 indications 378–83, 379, 380 acute liver failure 379, 381–2, 435 Alagille’s syndrome 50, 396 a1-antitrypsin deficiency 53, 379 autoimmune hepatitis 146, 380 biliary atresia 47, 331–2, 378 cholelithiasis 338 chronic liver disease see under chronic liver disease Crigler–Najjar syndrome 37, 38, 382 cystic fibrosis 205, 379 developing world 435, 435 fibropolycystic liver disease 173, 380 fulminant hepatic failure 121–2, 123, 381–2, 390 glycogen storage disorders 215, 216, 217, 379–80 hepatitis B 136, 380, 434 hepatorenal syndrome 278, 384 inborn errors of metabolism 379, 382–3 liver tumours 372, 373, 383, 385 mitochondrial energy defects 80, 229 neonatal haemochromatosis 79 neonatal liver disease 63, 378 Nieman–Pick disease 224, 225 organic acidaemias 87, 382 sclerosing cholangitis 148 tyrosinaemia type I 82, 379 urea cycle disorders 84 Wilson’s disease 254, 379 intestinal failure 407 living related 7, 389, 434 neurodevelopmental outcome 5, 396 nutritional support 12, 386, 386 outpatient monitoring after 397 postoperative management 390, 390–1 preparation for 385–6 pretransplant evaluation 6–7, 383, 383–5 primary non-function (PNF) 392 psychosocial support 6–7, 386 quality of life after 395–6 small bowel transplantation with see small bowel/liver transplantation surgical procedures 386–90 back table operation, liver reduction/splitting 387–8 donor operation 387 recipient operation 388–9 role of transplant co-ordinator 387 survival 394, 394, 394–5 tolerance 395 waiting list 386 liver tumours 363–77 benign 366–7, 373–4 drug-induced 150 epidemiology 363, 364 infiltrating 292–3 liver transplantation 372, 373, 383, 385 malignant 367–73 aetiology 363–5, 364 clinical features 367, 367 clinical staging 369, 369 diagnostic investigations 367–9, Plate 76 pathology 365–6 postportoenterostomy 331 prognosis 373 treatment 369–73 neonatal hepatitis syndrome 60 pathology 365–7

486

Index

vs. haemangiomas 175, 176 see also specific tumours local health team 2, 3 long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) 85, 86 deficiency 85, 86 long chain fatty acid oxidation defects 213 Long Chain Triglyceride (LCT) 9 loss of heterozygosity 363–4 lung disease see pulmonary complications; respiratory disease lupus erythematosus neonatal 59 systemic (SLE) 286–7 lymphocytes, chimerism phenomenon 411, 412 lymphohistiocytosis, haemophagocytic see haemophagocytic lymphohistiocytosis lymphoma cutaneous 309, Plate 65 primary hepatic 366 lymphoproliferative disease, post-transplant (PTLD) see post-transplant lymphoproliferative disease lysosomal storage disorders 213, 220–6, 221–2 neonatal ascites 76, 76 lysyl oxidase 244 magnetic resonance (MR) angiography 25, 344 magnetic resonance cholangiopancreatography (MRCP) 28 biliary atresia 327 choledochal cyst 334 cystic fibrosis 202, Plate 38 sclerosing cholangitis 147, Plate 26 magnetic resonance imaging (MRI) 21 ADPKD 166 cholangiography 21 hepatic haemangiomas 175–6, Plate 34 liver tumours 368 portal hypertension 344 magnetic resonance (MR) venography 31 malabsorption 266 cholestatic liver disease 9 dietary management 9 neonatal cholestasis 60, 61 post-Kasai 330 short bowel syndromes 404–5 malaria 425 Malassezia furfur 306 malignancy 292–3 choledochal cysts 334 cholelithiasis 338 cutaneous 309 see also under liver tumours Mallory’s hyaline 183 malnutrition 265 Alagille’s syndrome 50 assessment see nutritional assessment causes 7 chronic liver disease 262, 264–7, Plate 46 cystic fibrosis 202, 204, Plate 37 delayed tooth eruption 316 liver dysfunction in 295–6 liver transplantation and 381, 394, 435 management 266–7 neonatal cholestasis 60, 61 pathophysiology 265–6 post-Kasai 330 prevention/treatment see nutritional support as prognostic factor 264 skin manifestations 302 malonic aciduria 234 manganese 286, 404 mannitol therapy 118 mannose binding lectin 199 mannose supplementation 227–8 a-mannosidosis 222

marasmus 302 Marburg virus 101 Maroteaux–Lamy syndrome 222 Mauriac’s syndrome 187, 288 Mead Johnson (MJ) 13 measles 97 mebendazole 102, 103, 427 Meckel–Gruber syndrome 168 meconium ileus 53, 200 medium-chain acyl-CoA dehydrogenase (MCAD) deficiency 85, 231–2 medium chain triglycerides (MCT) abetalipoproteinaemia 237 in cholestasis 9, 10–11 neonatal liver disease 61 medullary cystic kidney disease (MCKD) 168 melanocytes 300 Menkes’ disease 245 Menkes’ protein (ATP7A) 243, 245 mental health, pre- and post-transplant 6–7 6-mercaptopurine (6-MCP) 293 Merkel cells 300 mesalazine 156 mesenchymal hamartoma 366, 374, Plate 76 cystic 173 neonatal jaundice 60 vs. undifferentiated sarcoma 365, 366 mesenchymal tumours, malignant 367 mesenchymoma, malignant see sarcoma, undifferentiated mesenterico-left portal (Rex) shunt 348, 349, 349 mesocaval shunt 348, 348, 349 metabolic acidosis fulminant hepatic failure 119 organic acidaemias 87 metabolic alkalosis, fulminant hepatic failure 119 metabolic disease, non-alcoholic fatty liver disease 187–8 metabolic liver disease developing world 423 fulminant hepatic failure 108, 110, 113 investigations 19, 19, 23, 75, 213 liver transplantation 379–80, 382 auxiliary 389–90 presenting in infancy/older child 211–42 clinical categories 211 diagnosis 211, 212, 213 presenting in neonates acute illness 75, 77–82 neonatal hepatitis syndrome 40, 51–8 see also inborn errors of metabolism; specific diseases metabolic syndrome (syndrome X) 184, 185 metallothionein 243 metformin 191 methotrexate hepatic sarcoidosis 295 hepatotoxicity 156, 293 3-methyl crotonyl glycinuria 234 3-methyl glutaconic aciduria 234 methylmalonic acidaemia (MMA) 87–8, 232–3, 234, 382 methylprednisolone intestinal graft rejection 414 liver graft rejection 392 small bowel transplantation 411 metronidazole organic acidaemias 87 post-transplant 390, 411 terminal ileal disease 285 TPN-induced liver disease 59 mevalonic aciduria 230, 234 miconazole 305 micro-chimerism, small bowel transplantation 411, 412, 415 microhamartomas 165–6

microsomal triglyceride transfer protein (MTP) defects 236 microvillus inclusion disease 404 minerals deficiencies 265, 266 supplements 10 mitochondrial acetoacetylCoA thiolase deficiency 234 mitochondrial disorders 75, 79–80, Plate 12 with multisystem involvement 385 non-alcoholic fatty liver disease (NAFLD) 184 presentation 284 mitochondrial DNA (mtDNA) depletion syndrome 79, 80, 228 rearrangements 228 mitochondrial respiratory (electron transport) chain defects 79–80, 228–9 diagnosis 79, 213, 228, Plate 12 management 80, 228–9 presentation 79, 228 modular feeds 9, 10, 12 Molecular Absorbent Recirculating System (MARS) 121, 253, 386 molecular biology 23 molecular mimicry 143 molluscum contagiosum 304 monoethyl glycinexylide (MEGX) 381 Morquio syndrome 222 motor impairment, hepatic encephalopathy 117 movement disorders, Wilson’s disease 248 MRCP see magnetic resonance cholangiopancreatography MRI see magnetic resonance imaging MRP2 gene 63 MTP gene 185 mucolipidoses 221–2 I (sialidosis) 221 II (I-cell disease) 221 III 221 mucopolysaccharidoses (MPS) 222 multidisciplinary team 1–3 effective working 2 roles within 2–3 multiple acyl-coenzyme A dehydrogenase defect 86 multiple carboxylase deficiency 88 multisystem organ failure 111 multisystem pathology 295–6 muscle biopsy 228, Plate 12 muscle phosphorylase deficiency 217 mushroom poisoning 113, 121 mycobacterial skin infections 308 Mycobacterium tuberculosis infection see tuberculosis mycological culture 310 mycophenolate mofetil (MMF) autoimmune hepatitis 145 transplant recipients 391, 411 myopathy, glycogen storage disease type III 216 NAC see N-acetylcysteine NAFLD/NASH see non-alcoholic fatty liver disease/non-alcoholic steatohepatitis nails clippings 310 fungal infections 306 white (Terry’s) 301 naloxone 301 NAPQI (N-acetyl-p-benzoquinoneimine) 151 naproxen, hepatotoxicity 153 nasogastric tube feeding 11 National Institutes of Health Acute Liver Failure (NIH ALF) study 107, 108, 108–9

Index necrosis, hepatic chronic hepatitis 129, Plate 24 drug-induced 149 fulminant hepatic failure 110, 123, Plate 23 mechanism 259 recovery 111 subacute 107 necrotizing enterocolitis (NEC) 403, 404 neointimal hyperplasia (NIH) 30 neomycin, in hepatic encephalopathy 118, 276 neonatal adrenoleukodystrophy (NALD) 229 neonatal cholestasis (NC) 38 a1-antitrypsin deficiency 52 consequences 60, 61 developing world 421–2, 422 nutritional support 61–2, 62 neonatal haemochromatosis (NNH) 78–9, 213, 382, Plate 11 neonatal hepatitis 38 idiopathic 45 preterm infants 45 neonatal hepatitis syndrome (NHS) 38–60 causes 40 chromosomal disorders 45 clinical features 38, Plate 1 cystic fibrosis 53, 203 endocrine disorders 40, 44–5 immune causes 40, 59–60 investigations 39, 39–41, 40, Plate 2, Plate 3 management 60–3, 61 metabolic liver disease 40, 51–8 miscellaneous causes 60 structural abnormalities 40, 45–51 toxic injury 58–9 neonatal jaundice 35–73 biliary atresia 46, 327 breast feeding associated 35, 36 neonatal hepatitis syndrome 38 physiological 35, 36 neonatal liver disease cystic fibrosis 201, 204–5 developing world 421–2, 422 liver transplantation 63, 378 management 61 nomenclature 38 see also neonatal hepatitis syndrome; neonatal jaundice neonatal screening biliary atresia 327 galactosaemia 77 hepatitis C 140 tyrosinaemia type I 82 neonates acutely ill see acutely ill infants ascites 76, 76–7 asphyxia 60 copper metabolism 246, 247 fulminant hepatic failure 107, 108, 109 hepatitis B immunization 129, 132–3, 431 infections 40, 41–4, 76 liver trauma 351 lupus erythematosus 59 sclerosing cholangitis 48–9, 146 TPN liver disease 404 see also infants; preterm infants nephrocystin 168 nephronophthisis (NPHP), juvenile 168 nephrotoxicity, immunosuppressive agents 395 neuroblastomas, vs. haemangiomas 175 neurodevelopmental assessment see developmental assessment neurological disease abetalipoproteinaemia 236 Alpers–Huttenlochler syndrome 231 CDG syndrome 227

Gaucher disease 223 glycogen storage disease type IV 216 Niemann–Pick disease 224, 225 Wilson’s disease 5, 248–9, 253 see also brain damage neurophysiological tests 23 neuropsychological assessment 4–5 pretransplant 384, 407 neurotransmitters, in encephalopathy pathogenesis 274 neutropenia, glycogen storage disease type I non-a 215 niacin 80 Nieman–Pick cells (foamy histiocytes) 57, 224, 225, Plate 8 Nieman–Pick disease (NPD) 223–6 type A (NPA) 57, 221, 223–4 type B (NPD) 221, 223–4 type C (NPC) 57, 221, 224–6 diagnosis 57, 213, 225, Plate 8 management and outcome 57, 225–6 presentation 57, 225 nifedipine gingival overgrowth 303, 318, Plate 67 liver transplant recipients 390 nitrates 272, 273, 273 nitric oxide (NO) 274 nitrogenous intestinal products 274 nitroglycerin 272, 273 nocardial skin infections 308–9 non A-G (non A-E) hepatitis 96, 97 developing world 432 fulminant hepatic failure 97, 109, 110, 122 liver transplantation 122 non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) 183–96 in adults 183–4 clinical features 187–8 diagnostic approach 188–9, 189, 190 differential diagnosis 188 epidemiology in children 186–7 histology 183, 189, Plate 36 obesity see under obesity outcome 191 pathogenesis 184, 184–5 treatment 189–91, 190 non-Hodgkin’s lymphoma, primary hepatic 366 non-steroidal anti-inflammatory drugs (NSAIDs) 152–3, 153 North American Indian familial cirrhosis 56 Notch proteins 49 NPC1 gene 57, 225 NPC2/HE1 gene 225 NTBC (2-(2-nitro-trifluoromethylbenzoyl)-1,3cyclohexenedione) 81, 82, 379 nurse specialist 2–3 Nutricia 13 nutritional assessment 8, 60 chronic liver disease 266, 381 cystic fibrosis 203 liver transplant recipients 397 nutritional supplements 9, 10 chronic liver disease 265, 266–7 developing world 423, 423 pretransplant 386, 386 prevention of dental disease 314, 316 nutritional support 7–12, 264–7, 265 acute liver disease 11–12 algorithm 8 cholestatic liver disease 9–11, 12 chronic liver disease 8–9, 264–7 common problems 10, 11 cystic fibrosis 204 developing world 435 fulminant hepatic failure 115 liver transplantation 12, 386, 386

487

nasogastric tube feeding 11 neonatal liver disease 60–2 post-small bowel transplant 412, 416 see also dietary management; enteral feeding; parenteral nutrition nystatin 390, 391 obesity 287 childhood 185–6 cholelithiasis 338, 339 non-alcoholic fatty liver disease (NAFLD; NASH) 183, 187, 287, Plate 35 epidemiology 186–7 pathogenesis 184, 185 treatment 190–1 octreotide acute variceal bleeding 345, 345 hepatorenal syndrome 278 portal hypertension 272, 273 see also somatostatin ocular abnormalities see eye abnormalities oedema 267–9 oesophageal varices 270, 342, Plate 48 band ligation see endoscopic variceal ligation biliary atresia 330 bleeding see variceal bleeding cystic fibrosis 205 endoscopic evaluation 344 endoscopic injection sclerotherapy 272, 273, 345–7, 346 oestrogens 339 ofloxacin 424 OGT 918 (N-butyldeoxynojirmycin) 223, 225–6 OKT3 413, 414 oliguria, postoperative 392 olsalazine 156 omeprazole fulminant hepatic failure 117 hepatotoxicity 156 liver graft recipients 391 ondansetron 301 onychomycosis 306 ophthalmic abnormalities see eye abnormalities ophthalmology 23 opioid antagonists k, in ascites 268 in pruritus 301 optic disc drusen 49 oral contraceptive pill 339, 344, 366–7 oral hygiene 314 gingival overgrowth and 318 liver graft recipients 318, 319 see also dental care organic acidaemias 86–8, 232–3, 233, 234 diagnosis 75, 213, 233–3 management 87, 233, 382 ornithine transcarbamylase (OTC) deficiency 83–4 Osler–Weber–Rendu disease 174 osteopenia 214, 266 osteoporosis 249, 330, 367 overweight 185 oxalosis, primary 383, 385, 389–90 oxidative stress, drugs to prevent/treat 191 D4-3-oxosteroid 5b-reductase deficiency 53, 54 oxysterol-7a-hydroxylase deficiency 54 oxytetracycline 305 packing, perihepatic, in trauma 353–4 palmar erythema 301 palmitoyl acylCoA oxidase deficiency 230 pancreas, in liver-small bowel composite grafts 409, 409 pancreatic disease, choledochal cysts 334 pancreaticobiliary malunion (channel) 325–6, 332–3, Plate 69 complications 334 surgical management 335

488

Index

pancreatitis choledochal cysts 333 fulminant hepatic failure 121 gallstone 340 progressive familial intrahepatic cholestasis 55 papillomas, bile duct 337 papular acrodermatitis of childhood 302 paracentesis 268, 278 paracetamol (acetaminophen) 151–2 metabolism 151, 151 non A-G hepatitis and 109 poisoning 151–2 clinical features 152 fulminant hepatic failure 110, 113, 151 histology Plate 23 liver transplantation 382 management 121, 152 prognosis 122 paramyxoviruses 43, 109 parasitic worms 102–3 parenteral nutrition (TPN) 12, 12 associated cholestasis 58–9, 286, 404–5 clinical features 58, 404 histology 58, 404, Plate 87 management 58–9, 286, 404–5 complications 58–9, 286, 286, 339 indicating small bowel transplant 402, 404–5, Plate 86 dependency, causes 403, 403–4 fulminant hepatic failure 115 inspissated bile syndrome and 336 liver transplant recipients 386 post-small bowel transplant 412 parents see family paronychia, chronic 306 partial thromboplastin time (PTT) 18 parvovirus B19 infection 97, 290 congenital 43 fulminant hepatic failure 109, 112 pathologists, developing world 433 Paul–Bunnell test 99 Pearson syndrome 228 Pediatric EndStage liver disease (PELD) score 264, 381 peer relationships 6, 13 peliosis hepatitis 150, 174 d-penicillamine challenge test 246, 250 Indian childhood cirrhosis 255, 256, 423 in pregnancy 254 toxicity 251–2 Wilson’s disease therapy 251, 251–3 penicillin 305 percutaneous biliary techniques 28–9 percutaneous cholecystogram 28–9 percutaneous transhepatic cholangiography (PTC) 21, 28 choledochal cyst 334 percutaneous transhepatic portography 344 pericarditis, constrictive 283, 344, Plate 49 periodontal disease 314, 317 peripherally inserted central catheters (PICCs) 31 peritoneal lavage, diagnostic 352 peritoneal venous shunts 269 peritonitis biliary see biliary peritonitis spontaneous bacterial 268, 278, 385 spontaneous perforation of bile ducts 335 peroxisomal 2-methylacyl-CoA racemase deficiency 54 peroxisomal disorders 56, 229–30, 230 diagnosis 213, 230 management 230 presentation 229 see also Zellweger syndrome

personality change, hepatic encephalopathy 117 petechiae, fulminant hepatic failure 116 PEX gene mutations 56, 229 P-glycoprotein MDR-3 gene 55 phenobarbitone in Crigler–Najjar syndrome 37–8 fulminant hepatic failure 119 neonatal hepatitis syndrome 62 radioisotope scanning 20 phenylbutyrate, in urea cycle disorders 83–4, 84 phenytoin fulminant hepatic failure 119 liver toxicity 155 phosphomannomutase deficiency 227 phosphomannose isomerase deficiency 227 phosphorylase kinase deficiency 217 phosphorylase system deficiencies 217 photosensitivity 302 phototherapy Crigler–Najjar syndrome 37 neonatal liver disease 63 physiological jaundice 36 physical appearance, altered 5–6 piperazine 103 piroxicam, hepatotoxicity 153 pituitary function testing 17–19 pityriasis versicolor 306 pityrosporum folliculitis 306, Plate 64 PKD2 gene 165 PKD genes 164–5, 165 PKHD1 gene 167 PLADO chemotherapy 370, 370–1 plantar warts (verrucae) 304 plant toxin, biliary atresia and 326 plasmapheresis, fulminant hepatic failure 121 Plasmodium falciparum 109, 425 Plasmodium vivax 425 platelet count fulminant hepatic failure 116 in hepatoblastoma 367–8 liver biopsy and 21, 22 platelet transfusions 117, 276 platypnoea 330 play specialist 2, 4 pleural effusions 277 Pneumocystis carinii infection Plate 55 pneumonia 277 ‘pollard willow formation’ 163 polyarteritis nodosa, hepatitis B 132 polycystic disease 162 polycystic kidney disease see autosomal dominant polycystic kidney disease; autosomal recessive polycystic kidney disease polycystic liver disease (PCLD) 171 polycystic ovary syndrome (PCOS) 185, 186, 187–8 polycystins 164–5, 173 polyductin 167 polyglandular syndrome type 1, autoimmune (APECED) 144, 289 polymerase chain reaction (PCR) 23 polysplenia syndrome (BASM) 46, 47, 324–5, 325 porphyria 234, 235–6 acute intermittent 234, 236 congenital erythropoietic 234, 236 cutanea tarda 234, 236, 302 hepato-erythropoietoic 234 variegate 234 porphyrins 236, 302 portal ductopenia 51 portal fibrosis, non-cirrhotic (hepatoportal sclerosis) 343, 427, 428

portal hypertension 341–50 ADPKD 166, 167 aetiology 342–4 biliary atresia 47, 330, 343 choledochal cysts 334 chronic liver disease 269–74, 342, 427–8 classification 342–4 clinical features 342–4 congenital hepatic fibrosis 169 cystic fibrosis 205 definition 342 developing world 427–8 extrahepatic aetiology 342 developing world 427 vs. cirrhosis 263 idiopathic (hepatoportal sclerosis) 343, 427, 428 intrahepatic 343 investigation 344–5 management 9, 9, 30, 271–4 pathophysiology 259, 269–71, 284, 342 posthepatic 343–4 prehepatic 342–3 pretransplant assessment 384 TPN-associated cholestasis 404 see also variceal bleeding portal vein cavernoma 343 cavernous transformation 25, 169 liver graft surgery 329, 330 occlusion (PVO) 342–3, 343 developing world 427 investigations 344, 345 management 345, 346, 350 shunt surgery 348, 349, 349 stenosis, after liver transplantation 394, Plate 85 thrombosis 342–3, 385 after liver transplantation 392 management 25, 345 portal venous system 269, 269–70, 342 development 340 portocaval shunts, congenital 341 portocholecystostomy 327–8 portoenterostomy, Kasai see Kasai portoenterostomy portography indirect 344 percutaneous transhepatic 344 portosystemic collaterals 270, 270, 342 portosystemic shunts, surgical 273–4, 347–9 congenital hepatic fibrosis 169, 170 emergency 272–3 liver transplantation after 350 procedures 348, 348 thrombosis 348–9 see also transjugular intrahepatic portosystemic shunt portovenous fistulae (PVF), intrahepatic 174, 177 post-transplant lymphoproliferative disease (PTLD) liver transplant recipients 393, 397 small bowel transplant recipients 414–15, 415, Plate 90 post-traumatic stress disorder (PTSD) 7 PPARA*3 gene 185 PPARG gene 188 praziquantel 103 prednisolone, autoimmune hepatitis 145 pregnancy, Wilson’s disease 253–4 prenatal diagnosis see antenatal diagnosis preterm infants bilirubin neurotoxicity 35 gallstones 339 neonatal hepatitis 45 TPN-associated cholestasis 58–9

Index primary non-function (PNF), liver grafts 392 Pringle manoeuvre 353 prion protein 246 procollagen VI, serum 202 progesterone 339 progressive familial intrahepatic cholestasis (PFIC; Byler disease) 54–6 progressive infantile poliodystrophy (Alper’s syndrome) 110 progressive neuronal degeneration of childhood (PNDC; Alper’s syndrome) 110, 230–1, 385 propionate, metabolism 235 propionic acidaemia (PA) 86–8, 232–3, 234, 382 propranolol 273, 273, 350 propylthiouracil, toxicity 109 prostaglandin, small bowel transplantation 411 prostaglandin E1 78 prostaglandin E2, cystic fibrosis liver disease 200 protein dietary deficiency 302 dietary restriction 9, 12 hepatic encephalopathy 118, 275–6 urea cycle disorders 84 nutritional deficits 265 supplementation 10, 267 synthesis, impaired 265–6 protein–energy balance 265 prothrombin time (PT) 18 biliary atresia 46 fulminant hepatic failure 116, 123 liver biopsy and 21, 22 liver transplantation timing and 381 portal hypertension 344 sclerosing cholangitis 147 proton pump inhibitors, hepatotoxicity 156 protoporphyria, erythropoietic 234, 236 pruritus 301 neonatal liver disease 62–3 progressive familial intrahepatic cholestasis 55–6 pseudoaneurysms 354 Pseudomonas aeruginosa infections 307–8 psychiatric disorders, Wilson’s disease 248 psychological assessment 4–5 pretransplant 384, 407 psychological support 4–7 fulminant hepatic failure 122 live-related donors 7, 389 liver transplantation 6–7, 386 neonatal liver disease 63 small bowel transplantation 407 psychologist 4, 6 puberty, liver transplant recipients 396 pulmonary complications chronic liver disease 276–7, 277 fulminant hepatic failure 120 pulmonary haemorrhage, fulminant hepatic failure 116, 120 pulmonary hypertension after shunt surgery 349 chronic liver disease 277 glucose-6-phosphatase deficiency 214–15 portal hypertension with 342 post-enterostomy 330–1 pulmonary infections, fulminant hepatic failure 120 pulmonary oedema, fulminant hepatic failure 120 purpura 302 pyloric stenosis 37 pyrantel pamoate 427 pyrazinamide, toxicity 155, 426 pyridoxine deficiency 266 Wilson’s disease 252

pyrimethamine 102 pyrrolizidine alkaloids 256 Q fever 109 quality of life 1 liver transplant recipients 395–6 postportoenterostomy 331 quinine 425 quinolones 154, 424 radioisotope scanning 20 biliary atresia 46, 327, Plate 3 choledochal cyst 334, Plate 3 cholelithiasis 339 cystic fibrosis 202 liver trauma 352 neonatal hepatitis syndrome 41, Plate 3 radiology developing world 433 diagnostic 19–21 interventional see interventional radiology liver tumours 368–9 pretransplant assessment 384 see also specific modalities radiotherapy intestinal allografts 417 liver tumours 373 ragged red fibres Plate 12 ranitidine 346 fulminant hepatic failure 117 hepatotoxicity 156 liver graft recipients 390, 391 rapamycin 411 rashes, skin 309–10 records, patient/parent-held 3, 13 red cell fragility disorders 290 Refsum’s disease, infantile (IRD) 229 regeneration, hepatic, fulminant hepatic failure 111, 123 rejection, graft see graft rejection renal biopsy 172 renal disease 287–8 ADPKD 166, 167 Alagille’s syndrome 50, 287 ARPKD 167, 168, 287 congenital hepatic fibrosis 168, 169 fibropolycystic liver disease 171–2 glucose-6-phosphatase deficiency 214 Wilson’s disease 249 renal dysfunction cirrhosis 287 fulminant hepatic failure 119 renal failure acute 119, 277 functional 119, 277–8 post-liver transplant 391–2 renal function longterm, liver transplant recipients 395 pretransplant assessment 384 reovirus, biliary atresia and 325 resection, liver in malignant disease 371–3 in trauma 353–4 see also hepatectomy respiratory alkalosis, fulminant hepatic failure 119, 120 respiratory assessment, pretransplant 384 respiratory disease cystic fibrosis 379 liver dysfunction 288 Niemann–Pick disease 224 obstructive and restrictive 277 see also pulmonary complications respiratory problems, fulminant hepatic failure 120 respiratory tract infections 120, 278 retrorsine 256 Rex mesenterico-left portal shunt 348, 349, 349

489

Reye-like syndrome 107, 231–2 fatty acid oxidation defects 85, 86, 235 investigations 212, 213, 232 metabolic liver disease 211 Reye syndrome (RS) 231–2 aspirin and 152–3, 231 atypical see Reye-like syndrome classic or idiopathic 231 investigation 110, 232 management 232 rhabdoid tumour, primary 366 rhabdomyosarcoma 336–7, 366, 383 aetiology 363 biliary tree 60 vs. undifferentiated sarcoma 366 Rhesus incompatibility 290, 338 rhizomelic chondrodysplasia punctata (RCDP) 229 ribavirin/interferon therapy, hepatitis C 142 riboflavin supplements 86 rickets 249, 266, 330 rifampicin neonatal hepatitis syndrome 62–3 toxicity 154–5, 426 ringworm 305–6, Plate 63 Rituximab 414–15 road traffic accidents 351, 351 Rochalimaea henselae 174 roseola infantum (exanthem subitum) 43, 99 Rotor syndrome 63 Roux loop biliary atresia 327, 328, 329 liver transplant recipients 389 obstruction 330 rubella 97 congenital 41 Salla disease 222 Salmonella infections 340 Salmonella typhi 102, 424 salt restriction 9, 9, 268 San Fillipo syndrome 222 sarcoidosis 294, 294–5 sarcoma, undifferentiated (embryonal) 365–6, Plate 76 clinical features 367 treatment 372 scalp lesions 310 Scheie syndrome 222 schistosomiasis (Schistosoma infections) 103, 294 school teacher 2 Scientific Hospital Supplies (S.H.S.) 13 scintigraphy see radioisotope scanning sclerosing cholangitis (SC) 146–8 aetiology 146 associated disorders 146, 146, 285 autoimmune (ASC) 146, 285 autoimmune/overlap syndrome 146, 148 CD40 ligand deficiency 293, Plate 56 clinical features 146–7 diagnosis 147, Plate 26 neonatal (NSC) 48–9, 146 primary 146 treatment 147–8 sclerotherapy, endoscopic injection see endoscopic injection sclerotherapy screening antenatal, hepatitis B 132 inborn errors of metabolism 88 neonatal see neonatal screening seat-belt injuries 351 sedation, hepatic encephalopathy 118 seipin 188 selenium 78 deficiency 266, 302 self-medication 13 Sengstaken–Blakemore tube 272, 345

490

Index

sepsis after percutaneous transhepatic cholangiography 28 complicating TPN 405 liver dysfunction 109, 295 liver transplantation and 385 portal vein occlusion 343 post-liver transplant 392, 393 see also infections septo-optic dysplasia 44, 288, 289 serology, pretransplant 384 severe combined immunodeficiency (SCID) Plate 55 severity of liver disease post-liver transplant survival and 394 pretransplant assessment 383–4 sexual precocity 367 shared care 2, 3 shock fulminant hepatic failure 120 septic 295 short bowel syndrome 338–9, 403, 403 pre-intestinal transplant assessment 406 small bowel transplantation 410 TPN-associated cholestasis 405 shunting procedures see portosystemic shunts, surgical Shwachmann’s disease 285 sialic acid storage disorder 222 sialidosis 221 sickle-cell disease 289, 289–90, 338, 340 Silymarin 191 sinusoidal dilatation, in cardiac disease 283, Plate 49 sirolimus 391 situs inversus 324, 325 skeletal abnormalities Alagille’s syndrome 49, Plate 6 Wilson’s disease 249 skeletal dysplasia, lysosomal storage disorders 220 skin 300–1 biopsy 23, 310–11 cancer 309 cultures 310 dysplastic lesions 309 function 301 graft-vs.-host disease 309 immunocompromised host 303 infections 304–9, 305 malignancies 309, Plate 65 rashes 309–10 scrapings 310 structure 300 skin manifestations/disorders 300–12 chronic liver disease 261, 301, 302, Plate 46 diagnostic approach 310, 310–11 liver disease 301–2 malnutrition 302 post-liver transplantation 300, 303–10 SLC25A13 gene 58 sleep disturbances, hepatic encephalopathy 117 slow acetylator phenotype 154 Sly syndrome 222 small bowel bacterial overgrowth 58, 59, 404–5 small bowel/liver transplantation cluster grafts 408, 408 composite grafts 409, 410 indications 407 postoperative management 410–11 small bowel transplantation 402–20 assessing graft function after 412–13 causes of graft loss 415 complications 413–15 contraindications 407 indications 402–5, 403, 407 longterm rehabilitation 416

postoperative management 410–13 preoperative management 407 present and future status 416–17 pretransplant evaluation 405, 405–8 procedure 407–10 donor operation 408–9 graft preservation 409 recipient operations 409–10 selection of donors 407–8 survival 403, 415–16 timing 407 small for gestational age, neonatal hepatitis syndrome (NHS) 38, Plate 1 smoking, a1-antitrypsin deficiency and 52 a-smooth muscle actin (SMA) 259 social relationships 6 social worker 2 sodium benzoate in hepatic encephalopathy 276 in urea cycle disorders 83–4, 84 sodium retention 268 sodium valproate hepatotoxicity see valproic acid hepatotoxicity somatostatin ADPKD 167 portal hypertension 272, 273, 345 see also octreotide specialist unit, multidisciplinary team 1–2 spherocytosis, hereditary 290, 338, 340 sphingolipid storage disorders 221 sphingomyelinase deficiency 57, 223–4 spider naevi (angiomata) 261, 301, Plate 46 spinal surgery/injury 338 spironolactone 268, 268, 273 splanchnic vasoactive agents 272, 273, 273, 278 splenectomy, variceal bleeding 349 splenomegaly biliary atresia 46 cystic fibrosis liver disease 201 developing world 427 hyperreactive malarial 425 neonatal hepatitis syndrome 38 portal hypertension 269 sickle-cell disease 289 small bowel transplant and 404, 406 splenoportography 21, 344 splenorenal shunts 348, 348, 349 sporadic fatal infectious mononucleosis (SFIM) 98, 99 SREBP-1c 184, 185, 191 staphylococcal scalded skin syndrome (SSSS) 308 staphylococcal skin infections 308 steatosis, hepatic (fatty liver) alcoholic liver disease 183 cystic fibrosis 53, 189, 200, 203, Plate 39 donor livers 434 drug-induced 150 large droplet (macrovesicular) 183 non-alcoholic see non-alcoholic fatty liver disease/non-alcoholic steatohepatitis obesity 287 small droplet (microvesicular) 183, 189 steely hair disease 245 stellate cells, hepatic (HSC), in cirrhosis pathogenesis 259, 260 stent placement 26 steroids see corticosteroids stools, acholic, biliary atresia 46, 327 streptococcal skin infections 308 streptomycin 426 subcutaneous layer 300 substrate deprivation therapy, Gaucher disease 223 succinylacetone 81, 81, 82 sucralfate 272, 346 fulminant hepatic failure 117 liver graft recipients 391

sudden infant death syndrome 85, 86 Sugiura procedure 273–4 sulindac, hepatotoxicity 153 sulphadiazine 102 sulphasalazine, hepatotoxicity 156 sulphonamides 154 superoxide dismutase 244, 244 super PLADO chemotherapy 370, 371 support, child and family 1–16 supranuclear vertical gaze palsy 225, Plate 8 surgical disorders 324–41 bile ducts 324–40 congenital vascular abnormalities 340–1 liver trauma 350–4 surgical management biliary atresia see Kasai portoenterostomy choledochal cyst 334–5 gallstone disease 340 liver trauma 352–4 liver tumours 371–3 spontaneous perforation of bile duct 335–6 variceal bleeding 273–4, 345–50, 347–50 sweet foods, avoidance 218 Sweet syndrome 215 syncytial giant-cell hepatitis, neonatal 43 syndrome X (metabolic syndrome) 184, 185 syndromic duct paucity see Alagille’s syndrome syphilis, congenital 42, 109 systemic cystic angiomatosis 174 systemic illness investigations 296 liver in 282–99 neonatal jaundice 37 systemic lupus erythematosus (SLE) 286–7 tacrolimus 284 adverse effects 393, 393 autoimmune hepatitis 145 graft-vs.-host disease 292 intestinal graft rejection 414 liver transplant recipients 390, 390–1 nephrotoxicity 395 small bowel transplantation 411, 415–16 topical 303–4 T-cell infusions, post-transplant lymphoproliferative disease 393, 414–15 teacher, school 2 team local health 2, 3 multidisciplinary see multidisciplinary team transplant 433 technetium trimethyl 1-bromo imino diacetic acid (TEBIDA) 20 teeth see tooth telangiectasia chronic liver disease (spider naevi) 261, 301, Plate 46 hereditary haemorrhagic 174 telephone consultation service 3 terlipressin 278, 345 Terry’s nails 301 tetracycline, toxicity 154, Plate 29 tetrathiomolybdate (TM) 251, 252, 253 thalassaemia 290, 338, Plate 51 hepatitis C 432 thiabendazole 103 thiamine deficiency 266 thiazolidinediones 191 thioctic acid 121 thiopentone coma, cerebral oedema 119 thrombocytopenia 116, 373 thrombocytosis 367–8 thrombolysis 26–7, 343, 345 thrombophilia, portal vein occlusion 342–3 thrombosis arterial 26, 27 venous see venous thrombosis thymoglobulin 414

Index thyroid function tests 17–19 ticarcillin 305 tinea capitis 306 tinea corporis 306, Plate 63 tinea cruris 306 tinea pedis 306 tinea unguium 306 tin-protoporphyrin 36, 37 TIPS see transjugular intrahepatic portosystemic shunt tissue adhesives 346 tissue-plasminogen activator (t-PA) 26–7 TNFa gene 185 alpha-tocopheryl polyethylene glycol succinate (TPGS) 62, 62, 78, 267 see also vitamin E toga virus 109 tolerance, liver transplant 395 tooth delayed eruption 316, 319, Plate 66 discoloration 314–15, 316, Plate 67 extractions 315–16, 319 TORCH infections 41–2 total parenteral nutrition see parenteral nutrition toxin-related hepatic injury diagnosis 113 fulminant hepatic failure 109, 109–10 neonatal hepatitis syndrome 58–9 pathology 110–11 Toxocara canis and catis 103 toxoplasmosis 102 congenital 41 TPN see parenteral nutrition transaminases see aminotransferases transcobalamin 368, 371 transduodenal sphincteroplasty 335 transforming growth factor-a (TGF-a) 173, 199 transforming growth factor-b (TGF-b) 259, 260 transfusion-associated hepatitis 136–7 transfusion transmissible virus (TTV) 96–7, 109, 432 transition to adult care 3, 14 transjugular intrahepatic porto-systemic shunt (TIPS) 26, 30, 348, 350, Plate 48 acute variceal haemorrhage 272–3 cystic fibrosis 205 fibropolycystic liver disease 172–3 pretransplant 385 refractory ascites 269 transplant co-ordinator 387 trauma, liver 338, 350–4 causes 350–1, 351 management 352–4, 353, 354 presentation and investigation 351–2, Plate 74 traumatic hepatic cysts 171 travel abroad 94, 96, 428 treatment adherence 5, 396 consent to 3–4 tremor, Wilson’s disease 248 trichosporonosis, cutaneous 307 trientine (triethylene tetramine dihydrochloride) 251, 252 trifunctional protein 85, 86 deficiency 85 trihydroxy cholestanoic acid (THCA) 229, 230 trihydroxy cholestanoic acidaemia 230 trisomies, chromosomal 364 trisomy 18 45 trisomy 21 (Down syndrome) 45, 338 T-tube drainage, spontaneous perforation of bile duct 336 tuberculosis (TB) 294, 294, 425–7 acute hepatitis 102 congenital 44 liver transplant candidates 434–5

neonatal 44 post-liver transplant 436 primary hepatobiliary 425–6 skin manifestations 308 therapy, hepatotoxicity 154–5, 426–7 tumour markers 368 Turner syndrome 188 typhoid (Salmonella typhi) 102, 424 Tyrolean childhood cirrhosis 254, 255, 255–6 tyrosinaemia type I 80–2, 232 antenatal diagnosis 82 clinical presentation 81, 283, Plate 13 diagnosis 81–2, 213, Plate 14 fulminant hepatic failure 111 hepatocellular carcinoma 81, 82, 278–9, Plate 15 management 82, 379 prognosis 82, 264 screening 82 tyrosinase 244 tyrosine metabolism 81 plasma or urine 19 UDCA see ursodeoxycholic acid ulcerative colitis (UC) 146, 146, 285–6 ultrafiltration, fulminant Wilson’s disease 253 ultrasound 20 ADPKD 166 biliary atresia 46, 327, Plate 2 Caroli’s disease 170 choledochal cyst 334, Plate 2 cholelithiasis 339 congenital hepatic fibrosis 169 cystic fibrosis 202, Plate 38 endoscopic (EUS) 21 guided liver biopsy 27 hepatic vascular anomalies 175 liver abscess 104, Plate 19 liver tumours 368, 371 neonatal hepatitis syndrome 41, Plate 2 non-alcoholic fatty liver disease 189 portal hypertension 344 sclerosing cholangitis 147 in trauma 351–2 umbilical vein catheterization 343, 345 universal infection control precautions 133 urea cycle disorders 75, 83–4, 213, 233–5 uridine diphosphate glucuronosyl transferase see bilirubin uridine diphosphate glucuronosyl transferase urinary tract infections 120, 278 ursodeoxycholic acid (UDCA) cardiac disease 284 cholelithiasis 339, 340 cystic fibrosis 203–4, 206, 285 inspissated bile syndrome 336 neonatal hepatitis syndrome 48, 62 non-alcoholic fatty liver disease 191 progressive familial intrahepatic cholestasis 55 sclerosing cholangitis 147 TPN-associated cholestasis 59, 405 V2 vasopressin receptor antagonists 268 vaccination, pretransplant 385 valacyclovir 99 valganciclovir 100 valproic acid hepatotoxicity 155, 385 clinical features 113, 155 histology Plate 29 pancreatitis 121 vancomycin 305, 411 vancomycin-resistant enterococcus (VRE) 393, 414 vanishing bile duct syndrome 392, Plate 82 see also bile duct paucity

491

variceal bleeding 269–74, 342 biliary atresia 330 congenital hepatic fibrosis 169 cystic fibrosis 205 management 271, 271–4, 381 drug therapy 272, 273 emergency 271–2, 345, 345 endoscopic treatment 272, 345–7, 346 portosystemic shunts 30, 272–3 pretransplant 385 prevention of recurrence 273, 273, 345 primary prophylaxis 273, 345, 350 Sengstaken–Blakemore tube 272, 345 surgical procedures 273–4, 347–50 pathophysiology 269–71, 342 Wilson’s disease 248 varicella see chickenpox varicella-zoster virus (VZV) acute hepatitis 98 fulminant hepatic failure 109 immunocompromised patients 305 treatment 99 varices 270, 342 bleeding see variceal bleeding ectopic 347 gastric 347 sclerotherapy/band ligation 272 see also oesophageal varices vascular access pre-small bowel transplant assessment 406, Plate 86 TPN-induced complications 405 vascular anomalies, hepatic 162, 173–7 Alagille’s syndrome 50 classification 173, 173–4 clinical features 174 congenital 29–30, 340–1 diagnosis 174–6, 175 future research 177 management and outcome 176–7 pathology 176 see also haemangiomas vascular disorders drug-induced 150 interventional radiology 29–30 neonatal hepatitis syndrome 60 see also vascular anomalies, hepatic vascular endothelial growth factor (VEGF) 176 vascular tumours, hepatic 366 vasoactive agents, splanchnic 272, 273, 273, 278 vasoactive intestinal polypeptide (VIP) 404 vasoconstrictors, splanchnic 273 vasodilatation, peripheral 120, 268 vasopressin 272, 273, 277, 345 analogues 278 venography, hepatic 344, Plate 74 veno-occlusive disease (VOD) 343 infants 60 post-bone marrow transplant 291, 292, Plate 53 venous access central 31 TPN-induced complications 405 venous catheterization complications 27 procedure 26 venous thrombosis central venous lines 31 complicating TPN 404, Plate 86 see also under portal vein venovenous bypass 388 ventilation, mechanical fulminant hepatic failure 118–19, 120 post-liver transplant 390 verrucae 304 very long-chain acyl CoA dehydrogenase (VLCAD) 85

492

Index

very long-chain fatty acids (VLCFA) 229, 230, 230 vincristine 176, 370 viral haemorrhagic fever 100–1 viral hepatitis acute 93–101 investigations 93, Plate 17 causes 92, 93 chronic 130–42 developing world 428–32 differential diagnosis 112 fulminant hepatic failure 107–9, 112, Plate 12 haematological disorders 290 non A-G see non A-G (non A-E) hepatitis see also specific types viral infections cutaneous, immunocompromised patients 304–5 post-small bowel transplant 414–15 Reye syndrome and 231 viruses biliary atresia aetiology 42, 325 hepatotropic 92, 93, 93 inducing autoantibodies 143 non-hepatotropic 92, 93, 93 vitamin(s) deficiencies 61, 265, 266 post-Kasai 330 supplements 10, 265, 267 abetalipoproteinaemia 237 cystic fibrosis 204 mitochondrial energy disorders 80, 228 neonatal cholestasis 61–2, 62 vitamin A carotenaemia and 302 cystic fibrosis liver disease 200 deficiency 266 supplementation 61, 62, 265, 267 vitamin B12 binding proteins 368

vitamin B12-responsive methylmalonic acidaemia 87 vitamin D deficiency 266, 330 supplementation 62, 62, 265, 267 vitamin E deficiency 61, 266, 330 supplementation abetalipoproteinaemia 237 chronic cholestasis in infants 62, 62 chronic liver disease 265, 267 non-alcoholic fatty liver disease 191 see also alpha-tocopheryl polyethylene glycol succinate vitamin K 266 deficiency 61, 266 supplementation chronic cholestasis in infants 62, 62 chronic liver disease 265, 267, 276 fulminant hepatic failure 115, 116 paracetamol overdose 152 volvulus, mid-gut 403 vomiting, management 10 Von Gierke’s disease 212–15 von Meyerburg complexes 165–6

well water, infantile copper toxicosis and 256 white nails 301 Wilms’ tumour 293, 363–4 Wilson’s disease (WD) 245, 246–54, 247 clinical presentations 247–9, 248, 261 developing world 423 diagnosis 19, 246, 249–51 fulminant hepatic failure 110, 113, 248, Plate 44 management 122, 253 prognostic index 253 gene see ATP7B gene genetics 245, 251 haplotype analysis 250–1 hepatic steatosis 189 liver transplantation 254, 379 neuropsychological impairment 5, 248, 253 pathology 249, Plate 45 pregnancy 253–4 presymptomatic 253 protein see ATP7B treatment 251, 251–4 Wolman disease 57, 221, 226 Wood’s light examination 306, 310

WAGR gene locus 363–4 waiting list, liver transplantation 386 walnut oil 10 Warren procedure 348, 348 warts, viral 304, 309, Plate 62 water supply, infantile copper toxicosis and 256 Watson–Miller syndrome see Alagille’s syndrome Wegener’s granulomatosis 294 weight gain, liver transplant recipients 396 weight loss, non-alcoholic fatty liver disease 190–1 Weil’s disease 101

xanthelasma 302 X-rays 20 yellow fever 100 yolk sac tumour, malignant 368 Zellweger spectrum disorders 229, 230 Zellweger syndrome (ZS) 56–7 clinical features 56, 229, Plate 7 fulminant hepatic failure 110 zidovudine 294 zinc deficiency 266, 302, 330 therapy, Wilson’s disease 251, 252–3