Liver Transplantation - Vademecum

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V ad e me c u m

LANDES BIOSCIENCE

V ad e me c u m

Table of contents 1. Liver Transplantation: An Overview 2. The Allograft Immune Response

9. Medical Management of the Liver Transplant Patient 10. Pediatric Liver Transplantation

3. Assessment for Liver Transplantation

Liver Transplantation

4. Management on the Liver Transplant Waiting List 5. The Liver Transplant Operation 6. Immunosuppression after Liver Transplantation 7. Graft Dysfunction 8. Recurrence of Disease after Liver Transplantation The Vademecum series includes subjects generally not covered in other handbook series, especially many technology-driven topics that reflect the increasing influence of technology in clinical medicine. The name chosen for this comprehensive medical handbook series is Vademecum, a Latin word that roughly means “to carry along”. In the Middle Ages, traveling clerics carried pocket-sized books, excerpts of the carefully transcribed canons, known as Vademecum. In the 19th century a medical publisher in Germany, Samuel Karger, called a series of portable medical books Vademecum. The Landes Bioscience Vademecum books are intended to be used both in the training of physicians and the care of patients, by medical students, medical house staff and practicing physicians. We hope you will find them a valuable resource.

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Michael R. Lucey James Neuberger Abraham Shaked

v a d e m e c u m

Liver Transplantation

Michael R. Lucey, M.D., F.R.C.P.I. University of Wisconsin School of Medicine Madison, Wisconsin, U.S.A. James Neuberger, D.M., F.R.C.P. University of Birmingham Birmingham, United Kingdom Abraham Shaked, M.D., Ph.D. University of Pennsylvania Medical Center Philadelphia, Pennsylvania, U.S.A.

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VADEMECUM Liver Transplantation LANDES BIOSCIENCE Georgetown, Texas U.S.A. Copyright ©2003 Landes Bioscience All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Printed in the U.S.A. Please address all inquiries to the Publisher: Landes Bioscience, 810 S. Church Street, Georgetown, Texas, U.S.A. 78626 Phone: 512/ 863 7762; FAX: 512/ 863 0081 ISBN: 1-57059-657-4

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While the authors, editors, sponsor and publisher believe that drug selection and dosage and the specifications and usage of equipment and devices, as set forth in this book, are in accord with current recommendations and practice at the time of publication, they make no warranty, expressed or implied, with respect to material described in this book. In view of the ongoing research, equipment development, changes in governmental regulations and the rapid accumulation of information relating to the biomedical sciences, the reader is urged to carefully review and evaluate the information provided herein.

Contents 1. Liver Transplantation: An Overview ................................. 1 Michael R. Lucey History ....................................................................................................... 1 The Donor Organ Shortage ........................................................................ 1 Outcome of Liver Transplantation .............................................................. 3

2. The Allograft Immune Response ....................................... 5 Peter Abt and Abraham Shaked The Alloimmune response .......................................................................... 5 Recognition of Self and Non-Self ................................................................ 5 Recipient T- and B-cell Activation .............................................................. 5 Stages of Allograft Response ........................................................................ 8 Classification of Allograft Rejection .......................................................... 11 Mechanisms of Immunosuppressive Drug Action ..................................... 12 Tolerance .................................................................................................. 12 Glossary .................................................................................................... 14

3. Assessment for Liver Transplantation .............................. 17 Michael R. Lucey Selection for Liver Transplantation ............................................................ 17 Assessment of Severity and Prognosis of Chronic Liver Disease ................. 17 Timing of Placement on the Waiting List ................................................. 19 Transplantation for Non-Life Threatening Disease .................................... 20 Allocation and Distribution of Donor livers .............................................. 20 Contraindications to Liver Transplantation ............................................... 20 Live liver donation .................................................................................... 20 Assessment of Medical, Surgical and Psychological Suitability ................... 22 Cardiac Assessment ................................................................................... 22 Pulmonary Assessment .............................................................................. 22 Renal Assessment ...................................................................................... 23 Endocrine Assessment ............................................................................... 25 Assessment for Primary Hepatic Malignancy ............................................. 25 Assessment for Infection ........................................................................... 26 Nutritional Assessment ............................................................................. 27 Bone Disease ............................................................................................. 27 Nutrition .................................................................................................. 27 Surgical Assessment .................................................................................. 28 Psychological assessment ........................................................................... 28 Specific Disorders ..................................................................................... 29 Retransplantation ..................................................................................... 34

4. Management on the Liver Transplant Waiting List ......... 36 James Neuberger Introduction ............................................................................................. 36 Prevention of Complications of End-Stage Liver Disease .......................... 36 Cancer Development ................................................................................ 38

Vaccinations .............................................................................................. 40 Progression of Medical Complaints ........................................................... 41 Temporary Suspension from the Waiting List ........................................... 41

5. The Liver Transplant Operation...................................... 42 Michael Crawford and Abraham Shaked Cadaveric Donors ..................................................................................... 42 The Cadaveric Donor Operation .............................................................. 42 Extended criteria donors ........................................................................... 46 The Recipient Operation .......................................................................... 48 Special Operative Problems ....................................................................... 54 Live Liver Donors ..................................................................................... 57

6. Immunosuppression after Liver Transplantation ............ 60 James Neuberger Drugs and Other Agents Used in Immunosuppression ............................. 61 Types of Immunosuppression ................................................................... 61 Medications Used for Immunosuppression ............................................... 61 Principles of Immunosuppression ............................................................. 67 Side-Effects of Immunosuppression .......................................................... 71 Tailoring the Immunosuppression to the Individual .................................. 71 Retransplantation for Chronic Rejection, Late Acute Rejection and Early Ductopenic Rejection ............................................................ 72 Co-Morbid Conditions ............................................................................. 72 Development of Lymphoma and Other Malignancy ................................. 72

7. Graft Dysfunction ........................................................... 74 Geoffrey H. Haydon Introduction ............................................................................................. 74 Investigation of Graft Dysfunction ........................................................... 74 Primary graft non-function ....................................................................... 74 Immunological Complications .................................................................. 74 Graft Infection .......................................................................................... 78 Graft Ischemia .......................................................................................... 81 Biliary Complications ............................................................................... 83 Recurrence of Disease After Liver Transplantation .................................... 84

8. Recurrence of Disease after Liver Transplantation .......... 86 Lisa Forman and Geoffery Haydon Hepatitis C Virus Infection ....................................................................... 86 Hepatitis B Virus Infection ....................................................................... 87 Hepatitis D virus Infection ....................................................................... 88 Hepatitis A Virus Infection ....................................................................... 88 Autoimmune Disease ................................................................................ 88 Metabolic Diseases .................................................................................... 90 Malignancy ............................................................................................... 92

9. Medical Management of the Liver Transplant Patient ..... 95 Anne Burke Long Term Morbidity and Mortality of Liver Transplantation ................... 95 Medical Consequences of Immunosuppression ......................................... 95 Cardiovascular Disease .............................................................................. 95 Renal Insufficiency ................................................................................... 98 Osteoporosis and Osteopenia .................................................................... 99 Malignancy ............................................................................................. 100 Infections After Recovery from Liver Transplantation ............................. 101 Vaccinations ............................................................................................ 102 Common Causes of Morbidity in Liver Transplant Recipients ................ 102 Pregnancy and Reproductive Health ....................................................... 104 Lifestyle .................................................................................................. 106

10. Pediatric Liver Transplantation ..................................... 107 Elizabeth B. Rand and Kim M. Olthoff Indications for Liver Transplantation in Children ................................... 107 Evaluation of Pediatric Candidates and Timing of Liver Transplantation ....................................................................... 107 PELD ..................................................................................................... 109 Pre-Operative Management .................................................................... 110 Surgical Issues and Options .................................................................... 110 Early Post-Operative Management .......................................................... 111 Subsequent Management ........................................................................ 112

Index ............................................................................. 114

Editors Michael R. Lucey M.D., F.R.C.P.I. Professor of Medicine Chief, Section of Gastroenterology and Hepatology University of Wisconsin School of Medicine Madison, Wisconsin, U.S.A.

James Neuberger, D.M., F.R.C.P. Professor in Medicine Liver Unit Queen Elizabeth Hospital Birmingham, United Kingdom

Abraham Shaked, M.D., Ph.D. Professor of Surgery Chief, Division of Transplantation University of Pennsylvania Medical Center Department of Surgery Philadelphia, Pennsylvania, U.S.A.

Contributors Peter Abt, M.D. Department of Surgery University of Pennsylvania Health System Philadelphia, Pennsylvania, U.S.A.

Geoffrey H. Haydon, M.R.C.P., M.D. Liver Unit Queen Elizabeth Hospital Birmingham, United Kingdom

Anne Burke, M.B., B.Ch., B.A.O. Division of Gastroenterology University of Pennsylvania Health System Philadelphia, Pennsylvania, U.S.A.

Kim M. Olthoff, M.D. Department of Surgery Fred and Suzanne Biesecker Center for Pediatric Liver Disease University of Pennsylvania Health System Philadelphia, Pennsylvania, U.S.A.

Michael Crawford, M.D. Departments of Upper Gastro-Intestinal and Transplant Surgery Royal Prince Alfred Hospital Sydney, New South Wales Australia Lisa Forman, M.D. Division of Gastroenterology and Hepatology University of Colorado Health Sciences Center Denver, Colorado, U.S.A.

Elizabeth B. Rand, M.D. University of Pennsylvania School of Medicine Fred and Suzanne Biesecker Center for Pediatric Liver Disease Children’s Hospital of Philadelphia Philadelphia, Pennsylvania, U.S.A.

Preface The purpose of this volume is to provide a short, didactic handbook for those clinicians (medical, surgical, nursing and others) who are involved in the care and management of people who may, are or have undergone liver transplantation. We are aware that there are several, large texts which provide a comprehensive account of liver transplantation. This volume is designed to complement and not replace them. Liver transplantation has developed rapidly over the last two decades and dogma is changing rapidly. This leads to controversy and debate which are the essence of academic medicine. We are also aware that different transplant programs have their own approach to managing patients. It is inevitable that many views and arguments cannot be put in such a book as this one. Where possible, we have tried to provide a consensus view. We have provided selected references for further reading and electronic addresses to source material, for the reader who wishes to probe deeper into any aspect of liver transplantation. We are grateful to the authors who have contributed to this book. We have tried to ensure a consistent style and hope the reader finds this useful and helpful. Finally, if there are any errors or omissions, the editors would be grateful if these could be identified, so that we may correct them in future editions. Michael R. Lucey James Neuberger Abraham Shaked August 2002

Liver Transplantation: An Overview

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CHAPTER 1

1

Liver Transplantation: An Overview Michael R. Lucey History Thomas Starzl carried out the first human liver transplant in 1963 in Denver. Initially the outcomes were very poor; however, the persistence of Starzl and his team was rewarded and in 1968 Calne set up the second transplant program in Cambridge. Patients were usually very sick at the time of transplant and few survived the post-operative care. Over the next two decades, the numbers of patients grafted gradually increased and survival rates improved. There is no one reason for this improvement, but better selection, improved anesthetic and surgical techniques, the use of powerful and specific anti-microbials and immunosuppressive agents all made significant contributions. In the 1980s, new programs developed primarily in North America and in Europe. Now liver transplantation has become a routine procedure for patients with end-stage liver disease. The decision to consider liver transplantation is based on: 1. An assessment of the severity of liver failure, 2. The prognosis for the patient in response to current medical/surgical therapy 3. The quality of the patent’s life (as a consequence of the liver disease) 4. The judgment on the potential for liver transplantation to restore the patient’s health. The determination of suitability is independent of the underlying diagnosis, and for that reason the conditions for which liver transplantation may be an appropriate therapy constitute a list of almost all liver diseases.

The Donor Organ Shortage The source for donor livers in the western world is almost exclusively from heart beating brain dead donors. Sophisticated schemes are required to identify potential donors, retrieve their organs, and transport the organs to the location of the potential recipient. At the same time, the number of potential recipients awaiting liver transplant continues to grow at a furious pace, outstripping the modest increases in donor numbers. This has meant that there are many more recipients for every donor liver. Thus in the United States in 2000, there were over 17000 patients on the waiting list, only 4579 cadaveric transplants done and 371 living related transplants. There were 1347 deaths on the waiting list. (See www.unos.org for current data) Liver Transplantation, edited by Michael R. Lucey, James Neuberger and Abraham Shaked. ©2003 Landes Bioscience.

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The disparity between donor availability and recipient number has led to growing numbers of patients on the waiting list for liver transplant. Innovative responses to the donor shortage have been introduced but while these approaches may help relieve the situation, they are unlikely to ease the effects of the organ shortage: 1. Non-heart beating donors. Non-heart beating donors are uncommon, and the frequency of primary graft non-function and later, biliary strictures are greater in these allografts. 2. Split livers—the division of a cadaveric organ between two recipients. However, only some cadaveric donor livers are suitable for splitting. 3. Living donation—the harvesting of liver segments from living donors. Many recipients lack a family member or friend who is suitable or willing for living donation. Moreover, living segmental liver transplantation poses real risks of morbidity and even mortality (1% or more) for the donor. 4. Use of marginal donors and extended use donor organs • Marginal donors: some donor livers are associated with a higher probability of primary non-function (the so-called marginal donor). Marginal organs include those from older or obese donors, or donors who are unstable prior to organ retrieval. Other marginal grafts include steatotic livers, in which histology demonstrates greater than 25% microvesicular or macrovesicular fat. These grafts are associated with a higher incidence of primary non-function of the allograft. • Extended use organs from patients infected with present or past viral hepatitis B or C and those with extrahepatic malignancy or treated bacterial infection. Organs from virus-infected donors are matched to a recipient already infected by the same virus, albeit only after the recipient is apprised and has given consent. An example would be putting an anti-hepatitis C positive liver into an antihepatitis C positive recipient, or an anti-HBcore positive liver into an HBsAg positive recipient. 5. Xenotransplants: the use of genetically modified animals, such as pigs or primates, is still a very long way from clinical use. While some of the problems of hyperacute rejection may be overcome, problems, such as chronic rejection, freedom from introducing infection (such as the porcine endogenous retrovirus (PERVs) as well as physiological concerns make it unlikely that this approach will provide a solution to the organ shortage in the next decade. 6. Increasing organ donation: there are wide variations in the rates of organ donation—between 8 and 37 donors per million. Attempts to increase organ donation by education have largely failed: the most successful model in Spain is dependent on provision of a well-organized system of donor co-ordinators and acceptance of older donors. 7. Future approaches may include stem cell transplantation and hepatocyte transplantation. Thus, it is unlikely that these methods will meet the needs of all potential recipients.

Liver Transplantation: An Overview

3

Table 1. Factors influencing the outcome of orthotopic liver transplantation Donor Factors: Donor age: older donors are less successful Donor gender: Significantly worse results when a female liver is given to a male recipient Donor liver fat content: >25% fat at increased risk of primary allograft non function Recipient Factors: Acutely ill: requiring ICU care before transplantation Acute renal failure Recipient diagnosis: (see Table 2) Factors independent of Donor or Recipient: Center activity—small centers have been linked to poor outcome. This is a controversial observation.

Outcome of Liver Transplantation Liver transplantation has become the treatment of choice for many forms of lifethreatening liver disease because of the continuing lack of less radical therapies and the gradual improvement in survival and quality of life after liver transplantation. Five-year survival in excess of 75% is expected for most patients, and patients who have survived more than 10 years after transplantation are commonplace in long established programs. The success of liver transplantation has occurred despite unacceptably high early mortality and morbidity in a subset of recipients. In addition, we now have to learn the best ways of managing the unwanted consequences of long term immunosuppression and recurrence of the original disease in the long-term survivor. The outcome of liver transplantation is dependent on donor organ and recipient factors. See Table 1. Donor factors, which reduce graft success, include donor age and transplantation of a liver allograft from a female donor into a male recipient. It is widely held that the fat content of the donor liver influences early graft function, perhaps by facilitating the generation of reactive oxidative species. Although the etiology of liver disease usually does not preclude liver transplantation, nevertheless, the cause of the underlying liver disease significantly affects the outcome after liver transplantation. • The best outcomes are observed in patients with chronic cholestatic disorders and in chronic liver failure from cirrhosis of many causes. • The outcome is worse among patients transplanted for fulminant liver failure and significantly worse in patients with malignant disease of the liver. • Retransplantation carries a poorer outcome than primary grafting. The outcome of liver transplantation is influenced by the severity of illness of the recipient prior to surgery. Patient and graft survival are significantly impaired in recipients requiring intensive care unit management or among patients with multisystem failure, prior to transplant. The allocation system currently in use in the

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Liver Transplantation

Table 2. Outcome of liver transplantation in the United States

1

Primary Diagnosis

N (94-95) 1 Year

Std Err N Survival%

5 Year

Std

Survival% Err Non-Cholestatic Cirrhosis 3520

86.2

0.6

10734 70.1

0.6

Cholestatic Liver Disease 939

89.4

1.1

3477

80.7

0.8

Biliary atresia

337

91.9

1.6

1549

82.1

1.2

Acute Hepatic Necrosis

392

77.5

2.2

1367

67.1

1.5

Metabolic Disease

274

88.7

2

978

79.9

1.5

Malignant Neoplasms

151

76.3

3.9

796

35.4

2.2

Overall

6271

87

0.5

20063 72.3

0.4

Based on The U.S. Scientific Registry of Transplant Recipients and The Organ Procurement and Transplantation Network. Transplant Data 1988-1996. Reference 1

United States, Spain and Germany ensures that donor livers are offered preferentially to such high-risk candidates. Finally, center characteristics influence outcome after liver transplantation, at least in the United States where it has been shown that mortality rates are significantly higher in centers that perform 20 transplants or fewer per annum, compared to centers which perform more than 20 annually.

Suggested Reading 1. 2.

3.

4.

The U.S. Scientific Registry of Transplant Recipients and The Organ Procurement and Transplantation Network. Transplant Data 1988-1996. (See: www.unos.org) Markmann J, Doyle HR, Morelli R, McMichael J, Doria C, Aldrighetti L et al. Hepatic retransplantation—An analysis of risk factors associated with outcome. Transplantation 1996; 61:1499-1505. Edwards EB, Roberts JP, McBride MA, Schulak JA, Hunsicker LG. The effect of the volume of procedures at transplantation centers on mortality after liver transplantation. N Engl J Med 1999; 341:2049-2053. Trotter JF, Wachs M, Everson GT, Kam I. Medical progress: Adult to adult transplantation of the right hepatic lobe from a living donor. N Engl J Med 2002; 346:1074-1082.

The Allograft Immune Response

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CHAPTER 2

The Allograft Immune Response Peter Abt and Abraham Shaked The Alloimmune Response In this Chapter there is a simplified account of the interaction between the host immune system and the allograft.

Recognition of Self and Non-Self The histocompatability antigens are a set of protein products that constitute the self-identity that is unique in each individual. T-cells are educated to identify and tolerate self antigen, whereas the encounter with any non-self antigen will lead to the initiation of immune response. The most recognized histocompatibility antigens are the class I and class II glycoproteins of the major histocompatibility complex (MHC) (Fig. 1, Table 1). Class I is expressed on all nucleated cells and in general is responsible for activating T-cells bearing the CD8 surface molecule (CD8+). Of the several class I genes, A and B are the most important for clinical transplantation. MHC class II glycoproteins are expressed primarily on dendritic cells, B-cells, and macrophages. As a group, these cells are also referred to as antigen presenting cells, due to their avidity by which they display peptide in conjunction with MHC. In general the greater the divergence between donor and recipient MHC antigens the stronger the immune response. Before being transported to the plasma membrane of the cell, MHC class I and class II undergo intracellular processing and are loaded with peptides in the antigen presenting cell (Fig. 2). Peptides that are derived from the allograft are recognized as non-self by T-cells, leading to initiation of immune response against the transplanted organ. The peptides which stimulate the immune response involved in acute cellular rejection of the liver allograft remain to be determined. The diagnosis of acute cellular rejection in liver allografts is dependent on the demonstration of a mixed inflammatory cell infiltrate in the portal triads. Biliary epithelium and venous endothelium are the early targets of cellular rejection on account of their rich expression of class I and II MHC antigens. In contrast, hepatocytes which express few class I or II MHC antigens are rarely the target of early acute cellular rejection

Recipient T- and B-Cell Activation Recipient T-cells are required for allograft rejection. The T-cell receptor is able to recognize donor MHC antigens displayed on the surface of the antigen-presenting

Liver Transplantation, edited by Michael R. Lucey, James Neuberger and Abraham Shaked. ©2003 Landes Bioscience.

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Figure 1. Schematic structure of MHC class I and class II.

Figure 2. Antigen processing and presentation. The antigen presenting cell presents exogenous protein bound to class II molecules to CD4+ T-cells and also processes intracellular protein and presents it with MHC class I to CD8+ T-cells. The T-cell receptors recognize peptide bound to MHC.

The Allograft Immune Response

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Table 1. Characteristics of MHC molecules Common features of MHC Class I and II glycoproteins • allelic diversity • antigen presentation Differing characteristics Class I MHC molecules: • expressed on all nucleated cells • activate T-cells bearing the CD8 surface molecule (CD8+) Class II MHC molecules: • expressed on dendritic cells, B-cells, and macrophages • activate T-cells bearing the CD4 antigen (CD4+)

cell. T-cell recognition is associated with the initation of complex intracellular signaling pathways that result in activation and proliferation of the T-cell (Fig. 3). There are two classes of T-cells based on the surface expression of CD4 or CD8 molecules. CD4 and CD8 molecules bind to the same MHC on the antigen presenting cell as the T-cell receptor. CD4+ cells are known as helper cells and play an important role in initiating and directing the immune response (Fig. 4). CD8+ cells also known as cytotoxic T-cells are responsible for cell directed cytotoxicity. Whether a T-cell, whose receptor has bound the MHC-peptide displayed on the antigen presenting cell, becomes activated, depends on a receiving a second set of signals (co-stimulation) from the antigen presenting cell. These costimulatory interactions act directly through cell surface receptor-ligand interactions and soluble cytokines that are linked to intracellular signaling pathways (Fig. 4). CD4+ T-cells are the dominant phenotype initiating acute cellular allograft rejection. Once activated the CD4+ T-cells undergo clonal expansion and differentiation. In doing so they secrete cytokines that attract other leukocytes to activate other T-cells and facilitate the differentiation of B-cells to plasma and memory cells. The pattern of cytokines elaborated by subsets of CD4+ and CD8+ stimulated T-cells is important in directing the alloimmune response. CD4 bearing Th lymphocytes (T helper) cells have been stratified into two classes of Th cells depending on the type of cytokines elaborated by the cells in question. The subdivision of Th cells is called the Th1 and Th2 paradigm. Precursor CD4 cells producing interleukin-12 promote Th 1 cells, whereas precursor CD4 cells producing interleukin-4 (IL-4) promote Th2 cells.Th1 cells secrete IFN-γ, IL-2, which promote cell-mediated cytotoxicity by activating macrophages and cytotoxic T cells. Th2 cells secrete IL-4 and IL-6, cytokines which promote allergic inflammation and stimulate B cells to produce antibodies. Furthermore, cytokines from Th 1 cells inhibit Th2 cells whereas cytokines from Th 2 cells inhibit Th1 cells. It appears in certain experimental situations that a Th 2 predominance is associated with the prolongation of graft survival or even tolerance (Table 2). While much attention has been given to T-cell activation, B-cells are also involved in the response. Donor antigen shed from the graft binds to surface Ig and is then internalized by the B-cell. The antigen is processed and presented on the B-cell

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Liver Transplantation

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Figure 3. T-cell receptor: The T-cell receptor (TCR) is composed of two subunits and is associated with CD3 proteins. Transcriptional activity is initiated in the nucleus via signaling pathways. (NFAT = nuclear factor of activated T-cells)

surface in conjunction with class II to recruit antigen specific T-cell help. The B-cell undergoes clonal expansion and differentiation becoming a plasma cell capable of producing soluble Ig (Fig. 5). Other B-cells will become memory cells.

Stages of Allograft Response The immunologic events surrounding transplantation of an allograft can be conceptualized as a series of steps starting with changes in the graft prior to transplantation and extending to the time of rejection.

Antigen Presentation and Allorecognition When first transplanted, the liver allograft has the immune phenotype of the donor. Initially therefore, the liver allograft expresses the MHC molecules of the donor, resulting in two pathways of antigen recognition. Whereas in the nontransplant setting, T cells recognize foreign (or non-self ) peptides bound to native (or self ) MHC molecules, the MHC molecules in the allogeneic liver are non self, and it is presumed that recipient T cells recognize intact donor MHC molecules as non-self because their three-dimensional stoichiometry resembles a self MHC bound to a foreign peptide, a concept referred to as molecular mimicry. This process is called direct antigen recognition and is thought to be the main mechanism for the immune response in acute cellular rejection. Later, there is migration of donor dendritic cells into the host, and migration of recipient APCs into the donor liver. This leads to a second pathway for alloimmune recognition, in which peptides derived

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The Allograft Immune Response

2

Figure 4. Cell surface proteins involved in T-cell activation. The T-cell receptor complex, including CD3 and CD4 or CD8 bind to an APC displaying MHC and peptide. Several costimulatory molecules such as CD28 are required for T-cell activation.

Table 2. Th 1 and Th 2 paradigm Differentiated by

Cytokines Produced

Function

Th1

IL-12

IL-2, IFN-γ

cell mediated cytotoxicity suppresses Th2-cell response

Th2

IL-4

IL-4, Il-5, IL-6

suppresses Th1-cell response promotes B-cell expansion

IL-10

from catabolism of the donor MHC molecules are presented by self MHC on recipient APCs. It is unclear whether the non-immunologic injury incurred by the donor liver in the process of organ retrieval, preservation and reperfusion contribute to the initiation or maintenance of the alloimmune response. The period of cold preservation, ischemia, and reperfusion leads to the differential expression of endothelial cell surface molecules and cytokines. These include adhesion molecules, interleukins, and

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Figure 5. Antibody structure. Heavy chains are in dark, light chains are white. The antigen binding sites are composed of heavy and light chains.

chemokines which attract inflammatory cells. Oxygen radicals produced during ischemia and reperfusion directly harm the graft. Helper T cells are thought to be the most important cells for initiating allograft cellular rejection. They are responsible for the production of cytokines, such as interleukin 2, which are necessary for clonal expansion of activated lymphocytes. The cytokines act in an autocrine fashion on CD4 expressing surface molecules (Th cells) and as a paracrine stimulus on other effector cells such as cytotoxic T cells (CD8 cells), macrophages and B cells.

Leukocyte Migration into the Allograft As part of the early evolution of the allograft immune response, recipient leukocytes are recruited to the donor allograft. This involves the elaboration of a series of soluble molecules as well as cell-to-cell interactions. Three main classes of receptors are credited with leukocyte migration.

The Allograft Immune Response

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• Selectins: primarily responsible for allowing the leukocyte to gently adhere to the endothelial surface • Integrins • Members of the immunoglobulin superfamily: responsible for extravasation of leukocytes into the allograft.

Graft Destruction CD8+ T-cells are the main effectors of graft destruction and cause cell death through direct cell contact. When activated by membrane binding to the allograft they release cytotoxic molecules termed perforin and granzyme. Perforins create holes in the target cell membrane and granzymes disrupt intracellular processing. Cytotoxic T-cells also have a cell surface protein termed Fas ligand which when bound to a receptor protein called Fas, which is present on target cells, results in death of the target cell by the process of apoptosis. Macrophages which have been activated by CD4+ T-cells are capable of causing tissue destruction through the release of cytotoxic cytokines or through direct cell lysis. The role of NK cells in organ allograft rejection is unclear. B-cells secrete specific antibody that binds to the allograft cell surface. The antibody induces tissue damage through the activation of the complement system (Fig. 6).

Classification of Allograft Rejection Allograft rejection is classified into three types based on the nature of the immune response after transplantation: 1. Hyperacute rejection 2. Acute cellular rejection 3. Chronic ductopenic rejection.

Hyperacute Rejection Hyperacute rejection is characterized by a rapid response of the host immune system to the allograft. Within minutes to hours of the transplant, preformed antibodies engage class I MHC or the ABO blood group antigens on the graft. The antibodies facilitate complement mediated lysis of the endothelium and initiate an inflammatory cell infiltrate. Hyperacute rejection is rarely observed in liver transplants, even among those with a positive crossmatch.

Acute Cellular Rejection Acute cellular rejection is due to an immune reaction mediated by recipient T lymphocytes’ response to donor MHC antigens. Antibodies and cytokines also contribute to the immunologic attack. The biliary epithelium and venous endothelium express MHC class I and II molecules and are the focus of the acute cellular rejection response. Hepatocytes which express few class I or II MHC antigens are rarely the target of acute cellular rejection. The principal clinical features of acute cellular rejection are: 1. Elevated liver transaminases and/or bilirubin 2. Lymphocytic infiltrates in the portal triads seen on biopsy

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Liver Transplantation

3. The development of graft dysfunction manifested by hyperbilirubinemia and subsequent impaired liver synthetic function. Acute cellular rejection is usually controlled with additional corticosteroid-based immunosuppression with no significant impact on graft or patient survival.

2

Chronic Ductopenic Rejection Chronic ductopenic rejection occurs months to years after transplantation. The mechanisms which underlie chronic rejection in any of the solid organs are less well understood than acute cellular rejection. Both immunologic and non-immunologic processes are implicated. The impact of chronic rejection on the liver allograft is on the intralobular bile ducts, a phenomenon termed the “vanishing bile duct syndrome” and is associated with chronic graft failure. It is believed that many if not all episodes of chronic ductopenic rejection are preceded by acute cellular rejection.

Mechanisms of Immunosuppressive Drug Action The rational design and use of drugs is based on an understanding of the immune response to the donor organ. These agents can be divided by classes based on their mechanism of action. The antimetabolites include azathioprine and mycophenolate mofetil. Both interfere with purine synthesis and clonal expansion of T- and B-cells (Fig. 7). Cyclosporine and tacrolimus exert their action by inhibiting calcineurin, a protein responsible for promoting cytokine induced gene activation. By inhibiting IL2 production they prevent activation of lymphocytes. Rapamycin (Sirolimus), one of the most recently approved antirejection drugs, is structurally similar to tacrolimus, and appears to inhibit the T-cell response to IL-2. Glucocorticoids bind to cytoplasmic receptors which are translocated to the nucleus where they regulate gene transcription by binding to specific gene regulatory regions. They interfere with many aspects of the immune system including the production of IL-1, IL-2, and IFN-γ. Antibodies recognize many surface antigen epitopes (polyclonal) or single cell surface antigen epitopes (monoclonal). Antithymocyte globulin and thymoglobulin are two polyclonal preparations of immunoglobulin to lymphocytes. OKT-3 is directed against the CD3 receptor on T-cells. Basiliximab and daclizumab are two monoclonal antibodies against the α chain of the IL-2 receptor. They are used for induction therapy and like the other antibodies result in depletion of the cells that bear the cell surface protein which they bind.

Tolerance The development of an immunologic state wherein the recipient is unresponsive to donor alloantigen, but yet the immune system is capable of recognizing and responding to other foreign proteins such as bacterial or tumor antigens without the need for immunosuppression is known as tolerance. Mechanisms of tolerance can be grouped into suppression, anergy, deletion, and ignorance. Suppression involves the inhibition of donor reactive T and B-cell responses by a “suppressor” cell population. While functional examples exist, it has been difficult

The Allograft Immune Response

13

2

Figure 6. Antibody mediated damage to graft endothelium. Recipient antibody binds to MHC on graft endothelium. Antibody initiates graft damage through antibody dependent cellular cytotoxicity (ADCC) and activation of the complement system.

Figure 7. Mechanism of action of commonly used immunosuppresants. Cyclosporine (CSA), tacrolimus (FK506), mycophenolate mofetil (MMF), azathioprine (AZA), FK506 binding protein (FKBP).

identifying a suppressor cell. Anergy occurs when T-cells encounter peptide-MHC complexes that they recognize, but the T-cell does not receive adequate co-stimulatory signals. Deletion, the destruction of alloreactive T-cells, is likely to occur in the thymus, and to a lesser extent in the periphery. Ignorance indicates that alloreactive T-cells are present, but do not respond to stimuli.

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Glossary

2

Acquired immunity: All immune processes utilizing immunological memory (see below). Acquired immunity is the basis of vaccination. Acute cellular rejection: Inflammation of the allograft elicited by genetic disparity between the donor and recipient, primarily affecting interlobular bile ducts and vascular endothelia, including portal veins and hepatic venules, and occasionally the hepatic artery and its branches. Allele: Alternative forms of the same gene Allogeneic: Genetically dissimilar donor and recipient pair of the same species. The converse is syngeneic. Allotype: Antigenic determinants that differ among individuals of the same species. Examples include different epitopes of the HLA system. Anergy: Immunologic tolerance in which lymphocytes become functionally unresponsive. Antigen presenting cell (APC): Functional descriptor of specialized cells bearing MHC cell surface molecules, by which they ‘present’ peptides which are the product of intracellular degradation of exogenous proteins recognized as non-self. Activated APCs also express co-stimulatory molecules. Macrophages and dendritic cells are paradigmatic APCs. Apoptosis: Also called programmed cell death. A specific form of cell death due to enzymatic degradation of DNA, without inflammation. B-cells: Lymphocytes capable of antibody production. Most arise from stem cells in bone marrow. B lymphocytes produce antibodies as circulating proteins or as stationary molecules. The latter, which constitute the B cell receptor, contain a hydrophobic transgenic sequence which tethers the immune recognition segment of the antibody to the cell surface membrane. Cell mediated immunity: Immunologic response based on cellular elements of the immune system. CD antigen: Cell surface antigens, classified according to ‘cluster of differentiation’ (CD), in which individual molecules are assigned a CD number on the basis of their reactivity with specific monoclonal antibodies CD3: A complex of molecules on the cell surface of T cells, that in association with the T cell receptor (TCR), activate intracellular signal transduction mechanisms when the TCR binds an antigen. Blockade of CD3 by a monoclonal antibody (Orthoclone OKT3) depletes the patient of T cells. CD4: Cell surface molecule expressed by functionally distinct subset of T lymphocytes. CD4 binds to an invariant part of the MHC class II molecule. CD4 bearing T cells usually act as T helper (Th) cells and recognize antigens processed by APCs and presented in conjunction with MHC class II molecules. CD8: Cell surface molecule expressed by functionally distinct subset of T lymphocytes. CD8 binds to an invariant part of the MHC class I molecule. CD8 bearing T cells usually act as cytotoxic T lymphocytes (CTLs) and recognize antigens processed by infected or injured nucleated cells and presented in conjunction with MHC class I molecules.

The Allograft Immune Response

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CD28: The best characterized co-stimulatory molecule. Cell surface molecule expressed by T lymphocytes, activated by binding of TCR and antigen ligand. CD 28 has two known ligands (variously named B7-1 or CD80 and B7-2 or CD86) which are expressed on the cell surface of activated APCs. CTLA-4: Cell surface molecule, structurally similar to CD28, which also binds B7-1 and B7-2. In contrast to the CD28-B7 interaction, linkage of CTLA-4 and B7 leads to an inhibitory signal that terminates the inflammatory response. Chemokine: Chemotactic cytokines that regulate leukocyte transit. Each type of leukocyte bears chemokine receptors on its cell surface that guides it to chemokines secreted in tissues. Chronic ductopenic rejection: Defined by two histopathological features: obliterative vasculopathy and bile duct loss Clone: Genetically identical cells derived from a common ancestor. Co-stimulatory signal: Non-antigen specific interaction between lymphocytes and antigen presenting cells which uses cell surface molecules expressed on APCs to bind to receptors on lymphocytes (e.g., CD 28 on lymphocytes and B7-1 on APC). Co-stimulatory signals enhance the immune response by promoting lymphocyte clonal expansion and cytokine production and are necessary for T cell activation. Interaction of T lymphocyte and APC in the absence of co-stimulatory signals leads to anergy or apoptosis of the T cell. A parallel receptor ligand interaction which is inhibitory of the immune response is described through CTLA-4. Cytokine: A large family of low molecular weight soluble proteins involved in regulating cellular activity. Includes the chemokines (see above). Cytotoxic T lymphocyte (CTL): T lymphocyte that kills its target upon recognizing complexes of peptides and MHC complexes on the target cell membrane. Cytotoxic T cells usually express the CD8 cell surface molecule. Epitope: The structure within an antigen that is recognized by an antigen receptor (antibody or T cell receptor). Graft versus host disease (GVHD): Clinical syndrome caused by immune reaction of allogeneic lymphocytes contained within allograft tissue reacting against alloantigens in the recipient (usually in skin, liver, and gastrointestinal tract). Haplotype: Closely linked alleles on the same chromosome, usually inherited as a group and linked to inheritance of some phenotypic characteristic. Helper T cell: T lymphocytes that secrete cytokines required for the immune function of other cells in the immune system. MosT helper T cells express the cell surface molecule CD 4. Human leukocyte antigens (HLA): The major histocompatibility complexes in humans. Humoral immunity: Immunologic response involving antibodies. Idiotype: An antigenic determinant within the binding site of an antibody that is recognised by another antibody. Immunologic memory: The ability of the immune system to recall an encounter with a specific antigen, and to generate a greater response in a subsequent exposure to the same alloantigen. Immunologic memory results from the generation of

2

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memory T and B cells during the initial encounter with an alloantigen, and is the characteristic feature of ‘acquired immunity’. Innate immunity: All immunologic defenses that lack immunologic memory. The characteristic feature is that the response remains unchanged however often a specific immunogenic moiety (immunogen) is encountered. This contrasts with ‘acquired immunity’ (see above). Isograft: Transplant between genetically identical members of the same species such as inborn strain of animals or twins. Also known as a syngeneic transplant. Major histocompatibility complexes: Histocompatibility antigens expressed on cell surfaces which are the markers by which the immune system distinguishes self from non-self. In humans, the MHC molecules are called HLA (see above). Memory cells: Cells with lasting response to certain immunologic epitopes. Natural killer (NK) cell: Lymphocytes that have an innate ability to kill infected or damaged cells, without requiring interaction with MHC surface molecules. T-cell: Lymphocyte which undergoes selection in the thymus. T cells are the only cells essential to the acute cellular rejection response. T cells are distinguished by their cell surface receptor (TCR). T cells are subdivided into categories: T helper cells and T suppressor cells. Tolerance: An immunologic state in the absence of immunosuppression wherein the recipient is unresponsive to donor alloantigens, while retaining the capacity to recognize and respond to other foreign proteins such as bacteria or tumor antigens. Vaccination: The exposure of a naïve host to a harmless version of a pathogenic immunogen (an altered pathogen, or molecular mimic) which in turn generates memory cells but not the pathologic consequences of the infection itself (the primary immune response). The immune system is thus primed to deliver an enhanced secondary immune response in the event that the host is exposed to the infectious agent in the future. Xenotransplantation: Transplantation across species. The graft is called a xenograft. Based on Delves and Roitt, New Engl J Med 2000; 343:37-49; and Sayegh and Turka, New Engl J Med 1998; 338:1813-1821.

Suggested Reading 1.

2. 3.

4.

Delves PJ, Roitt IM. The immune system-the first of two parts. New Engl J Medicine 2000; 343:37-49. The immune system-the second of two parts. New Engl J Med 2000; 343:108-117. Sayegh MH, Turka LA. The role of T-cell co-stimulatory activation pathways in transplant rejection. New Eng J Med 1998; 338(25):1813-1821. Wiesner RH, Batts KP, Krom RA. Evolving concepts in the diagnosis, pathogenesis, and treatment of chronic hepatic allograft rejection. Liver Trans Surg 1999; 5:388-400. Wiesner RH, Demetris AJ, Belle SH, Seaberg EC, Lake JR, Zetterman RK et al. Acute hepatic allograft rejection: incidence, risk factors, and impact on outcome. Hepatology 1998; 28:638-645.

Assessment for Liver Transplantation

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CHAPTER 3

Assessment for Liver Transplantation Michael R. Lucey Selection for Liver Transplantation Evaluation of candidates for liver transplantation can be reduced to three core questions: • What is the severity and prognosis of the patient’s liver disease? • Are there confounding medical, surgical or psychological factors which would reduce the expectation of a successful liver transplant? • What are the wishes of the patient in regards to liver transplantation? These questions are best addressed in a multidisciplinary process. The evaluation may be carried out in an outpatient setting. The prospective candidate is assessed by transplant surgeons and physicians, social workers, and selected subspecialists including psychiatrists, cardiologists, pulmonologists and nephrologists. Previous investigations including radiographs and biopsies are retrieved and new investigations are ordered where necessary. When the information gathering segment of the evaluation is complete, the patient is presented to the transplantation evaluation committee and a decision is made regarding placement on the transplant waiting list. Liver transplant programs must inform and educate prospective recipients and their families of the risks and benefits of liver transplantation. It is important to provide the patient with the opportunity to withdraw from transplant assessment if they do not wish to proceed. Conversely, whenever the transplant program determines that the patient is not a suitable candidate, the program should facilitate the patient in receiving a second opinion regarding their suitability, if they should so wish.

Assessment of Severity and Prognosis of Chronic Liver Disease The severity of liver failure in patients with chronic liver disease can be assessed by several models although the two models currently used are the Child-Pugh classification and the MELD score (model for end-stage disease).

Child-Turcotte-Pugh Class (Table 1) This scoring scheme is an empiric compilation of five features of end-stage liver failure: • Ascites • Encephalopathy Liver Transplantation, edited by Michael R. Lucey, James Neuberger and Abraham Shaked. ©2003 Landes Bioscience.

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• Prothrombin time • Serum bilirubin • Serum albumin It was developed originally as an instrument to predict outcome after portacaval shunt surgery. Later Pugh modified it for a study of esophageal transection for bleeding esophageal varices and modified the score for patients with cholestatic diseases. It has been adopted as the most easily administered clinical tool to assess severity of cirrhosis. Survival of cirrhotic patients declines with worsening Child’s class. The Child’s class is useful for segregation of cirrhotic patients according to risk of dying. It does not indicate prognosis for an individual patient with cirrhosis. Furthermore, its origin as an empiric instrument for specific circumstances related to portal hypertension make it less useful as a prognostic guide in many circumstances in which liver transplantation is under consideration. These include patients with chronic cholestatic diseases, liver tumors or fulminant liver failure. The Child-Pugh classification has not been verified in childhood disorders.

Table 1. Child-Turcotte-Pugh classification Variable Encephalopathy Ascites Bilirubin (mg/dl) Albumin (g/dl) Prothrombin time (sec. prolonged) (INR)

None None <2 >3.5 <4 <1.7

Points 1 Moderate Slight 2-3 2.8-3.5 4-6 1.7-2.3

2

3

Severe Moderate >3 <2.8 >6 >2.3

Primary Biliary Cirrhosis/Primary Sclerosing Cholangitis Bilirubin

1-4

4-10

>10

Scores are summed to determine Child’s class: A = 5-6, B = 7-9 and C = 10-15.

MELD Score The MELD score is based on the following three variables: • INR (International Normalized Ratio) • Serum bilirubin • Serum creatinine To obtain the MELD score for any patient, access the Internet at: www.unos.org or: www.mayo.edu/int-med/gi/model/mayomodl-5-unos.htm There are other prognostic scoring schemes: • Primary biliary cirrhosis: sustained elevation of total bilirubin is the single most influential factor in predicting outcome. Patient age, serum albumin, prothrombin time and the presence of edema are minor influential factors. The presence of cirrhosis is a weak prognostic factor. • Primary sclerosing cholangitis: patient age, serum bilirubin, albumin and

Assessment for Liver Transplantation

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aspartate transaminase and a history of variceal hemorrhage have been constructed into a prognostic instrument. Although the allocation priority scheme in the United States does not incorporate prognostic scoring schemes specific to either primary biliary cirrhosis, or primary sclerosing cholangitis, these scoring schemes allow transplant physicians to recognize patients with poor prognosis.

3 Table 2. Indications for consideration of liver transplantation in patients with chronic liver disease Recurrent gastroesophageal variceal hemorrhage Refractory ascites Spontaneous bacterial peritonitis Severe hepatic encephalopathy Hepatorenal syndrome Profound non-responsive pruritus of cholestatic liver disease Severe hepatic osteopathy Hepatocellular carcinoma Progressive rise in serum alpha-fetoprotein without mass Refractory bacterial cholangitis Severe coagulopathy due to liver failure Severe sustained fatigue and weakness Severe malnutrition Hepatopulmonary syndrome

Timing of Placement on the Waiting List A useful approach to the often difficult questions regarding timing of placement of a patient with liver disease on the transplant waiting list is to consider compensated (or stable) and decompensated cirrhosis. Stable cirrhosis is defined as cirrhosis in a patient who has never experienced any one of the four cardinal features of decompensation: variceal hemorrhage, accumulation of ascites, jaundice associated with cirrhosis, or encephalopathy. Decompensated cirrhosis: cirrhosis and the onset of at least one of these clinical phenomena is defined as decompensated cirrhosis. The onset of decompensation is associated with significantly impaired survival and indicates the need to evaluate for liver transplantation. Spontaneous bacterial peritonitis and/or hepatorenal failure are indicators of significantly worsened prognosis, and should prompt transplantation evaluation. Indications for evaluation of liver transplantation are shown in Table 2. Paradoxically, some of these indications may, when severe, become contraindications to transplantation.

Transplantation for Non-Life Threatening Disease Liver transplantation is also indicated for conditions which cause unacceptable loss of quality of life: • Lethargy: is associated with chronic liver disease. However it is important

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to exclude treatable causes such as depression, hypothyroidism, or unwanted effects of medication. • Pruritus: All therapeutic options are tried before transplantation, when liver function is well maintained. Such therapies include cholestyramine, cholestipol, rifampin, naltrexone, ursodeoxycholic acid, phenytoin, and plasmapheresis. • Hepatic osteodystrophy: when progressive may be an indication for transplantation.

Allocation and Distribution of Donor Livers Different countries have adopted different approaches to allocation of cadaveric donors of solid organs for transplantation: US: In the US, there is no Federal limitation on the number of transplant centers. Patients are centrally listed and available organs allocated to the individual recipient. At present allocation gives priority to the sickest patient. The greatest priority is given to patients with fulminant hepatic failure or primary allograft non-function, and for certain pediatric indications. For all other candidates, priority is determined by the MELD or PELD (the pediatric scoring system) score. An adjustment has been made for patients with hepatocellular cancer. For an up to date account of these variations on the MELD/PELD scheme, consult the UNOS website (www.unos.org). UK: The number of centers designated for NHS (public funded) treatment is controlled by central government. The six transplant units have areas (according to their contracted activity) and any organ offered in their area can be used for a listed patient. Supra-urgent patients (those with fulminant hepatic failure) will have national priority. The individual unit determine which recipient should receive donor organs offered to that area. The units have agreed indications and contra-indications to ensure equity and justice. (See www.uktransplant.org.uk) Europe: European countries have adopted a range of approaches to organ retrieval, allocation and distribution. For more information see: www.eurotransplant.nl.

Contraindications to Liver Transplantation Absolute and relative contraindications to liver transplantation are shown in Tables 3 and 4.

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Table 3. Absolute contraindications Severe (uncontrolled) infection outside the hepatobiliary system Metastatic cancer (except some neuroendocrine cancers) Extra hepatic cancer (other than local skin cancer) Cholangiocarcinoma Advanced cardiopulmonary disease AIDS Severe pulmonary hypertension Technical considerations (e.g., widespread intra-abdominal venous thrombosis)

Table 4. Relative contraindications Recent drug or alcohol abuse Age >70 years HIV infection, without AIDS Inability to be compliant with immunosuppression protocol and/or participate in routine post-transplant medical follow-up Advanced chronic renal disease Moderate pulmonary hypertension

Live Liver Donation The use of live donors for liver transplantation was developed in response to the inadequate donor organ supply. Live liver donation began with left lobe resection from adults for transplantation into babies and small children. More recently, adult to adult transplantation, in which the right lobe of a healthy adult is resected and transplanted into an adult with severe liver disease, has been adopted by many transplant programs in North America and Europe. Live liver donation places the healthy living donor at risk and mandates that a careful selection process be applied to the donor. The mortality for a donor of a hepatic right lobe is up to 2%. In brief, a consensus has emerged that donors for adult to adult transplant must be: • Healthy • Of identical or compatible ABO type • Able to give informed consent and understand the risks of being a living donor • Have sufficient body mass to provide a donor graft with a graft recipient • Graft to recipient weight ratio (GRWR) of at least 0.8, and preferably 1.0., whilst leaving at least 25% of the native liver remaining in the donor. The selection of recipients to receive a donor partial hepatectomy is less well defined. At the time of writing, there is an emerging consensus that adult to adult live liver donation should be offered to patients who demonstrate increased urgency without requiring ICU-based life support. Very ill unstable patients (i.e., patients requiring ICU based life support) need of a full size graft. The very stable patient who is not in danger of foreseeable death can wait safely and may get a cadaveric organ. The patients most appropriate for receiving a graft from adult to adult living liver donation are those who have recovered from an episode of decompensation,

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those who manifest a gradual decline, and patients with newly diagnosed small hepatocellular cancer.

Assessment of Medical, Surgical and Psychological Suitability

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All patients must undergo full history and examination. History of vaccination and need for further vaccination is covered in Chapter 4.

Cardiac Assessment A history of systemic hypertension, angina pectoris, myocardial infarction or age greater than 45 years necessitates a cardiology evaluation. This includes: • Chest radiography (standard in all patients) • Stress cardiography • Echocardiography • In selected cases coronary angiography (selected patients) However, the degree of abnormality that precludes transplantation has not been established or agreed. The echocardiogram provides evidence of cardiac function and an estimate of pulmonary artery pressure (see porto-pulmonary hypertension below). It is often difficult to interpret ejection fraction (EF) data in patients with endstage liver failure and ascites. These patients have low systemic vascular resistance, and this lack of ‘afterload’ means that even a cardiomyopathic heart can have an apparently ‘low normal’ EF. No absolute thresholds of EF have achieved consensus for acceptance as a suitable candidate for liver transplantation. Similarly, there is no consensus on how to interpret a prior history of coronary artery bypass grafting or myocardial infarction, but many of these patients may be excluded from liver transplantation. A history of symptomatic peripheral vascular disease should lead to formal evaluation of peripheral arterial flow. Significant claudication supported by flow data will usually exclude the patient from transplantation.

Pulmonary Assessment Clinical Evaluation A history of dyspnea on moderate exertion, chronic cough or any degree of hemoptysis are unequivocal warning signals of pulmonary disease. If the peripheral oxygen saturation is low, arterial blood gases should be measured both lying and standing, with and without oxygen. A low oxygen saturation, which declines when the patient assumes a standing position (orthodeoxyia), suggests hepatopulmonary syndrome. This requires full pulmonary investigation such as ‘bubble echocardiography’ to assess vascular shunting. Patients with symptomatic chronic obstructive pulmonary disease (COPD) or other evidence of significant pulmonary disease need: • Formal spirometry and • Measurement of diffusion capacity

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There are no absolute thresholds that determine that a patient is unsuitable for surgery or postoperative recovery. Patients should be strongly advised to stop smoking cigarettes and other tobacco products whether or not there is manifest lung damage. However, most programs do not exclude patients who are unable to stop tobacco use.

Porto-Pulmonary Hypertension Idiopathic pulmonary hypertension associated with portal hypertension is called porto-pulmonary hypertension. It is defined by high mean pulmonary artery pressure (MPAP) (normal <25 mm/hg), high pulmonary vascular resistance (PVR) (normal <120 dynes.centimeters -5) and normal pulmonary capillary wedge pressure (PCWP). Evidence of pulmonary hypertension on echocardiography requires right heart catheteriztion. Mild to moderate (MPAP <35 mm/Hg) poses no risk for transplantation. Severe porto-pulmonary hypertension is associated with high intraand post-operative mortality. The utility of liver transplantation with simultaneous continuous administration of prostacycline, or combined liver-lung transplantation in patients with porto-pulmonary hypertension is unknown.

Hepatopulmonary Syndrome Portal hypertension may also be associated with abnormal intrapulmonary shunts that result in VQ mismatch and hypoxia. This is called hepatopulmonary syndrome. Hepatopulmonary syndrome may gradually resolve after successful liver transplantation, although the restoration of arterial partial pressure of oxygen (Pa O2) to normal may take months.

Cystic Fibrosis The colonization of the affected lungs by Burkholderia cepacia is an absolute contraindication.

Renal Assessment Many patients with acute or chronic liver failure have concomitant impairment of renal function. The causes of renal failure in patients with serious liver disease include: • Established parenchymal kidney injury either related to the cause of liver disease (such as HCV infection) or independent of it. • The patient with end-stage liver failure is at risk for acute insults to the kidney as a consequence of the acute decompensation such as: • A result of interventions and therapies which compromise the kidney as due to over-use of diuretics or nephrotoxic drugs and contrast medium • Hypotension • Hepatorenal failure. This is a complex disorder in which homeostatic mechanisms in the splanchnic and renal vasculature act together to produce a ‘pre-renal type’ renal failure in which there is vasoconstriction of the intrarenal arterioles, and avid retention of sodium from the glomerular fitrate. Treatment is by correction of

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intra-vascular volume contraction (usually with albumin) and occasionally, glypressin, somatostatin, midodrine, TIPS. The assessment of renal function: • Inspection of urine • Laboratory investigation of the urine for protein, blood and electrolytes • Measurement of serum creatinine.

3

Microscopy Microscopy of the urine may reveal nephritic sediment (red cell casts, white cell casts).

Low Urinary Sodium Hepatorenal syndrome and prerenal uremia both produce avid retention of filtered sodium and reduced urinary sodium. Urinary sodium is measured on a ‘spot urine’ and a level less than 10 mEq per ml is the standard threshold for recognizing sodium retention. This result is confounded by recent exposure to loop diuretics.

Urinary Protein Many patients with end-stage liver failure have peripheral edema and reduced serum albumin concentrations. Hypoalbuminemia in cirrhotic patients is often attributed to synthetic failure and it is easy to overlook renal protein loss. Diabetic renal disease or glomerulonephrititis associated with chronic infection with hepatitis B or C are common causes of nephrotic syndrome in ‘liver patients’. Spot urine protein levels should be checked in all candidates for liver transplantation, and a formal 24-hour collection made in anyone with detectable protein.

Glomerular Filtration Serum creatinine is a inaccurate indicator of glomerular filtration in cirrhotic patients, especially those with ascites or malnutrition. Formal measurement of glomerular filtration rate is appropriate whenever there is concern that the full extent of renal impairment might be masked. An elevated serum creatinine has been repeatedly found to be an independent risk factor predicting a worse outcome after liver transplantation. There are many causes for lowered graft and patient survival in patients with elevated serum creatinine prior to transplantation suggesting that serum creatinine is acting as a surrogate for many high risk factors.

Combined Liver-Kidney Transplantation There is controversy about the relative value of isolated orthotopic liver transplantation in the face of established renal failure, compared with combined liver kidney transplants. If the kidney failure is mainly due to hepatorenal syndrome, then the patient should receive an orthotopic liver transplant only. If there is advanced intrinsic kidney disease, serious consideration must be given to dual organ replacement.

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Endocrine Assessment Diabetes Many patients with end-stage liver failure are diabetic or have insulin resistance. Retrospective analysis suggests that persons with diabetes mellitus requiring insulin or hypoglycemic tablets therapy have a worse outcome after transplantation, as a result of cardiac, renal or microvascular damage. The value of pancreas transplantation in diabetic patients undergoing liver transplantation is controversial and probably should be confined to centers studying combined transplants according to a prospective protocol.

Sexual Endocrinology Many women capable of menstruation experience amenorrhoea as a result of end-stage liver failure. Specific investigation of ‘ovarian failure’ is not necessary in these circumstances. Menstrual periods are restored in 80% of these women within three months of successful liver transplantation. Male impotence is common in end stage liver failure. While liver transplantation may restore male sexual function, the causes are often multifactorial (especially diabetes, and drugs such as anti-hypertensives).

Thyroid Disease Thyroid disease (hypo- or hyper-thyroidism) is associated with many chronic liver diseases and thyroid function should be routinely checked in all, and corrected where appropriate. In the sick patients, pseudo-hypothyroidism may be present but does not require intervention.

Assessment for Primary Hepatic Malignancy Primary Liver Cell Cancers Hepatocellular Carcinoma The development of liver cell cancer is suggested by the development of spaceoccupying lesions on liver imaging or a rising serum alpha-fetoprotein level. All candidates for liver transplantation should undergo a careful evaluation for cancer, including: • Measurement of serum alpha feto protein • Imaging of the liver parenchyma. The choice of cross sectional image of the abdomen includes sonography plus Doppler studies, spiral CT or MR imaging. Analysis of the UNOS database up to 1996 shows a five year survival for all patients undergoing liver transplantation for malignant neoplasms to be 35.4% (n=796), compared with 72.3% for all liver transplants (n=20,063). In contrast, acceptable outcomes occur when tumors meet the following criteria: • Small unifocal hepatocellular carcinomas, defined as less than 5 cm in greatest diameter

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Liver Transplantation

• Few multifocal hepatocellular carcinomas, defined as up to three tumors whose greatest diameter is no more than 3 cm • Without evidence of vascular invasion or extrahepatic spread Biopsy confirmation of a tumor is usually contra-indicated, as it is likely to spread the tumor along the biopsy track.

3

Other Primary Liver Cancers ‘Slow growing’ tumors such as hepatoblastomas and neuroendocrine tumors are occasionally considered appropriate for transplantation.

Cholangiocarcinoma There is general agreement that patients with cholangiocarcinoma should not receive liver transplantation, except within a defined research protocol (see discussion page 36). The detection of cholangiocarcinoma is often difficult.

Extrahepatic Malignancy Screening and Those with a Past History of Cancer A past history of malignancy provides a difficult challenge for the transplant assessment team to determine how many disease free years are required to reduce the chance of recurrence to an acceptable minimum. All adult women need gynecologic assessment including ‘Pap’ cervical cytology smear. Women over 40 years should undergo mammography. All patients greater than 40 years should be considered for occult colon cancer with hemoccult testing followed by colonoscopy wherever the screening is positive. Where there is a higher risk, as those with ulcerative colitis, a colonoscopy should be done. Sigmoidoscopy is inadequate, as there is a high incidence of right sided colon cancers All men older than 45 years should undergo testing for prostatic specific antigen (PSA).

Assessment for Infection TB Screening for tuberculosis includes chest radiograph and, in patients at risk, placement of PPD (purified protein derivative). Candidates who are PPD positive may be treated with antituberculosis monotherapy (e.g., Isoniazid for 6 months) prior to transplantation or treatment may be postponed until after the transplant.

HIV All patients should be screened for antibodies to human immunodeficiency virus (HIV). The role of liver transplantation in HIV-infected patients with end-stage liver failure is controversial.

Assessment for Liver Transplantation

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Other Viruses Antibodies to Hepatitis A, B and C, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and herpes simplex virus (HSV) are measured as baseline studies. In the case of CMV, the viral status of the donor and recipient predict the risk of CMV disease after transplant.

Nutritional Assessment Protein and Calories Many patients with end-stage liver failure are malnourished and malnutrition is associated with a poor outcome after transplantation. Unfortunately, it is difficult to restore nutritional well being in outpatients with liver failure. Many liver patients are already on restricted diets: sodium restriction to diminish poorly controlled ascites, protein restriction to control recurrent hepatic encephalopathy, and fluid restriction in hyponatremic patients. Most cirrhotic patients, even those with intermittent hepatic encephalopathy, can tolerate 80 grams of protein per day.

Vitamins People with chronic cholestasis and those on bile acid sequestrants (such as cholestyramine) are at risk of malabsorption of fat-soluble vitamins. • Vitamin K should be used in patients with prolonged clotting, • Vitamin D levels (serum 25 hydroxycholecalciferol) should be measured and replenished where needed, • Vitamin A replacement should be considered when there is the possibility of deficiency.

Bone Disease Patients with chronic liver disease may have many reasons for excessive bone loss: chronic cholestasis, corticosteroids, chronic alcoholism, and postmenopausal state in women. Bone densitometry should be considered in: • Female candidates above the age of 45 years • Patients who have received corticosteroids for at least one year • Patients with a history of chronic cholestatic disorders

Treatment

• Supplementation with Vitamin D and calcium as appropriate. • Add etidronate or palmidronate in patients shown to be osteoporotic.

Nutrition Patients with cirrhosis from any cause tend to be malnourished. Malnutrition is associated with a poor outcome after liver transplantation. Reasons for malnutrition include: • Anorexia (common) • Inappropriate dietary advice. In particular, patients with end-stage liver

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failure should be encouraged to ingest up to 2 grams/kg of protein per day. The risk of hepatic encephalopathy from dietary protein has been overstated. • Malabsorption • Associated pancreatitis • Associated celiac sprue (associated with autoimmune hepatitis and PBC) Where there is evidence of malnutrition, candidates for transplantation should have a formal assessment of their nutritional state. This should include: • Dietary assessment • Height, weight and body mass index (measured as weight(kg)/height(m2)) If there is evidence of malnutrition: • Assessment of possible malabsorption • Assessment of nutrition: measure mid-arm circumference and skin-fold thickness • Give dietary advice: aim for calorie intake 35-50kcal/kg ideal body weight and, unless hepatic encephalopathy is a clinically significant problem, ensure the daily protein intake is at least 1.3-1.5g /kg ideal body weight. • If the patient cannot tolerate such an intake, consider nutritional supplements. Obese patients are at greater risk of morbidity and mortality after transplantation and therefore should be advised to lose weight.

Surgical Assessment There are few surgical contraindications to liver transplantation. Any prior surgery in the right upper quadrant increases the risk of surgery and probable blood loss. Extensive thrombosis of the portal venous system including the superior mesenteric vein may preclude transplantation. Careful radiological assessment is mandatory in these patients. Angiography remains the gold standard, but in many instances, magnetic resonance (MR) scanning with gadolinium angiography has largely replaced formal angiography, avoiding intravenous contrast in patients with marginal renal function.

Psychological Assessment All patients should be assessed for any psychological factors that might affect the survival and quality of life after transplantation. The transplant evaluating team must seek the opinion of psychiatric experts to assess prognosis of the psychiatric disorder. The psychological assessment may be confounded by hepatic encephalopathy. Patients with a combination of end stage liver failure, hepatic encephalopathy and a history of significant psychiatric disorder present some of the most difficult dilemmas which come before the transplant evaluating team.

Assessment for Patients with Alcoholic Liver Disease and a History of Drug Addiction More than 80% of transplant programs in North America and Europe include assessment by a psychiatrist or addiction specialist in the evaluation of patients with

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alcoholic liver disease. Assessment is directed to determining the likelihood that the candidate will remain abstinent from addictive substances both before and after transplant and will comply with all aspects of follow-up. Although it remains controversial as an indicator of future abstinence, the great majority of liver transplant programs in North America and Europe either require or place a value on a period of abstinence in determining whether to place an alcoholic patient on the waiting list. Many programs will use an approach that also assesses the patient’s acceptance of alcoholism, their social support to remain abstinent, and their use of behavior modifying programs such Alcoholics Anonymous. Whether such assessments distinguish accurately future drinkers from abstainers remains in doubt. Many programs insist that the alcoholic or addicted candidate participate in addiction therapy as a prerequisite to either placement on the transplant list, or to reception of a donor liver. The degree of physical impairment due to liver failure dictates the capacity of the candidate to acquiesce to required treatment. Furthermore, there is no consensus on how best to manage a patient found to have returned to alcohol use while waiting for transplantation. Many centers will ‘recycle’ the patient though alcoholism assessment and reconsider replacement on the list after achieving a certain period of sobriety. This period is usually set arbitrarily at 6 months. It remains uncertain whether the presence of a major psychotic disorder (bipolar disease, unipolar depression, and schizophrenia) should preclude liver transplantation. Candidates who carry a diagnosis of major psychosis are often functional on therapy.

Specific Disorders Fulminant and Subfulminant Hepatic Failure (FHF, SHF) Acute hepatic injury presents as a sudden increase in previously normal liver transaminase. Acute hepatic injury in the absence of hepatic encephalopathy almost always resolves. FHF is defined as the development of acute hepatic encephalopathy (see Table 5) within 8 weeks of the onset of symptomatic hepatocellular disease in a previously healthy person. Sub-acute hepatic failure is also termed submassive hepatic necrosis, subfulminant hepatic failure, subacute hepatic failure and late-onset hepatic failure. It is defined by the development of acute hepatic encephalopathy within 9 to 26 weeks of the onset of symptomatic hepatocellular disease in a previously healthy person. It is characterized by a slow and fluctuating illness, with usually mild encephalopathy and progressive ascites. Unlike FHF, the INR is rarely more than 3.0. These patients usually die unless they are transplanted. Cerebral edema, leading to increased intracranial pressure (ICP), is a common feature of severe fulminant hepatic failure and may cause permanent cerebral injury and death. The onset of cerebral edema may occur during surgery and in the first 48 hours post-transplantation. Fulminant hepatic failure and submassive hepatic necrosis are always accompanied by severe coagulopathy. The causes of fulminant hepatic failure are shown in Table 6.

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Table 5. Clinical grades of acute hepatic encephalopathy Grade

Mental State

Asterixis Findings

Electroencephalogram

I.

Altered affect, subtle loss of mental acuity, slurred speech

Slight or none

Normal

II.

Accentuation of stage I, drowsiness, Inappropriate behavior, loss of sphincter control

Easily elicited

Abnormal, generalized slowing

III.

Sleepy but rousable, marked confusion, can answer simple questions only

Present when patient can cooperate

Always abnormal

IV.

Coma

Cannot cooperate

Always abnormal

3

IVa. IVb.

Responds to pain No response to pain

Acetaminophen toxicity is the most common cause of acute liver injury and fulminant hepatic failure in Great Britain. Alcoholics, those on enzyme inducing drugs and those who are malnourished, are at particular risk of acetaminopheninduced hepatic failure. Acetaminophen-induced liver injury in alcoholics is the most common cause of fulminant hepatic failure in the US. Acute viral hepatitis is an important cause of both fulminant and subfulminant failure. In many cases, the cause of FHF is not clear and there are no serological clues as to the diagnosis. These patients are often classified as non-A non-B non C hepatitis but a more accurate term is sero-negative hepatitis as there is usually no evidence for a viral cause The causes of subfulminant hepatic failure are similar to those for FHF, once the causes of the most acute forms of acute hepatic injury such as acetaminophen-induced liver injury have been omitted. Ischemic hepatitis (also called ‘shock liver’) usually recovers with medical support. Most patients with FHF have a small, shrinking liver. An enlarged liver is associated with either venous-outflow obstruction or infiltration by tumor. In such cases, where venous outflow obstruction has been excluded by imaging, a liver biopsy should be considered.

Assessment for Liver Transplantation

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Table 6. Causes of fulminant hepatic failure and subfulminant hepatic failure Viral Infection Hepatitis A Hepatitis B Hepatitis B and D Hepatitis C Other viruses (less common) Herpes (in immunosuppressed persons, including pregnant women) Cytomegalovirus Epstein-Barr Varicella Adenovirus Poisons, Chemicals and Drugs (Note: assume that ANY drug, herbal remedy or toxin may be associated with liver damage) Amanita phalloides Acetaminophen (paracetamol) Halogenated volatile anesthetics (especially halothane) Isoniazid and other anti-TB medication Valproate Monoamine oxidase inhibitors Ecstasy Ischemia and Hypoxia Hepatic vascular occlusion Acute circulatory stroke Heat stroke Gram-negative sepsis Miscellaneous Acute fatty liver of pregnancy Reyes syndrome Wilson’s disease* Hodgkin’s disease and other lymphomas Malignant infiltration Hereditary fructose intolerance Galactosemia, tyrosinemia Idiopathic hepatitis (also called non-A to non-E) *strictly not FHF as almost all patients have established cirrhosis at the time of presentation

Predicting Outcome in Fulminant hepatic failure and Subacute hepatic necrosis In general, the deeper the coma, the worse the outcome. Paradoxically, rapid onset of encephalopathy is a favorable prognostic sign, whereas delay in the onset of encephalopathy after the onset of jaundice indicates a lack of spontaneous recovery and is unfavorable prognostic factor. Consequently, most acetaminophen-induced fulminant hepatic failure patients who experience grade III coma recover spontaneously, while submassive hepatic necrosis has a particularly poor outcome.

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Criteria for determining the prognosis of fulminant hepatic failure are shown below (Table 7).

Table 7. Prognostic criteria for predicting requirement of liver transplantation in patients with fulminant hepatic failure

3

Acetaminophen Toxicity: pH <7.3 (irrespective of grade of encephalopathy) or Prothrombin time >50 seconds and serum creatinine >3.4 mg/dL (300 µmol/L) in Patients with grade III or IV encephalopathy: Arterial blood lactate >3.5 mmol/l is associated with a high mortality. All Other Causes: Prothrombin time >50 seconds (irrespective of grade encephalopathy) or Any three of the following variables (irrespective of grade of encephalopathy): Age <10 years or >40 years Liver failure due to halothane or other drug idiosyncrasy or idiopathic hepatitis Duration of jaundice prior to encephalopathy >7 d Prothrombin time >25 seconds Serum bilirubin >17.5 mg/dL (300 µmol/L) Adapted from O’Grady et al. Gastroenterology 1989; 97:439. The prothrombin time thresholds have been reduced for application in the US due to differences in laboratory methods to assay prothrombin time between Europe and US. In Europe, prothrombin times should be multiplied by 2.

These criteria separate acetaminophen-induced FHF from all other causes. Druginduced hepatic failure, other than that caused by acetaminophen, has a poor prognosis. Examples include hepatic failure due to phenytoin or halothane. HBVand HAV-induced hepatic failure have a better outcome than idiopathic (presumed viral) fulminant hepatic failure. Patients younger than 2 years or older than 40 years have a poor prognosis. Renal failure is also a poor prognostic factor. Some have recommended serum factor V levels as an indicator of when to proceed to transplant. A factor V level of less than 20% is a poor prognostic indicator. Acidosis is a valuable prognostic factor, particularly in acetaminophen- induced fulminant hepatic failure. Whilst listed and awaiting a suitable donor organ, the patient may deteriorate (sepsis, cardiovascular or pulmonary failure, or cerebral edema) which may make transplantation impossible. For this reason, human heterotopic auxiliary transplants, live donor segmental liver transplantation, extracorporeal perfusion through human or pig livers or artificial hepatocyte perfusion devices, and xenografts have been attempted to sustain the patient until spontaneous recovery develops or a suitable organ is found.

Assessment for Liver Transplantation

33

Chronic Hepatitis C The problem of chronic hepatitis C relates to the recurrence after transplantation. Strategies to reduce HCV RNA are currently being evaluated. This is discussed in Chapter 8.

Hepatitis B Infection HBV: Markers for active viral replication such as HBeAg and HBV DNA used to be considered relative contraindications to liver transplantation. The advent of anti-viral agents including lamivudine and postoperative management protocols using HBIg has allowed successful transplantation in high-risk patients. Patients who have circulating HBV DNA should receive treatment with lamivudine while awaiting transplantation. Antibodies to hepatitis D should be measured in HBsAg positive patients. Co-infection by hepatitis D ameliorates the severity of post-transplant hepatitis B infection. Management of HBV after transplantation is discussed in Chapter 8.

Hemochromatosis Patients with hemochromatosis have a worse outcome after liver transplantation than patients with other diagnoses. Some of this effect is due to failure to recognize hemochromatosis during the pre-transplant evaluation. All candidates should have serum iron, transferrin and transferrin saturation, and ferritin estimated. We recommend the measurement of the hemochromatosis gene test (HFE) in anyone with iron saturation in excess of 45% or in anyone with a suggestive history for hemochromatosis (personal or family history of diabetes, cirrhosis, and arthritis). HFE is positive as a homozygous test for the major allele (C282Y) or heterozygous for both the major and minor allele (H62D) in 80% or more of affected persons depending on the ethnic diversity of the population in question. Diabetic candidates for liver transplantation need particularly careful cardiac assessment.

Primary Sclerosing Cholangitis Colitis and Colon Cancer Those with PSC and inflammatory bowel disease (IBD) have a greater risk of both cholangiocarcinoma and colon cancer than patients with IBD alone. Since the colon cancer is likely to develop in the right colon, all patients should have a colonoscopy to assess the presence and degree of colitis as well as exclude colon cancer. Colectomy at the time of transplantation does not seem to add to the risks of the procedure.

Cholangiocarcinoma Because the tumor spreads early along the lymphatics and nerves, the detection of cholangiocarcinoma is a contraindication for transplantation. Exclusion of cholangiocarcinoma is difficult as the tumors are often not visualized on imaging, whether by ultrasound, CT, MR or PET scanning. Bile cytology, while specific, is not sensitive and ERCP is associated with a risk of inducing severe cholangitis and/

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or pancreatitis. Serum markers, such as CEA and CA19-9 may help but have not the specificity nor sensitivity required.

Non-Alcoholic Fatty Liver

3

Non-alcoholic steatohepatitis (NASH) and it’s variant non-alcoholic fatty liver disorder (NAFLD) are terms used to describe an idiopathic clinico-pathological spectrum of disorders characterized by macrovesicular and microvesicular deposition within hepatocytes. NASH is associated with histologic appearances of inflammation in the hepatic lobule often with Mallory’s hyaline, in the absence of alcohol consumption. NASH occurs in conjunction with insulin resistance, obesity, and hyperlipidemia, although not all patients exhibit all of these elements of the syndrome. NASH may progress to fibrosis within the liver and is thought to be an important cause of cryptogenic cirrhosis. Some patients with cryptogenic cirrhosis thought to be due to NASH progress to liver failure and are candidates for liver transplantation.

Celiac Sprue Because of the association between celiac sprue and autoimmune disorders such as autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis, all caucasian candidates for orthotopic liver transplantation should be screened for celiac disease by measurement of serum anti-endomysial antibodies. When positive, a duodenal biopsy is mandatory.

Retransplantation Early Retransplantation Early retransplantation (usually defined as within the first 30 days) is required for primary allograft non-function, hepatic artery thrombosis and massive hemorrhagic necrosis. Such patients behave like those with fulminant hepatic failure, and require emergency placement on the waiting list.

Late Retransplantation Late retransplantation is required for management of graft failure due to recurrent disease, vascular or biliary problems, or chronic ductopenic rejection. Survival is less than that observed for primary graft recipients. Retransplantation on account of recurrent viral hepatitis has a poor outcome due to aggressive recurrence of the underlying disorder. Further attempts at rescue with second, third or fourth grafts are associated with progressively poorer outcomes in mortality and morbidity.

Suggested Reading 1. 2. 3. 4.

Krowka MJ. Hepatopulmonary syndromes. Gut 2000; 46:1-4. Lee WM. Management of acute liver failure. Seminars in Liver Disease 1996; 16:369-378. Cardenas A, Uriz J, Gines P, Arroyo V. Hepatorenal syndrome. Liver Trans 2000; 6:S63-571. Neuberger J, Schulz KH, Day C, Fleig W, Berlakovich GA, Berenguer M et al. Transplantation for alcoholic liver disease. J Hepatol 2002; 36:130-137.

Assessment for Liver Transplantation 5. 6.

35

Trotter J F, Wachs M, Everson GT, Kam I. Adult-to-Adult transplantation of the right hepatic lobe from a living donor. N Engl J Med 2002; 346:1074-1082. Markmann JF, Markowitz JS, Yersiz H, Morrisey M, Farmer DG, Farmer DA et al. Long-term survival after retransplantation of the liver. Ann Surg 1997; 226:408-418; Discussion 418-420.

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CHAPTER 4

Management on the Liver Transplant Waiting List 4

James Neuberger Introduction Whilst awaiting liver transplantation, the patient should be closely monitored for several reasons: • To ensure that the patient is receiving prophylaxis for complications of the liver disease • To detect any new problems which may affect the success of the transplant • To ensure the patient is as fit as possible for the procedure

Prevention of Complications of End-Stage Liver Disease The patient awaiting liver transplantation, like any other patient with end-stage cirrhosis, is at risk of complications which may affect survival or the successful outcome after transplantation (Table 1).

Variceal Hemorrhage In portal hypertension due to cirrhosis, the threshold of portal hypertension necessary for variceal hemorrhage is a transinusoidal gradient (portal pressure less inferior vena caval pressure) of 12 mm Hg. The likelihood of a variceal hemorrhage is predicted by: • The degree of portal hypertension • Severity of liver disease • Endoscopic appearances: size of varices, presence of red spots • History of previous variceal hemorrhage The probability of bleeding or re-bleeding from esophageal varices can be reduced by pharmacological or physical means. Prophylaxis is indicated in those patients with cirrhosis who: • have had a previous variceal bleed • are at high risk (varices in a patient who is Child’s class B or C or has large varices) The initial choice is with a non-cardioselective beta-receptor antagonist such as propranolol or nadalol. This effect of beta-blockade may be assessed either by: • pulse, either a reduction of resting pulse by 25% or to 60 bpm. These are indirect measures of changes in portal pressure gradient and may Liver Transplantation, edited by Michael R. Lucey, James Neuberger and Abraham Shaked. ©2003 Landes Bioscience.

Management on the Liver Transplant Waiting List

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Table 1. Potential complications in patients with cirrhosis awaiting liver transplantation -Variceal hemorrhage -Development of hepatocellular carcinoma -Development of portal vein thrombosis -Renal failure and electrolyte disturbance -Spontaneous bacterial peritonitis -Encephalopathy -Malnutrition -Sepsis -Osteopenia

overestimate the decline in pressure. • reduction in measured portal pressure to either less than 12 mm Hg or 25-50% below the initial portal pressure About 30% of patients are unable to tolerate beta blockade in sufficient doses so mechanical methods should be considered. Long acting nitrates given in conjunction with non-selective beta receptor antagonists may have some additional efficacy. • Prophylactic sclerotherapy • Prophylactic band ligation • Transjugular intrahepatic porto-systemic shunt (TIPS) Band ligation is preferable to sclerotherapy, as the latter is more likely to cause esophageal ulceration or peri-esophageal abscess in the post-operative period. TIPS is effective in reducing portal pressure and preventing variceal hemorrhage. However, there are potential problems: • The presence of the stent may complicate transplant surgery • Stent thrombosis and narrowing may occur. The benefits of longterm anticoagulation as a means of preventing stent occlusion are uncertain • TIPS is associated with deterioration in hepatic function when attempted in patients with severely compromised hepatic function (elevated serum bilirubin, renal failure or marked coagulopathy)

Spontaneous Bacterial Peritonitis Patients with ascites, which results from portal hypertension, are at risk of spontaneous bacterial peritonitis (SBP). The predictive factors for SBP are: • a previous episode of SBP • ascitic protein < 1 mg/dl Antimicrobial therapy has been shown to be effective in reducing the probability of developing SBP from Gram negative organisms but has no impact on the rarer instances of SBP from Gram positive organisms. Furthermore, prophylaxis has not been shown to affect mortality among patients with a history of SBP or who have

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‘high-risk’ indicators for a first episode. There are many regimens for prophylaxis against SBP: • Norfloxacin 400mg/day • Ciprofloxacin 250mg/day or 500 mg once per week • Co-amoxyclav one tablet/day • Trimethoprim/cotrimoxazole one tablet/day

Renal Function and Electrolyte Balance

4

Patients with end-stage liver failure are at risk of renal failure, occurring spontaneously (hepatorenal failure) or due to iatrogenic intervention. Patients with ascites are at greatest risk, because the factors leading to ascites development (portal hypertension, splanchnic vasodilation, and peripheral vasodilatation) are also the factors promoting renal impairment through the development of intrarenal vasoconstriction and renal sodium retention. Renal function should be monitored carefully and any episode of renal impairment should be investigated fully. Care must be taken to avoid precipitating renal impairment by: • Avoidance of nephrotoxic drugs (such as gentamicin) • Avoidance of non-steroidal anti-inflammatory agents • Avoidance of intravenous contrast material • Monitoring the use of diuretics very closely and discontinue if serum urea >8mmol/l, serum creatinine > 150µmol/l or serum sodium<120mmol/l • Avoidance of hypovolemia: in particular, reduce diuretics when patient likely to become dehydrated (as in hot weather). Hyponatremia, due to impaired free water clearance, often exacerbated by diuretics, is common in end-stage liver failure. When the serum sodium concentration is less than 120 mmol/L, there is a high risk of central pontine myelinolysis during or soon after liver transplantation. Treatment of hyponatremia includes withdrawal of diuretics, restriction of water intake, and in rare cases dialysis. Many programs will attempt to restore the serum sodium concentration to greater than 120 mmol/ L before starting the procedure.

Cancer Development Hepatocellular Carcinoma (HCC) HCC may be the indication for liver transplant or may develop during the waiting period. Follow-up of transplant candidates will differ:

Follow-up of Patients with Known HCC In patients known to have HCC, it is important to monitor the growth of the tumor since during this time transplantation may no longer be indicated. Features indicating transplantation may no longer be appropriate include: • More than three detectable nodules • Tumor diameter greater than 5 cm • Spread of tumor outside the liver • Invasion of the portal vein or hepatic artery by tumor. This may be

Management on the Liver Transplant Waiting List

39

recognized as clot formation and a presumption drawn that the clot is malignant. The serum alpha feto protein (AFP) level is a poor guide to the size of the cancer but the rate of rise is a reasonable guide to the rate of growth. The frequency of repeat imaging of the tumor will depend on the size and location of the tumor: for example, a large tumor close to the margin of the liver will require more frequent monitoring than a small 1 cm tumor in the right lobe. As an approximate guide, we suggest the following follow-up schedule: • Serum AFP every month • Liver ultrasound or CT every 3 months • Chest x-ray every 6 months. The role of ablative therapy (radiofrequency ablation, cryotherapy, chemoembolization, alcohol injection) in this situation is uncertain.

Follow-Up of Patients Without a Known HCC (the ‘At-Risk’ Group) The main risk factors for the development of HCC include the presence and duration of cirrhosis, male sex and chronic viral infection. There are no established guidelines regarding the best screening protocol for at-risk patients. • Serum AFP measurement: There are many causes of an elevated serum AFP. Elevations of serum AFP, often in the range of 100-500 ng/ml are particularly common among patients infected by HCV. Sustained, progressively rising serum AFP levels demand a full assessment for HCC. In the absence of rising levels, repeat levels every 3-6 months are appropriate for cirrhotic patients awaiting liver transplantation. • Imaging of the abdomen (sonography or CT scanning) should be done every 6 months whilst awaiting a liver transplant.

Cholangiocarcinoma In general, the known presence of cholangiocarcinoma is a contra-indication for liver transplantation. However, such cancers are very difficult to detect using either serological tests (such as CA19-9 or CEA) or imaging techniques (such as ultrasound, CT or MRI scanning). There is little evidence to suggest that assessment by serological or imaging is of value although the development of progressively dilated bile ducts may herald the onset of a cholangiocarcinoma.

Other Cancers Patients awaiting liver transplantation are susceptible to the development of extrahepatic malignancy. It remains uncertain whether the presence of cirrhosis or which of the diseases predisposing to cirrhosis are associated with a greater probability of developing cancer. The most common extrahepatic cancers to bear in mind are colon cancer in patients with ulcerative colitis. These patients should have full colonoscopy every year while awaiting liver transplantation. Annual mammography and cervical screening (‘Pap smears’) should be maintained in women of 40 years or more who are awaiting transplantation. Annual

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Table 2. Immunizations in adults awaiting liver transplantation Vaccine

Type of Vaccine

Dose Regimen

Comment

Tetanus-diphtheria

Toxoid vaccine

3 doses in naïve patients at 0, 4 weeks and 6-12 months

Persistent immunity up to 10 years

Poliomyelitis

Trivalent Naïve: 3 doses at inactivated whole 0, 4 weeks and virus vaccine (IPV) 6-12 months

Booster every 10 years

Influenza

Trivalent split or subunit vaccine

One dose.

Annual booster prior to ‘flu season’

Hepatitis B

Recombinant or plasma-derived subunit vaccine

3 doses at 0, 4 weeks and 6 months

Monitor anti-HBs; if <10 IU/L repeat booster dose

Hepatitis A

Inactivated whole- 2 doses, at 0 and virus vaccine 3-6 months

Persistent immunity up to 10 years.

Pneumococcus

23-valent polysaccharide vaccine

One dose.

Persistent immunity up to 6 years

H influenzae type b Polysaccharide conjugate vaccine

One dose

Complete immunization > 6 weeks prior to Tpx

Varicella

Live-attenuated vaccine

2 doses 6 weeks apart

Complete immunization 4 weeks prior to Tpx

Mumps-measlesrubella (MMR)

Live-attenuated vaccine

One dose

Complete rubella immunization 4 weeks prior to Tpx

4

Adapted from Stark K, Gunther M, Schonfeld, Tullius SG, Bienzle U. Immunizations in solid-organ transplant recipients. Lancet 2002; 359: 957-965 Tpx indicates transplantation

prostatic specific antigen (PSA) levels should be measured in men over 45 years who are on the waiting list for liver transplantation.

Vaccinations Most candidates for liver transplantation will have been vaccinated against or exposed to many of the viral pathogens which might prove harmful after liver transplantation. It is appropriate therefore to assess the immunity to potential viral pathogens as part of the transplant evaluation. Serologic markers to CMV, EBV,

Management on the Liver Transplant Waiting List

41

HSV, varicella, HBV, HCV and HAV are checked as a routine measure. Patients without immunity to the viruses listed in Table 2 should be vaccinated if time permits. Candidates for liver transplantation should receive annual influenza immunization.

Progression of Medical Complaints Hypertension Patients with systemic hypertension will need monitoring to ensure that the blood pressure is optimally controlled. If there is any cardiac abnormality on screening, then it may be helpful to repeat the ECG and echocardiograph at 6 monthly intervals.

Diabetes Mellitus Patients with established diabetes mellitus will need careful monitoring to ensure that the blood sugar is within acceptable limits; when normoglycemia cannot be maintained by dietary methods or with oral hypoglycemic agents, then insulin should be instituted.

Alcoholism and Other Addictions Alcohol addicted persons should have their alcohol use monitoring whilst awaiting transplantation. This can be achieved by asking the patient and their family about drinking relapses and by random checks of blood and urine screens. Smoking cessation: patients are advised to stop smoking, and formal smoking cessation programs are worth attempting.

Temporary Suspension from the Waiting List Patients may be suspended from the waiting list for several reasons and returned to the active list when the temporary problem is resolved. Temporary events leading to suspension from the list include: • Intercurrent infections • Variceal bleeding • Alcohol use by alcoholics

Suggested Reading 1. 2.

3. 4. 5.

Runyon BA. Management of adult patients with ascites caused by cirrhosis. Hepatology 1998; 27:264-272. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis New Eng J Med 1996; 334:693-699. Schafer DF, Sorrell MF. Hepatocellular carcinoma. Lancet 1999; 353:1253-1257. Sharara AI, Rockey DC. Gastroesophageal variceal hemorrhage. New Eng J Med 2001; 345:669-681. Stark K, Gunther M, Schonfeld, Tullius SG, Bienzle U. Immunizations in solidorgan transplant recipients. Lancet 2002; 359:957-959.

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CHAPTER 5

The Liver Transplant Operation Michael Crawford and Abraham Shaked Cadaveric Donors

5

Donor Selection The cadaveric liver transplant begins with a donor offer from an Organ Procurement Organization (OPO) coordinator. The information in Table 1 should be obtained from the coordinator in each case. The surgeon determines, based upon the donor and relevant recipient factors, the suitability of the donor for liver procurement. Donor suitability can sometimes only be determined intra-operatively or with a liver biopsy.

Pre-Op Donor Management The patients’ team carries out the pre-operative management of a potential donor. Once a donor has been identified and consent obtained, a transplant coordinator is frequently on site to give advice about management. Brain dead patients may undergo severe physiologic disturbances due to events such as Cushings’ response and diabetes insipidus. These place the donor organs at risk and should be diagnosed early and treated aggressively. Table 3 shows some of the common syndromes encountered in donors, and their management until procurement can be arranged.

The Cadaveric Donor Operation The patient is positioned supine on the table, muscle relaxation given, gastric tube placed, and prepped from neck to groins. An incision is made from sternal notch to symphysis pubis. The round ligament is divided and falciform ligament taken down towards suprahepatic inferior vena cava (IVC). A median sternotomy is performed and retractors are placed. (see Fig. 1) The falciform dissection is continued to the IVC, the left triangular ligament is taken down. The gastrohepatic ligament is incised; any accessory or replaced left hepatic artery is identified and preserved. A full mobilization of the right colon and small intestine is performed beginning at the appendix, mobilizing the right colon and small bowel up and to the left, passing behind the second and third parts of the duodenum. The superior mesenteric artery limits this dissection. The infrahepatic IVC is thus exposed and the upper border of the renal veins are defined as they enter it. Liver Transplantation, edited by Michael R. Lucey, James Neuberger and Abraham Shaked. ©2003 Landes Bioscience.

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Table 1. Donor information ABO Donor age and sex Donor size (height and weight) Cause of death Time in hospital Hospital course, including history of arrest, and stability of blood pressure and requirement of inotropes Pulmonary status Results of virus screening for hepatitis, HIV etc. Pertinent past medical history (tumors, infections etc.) Previous surgical history Previous drug and alcohol history Results of electrolytes and liver function studies Results of relevant pre-operative imaging

Table 2. Donor definitions Extended Criteria

Livers which are less than perfect due to previous donor history or current condition of donor

Brain Dead or Heart-Beating Donors

Heart still beating, brain death declared by clinical or investigational findings

Non-heart beating donors

Fail brain death criteria, procurement occurs after cardiac death has been declared

-Controlled

Support is withdrawn and death is declared

-Non-Controlled

Cardiac arrest occurs despite continued support

Table 3. Pre-operative management of the donor Problem

Management

Aim

Hypotension

Transfusion, dopamine, levo-thyroxine, Epinephrine Beta blockers or other anti-hypertensives Diuresis and oxygen delivery Dextrose replacement

Maintenance of good perfusion to donor organs

Hypertension Hypoxia Diabetes insipidus Acidosis Severe instability

Prevent acute hypertensive injury to donor organ. Maintain adequate oxygenation of donor organs Avoid hypernatremia

Bicarbonate replacement Avoid end organ acidosis Urgent procurement Minimize time of organ injury

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Liver Transplantation Figure 1. Donor setup.

5

The ligament of Treitz is taken down and the inferior mesenteric vein (IMV) is exposed and isolated. The aorta is then dissected just above its bifurcation, umbilical tapes are placed around it for control later. The bowel is returned and the common bile duct (CBD) is dissected just above the duodenum in the hepatoduodenal ligament. It is ligated distally and incised above the tie. The gallbladder is incised and emptied, then flushed with normal saline until the effluent at the incised CBD is clear. The supraceliac aorta is exposed by incising the right crus of the diaphragm. Umbilical tape is placed around the aorta. Heparin 30,000 units are given. The distal IMV is ligated and the proximal IMV is cannulated, with the cannula passed into the portal vein. The distal aorta is ligated and the proximal aorta incised and cannulated with a large bore infusion catheter. The inferior vena cava is exposed within the pericardium. The right pleura is opened to allow blood to pool in the right chest. In a coordinated fashion, the IVC (or right atrium) is cut, the supraceliac aorta is clamped and the infusion of preservation solution into the IMV and aorta is begun. Ice is quickly placed over the liver and other intra-abdominal organs. Suction catheters are placed in the chest to take the warm blood coming out of the IVC away from the liver. Infusion of preservation solution continues until the effluent from the IVC is clear (usually around 4-5L total). The IVC is completely transected in the chest and the posterior pericardium is opened from side to side exposing the esophagus and thoracic aorta.

The Liver Transplant Operation

45

5

Figure 2. Donor porta-hepatis.

The diaphragm is divided sagitally in front of the esophagus well to the left of the suprahepatic IVC. The right diaphragm is then divided, well lateral to the right coronary ligament, and continued towards the infrahepatic IVC. The IVC is transected above the renal veins and a suction catheter placed at this point. The CBD is completely transected and the peritoneum above the duodenum is incised to allow the duodenum to peel downwards. The right gastric artery is ligated and divided. The gastroduodenal artery (GDA) is exposed and followed to its origin from the hepatic artery. It is then ligated and divided away from the hepatic artery. (see Fig. 2) The hepatic artery is followed proximally on its left side, dividing the lymphatic and nervous tissue that overlies it here. The coronary vein will be seen and can be divided. It usually lies over the origin of the splenic artery, which can be dissected for a centimeter or two and then transected, once the celiac axis is clearly identified. The dissection is continued proximally along the left side of the celiac to the aorta. The length of supraceliac aorta is exposed on its left side by division of the crus of the diaphragm. The supraceliac aorta is transected at the level of the clamp and the aorta just to the left of the celiac incised and continued superiorly to the point of transection. The duodenum is now further mobilized away from the porta hepatis. And the tissue lateral to the portal vein is dissected toward the portal vein (PV) taking care to look for a replaced right hepatic artery. With the anterior surface of the vein exposed,

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Liver Transplantation

the pancreas is split at the neck to expose the portal vein origin. The superior mesenteric and splenic veins are then transected. The portal vein segment is passed beneath the duodenum to lie with the other hepatic structures. If there is no replaced right hepatic artery, the nerves and lymphatic tissue lying behind the portal vein are divided all the way to the aorta between the celiac and SMA. If there is a replaced right hepatic artery, then it is preserved and the SMA is included in the aortic patch. The aortic patch is completed around the celiac origin and lifted up with the other portal structures. Cutting across the right adrenal gland and dividing the hepato-pulmonary ligament completes the donor hepatectomy. The liver is surrounded by University of Wisconsin (UW) solution in a bag and then stored in ice for transportation. The back table dissection is carried out with the liver sitting in UW solution surrounded by ice. The coronary ligaments are first taken down exposing the suprahepatic IVC. The diaphragm is carefully dissected off the IVC, ligating any phrenic veins. The infrahepatic cava is dissected free, after dividing the diaphragm between the aorta and IVC. The right adrenal vein and any other external branches are ligated and the adrenal gland removed. The portal vein is dissected towards the liver with ligation of any small branches along its course until the bifurcation is seen. The PV is then cannulated with intravenous tubing, secured and tested for leaks. The artery is then dissected in segments from aorta towards splenic, and then splenic towards GDA. Small branches are ligated. The splenic is left open for ‘blowout’ on reperfusion. It is leak tested, an aortic patch is created (1-2mm brim) and the liver is covered by UW solution until required for implant.

Extended Criteria Donors Extended criteria donors fall outside of the range of ideal or very suitable donors and include the factors outlined in Table 4. Extended criteria donors are used to expand the donor pool. They should be carefully matched with appropriate recipients. The cold ischemic time for extended criteria donors should be kept to a minimum so that the risk of primary non-function in the recipient is reduced. Extended criteria donor recipients are also more likely to suffer with more severe reperfusion syndrome, and the graft should thus be ‘washed out’ extensively prior to reperfusion.

Controlled Non-Heart-Beating Donors This is a special group of extended criteria donors. These are donors for whom recovery is hopeless, and are on ‘life support’, but fail to fulfill the criteria of ‘brain death.’ The donor is brought to the operating room and prepped and draped. Perfusion lines are primed with University of Wisconsin Solution. Heparin (300 unit/kg) and intravenous hydrocortisone 1000 mg are administered, and then ‘life support’ is withdrawn. A physician from the donors’ treating team pronounces the patient deceased according to clinical or electrical evidence. (If pronouncement does not occur within 1 hour after withdrawal of life support, then the procurement is abandoned and the donor is returned to the intensive care unit.) Following the

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Table 4. Extended criteria donors Age >70 years Prolonged pre-mortal hospital stay Hemodynamic instability or requirement for large doses of inotropes Pre-mortal cardiac arrest Alcohol or drug dependency Elevated liver function tests or serum sodium Fatty liver Hepatitis infected liver History of malignancy Non-heart beating donor

declaration of death, a mandatory wait period, determined by local policy (usually around five minutes), is allowed to elapse before the surgery begins. The objective in this operation is for rapid perfusion of the organs with preservation solution and cooling. A midline laparotomy and sternotomy is performed, the aorta is cannulated just above the bifurcation, and cold perfusion begun. The right atrium is opened for venting, and the thoracic aorta is clamped. The abdomen is filled with ice. The portal vein flush can be given either in situ or on the back table. After 3-5 liters of cold UW solution has been perfused, the liver (and other relevant organs) is expeditiously removed. The bile duct is flushed on the back table. Critical judgment is required if the time between discontinuation of life support and death is prolonged, as these organs suffer from significant warm ischemia which can be manifest as primary non-function, acute cellular rejection or biliary stricture formation in the recipient.

Split Liver Grafts The initial preparation is as for whole organ procurement. Prior to cannulation and perfusion attention is turned to the portahepatis. The left hepatic artery is identified and dissected free near its origin and followed up to the umbilical fissure. The left portal vein is now dissected and small caudate branches of the portal vein are ligated and divided. The liver bridge between segment VI and III is divided (if present) where it crosses the umbilical fissure. This exposes the fissure with multiple small portal vein branches that cross between the umbilical vein and segment IV here. These are ligated and divided. After division of these branches, the left hepatic duct is identified lying above the artery and divided. (see Fig. 3) The left hepatic vein is dissected free of the middle hepatic vein over a short distance. Parenchymal dissection can now begin just to the right of the falciform ligament. This is best done using electrocautery with ligation of any major structures crossing between the left lateral segment and segment IV. This dissection is continued until the entire left segment is freed and the caudate lobe is exposed near the insertion of the gastrohepatic ligament.

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Liver Transplantation

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Figure 3. Split donor technique.

The cannulas are then placed and the organs perfused and dissected as per whole organ. The left lateral segment is removed by dividing the relevant vessels. The left hepatic artery can be taken at its origin, or the aortic patch and common hepatic artery can be kept with the left lateral segment by dividing the right hepatic artery at its origin.

The Recipient Operation The patient is positioned supine on the operating table with arms extended to 90 degrees. A large bore peripheral cannula, arterial line and a Swan Ganz catheter are generally used for intra-operative management and fluid replacement. If percutaneous bypass is to be used, then the right internal jugular vein is cannulated with the large bore cannula at this time. A nasogastric tube and a Foley catheter are placed and a warming blanket or device is set up. The patient is prepped and draped from neck to groins leaving particularly the left groin exposed for cannulation for bypass. A bilateral subcostal incision with a midline upper extension is made, the round ligament is divided, and the falciform ligament is taken down towards the suprahepatic IVC. Subcostal retractors are placed and the dissection continues until the right and left hepatic veins are exposed. The left triangular ligament is taken down and the left

49

The Liver Transplant Operation Figure 4. Incision.

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Figure 5. Recipient porta hepatis.

lateral segment retracted medially. The gastrohepatic ligament is incised and continued cephalad, ligating any vessels crossing it. Attention is turned to the porta hepatis, any adhesions are taken down and inferior retractors are placed. The peritoneum is scored level with the lower border of the caudate lobe. The cystic duct and artery are ligated and divided freeing the right

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Liver Transplantation

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Figure 6. Recipient setup with bypass lines.

edge of the hepatoduodenal ligament. The dissection is deepened stepwise until the hepatic arteries and common bile duct (CBD) are exposed. These are ligated and divided. Dissection continues through the neural and lymphatic tissue until the portal vein is exposed. The portal vein is dissected carefully, ligating any small tributaries. Once sufficient length has been dissected on all sides, the remainder of the hepatoduodenal ligament tissue can be divided. (see Fig. 5) The left femoral vein is now cannulated using Seldinger technique and secured in place. Air in the lines is expelled and the patient is placed on systemic venous bypass. The portal vein is isolated with umbilical tape and a ‘snugger.’ The assistant controls the vessel with a large Debakey forceps. The distal portal vein is ligated near its bifurcation, and incised just below this. The bypass cannula is inserted to the level of the portal vein origin and secured with the umbilical tape snugger. The snugger is secured to the bypass tubing with further tape, and the portal vein transection is completed. The portal system is added to the circuit placing the patient on portal venous bypass. (see Fig. 6) The dissection of the infrahepatic IVC is begun by scoring the overlying peritoneum and extending this line along the left side of the IVC up to the level of the phrenic vein, while retracting the liver and caudate lobe to the right so that the posterior aspect can be freed.

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Figure 7. Caval anastomosis.

The right triangular and coronary ligaments are taken down with the liver retracted to the left, exposing the right posterior aspect of the IVC. The right adrenal vein is ligated and divided. The infrahepatic IVC is clamped below the level of the right adrenal vein stump. The suprahepatic IVC is clamped in a manner to ensure that a good posterior length is available. The liver is dissected off the IVC inferiorly ligating any caudate tributaries until a suitable length for anastamosis has been obtained. The infrahepatic IVC is transected. The hepatic veins are the transected and the suprahepatic IVC is transected below the hepatics. The liver is removed and careful hemostasis is obtained. The diaphragmatic peritoneum corresponding to the bare area of the liver can be oversewn if desired for hemostasis. The supra hepatic IVC is prepared for anastamosis by dividing the caval bridge between the middle and left hepatic veins and the dividing between this and the IVC. The bridge between the right hepatic vein and IVC is likewise divided. The IVC is the checked at both ends for holes or tributaries. There are usually one or two phrenic veins which require over-sewing (knots tied on the outside.) The donor liver is delivered to the table and re-checked for IVC integrity. The posterior wall of the suprahepatic caval anastamosis is completed from the ‘inside’ running from patients’ left to right, using an everting or ‘lipping’ technique. The

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Figure 8. Vascular anastamosis.

same suture is continued along the front wall around half way from right to left and then the remaining front wall is sutured from left to right and tied to the original suture. (see Fig. 7) The cannula in the donor portal vein is flushed with 700-1000 cc of cold Ringer’s lactate solution while surgical attention is turned to the infrahepatic IVC. This anastamosis is performed as described for the suprahepatic above. The portal bypass line is clamped and the cannula removed from the recipient portal vein with a clamp placed. The donor portal vein is measured up for length with the recipient vein. The anastamosis is performed in the manner described for the IVC except 5 or 6/0 prolenes are used and the following suture is ‘placed’ rather than pulled taut. Prior to tying, the vessel is temporarily opened to flush out any clot. A ‘growth factor’ or air knot of 30-50% the diameter of the portal vein is used for the final tie. This slack is taken up by expansion of the vein upon reperfusion.

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Figure 9. Bile duct.

The liver is now ready for reperfusion. The suprahepatic caval clamp is first removed and the suprahepatic anastamosis and cava is checked for leaks. The infrahepatic clamp is released with warning given to the anesthesia team. When the anesthesia team are ready, the portal clamp is released and the liver reperfused. The femoral vein cannula can be clamped and removed once the patient is hemodynamically stable. The recipient hepatic artery is dissected toward the celiac, beyond the level of the GDA where it is clamped. The GDA is ligated distally and divided well away from the hepatic artery. A branch patch is created using the distal hepatic artery and GDA. The lumen can be gently dilated using a mosquito forceps. The anastomosis is performed patch to patch using 6/0 prolene. (see Fig. 8) The vessel is allowed to ‘blow out’ any clot via the open donor splenic artery prior to opening up to the liver. The donor splenic artery is then ligated. The entire operative bed is checked in a systematic manner for hemostasis. The donor gallbladder is dissected fundus down until it is suspended by the cystic duct. The cystic duct can be dissected all the way to the common bile duct (CBD). The donor CBD is divided at the level of the cystic duct junction. The recipient bile duct and its blood supply are mobilized over a length of around 2 cm, and then divided just below the tie. The bile duct anastamosis is performed using 5/ 0 interrupted sutures (knots outside). A T-tube is optional. A hemostatic check is made and the abdomen irrigated well. Three suction drains are placed: 1) along the right border of IVC to suprahepatic caval area; 2) abutting the porta hepatis and bile duct anastamotic area; and 3) along the left side of the IVC to the suprahepatic area. The wound is closed in a careful manner to prevent ascitic leak and hernias.

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Liver Transplantation

Special Operative Problems Previous Operation(s)

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The re-operative abdomen presents special operative challenges to the liver transplant surgeon. Adhesions, formed after previous surgery, are generally dense and have large venous collaterals running through them. The incision remains the same with special care when entering the abdomen, so as not to damage bowel stuck to previous incisions. The incision is gradually deepened and continued into the peritoneal space using careful electrocautery dissection to separate the abdominal contents from the wound. The round ligament is divided. The liver surface is sought and abdominal contents are dissected down and off the anterior surface of the liver. Once the incision edges and anterior surface of the liver are clear, subcostal retractors are placed. The left lobe of the liver should be mobilized in the normal fashion and the gastrohepatic ligament divided. This helps define the left edge of the porta hepatis. The key to this surgery is to start the dissection toward the porta hepatis from the sides, taking down adhesions from the inferior surface of the liver until the ‘normal’ anatomy is clear. This is done by staying in the plane right next to the liver, and if in doubt venturing a little into the liver rather than away from it. An argon beam coagulator is invaluable in this surgery for drying up the bleeding liver surface. Coming across the gallbladder fossa following prior cholecystectomy is usually difficult because the duodenum may be firmly adhered in this region. When dissecting from the right, the plane of dissection continues across the gallbladder fossa and then should leave the liver surface and continue between the porta hepatis and the falciform ligament. The duodenum and other adhesive elements are gently dissected down off the porta hepatis. From either side the epiploic foramen can be gently probed digitally and reconstituted. The remainder of the operation is as for the naïve abdomen except that care is taken to ensure hemostasis of all the previously adhered abdominal contents.

Retransplantation The retransplant of the liver begins as described above for previous surgery. The operation is essentially as for the primary graft except for the following potential deviations. In the dissection of the porta hepatis; the hepatic artery from the previous transplant is likely to be folded and redundant and is found to lie more superficial than expected. Great care is taken when dissecting the portal vein to avoid close dissection of the previous anastamosis, lest it be inadvertently disrupted until proximal control is gained. The native suprahepatic IVC may be significantly shortened and weakened by the previous anastamosis here, and if an attempt were made to replace the cava, as described above, there can be significant risk for loss of integrity of the suprahepatic anastamosis. Therefore many surgeons elect to sew in the new liver with a ‘piggy back’ (end to side) technique. This of course preserves the first graft IVC.

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Figure 10. Portal thrombectomy.

The arterial anastomosis should be made more proximally than the original and may necessitate using a splenic artery branch patch. The portal venous anastomosis is rarely a concern, since the original anastomosis can be preserved if needed for extra length. The bile duct reconstruction frequently requires a Roux-en-Y hepaticojejunostomy.

Portal vein Thrombosis Portal vein thrombosis leads to larger and higher pressure collateral vessels, and extra care is required during the initial dissection. Most portal vein thromboses are partial and can either be ignored or removed. The technique for thrombectomy is as follows: The portal vein is controlled proximally by the assistant with a large forceps and ligated near the bifurcation. A longitudinal incision is made in the anterior wall. 5/0 prolene stay sutures are placed on either side. A plane is developed between the vein wall and the thrombus using a carotid dissector. The distal end of the thrombus is grasped and delivered out of the vein. Gentle upwards traction is placed on the thrombus while the portal vein wall is peeled off it proximally. (see Fig. 10) The controlling forcep will need to be released briefly to deliver the proximal thrombus (which usually extends at least to the portal vein origin). Now a large Fogarty balloon catheter is passed proximally to sweep the portal vein of any further, loosely adherent thrombus. The portal vein is opened and flushed to determine flow and bypass proceeds in the usual manner. In the unusual circumstance that the portal vein is completely thrombosed and cannot be cleared using the method above or if the flow is poor, a jump graft using donor iliac vein to superior mesenteric vein may be required.

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Table 5. Selection criteria for right lobe donors Test Phase 1 Over the phone & Local doctor

5

Ideal

Age History

Young adult No significant illnesses or previous abdominal surgery Blood group ABO identical Liver function tests Normal BUN Creatinine Normal

Exclude <18, >50 y old Significant morbidities, previous cholecystectomy is a relative contra-indication ABO incompatible Abnormal Significantly abnormal renal function

Meet with transplant surgeon and briefing of procedures, risks, and benefits Phase 2 Transplant Center

Imaging (Volumetric MRI or CT scan)

Further labs Psychosocial evaluation

Phase 3 Transplant Center

Liver Biopsy (center variability on its use) Celiac and Superior mesenteric angiography and portal venography

No pathology identified. Suitable volume for donation (donated segment >1% of weight of recipient). No steatosis. HIV, Hepatitis virology negative Stable with good social supports

Pathology identified in liver, steatosis, donor segment <0.8% of body weight of recipient, remnant <0.7% of donor weight.

Normal liver

Fibrosis, hepatitis, significant steatosis >10%

Normal anatomy, or replaced left hepatic artery, completely replaced right hepatic artery ERC or MRC Normal biliary (center variability anatomy. on their use)

Positive HIV or hepatitis serology Drug or alcohol dependency, no social support. Marginal if significant psychiatric history.

Accessory right hepatic from SMA in the present of normal right.

Large segment four duct draining to right hepatic duct well above the bifurcation

Previous TIPS Procedure A perfectly placed TIPS (Trans-jugular intra-hepatic porto-systemic shunt) is intrahepatic in its course and does not present any particular problem. However, the TIPS can extend into the extrahepatic portal vein or back up into the right atrium. For extension into the portal vein, the vein is transected short on the recipient below the shunt. If this cannot be done then a jump graft to the SMV may be required.

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The TIPS extending into the IVC or the right atrium is a more dangerous problem. It is essential that the suprahepatic clamp be placed above the end of the shunt. This is achieved by more aggressive dissection of the diaphragm off the cava here and by ‘pinching’ off the right atrium with the suprahepatic clamp. A useful technique is to place a smaller clamp on as high as possible and then placing a larger clamp outside and thereby above the first clamp.

Live Liver Donors Living donation for liver transplantation has been practiced in children since 1989. This has predominantly been the transplant of the left lateral segment of a healthy adult into a small child or infant. The donor procedure for left lateral segment (similar to the split liver described above) is safe and relatively straight forward, and the results for recipients have been excellent when compared to cadaveric grafts. Since 1995, live donors have been used for liver transplants in adults, and in the past few years this practice has increased greatly. The most common graft from a live donor for an adult recipient is a right lobe (segments V-VIII) with or without the middle hepatic vein. Healthy donors are selected according to criteria included in Ttable 5.

The Right Lobe Living Donor Operation With the patient positioned supine and a nasogastric tube and Foley catheter in place, a subcostal incision, with vertical upper extension, is made. The falciform ligament is taken down and the suprahepatic IVC is exposed with dissection of the right hepatic vein insertion. Any adhesions around the gallbladder or porta hepatis are taken down and a fundus down cholecystectomy is performed. After a limited exploratory dissection of the porta hepatis, a cholangiogram is performed via the cystic duct. It is helpful to have dissected some way up into the porta hepatis, taking down the hilar plate to expose the confluence of the hepatic ducts, which is marked with a forceps for confirmation on the cholangiogram. If a segment IV duct is joining the right hepatic duct, then an assessment needs to be made whether to proceed, as this portion of the right hepatic duct will need to remain with the donor. All of the porta hepatis dissection should be limited to the right side of the common bile duct. Attention is turned to the right hepatic artery, which is identified as it passes beneath the common hepatic duct. It is dissected well up into the liver to facilitate the dissection of the hepatic duct and portal vein. The right hepatic duct is dissected and transected several millimeters from the confluence, the donor side is suture ligated. It is more common than not to have two hepatic ducts on the donor side, and these are marked with prolene sutures to aid identification later. Retracting the common bile duct and the hepatic artery to the patients left exposes the right portal vein. Dissection of the right portal vein continues up towards the right lobe of the liver working on both sides of the hepatic artery until the bifurcation of the portal vein is clearly seen. Now the posterior portal vein is dissected and caudate branches of the vein are ligated and divided. Approximately 2 cm of right portal

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Liver Transplantation Figure 11. Right lobe vascular anastamosis.

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Figure 12. Hepatico-jejunostomy.

vein should be freed on all sides in this manner until a right angle forceps can be safely passed around the right portal vein. The right triangular and coronary ligaments are taken down exposing the right posterolateral aspect of the inferior vena cava (IVC). The liver is returned to its anatomical position and the peritoneum overlying the anterior surface of the infrahepatic IVC is dissected and freed. Dissection is continued up towards the liver. The caudate lobe is elevated off the cava and small tributaries from the caudate lobe are ligated and divided. Small tributaries from the right lobe are likewise ligated and divided. Larger tributaries (> 5 mm) are preserved for re-implantation. In such a manner, the entire anterior and right lateral surfaces of the cava are exposed up to the level of the right hepatic vein which is now dissected working both from above and below until it can be isolated with a vessel loop.

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The caudate process between the right portal vein and the IVC is scored. The line of resection is marked on the surface of the liver. This line runs from between the middle and right hepatic veins to the left side of the gallbladder fossa, and then down the inferior surface of the liver to the IVC. Parenchymal dissection is undertaken using the technique preferred by the operating team. During this dissection it is usual to encounter two significant middle hepatic vein tributaries; one from segment V and one from segment VIII. When these are large some centers re-implant one or other of these into the recipient cava using a venous conduit. Once completed the two parts of the liver with their respective blood supplies should be left until the recipient hepatectomy is completed. A completion cholangiogram can be performed to exclude stricture or leak at the sight of the oversewn right hepatic stump. The liver segment is removed by clamping vessels (inflow before outflow) on the remnant side and dividing the vessels. The graft is immediately placed on ice and flushed via the portal vein and hepatic artery with preservation solution. The donor ends of the vessels are oversewn and the wound is closed with drains to the cut surface of the liver.

The Live Donor Right Lobe Recipient Operation The hepatectomy is undertaken as for the whole organ recipient except that the bile duct and the vessels are left especially long and the inferior vena cava is left in place by ligating caudate lobe tributaries. The left and middle hepatic veins are over sewn. The right hepatic vein opening can be extended into the IVC inferiorly for a wide-open anastamosis. The segment is sewn in beginning with the right hepatic vein which lies best if sewn up-to-down instead of left-to-right (this is not tied down until after flushing the liver). The hepatic arterial anastomosis is completed, usually using the hepatic artery bifurcation as a patch. The liver is flushed through the portal vein and the hepatic vein is tied down. The portal venous anastomosis is carried out as usual, and the liver is reperfused with portal and arterial blood. The type of bile duct anastomosis is determined by the donor anatomy. A duct to duct anastomosis is usually possible, although a Roux-en-Y hepaticojejunostomy may be required for biliary reconstruction. Hemostasis is obtained, drains are placed and the abdomen is closed as usual.

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CHAPTER 6

Immunosuppression after Liver Transplantation James Neuberger

6

The purpose of immunosuppression is to prevent the body’s immune system destroying or damaging the graft. Since currently available drugs are not specific for graft alloantigens, the clinician must maintain a balance between underimmunosuppression, leading to graft rejection, and over-immunosuppression, leading to the consequences of immunodeficiency such as sepsis and malignancy. The clinician should also be aware of, and attempt to minimize, the unwanted effects of longterm use of these agents. In the early days of liver transplantation, the protocols for liver allograft recipients were derived by extrapolation from renal transplantation. It has become clear, however, that different approaches need to be adopted: for example, in liver allograft recipients, tolerance may develop and those strategies that aim to abolish early acute rejection may inhibit the development of tolerance. While acute rejection is associated with a poor outcome in renal transplantation, there is no evidence that acute cellular rejection, which is reversed by short periods of increased immunosuppression (socalled ‘reversible acute cellular rejection’), has any untoward effect on liver graft survival. There have been comparatively few studies on which to base a rational approach to immunosuppression: the success of liver transplantation has meant that to demonstrate significant improvement in graft survival or a reduction in the immunosuppressive-related morbidity, a large number, of patients needs to be followed for long periods of time. In the present climate, this is usually difficult. Furthermore, the introduction of newer agents, or improved formulations of existing drugs, means that the conclusions of randomized trials may be superseded before results are available. Most centers have adopted a common approach to the principles of immunosuppression but differ significantly in the details. Therefore, in this Chapter, the principles of immunosuppression will be outlined together with a description of the consequences of over-immunosuppression. Details of those drugs that are currently available and those shortly to be licensed will be described.

Liver Transplantation, edited by Michael R. Lucey, James Neuberger and Abraham Shaked. ©2003 Landes Bioscience.

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Table 1. Physical methods of immunosuppression Types of physical immunosuppression include: Blood transfusion Removal of lymphocytes: Leucophoresis UV or total body irradiation Thoracic duct drainage Thymectomy, splenectomy Plasmaphoresis Photophoresis after lymphocyte priming

Drugs and Other Agents Used in Immunosuppression The drugs and other agents and procedures used for immunosuppression are shown in Table 1 and details of those drugs and agents licensed for immunosuppression are shown in Tables 2 to 13.

Types of Immunosuppression Immunosuppression may be physical or pharmacological. Physical methods, as shown in Table 1, are rarely used in liver transplantation.

Medications Used for Immunosuppression Purine Analogues Azathioprine has been used for many years in transplantation (see Table 3). It is metabolized by thiopurine methyltransferase to the active component 6mercaptopurine (6-MP), an analogue of the natural purines hypoxanthine and adenine. 6-MP is then metabolized to thioinosine monophosphate which inhibits synthesis of DNA precursor molecules and interferes with nucleic acid synthesis during clonal expansion of lymphocytes. People who have low levels of thiopurine methyltransferase are more susceptible to the side effects of azathioprine but may tolerate 6-MP. The rationale for long-term use of azathioprine is not well established although several studies have suggested an increased probability of chronic rejection in patients not taking azathioprine. Following the introduction of azathioprine (usually at a dose of 1-2 mg/kg/day), the white count should be monitored twice monthly for 3 months: if the white count falls below 4.0 x 10.9/l, the dose should be halved; if the white count falls below 3.0 x 10.9/l, azathioprine should be discontinued. Venoocclusive disease and hepatitis are the most serious forms of liver dysfunction associated with azathioprine and usually develops within the first 6 months.

IMPDH Inhibitors (Table 4) Mycophenolate mofetil acts by inhibition of inosine monophosphate dehydrogenase, it is colloquially referred to as ‘MMF’.

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Table 2. Pharmacological methods of immunosuppression

6

Types of pharmacological immunosuppression include: Depletion of lymphocytes Polyclonal antibodies to lymphocytes (e.g., ALG, Thymoglobulin) Monoclonal antibodies to lymphocytes (e.g., OKT3) Inhibition of lymphocyte activation Corticosteroids Immunophilin-binding drugs Calcineurin-inhibitors: Cyclosporin Tacrolimus TOR inhibitors: Sirolimus (formerly known as rapamycin) Inhibitors of de novo nucleotide synthesis Purine synthesis inhibitors (IMPDH inhibition) Mycophenolate mofetil Mizoribine Pyrimidine synthesis inhibitors ((DHODH inhibition) Leflunomide Brequinar Antimetabolites Azathioprine Cyclophosphamide Inhibition of lymphocyte activation/trafficcking/interaction Inhibition of trafficking FTY720 Inhibition of interactions Antibodies to ICAM-1 Antibodies to IL2-R CTLA-4 Ig

Table 3. Immunosuppressive drugs: Azathioprine Drug name

Azathioprine

Mechanism of action

Anti-metabolite; metabolised to 6mercaptopurine and then active agent interferes with DNA and RNA synthesis so inhibits T and B lymphocyte differentiation and proliferation Leukopenia (significant 15%) Nausea and vomiting Hepatotoxicity (especially venoocclusive disease) Pancreatitis Pneumonitis Megaloblastosis 1-2 mg/kg/day Allopurinol (avoid) ACE inhibitors Used as a second-line drug

Side-effects

Doseage Drug interactions Notes

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Immunosuppression after Liver Transplantation

Table 4. Immunosuppressive drugs: Mycophenolate mofetil Drug name

Mycophenolate mofetil

Mechanism of action

Prevents T and B cell proliferation by inhibition of de novo purine synthesis by inhibition of monophosphate dehydroge-

inosine nase (IMPDH) Side-effects

Diarrhea (15%) Leucopenia (5%) anemia, thrombocytopenia, Rarely GI hemorrhage and perforation hematuria, hypertension, hyperglycemia, disturbances of electrolytes and blood lipids, peripheral edema, dyspnea, cough, dizziness, insomnia, tremor. Hypersensitivity reactions

6

Dosage

1 to 2g/day in divided doses

Drug interactions

May compete with drugs that undergo active renal tubular secretion Probenecid Acyclovir

Some antacids and cholestyramine reduce tion

absorp-

Table 5. Equivalence of corticosteroids Prednisolone/Prednisone Betamethasone Cortisone acetate Deflazacort Dexamethasone Hydrocortisone Methylprednisolone Triamcinolone

5 mg 750 µg 25 mg 6 mg 750 µg 20 mg 4 mg 4 mg

(Derived from the British National Formulary, 2000)

Notes alternative to calcineurin-inhibitor sparing

Teratogenic in animals. Used as azathioprine or in protocols

Glucocorticoids These agents have both anti-inflammatory and immunosuppressive effects. The glucocorticoids bind to the glucocorticoid receptor and the complex then translocates to the nucleus where, after binding to DNA, protein synthesis is affected.

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Table 6. Immunosuppressive drugs: Corticosteroids Drug name

Prednisolone/prednisone

Mechanism of action

Anti-inflammatory; stimulates migration of T cells from intravascular tissue to lymph nodes; inhibits production of T cell lymphokines

Side-effects

Increased tendency to diabetes mellitus Osteoporosis Impaired wound healing and increased skin bruising Sodium and fluid retention, potassium depletion Hypertension Muscular weakness, myopathy and muscle wasting Aseptic necrosis especially of femoral head Cataracts, glaucoma, raised intra-ocular pressure Cushingoid facies Retardation of growth Headaches, pseudotumor cerebri Mood change (euphoria, hypomanic psychosis, depression) Weight gain May increase risk of peptic ulceration or retard ulcer healing

Dosage

Maintenance up to 20 mg/day; treatment of rejection 200 mg/day for 3 dats or 3 days

Drug interactions

NSAIDs

Notes

Other forms of steroids—see Table 5

6

Among the intra-nuclear functions altered by glucocorticoids is synthesis of nuclear factor kappa B (NF-κB), resulting in apoptosis of lymphocytes. There are many different glucocorticoids used in transplantation and the potency on a weight for weight basis varies and is summarised in Table 5. There is increasing evidence that corticosteroids can be withdrawn by three months or earlier in most liver transplant recipients. In contrast, some centers maintain corticosteroids in patients grafted for autoimmune hepatitis to prevent recurrent disease in the allograft (see Table 6).

Calcineurin Binding Drugs (Tables 7 and 8) Both cyclosporin and tacrolimus bind to immunophilins which are widely distributed intracellular proline isomerases. Cyclosporin binds to cyclophilin and tacrolimus to the FK-binding protein which results in inhibition of calcineurin which inhibits activation of transcription factors such as NFATc, a transcriptional factor responsible for the calcium activation of cytokine genes during the immune response.

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Table 7. Immunosuppressive drugs: Cyclosporin Drug Name

Cyclosporin

Mechanism of action

Binds to immunophilins (cyclophilin). Inhibition of T cells; suppresses T-cell activation by inhibiting synthesis and release of IL-2 and other lymphokines

Side-effects

Renal impairment (30-40%); hepatotoxicity (10%); hypertension (30%); gum hypertrophy (10%); hirsutism (40%); tremor (40%) Convulsions (3%) Headaches (40%) Hyperkalemia Hyperuricemia Gout

Dosage

Adjust to maintain trough whole blood levels (measured by RIA) between 100-250 ng/ml (target levels vary between centers and according to time after transplantation and graft function)

Drug interactions

See Table 8

Notes

Several formulations available: as they have different absorption profiles the different formulations may not be interchangeable

Other down-stream effects are thought to relate some of the side effects of this class of drugs including diabetes and renal impairment. Tacrolimus is well absorbed from the upper GI tract. Consequently, there is rarely an indication to give tacrolimus intravenously. The starting dose is 0.1 mg/kg/day in two divided doses: target levels for the first three months lie between 10 and 15 ng/ml (trough whole blood levels measured by RIA) and between 5 and 10 ng/ml thereafter. Cyclosporin is fat soluble, and absorption is variable from the gut, especially in the early post-operative period when bile production and flow may be compromised. The microemulsion form is absorbed in a more consistent fashion and there is rarely a need to administer cyclosporin intravenously. The starting dose is 8 mg/kg/day and the dose adjusted to trough whole blood levels between 150 and 200 ng/ml for the first three months and 100-150 ng/ml thereafter. However, measurement of blood levels taken 2 hours post dose (otherwise called C-2) may provide a better assessment of drug monitoring. Tacrolimus and cyclosporin are metabolized by oxidation through the cytochrome P450 system. The liver is the main site of metabolism, although minor metabolism occurs in the gut. Drugs which induce or inhibit cytochromes P450, such as erythromycin, ketoconazole or rifampicin, interact with tacrolimus and cyclosporin and may affect drug levels. Drug interactions are listed in Table 9.

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Table 8. Immunosuppressive drugs: Tacrolimus

6

Drug Name

Tacrolimus

Mechanism of action

Binds to FK-binding protein 12; inhibits synthesis and release of IL-2

Side-effects

Diabetes mellitus Hypertension Headaches Tremor Convulsions Nephrotoxicity Renal impairment Myocardial hypertrophy

Dosage Target

Maintain trough whole blood levels measured by RIA between 5-15 ng/ml. levels vary between centres, time after transplantation and renal and hepatic function

Drug interactions

See Table 8

Notes

Not licencsed for use in pregnancy (although no evidence of increased teratogenicity compared with cyclosporin

Calcineurin inhibitors (cyclosporin and tacrolimus) are the current mainstays of maintenance immunosuppression. Both agents are associated with significant side effects in the long term. There are several studies comparing the two drugs and these suggest that tacrolimus may be superior. For both drugs, target levels have been derived from clinical experience although the dose should be adjusted in the light of complications (such as renal impairment or symptoms such as headaches or tremors) and liver function.

TOR Inhibitors (Table 10) Sirolimus (previously known as rapamycin) inhibits lymphocyte proliferation mediated by cytokines such as IL-2 and IL-4. Sirolimus, like tacrolimus, binds to the immunophilin called FK binding protein (FKBP) but it does not inhibit the calcineurin pathway. The Sirolimus-immunophilin complex interacts with a protein kinase called TOR (‘target of rapamycin’) that is integral to a signal transduction pathway regulating the synthesis of proteins required for cell-cycle progression in both lymphoid and non-lymphoid cells. Sirolimus is poorly absorbed from the gut. It is widely distributed in many tissues. The liver is the principal organ of metabolism, via the cytochome P450 3A4 system. The half-life is approximately 50-70 hours in healthy subjects and renal transplant recipients and is considerably lengthened in patients with chronic liver dysfunction. The most frequently reported adverse effects in subjects receiving Sirolimus are mild

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Table 9. Drugs which affect levels and toxicity of the calcineurin inhibitors and Sirolimus Increase levels (usually by inhibition Bromocryptine of cytochrome P450 3A4 or reduced Cimetidine clearance) Cisapride Clarithromycin Danazol Diltiazem Erythromycin Fluconazole Grapefruit juice Itraconazole Ketoconazole Methylprednisolone Metoclopramide Nicardepine Statins (HMG CoA reductase inhibitors) Verapamil Protease inhibitors Decrease levels (usually induction of cytochrome P450 3A4)

Barbiturates Carbamazepine Phenytoin Rifampicin St. John’s wort (Hypericum)

Increase toxicity

Amphotericin B Cimetidine Gentamicin NSAIDs Ranitidine Tobramycin Vancomycin

Decrease toxicity

-

dose-related thrombocytopenia and leukopenia, and hyperlipidemia, affecting both serum triglycerides and cholesterrol. Among the other effects reported include nausea, vomiting, hypertension, elevations in serum creatinine, elevations in liver-associated enzymes and acne. Isolated cases of interstitial pneumonitis or hepatic arterial thrombosis have also been observed in patients receiving Sirolimus.

Immunosuppressive Antibodies (Tables 11, 12 and 13) Antibodies may be mono- or polyclonal. Some preparations react with epitopes expressed by all lymphocytes whereas others recognize epitopes expressed by subsets of lymphocytes only. All are profoundly immunosuppressive. Some centers use polyclonal antibodies to lymphocytes (e.g., ALG, Thymoglobulin) for induction (see Table 9).

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Table 10. Immunosuppressive drugs: Sirolimus Drug name

Sirolimus (AKA rapamycin)

Mechanism of action

Inhibits T cell activation

Side-effects

Hyperlipidemia (40%) Hypercholesterolaemia (40%) Thrombocytopenia Gastrointestinal disturbances Interstitial pneumonitis Hepatic artery thrombosis May impair wound healing

Dosage

2 mg/day Should be taken 4 hours after cyclosporin Monitoring of drug levels is not required in most patients (except in children, renal or hepatic impairment, with concurrent administration of enzyme inducers/inhibitors of CYP 3A4 or if cyclosporine discontinued)

Drug interactions

As for calcineurin inhibitors

Notes

Anti-proliferative in vitro. May be effective in reducing malignant cell proliferation and in intimal call proliferation

6

Principles of Immunosuppression The management of immunosuppression can be considered in five phases: • Induction • Maintenance • Treatment of acute rejection • Treatment of chronic rejection • Withdrawal of immunosuppression

Induction of Immunosuppression There is no consensus for the optimal method for induction of immunosuppression. Some centers use mono- or polyclonal antibodies, in combination with other immunosuppressive agents. Other centers use intra-operative corticosteroids.

Maintenance of Immunosuppression Currently most centers use a combination of corticosteroids, azathioprine and a calcineurin inhibitor although some use monotherapy (calcineurin inhibitor alone) or dual therapy (calcineurin inhibitor with azathioprine or mycophenolate) but there

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Table 11. Immunosuppressive drugs: Polyclonal antibody preparations Drug name

Anti-thymocyte globulin (ATG), Antilymphocyte globulin (ATGAM)

Mechanism of action

Polyclonal antibodies raised in mammals against human lymphocytes or lymphocyte subsets.

Side-effects

Hypersensitivity; anaphylaxis; headache, dizziness, muscle pain, lymphopenia, leukopenia, thrombocytopenia (usually transient); nephrotoxicity

Dosage

Different preparations vary in their activity. See manufacturers instructions

Drug interactions Notes

Test for sensitivity before administration of first dose. Increases the risk of CMV. Use CMV prophylaxis in selected patients

Table 12. Immunosuppressive drugs: Monoclonal antibodies to T lymphocytes Drug name Mechanism of action Side-effects

Dosage Drug interactions Notes

Anti-CD3 Binds to and blocks the CD3 receptor on T cells and prevents signal transduction Treatment is associated with a cytokine release reaction (‘shake and bake syndrome’) which may be severe. Pre-treatment with methylprednisolone may prevent the syndrome. Other side-effects include profound lymphopenia, seizures, encephalopathy, aseptic meningitis, cerebral edema, and anaphylactic responses (such as wheezing, rigors and hypertension). 5 mg/day intravenously for 10-14 days Avoid the concomitant use of NSAIDs and cyclosporin (increased CNS side-effects), corticosteroids (increased risk of psychosis) Muromonab-CD3 is a monoclonal antibody ; should be avoided in patients with anti-murine antibody titres >1:1000; uncompensated fluid overload or patients with heart failure or with a history of seizures. Avoid in pregnancy or breast feeding.

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Table 13. Immunosuppressive drugs: Antibodies to IL-2 receptor Drug name receptor) Mechanism of action

6

Basiliximab; daclizumab (antibodies to IL-2 These bind to and block the alpha unit of the IL-2 receptor on activated T cells and so inhibits IL-2 binding and inhibits IL-2 activation

Side-effects

Anaphylaxis

Dosage

See below

Drug interactions

None known

Notes

There are two preparations: Basiliximab is a chimeric monoclonal antibody and is given at a dose of 20 mg within 2 hours of surgery and at 4 days (children below 15 years have a smaller dose) Daclizumab is a humanized monoclonal antibody: the dose is 1 mg/kg/dose for 5 doses, the first within 24 hours of transplantation The initial dose required for liver transplants may be greater than for other solid organ recipients due to loss of antibody in ascites drained at laparotomy, and in ascitic or pleural fluid drained during the peri-operative period.

are few data to define the optimal regime. The introduction into clinical practice of newer drugs such as Sirolimus will allow the clinician to tailor the immunosuppressive regime more closely to the patient.

Treatment of Acute Rejection Acute rejection should, whenever possible, be confirmed prior to treatment using histology obtained either by liver biopsy; fine needle aspiration biopsy is used occasionally. Although many serological markers in blood and bile have been described, none has been shown to be of adequate sensitivity and specificity to confirm rejection. It is rarely possible to distinguish reliably between rejection and infection without histology. The mainstay of immunosuppression for early acute rejection is high dose corticosteroids: regimes vary between centers and there are no good data to demonstrate superiority of any one regime. Typical regimes are: • Prednisolone 200 mg/day for 3 days • Methyl prednisolone 0.5-1 g/day for 3 days The rate of reduction of corticosteroid pulses to maintenance steroids varies from center to center.

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Treatment of Chronic Rejection Chronic rejection of the liver allograft has many names: chronic ductopenic rejection, vanishing bile duct syndrome, chronic rejection. Chronic ductopenic rejection may lead to loss of the graft. It is treated by increased immunosuppression, including conversion to tacrolimus from cyclosporin or switching to Sirolimus.

Withdrawal of Immunosuppression The observation that some patients have maintained long-term good graft function after discontinuing immunosuppression has led some centers to embark on carefully controlled trials of withdrawal of all immunosuppression in long-term (>5 years) survivors with good graft function, or in subjects with major impediments to continued use of immunosuppressant, such as malignant disease. These studies have demonstrated that it is possible to withdraw all immunosuppression in about 20% of carefully selected patients. The remainder required maintenance immunosuppressants or their reintroduction if they had been stopped. The usual reason for failure to withdraw immunospressants was late onset acute cellular rejection, which was then controlled by adjusted phamacotherapy. Those recipients grafted for nonautoimmune diseases, without episodes of acute rejection and with a good HLA match are more likely to be able to withdraw immunosuppression.

Side-Effects of Immunosuppression The side-effects of immunosuppression may be due either to • The effect of immunosuppression itself (especially infection and malignancy) • The effects of individual drugs These are discussed in detail in Chapter 9.

Tailoring the Immunosuppression to the Individual Since different drugs have differing effects and side-effects both on the patient and the disease, it is important not to adopt one regime for all patients but to tailor the drug regime for the individual. The probability of developing acute rejection is, in part, dependent on the indication for transplantation so that patients grafted for viral hepatitis (especially B) and alcohol-associated liver disease have a much lower probability of developing early rejection than those grafted for autoimmune diseases such as PBC or AIH.

Inter-Current Bacterial Infections Currently available immunosuppressants will not only reduce the risk of rejection but will predispose the patient to infection. The balance between over- and underimmunosuppression is even more difficult to maintain in the presence of active sepsis. The general approach is to reduce the immunosuppression but the onset of graft rejection may not only herald the need for high-dose immunosuppression but hepatic impairment is associated with a further reduction in the host defences against infection. In the presence of bacterial infection, early detection and vigorous treatment with appropriate antimicrobials is clearly required; depending on liver function,

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steroids should be reduced initially. Remember, however, in maintaining the balance between rejection and infection, with rejection the graft will be lost but with infection the patient will be lost.

Intercurrent Viral Infection The most common viral infection during the early post-operative period is cytomegalovirus (CMV). CMV is associated with chronic rejection: this may be related to a direct effect of CMV on the biliary epithelial cells and, in part, to the reduction in immunosuppression. It is important, therefore, to reduce the immunosuppressive therapy in association with active antiviral treatment. A common practice is to stop azathioprine and reduce the calcineurin inhibitor.

Tuberculosis

6

Because of the severe course of reactivation of tuberculosis in the patient on immunosuppression, most centers use prophylactic treatment with Isoniazid 100 mg/day in those at risk. Isoniazid should be given with pyridoxine. Treatment should be for at least one year. The interaction between the immunosuppression and recurrent viral disease, such as HCV or HBV, is discussed in Chapter 8.

Retransplantation for Chronic Rejection, Late Acute Rejection and Early Ductopenic Rejection These are associated with an increased risk of developing graft loss and therefore many centers are using a combination of corticosteroids, tacrolimus and mycophenolate or Sirolimus.

Co-Morbid Conditions Pregnancy and Breast Feeding See Chapter 9: if the recipient is likely to become pregnant after transplantation, consideration should be given to the appropriate choice of drugs.

Diabetes Mellitus The tendency of calcineurin inhibitors to induce diabetes mellitus is controversial. Tacrolimus may be more diabetogenic than cyclosporin. Most transplant programs do not switch from tacrolimus to cyclosporin, on account of diabetes mellitus. Those diabetics given corticosteroids may have an increased requirement for insulin or oral agents.

Renal Impairment Renal impairment may occur following transplantation for many reasons (such as IgA nephropathy, HCV associated glomerulonephritis, diabetic nephropathy or associated with the inappropriate prescription of non-steroidal anti-inflammatory drugs or nephrotoxic drugs such as gentamicin). In the presence of peri-operative renal failure, some centers avoid the use calcineurin inhibitors. If renal impairment develops in associated with calcineurin inhibitor use, most centers will reduce or discontinue the calcineurin inhibitor (see Chapter 9).

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Development of Lymphoma and Other Malignancy This is discussed in Chapter 7. Lymphoma post transplantation may be associated with EBV infection. Treatment is with aggressive therapy of the lymphoma and a reduction in the immunosuppressive regime; some centers discontinue all immunosuppression during chemotherapy.

Suggested Reading 1. 2.

3.

Micromedex Information System; http://www.micromedex.com; [email protected] Devlin J, Doherty D, Thomson L, Wong T, Donaldson P, Portmann B et al. Defining the outcome of immunosuppression withdrawal after liver transplantation. Hepatology 1998; 27:926-933. Jain A, Kashyap R, Marsh W, Rohal S, Khanna A, Fung JJ. Reasons for long-term use of steroid in primary adult liver transplantation under tacrolimus. Transplantation 2001; 71(8):1102-1106.

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CHAPTER 7

Graft Dysfunction Geoffrey H. Haydon Introduction The causes of graft dysfunction occurring after liver transplantation may be classified either according to the time period post-transplantation (Table 1) or to the etiology of the graft dysfunction. It should be emphasised that any of these conditions may become evident at any time after liver transplantation, and Table 1 lists the most common times for presentation.

7

Investigation of Graft Dysfunction The general diagnostic approach is outlined in Table 2. Investigation of each of the complications above is considered under the appropriate heading.

Primary graft non-function Primary graft non-function is defined as failure of the graft to function in the first post operative week. It is manifested by: • Failure to regain consciousness • Sustained elevations in transaminases • Increasing coagulopathy • Acidosis • Poor bile production Primary graft non-function may be due to: • Massive hemorrhagic necrosis • Ischemia/reperfusion injury • Hepatic artery thrombosis • Idiopathic It may be difficult to distinguish non-function which will not recover, from early poor function wherein graft function will return to normal after a period of systematic support. The value of agents such as prostaglandins and n-acetyl cysteine in these circumstances is uncertain.

Immunological Complications Acute Cellular Rejection (ACR) -Definition: • “Inflammation of the allograft elicited by genetic disparity between the Liver Transplantation, edited by Michael R. Lucey, James Neuberger and Abraham Shaked. ©2003 Landes Bioscience.

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Graft Dysfunction

Table 1. Etiology of graft dysfunction more than one-month post transplantation. Time Period Post-OLT

Diagnosis

1-6 months

Acute cellular rejection Opportunistic infection -Viral: CMV; EBV (HSV, VZV less common) Vascular -Hepatic artery thrombosis Recurrent viral hepatitis Biliary tract abnormalities

6-12 months

Acute cellular rejection Recurrent viral hepatitis Biliary tract abnormalities Chronic ductopenic rejection Hepatic artery thrombosis

>12 months

Recurrent viral hepatitis Biliary tract abnormalities Acute cellular rejection Chronic ductopenic rejection Recurrent autoimmune disease (PSC; PBC; AICAH) Hepatic artery thrombosis Steatohepatitis

Table 2. Graft dysfunction according to pathogenesis • Immunological complications: acute cellular rejection; chronic ductopenic rejection • Primary viral infection: CMV; HSV; EBV • Graft ischemia: hepatic artery thrombosis • Biliary complications: biliary leaks; bile duct strictures; choledocholithiasis and cholangitis • Recurrent disease: viral hepatitis (HCV; HBV); PBC; PSC; AICAH, NASH

donor and recipient, primarily affecting interlobular bile ducts and vascular endothelia, including portal veins and hepatic venules, and occasionally the hepatic artery and its branches”. -Incidence: • Occurs in 20% to 80% of grafts. -Timing: • First occurs between 5 and 30 days post-transplantation; 80% of ACR occurs in the first 10 weeks post-transplantation. ACR may still occur thereafter. -Clinical Findings: • Usually asymptomatic, although in late or severe cases, fever and hepatomegaly occur. When bile is collected, it is noted to be pale and watery.

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Table 3. Banff criteria grade of histologic injury Subjective Grade

Criteria

Indeterminate

Portal inflammatory infiltrate that fails to meet criteria for the diagnosis of acute rejection Rejection infiltrate in a minority of the triads, that is generally mild and confined within the portal spaces Rejection infiltrate expanding most or all of the triads As above for moderate, with spillover into periportal areas and moderate to severe perivenular inflammation that extends into hepatic parenchyma and is associated with perivenular hepatocyte necrosis

Mild Moderate Severe

Banff grading of acute liver allograft rejection. Global assessment of rejection grade made on review of the biopsy and after diagnosis of rejection has been established.

7

-Investigations: • Liver chemistry tests are usually abnormal (but non-specific) and blood leukocytosis and eosinophilia are frequently present. The gold standard for diagnosis of acute cellular rejection remains liver histology. The histological features are mixed inflammatory infiltrate in the portal triads, bile duct damage, and vascular endothelial damage. The Banff criteria grade of the severity of histological injury (see Table 3). The differential diagnosis of deteriorating graft function is infection, graft ischemia and biliary obstruction. The gold standard for diagnosis of ACR remains liver histology. -Treatment (this is described in Chapter 6) -Prognosis: • A single episode of easily reversed acute cellular rejection confers a better patient and graft survival than observed in patients who never experience rejection. In contrast, acute cellular rejection that does not respond to increased immunosuppression (steroid resistant rejection) is associated with graft loss.

Chronic Ductopenic Rejection -Definition: • Chronic ductopenic rejection is defined by two histopathological features: obliterative vasculopathy and bile duct loss (Table 4). It is also called chronic rejection and chronic vanishing bile duct syndrome. -Incidence: • Most programs report less than 5% of grafts develop chronic ductopenic rejection.

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Table 4. Reported risk factors for chronic ductopenic rejection Highly Probable: -Retransplantation for chronic rejection -Late acute rejection episodes -Steroid-nonresponsive acute cellular rejection Controversial Associations: -Underlying liver disease -AICAH -PBC -PSC -Positive lymphocytotoxic cross-match -CMV infection -Recipient age -Donor/recipient of different ethnic origins -Male donor allograft into female recipient -Cyclosporin based immunosuppression (compared with tacrolimus regimes)

Table 5. Histological features and grading of chronic ductopenic rejection Bile duct loss*, without centrilobular cholestasis, perivenular sclerosis, or hepatocyte ballooning or necrosis and dropout Bile duct loss*, with one of the following four findings: -centrilobular cholestasis -perivenular sclerosis -hepatocellular ballooning -hepatocyte necrosis and drop-out Bile duct loss*, with at least two of the four following findings: -centrilobular cholestasis -perivenular sclerosis -hepatocellular ballooning -centrilobular necrosis and drop-out *Bile duct loss: >50% of triads

-Timing: • Chronic ductopenic rejection may occur at any time after liver transplantation, but is usually seen in the first postoperative year. -Clinical Findings: • As with ACR, most patients are free of symptoms. Some have generalized systemic symptoms or complain of increasing jaundice and cholestatic symptoms. • Risk factors for chronic ductopenic rejections are shown in Table 4. -Investigations: • Liver chemistry tests usually demonstrate a relentless rise in markers of cholestasis. Liver biopsy is essential to make the diagnosis of chronic ductopenic rejection. Special cytokeratin stains to identify biliary epithelia are useful when assessing bile duct loss. Vascular lesions may be absent on

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Table 6. Differential diagnosis of cholestatic liver disease in the transplanted liver Chronic ductopenic rejection Biliary obstruction Viral hepatitis (viral cholestatic hepatitis) Sepsis Drug hepatotoxicity Recurrent primary biliary cirrhosis Recurrent primary sclerosing cholangitis

7

needle biopsy specimens (Table 5). • Hepatic angiography may show vascular injury. -Differential Diagnosis (Table 6) -Treatment (this is described in Chapter 6) -Prognosis: • Approximately 30% of patients with chronic ductopenic rejection respond to conventional additional immunosuppressive therapy. In those who do not respond to standard immunosuppression, re-grafting is the only other option.

De Novo Autoimmune Hepatitis In a small number of liver transplant recipients a syndrome resembling autoimmune hepatitis Develops. It is characterised by biochemical hepatitis, autoantibodies and histologic appearances of inflammatory hepatitis. The hepatitis usually responds to reintroduction or increased doses of corticosteroids.

Graft Infection Infection is a major cause of morbidity and mortality post-transplantation; there is also a complex interplay between the immune system and infectious agents.

CMV Disease -Timing: • Commonly within 2-3 months, and rarely within the first month of transplantation -Clinical Presentation: • Triad: fever; leukopenia; thrombocytopenia • May present as: hepatitis; pneumonitis; GI tract infection (esophagitis, gastritis, duodenititis, and colitis) -Diagnosis of CMV Disease: • Abnormal liver chemistry tests • CMV PCR positive when there is active viremia or shedding of virus (specificity 50-60%) • Typical CMV inclusion bodies demonstrated on liver biopsy. May also be seen in rectal or duodenal biopsies

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• CMV PCR of liver biopsy -Risk Factors for CMV Infection: • The respective serological status of the donor and recipient is most important and must be documented: seronegative recipients of a graft from a seropositive donor have the highest risk of infection • Infection may be transmitted by the graft; blood products; reactivation of previous infection or superinfection by a CMV variant • Patients with septic biliary complications (including hepatic artery thrombosis) • Patients transplanted for fulminant hepatic failure • Recipients treated with muromab OKT3 or thymoglobulin. The risk of CMV in recipients of monoclonals directed against the IL-2 receptor remains uncertain -Prophylaxis against CMV Infection: • Ganciclovir and acyclovir are highly effective against CMV reactivation; re-infection or new disease • Studies comparing the two drugs suggest that ganciclovir produces a more significant reduction in infection than acyclovir • Individual programs determine policy regarding prophylactic regimes against CMV. Prophylaxis may be restricted to high risk patients, but are not essential for all recipients -Treatment of CMV Graft Infection • Immunosuppression should be reduced (azathioprine usually stopped) • A 14 day course of intravenous ganciclovir (10 mg/kg/day IV in 2 doses) is most effective. Many programs follow this with 6 weeks oral ganciclovir. • Second line therapy: Foscarnet 60 mg/kg every 8 hours for 14 days (avoid in renal failure); CMV Ig • Third line therapy: Cidofovir 5 mg/kg once weekly for 2 weeks, followed by 5mg/kg every 2 weeks (also avoid in renal failure).

EBV Hepatitis (Table 7) -Timing: • No specific timing after liver transplantation. -Clinical Presentation: • Infectious mononucleosis syndrome (fever; fatigue; lymphadenopathy; pharyngitis) -Diagnosis of EBV hepatitis • Abnormal liver chemistry tests • Liver biopsy: well-differentiated mononuclear B lymphocytic portal infiltrate without bile duct damage. EBV does not infect hepatocytes, biliary epithelium or vascular endothelium • PCR for EBV DNA (serum and biopsy sample) -Prophylaxis against EBV Infection:

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Table 7. Clinical and histological features of EBV related graft dysfunction Disease/ disorder

7

Clinical features Histology

Therapy

Outcome

Post-transplant Fatigue, fever, Mild increase in Acyclovir infectious rash, sore throat, portal infiltrates mononucleosis lymphadenopathy (IM)

Self-limited disease/ resolved

Polyclonal B- Similar to acute cell hyperplasia IM with severe hepatitis, bone marrow failure and ARDS

Decreased immunosuppression; treat with acyclovir or ganciclovir

Responds to antiviral treatment/ resolves

Polyclonal Nodal and extra- Polymorphic proliferation B- nodal lympholymphocytic cell lymphoma cytic proliferation infiltrate in patients treated with immunosuppressive medication

Withdraw immunosuppression; treat with acyclovir, ganciclovir or anti-B cell monoclonal Ab

Most progress to lymphoma and have a low survival rate

Monoclonal polymorphic B-cell lymphoma

Withdraw Aggressive immunosupdisease with pression; treat survival rate with chemoof less than therapy; radio- 1 year therapy or surgical resection

Prominent portal lymphocyte and (plasma cell) infiltrate

Nodal and extra- Polymorphic to nodal lymphomonomorphic cytic proliferation lymphocytic in patients treated proliferation with immunodepending on suppressive the stage of medications disease

• None is necessary -Treatment of EBV hepatitis: • A decrease in the immunosuppressive therapy will result in resolution of both symptoms and histopathological findings -Outcome of EBV infection after liver transplantation: • Excellent prognosis

Post-Transplant Lymphoproliferative Disorders (PTLD) (Table 7) Malignancies occur in solid organ transplant recipients with a frequency 101000 times that of the normal population. After skin cancer, lymphoma has the second highest incidence in the immunosuppressed patient. The association of EBV with post-transplant lymphoproliferative disorders has been well described and the presence of EBV-specific proteins and fragments of EBV genome demonstrated consistently in PTLD. There are three clinical disorders of differing presentations and prognosis, which may involve graft dysfunction in PTLD. Polyclonal B-cell Hyperplasia -Clinical Presentation:

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• As for infectious mononucleosis. -Subpopulation: • Young patients in second to fourth decade, who are profoundly immunosuppressed -Histology: • Polyclonal B-cell lymphoproliferation -Treatment: • Acyclovir -Outcome: • Usually excellent response to acyclovir Polymorphic B-cell Lymphoma -Clinical Presentation: • Patients present with infectious mononucleosis-like symptoms and then develop a rapidly disseminated lymphoproliferation involving the liver, spleen and other visceral organs -Histology: • Polymorphic B-cell lymphoproliferation -Treatment: • Immediately withdraw immunosuppression and initiate anti-viral therapy -Outcome: • Usually fatal Monoclonal Polymorphic B-cell Lymphoma -Clinical Presentation: • Usually older patients more than 5 years post-transplant. Prominent extranodal masses develop in the central nervous system, gastrointestinal tract and liver -Histology: • Non-Hodgkin’s lymphoma with a monomorphic pattern and monoclonal immunoglobulin expression -Treatment: • Withdraw immunosuppression. Surgical resection of masses with adjuvant radiotherapy and chemotherapy -Outcome: • Aggressive disease with high mortality at 1 year

Graft Ischemia Hepatic Artery Thrombosis (HAT)

• Hepatic artery thrombosis is one of the principal causes of morbidity and graft loss following liver transplantation -Presentation (Table 8) -Incidence: • This has been described as high as 10%; technical aspects of the arterial anastomosis are important particularly for early thrombosis, but with

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Table 8. Presentation of hepatic artery thrombosis (HAT) Clinical Presentation Acute graft failure Massive rise in liver enzymes (particularly transaminases). This is a feature of HAT presenting immediately after transplantation. Unexplained septicaemia Biliary tract problems -Leaks -Abscess -Breakdown of biliary anastomosis Liver abscess (may be sterile, also called a biloma)

7

improvement in surgical technique it is likely that the incidence is falling. It is a recognized component of the small sized graft syndrome in recipients of adult to adult right lobe grafts -Timing: • It is most common within the first month after transplantation, but may occur at any time -Clinical Sequelae: • Graft necrosis • Intrahepatic abscesses. Also called ‘bilomas’ • Infarction of the bile ducts with bile leakage and gram negative sepsis. -Diagnosis of hepatic artery thrombosis: • Doppler sonography (sensitivity for diagnosis of hepatic artery thrombosis: 60-92%) • Confirmed by arteriography (CT, MR or arteriograms) -Risk Factors: • Technical aspects of the arterial anastomosis • Raised hematocrit • Low donor/recipient age ratio • Procoagulant syndromes • Smoking • CMV infection (followed by rapid procoagulant response) • Adult to adult right lobe transplantation -Treatment: • Early thrombosis is an indication for urgent regrafting • Patients with late thrombosis may survive with conservative therapy and satisfactory graft function • There are anecdotal reports of a good response to thombectomy and thrombolytic therapy

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Hepatic Artery Stenosis Stenosis of the hepatic artery may present with unexplained elevated liver chemistry tests. Doppler sonography and hepatic arteriography are required to confirm the diagnosis. Resection of the stenosed portion or angioplasty are the treatments of choice when graft function is well preserved. Hepatic artery stenosis presenting with severely compromised graft function may require urgent retransplantation.

Portal Vein Thrombosis This can occur in up to 3% of recipients; the diagnosis is often suggested by the subsequent development of gastroesophageal varices or other signs of portal hypertension. Treatment is usually management of the complications of portal hypertension. Thrombectomy or angioplasty are rarely feasible.

Biliary Complications Biliary tract complications are the most frequent late complication of liver transplantation with an incidence of 15-20%. Biliary leaks occur at T-tube withdrawal in up to 30 % of patients who have a biliary drainage tube placed at time of transplant. Among the important factors which have been implicated in the pathogenesis of biliary strictures or leaks are: • The arterial supply to the biliary tree: biliary epithelial cells are particularly susceptible to interruption of their arterial blood supply; so that if this is compromised by even relative ischemia, bile duct necrosis will follow • Bile composition: the composition of bile is altered following transplantation, predisposing to supersaturation with cholesterol and stone formation • Denervation of the liver may inhibit or alter the composition of bile. Biliary complications have been recorded in up to 20% of recipients of living donor adult to adult right lobe grafts -Early biliary complications: • These can be recognized by the appearance of bile in surgical drains and the measurement of drain fluid bilirubin, in patients without T-tubes -Late biliary complications: • Biliary leak following withdrawal of peroperative biliary drainage tube (often referred to as a ‘T-tube’) • Biliary strictures (see below) • Ascending cholangitis • Increasing cholestasis • The biliary cast syndrome -Investigations: • When the patient is septic, a full sepsis screen is undertaken • Increasing cholestasis is investigated by ultrasound (or CT) and collections drained under ultrasound guidance • The integrity of the biliary tree can be assessed by T-tube cholangiography, endoscopic retrograde cholangiography or by magnetic resonance cholangiopancreatography. Biliary leaks may resolve if stented by ERC

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• If these investigations are normal, a liver biopsy is necessary to exclude chronic ductopenic rejection

Biliary Leaks These occur because of ischemic necrosis at the anastomosis or following removal of a T-tube.

Bile Duct Strictures

• These are usually classified as anastomotic or non-anastomotic; anastomotic being most common. Non-anastomotic strictures may be caused by long warm ischemic times during transplant surgery or by thrombosis of hepatic artery radicals (ischemic cholangiopathy); they are associated with ABO mismatches, and are a feature of recurrent PSC (see Chapter 8). Bile leaks that heal spontaneously may result in anastomotic stricturing. • Biliary leaks following the removal of a T-tube are best stented via the endoscopic or percutaneous route. Anastomotic strictures usually require surgical reconstruction with excision of the stricture and re-anastomosis to a Roux loop of jejunum. Stenting may be palliative in selected cases.

7

The Biliary Cast Syndrome

• Associated with biliary stricture formation and ischemic injury to the biliary tree. May be more common with ‘non-heart beating donors’. In addition to strictures the extrahepatic and ultimately the intrahepatic biliary trees are clogged with cast material/sludge. Cholesterol is the main component of biliary cast matter • Presents with intractable pruritus • Managed by serial removal of biliary cast material/sludge by ERC or by percutaneous cholangiography • May require retransplantation

Recurrence of Disease After Liver Transplantation Recurrence of disease following liver transplantation remains a problem for the long-term survivor in several indications and may affect graft function and survival. It does however, provide useful information about the pathogenesis of the underlying disease process. Recurrent disease is described in Chapter 8.

Suggested Reading 1. 2. 3.

4.

Demetris AJ, Batts KP, Dhillon AP et al. Banff scheme for grading liver allograft rejection: an international consensus document. Hepatology 1997; 25:658-663. Dousset B, Conti F, Cherruau B et al. Is acute rejection deleterious to long-term liver allograft rejection? J Hepatol 1998; 29:660-668. Demetris AJ, Seaberg E, Batts KP et al. Reliability and predictive value of the NIDDK transplantation database nomenclature and grading system for cellular rejection of liver allografts. Hepatology 1995; 21:408-416. Demetris A, Adams D, Bellamy C et al Update of the International Banff Schema

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6.

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for Liver Allograft Rejection: Working recommendations for the histopathologic staging and reporting of chronic rejection. An International Panel. Hepatology 2000; 31:792-799. Wiesner RH, Demetris AJ, Belle SH, Seaberg EC, Lake JR, Zetterman RK et al. Acute hepatic allograft rejection: Incidence, risk factors, and impact on outcome. Hepatology 1998; 28:638-645. Heneghan MA, Portmann BC, Norris SM, Williams R, Paolo Muiesan P, Mohamed Rela M et al. Graft dysfunction mimicking autoimmune hepatitis following liver transplantation in adults. Hepatology 2001; 34:464-470.

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CHAPTER 8

Recurrence of Disease after Liver Transplantation Lisa Forman and Geoffery Haydon Recurrence of disease following liver transplantation remains a problem for the long-term survivor in several indications and may affect graft function and survival. It does however, provide useful information about the pathogenesis of the underlying disease process.

Hepatitis C Virus Infection

8

-Incidence and Prevalence: • Graft infection with hepatitis C virus (HCV) is universal • 100 % of patients have persistence of HCV RNA after transplantation • Serum HCV RNA levels decrease during surgery, both when the recipient native liver is removed and when the donor organ is reperfused. Afterwards the concentrations of circulating HCV RNA increases as early as day 3 post-transplantation and the levels at 1-3 months are greater than pretransplant levels. • An acute hepatitic syndrome occurs in many HCV infected patients in the first 4 months post-OLT. It may be difficult to distinguish HCV recurrence from acute cellular rejection or a combination of the two. • Chronic hepatitis is found in 50% of patients at 2 years and 70% at 4 years. • The prevalence of hepatic cirrhosis in graft recipients at 5 years is at least 10% • Up to 10 % of HCV infected recipients develop a cholestatic syndrome associated with ballooning degeneration of hepatocytes, which has been called ‘fibrosing cholestatic hepatitis’. It occurs in the first year and is associated with very high circulating HCV RNA levels. It has a poor prognosis. Investigation of HCV after liver transplantation: • Biochemical profile • HCV RNA levels in serum • Liver biopsy Many factors have been associated the severity of recurrent disease (See Table 1). Liver Transplantation, edited by Michael R. Lucey, James Neuberger and Abraham Shaked. ©2003 Landes Bioscience.

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Table 1. Risk factors for recurrent HCV hepatitis Highly probable risk factors: • High levels of immunosuppression. Data implicate use of OKT3, and pulse corticosteroids. Data on choice of calcineurin inhibitor or the effect of MMF are unclear. • Age of donor liver • Retransplantation Putative risk factors for which data are uncertain: • HCV genotype 1 • CMV infection • HLA match • Acute cellular rejection • MHC donor/ recipient match • Ethnicity • Recipient of a live donor hepatic graft

Treatment of Recurrent HCV Pre-Transplant Therapy • Treatment of the recipient in anticipation of liver transplantation. The difficulty is achieving an adequate viral response on account of the intolerance of patients with cirrhosis for combination antiviral therapy

Post Transplant Therapy • Interferon and ribavirin The unwanted effects of therapy have hampered attempts at treatment in the first few weeks after transplant. Early Therapy (First 6 Months After Transplantation) • Occasional patients have eradicated the virus with combination therapy using interferon alfa 2b and ribavirin. This should confined to investigational studies. Late Therapy (>6 Months After Transplantation) • Viral eradication has been recorded in 20% of patients receiving combination interferon alfa 2b and ribavirin. Dose reductions of either agent have been required in many patients. -Prognosis: • Initial data suggested that graft survival at 5 years was no different than in other indications; however, more complete recent studies suggest that graft and patient survival are reduced.

Hepatitis B Virus Infection -Incidence and Prevalence: • The early experience of liver transplantation for chronic HBV infection highlighted a significant adverse effect of infection on graft and patient survival. Aggressive re-infection and progression to cirrhosis and sub-acute

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graft failure were almost universal; the overall outcome was inferior to other etiologies. HBV infection presenting as FHF had a better prognosis for post transplant hepatitis on account of the low level of pre-transplant HBV DNA. -Investigation of Recurrence: • Biochemical profile • HBsAg and Anti-HBs titer • HBV DNA • Liver biopsy - Risk Factors for Recurrent HBV Hepatitis: • Evidence of active viral replication as shown by pre-transplant serum HBV DNA levels and/or HBeAg status The role of vaccination against HBV in this population is controversial. • Prophylaxis against infection • All candidates who are actively replicating HBV should receive lamivudine pre-transplant as discussed in Chapter 5 • Post transplant: patients should receive hepatitis B immunoglobulin (HBIg). Many centers combine HBIg with lamivudine. The dose, mode of administration and duration of treatment with HBIg is uncertain. Some centers titrate the dose of HBIg to maintain levels of circulating anti-HBs > 100 IU/ml. The main side effect of i.v. HBIg is severe back and chest pain • Post transplant Treatment of Recurrent HBV Graft Hepatitis Lamivudine has allowed effective transplantation of patients who are HBV DNA positive, although re-infection has occurred in a minority of patients following the emergence of lamivudine resistance (YMDD mutations) Other strategies being evaluated include the use of other antiviral drugs, such as adefovir, tenofavir and entecavir, and HBV vaccination

Hepatitis D Virus Infection • HDV is a rare cause of liver failure leading to transplantation. Treatment strategies are the same as for HBV

Hepatitis A Virus Infection • Anecdotal reports of patients transplanted for fulminant HAV show infection of the graft may occur, but it is of little clinical significance

Autoimmune Disease Primary Biliary Cirrhosis -Incidence and Prevalence: • Following transplantation, anti-mitochondrial antibodies remain positive in 72-100% of cases; however, the persistence of these antibodies does not indicate recurrent disease

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• Diagnosis of recurrent PBC is made on histological appearances • Follow up studies suggest that PBC may affect up to 20%-40% of recipients at 10 years after transplantation • Recurrence of PBC does not appear to affect allograft or patient survival. -Investigation of Recurrence: • Biochemical markers, such as serum alkaline phosphatase have a low sensitivity and specificity • Serum IgM levels fall immediately after transplantation; they rise again in some patients with recurrence • Histologically, there is overlap between PBC recurrence, chronic rejection and chronic HCV infection in the graft • Granulomatous destruction of bile ducts is considered pathognomonic -Risk Factors: • There are suggestions that the type of immunosuppression may influence the incidence of disease prevalence. In particular, there may be an increased susceptibility to recurrence with tacrolimus immunosuppression -Treatment of Recurrent PBC • The same principles may apply as pre-transplantation; ursodeoxycholic acid is usually prescribed, albeit without definitive data on it’s effect -Prognosis: • Long-term follow up data are awaited • There seems to be little adverse effect on graft function and the majority of patients are asymptomatic.

Primary Sclerosing Cholangitis Most patients transplanted for PSC have a choledochojejunostomy with a Roux loop. Differentiation of recurrent PSC from secondary sclerosing cholangitis may be difficult in the transplant setting. Causes of non-anastomotic biliary strictures are discussed in Chapter 7. -Incidence and Prevalence: • Possibly 20% of graft recipients -Investigation of Recurrence: • Differentiation between primary sclerosing cholangitis and the onset of secondary sclerosing cholangitis may be difficult • Imaging of biliary tree (MRCP or PTC) • Liver biopsy may show characteristic ‘onion skin’ fibrosis around interlobular bile ducts -Prognosis: • Long-term follow up data are awaited

Autoimmune Hepatitis (AIH) The distinction between graft hepatitis and recurrent AIH is difficult; there are no unequivocal criteria for the diagnosis of recurrent AIH. Therefore, the literature on this topic is confusing. -Incidence and Prevalence

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• There is graft recurrence of AIH in between 10 and 60% of recipients • De novo graft AIH also occurs in a small proportion of patients • Acute rejection in patients transplanted for AIH occurs in upwards of 80% of individuals, but its prognostic significance is uncertain -Risk Factors • Low maintenance immunosuppressive regimes • Absence of azathioprine • The role of HLA matching is conflicting -Treatment of Recurrent AIH • Many programs maintain long-term corticosteroid therapy in low doses (<10 mg per day) • Prevention of recurrent AIH is possible if patients are maintained on a small dose of prednisolone after transplantation (5-10 mg), although immunosuppression should be tapered to the minimum tolerated regimen for each patient. This requires close supervision and regular liver biopsies. -Prognosis: • Long-term follow up data are awaited

8

Metabolic Diseases Recurrence of the original disease, both hepatic and extrahepatic, depends on both the location of the primary metabolic defect and its target organs. Transplantation “cures” the patient for those metabolic diseases in which the primary defect resides in the hepatocyte itself. These include metabolic disorders in which the liver is damaged, and those disorders in which liver function remains intact but which are associated with severe damage to other organs (See Table 2). In the latter group, the recipient ‘explanted’ liver may be perfectly healthy except for the single metabolic defect. Occasionally these explants have then been used to provide a liver graft to another recipient in whom the metabolic defect will is not of immediate concern. This has been called ‘the domino procedure’. Other metabolic diseases are associated with a more generalized metabolic defect and the original disease may recur. Examples include hemochromatosis, NiemannPick disease, Gaucher’s disease, cystic fibrosis, and protoporphyria.

Hemochromatosis • Defect in hemochromatosis is dysregulation of iron absorption in the enterocyte • Hepatic iron reaccumulation occurs after transplant, but long-term followup is needed to establish the rate and risk for hepatic iron reaccumulation in allograft • There have been no reports of graft failure attributed to iron overload • Patient survival after transplant in patients with hemochromatosis is less than for other forms of cirrhosis. This phenomonon appears to be related to cardiac and infectious complications and may also be related to lack of pre-transplant diagnosis and treatment. Several reports have suggested that iron depletion prior to transplant can improve postoperative sur-

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Table 2. Metabolic diseases cured by liver transplantation Associated with Liver Damage: • Wilson’s disease • α1-anti-trypsin disease • tyrosinemia • Crigler-Najjar syndrome • Byler’s disease Not associated with liver damage: • primary oxaluria • amyloidosis • primary hypercholesterolemia

vival. Clinical approach: • Monitor serum ferritin and iron saturation in these patients on an annual basis • Consider venesection if there is evidence of excessive iron overload. There have been several reports of patients who inadvertently received livers from donors with hemochromatosis. In the short term, these recipients have shown a progressive and rapid reduction in hepatic iron concentration over time.

Wilson’s Disease • Liver transplantation does not always completely reverse the nervous system complications associated with WD but significant improvements are often seen. • Liver transplantation does not fully correct copper kinetic measurements to normal, although it does result in normalization of serum copper and ceruloplasmin. • Transplantation converts the response to one similar to that found in a heterozygote for WD. • Despite incomplete metabolic normalization, transplantation effectively cures the patient as the heterozygote state is not associated with clinical disease.

Amyloidosis • Transthyretin amyloidosis is a group of hereditary, often fatal, systemic disorders caused by mutant TTR. • Familial amyloidotic polyneuropathy is the commonest hereditary form and is a systemic disease that most seriously affects the heart, kidneys and eyes. • Although hepatic amyloidosis is common, clinically significant liver failure is rare • Liver transplantation replaces mutated with donor wild-type TTR and halts amyloid production and further systemic amyloid deposition. After transplant, improvement in extrahepatic symptoms may occur, especially in gastrointestinal disturbances. Liver transplant may prevent further de-

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cline and the onset of new complications • Survival after transplantation is determined by disease duration, hereditary and geographic factors, nutritional status, gastrointestinal and cardiac involvement. 5-year survival of 75% has been reported

Alcoholic Liver Disease (ALD)

8

Survival rates after liver transplantation are similar among alcoholics and nonalcoholics, at least in the short and intermediate term. Long term follow-up data are needed. -Incidence: • Up to 30% adult recipients are affected by alcohol addiction • A return to alcohol use within 5 years of transplantation is seen in up to 50% of those grafted for ALD • A return to alcohol consumption is usually seen in the first year • Drinking to excess is reported in up to 10% of alcoholic liver transplant recipients within 5 years • Graft injury, due to alcohol excess, is rare • Other medical problems, such as infection, pancreatitis, alcohol withdrawal occur in in these recipients who relapse to abusive drinking -Risk Factors: • It is difficult to identify those patients who are at risk of relapse • The period of abstinence prior to transplant is an insensitive prognostic indicator for alcoholic relapse -Therapy: • The efficacy of alcoholism therapy in post transplant patients is unproven but all such patients should be offered support and therapy

Malignancy Hepatocellular Carcinoma Liver transplantation is potentially curative in a subset of patients with HCC with a small tumor burden Incidence • Initial series described a very high tumor recurrence rate, but the majority of included patients with advanced HCC. Recurrence is negligible if the criteria outlined in Chapter 3 are met and survival is excellent with a 4year survival rate of 75%, and rate of recurrence-free survival of 83% • Tumor recurrence is usually observed in the liver and less frequently the lungs. Recurrence has been observed at the site of prior liver biopsy suggesting seeding of tumor along biopsy site tract • Therapy of HCC after liver transplantation is ineffective, and the prognosis is poor

Cholangiocarcinoma The majority of studies have reported poor survival after transplantation with one, two, and five-year survival ranging from 53-72%, 32-48%, and 17-25%

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respectively. The main explanation for poor survival is a high incidence of tumor recurrence. Tumor recurrence occurs early; 85% of recurrences occur within 2 years of transplant. Recurrence is most common in the allograft, followed by lung.

Metastatic Neuroendocrine Tumors There has been little experience with liver transplantation in secondary hepatic tumors. In contrast to many other carcinomas, neuroendocrine tumors generally behave less aggressively and have a slower growth rate and patients with such tumors are more likely to benefit from liver transplantation. Reports have been confined to small numbers of patients and short follow-up, Despite overall good medium-term survival, tumor recurrence is common (most commonly in liver, followed by bone) and recurrence free 5-year survival does not exceed 24%. Despite this, transplantation offers relief of symptoms from the neuroendocrine tumors.

Cryptogenic Cirrhosis • It is clear that many cases of cryptogenic cirrhosis are due to clandestine NASH. • Recurrence of NASH has been recorded among patients transplanted for NASH • No data are available about the long term consequences of NAFLD or NASH in liver allografts, nor are there data on strategies to prevent fat accumulation

Suggested Readings 1. 2. 3.

4.

5.

6.

7.

8.

Perrillo R, Rakela J, Dienstag J et al. Multicenter study of lamivudine for hepatitis B after liver transplantation. Hepatology 1999; 29:1581-1586. Samuel D, Muller R, Alexander G et al. Liver transplantation in European patients with the hepatitis B surface antigen. N Engl J Med 1993; 329:1842-1847. Ottobrelli A, Marzano A, Smedlie A et al. Patterns of hepatitis Delta virus reinfection and disease in liver transplantation. Gastroenterology 1991; 101:1649-1655. Feray C, Caccamo L, Alexander GJM et al. European collaborative study on factors influencing outcome after liver transplantation for hepatitis C. Gastroenterology 1999; 117:619-625. Ratziu V, Samuel D, Sebagh M et al. Long-term follow-up after liver transplantation for autoimmune hepatitis: evidence of recurrence of primary disease. J Hepatology 1999; 30:131-141. Forman LM, Lewis JD, Berlin JA, Feldman HA, Lucey MR. The association between hepatitis C infection and survival after orthotopic liver transplantation Gastroenterology 2002; 122:889-896. Harrison RF, Davies MH, Neuberger JM et al. Fibrous and obliterative cholangitis in liver allografts: Evidence for recurrent primary sclerosing cholangitis. Hepatology 1994; 20:356-361. Garcia RFL, Garcia CE, McMaster P, Neuberger J. Transplantation for primary biliary cirrhosis: Retrospective analysis of 400 patients in a single center Hepatology 2001; 33:22-27.

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14. 15.

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Brandhagen DJ, Alvarez W, Therneau TM et al. Iron overload in cirrhosis-HFE genotypes and outcome after liver transplantation. Hepatology 2000; 31:456-460. Schilsky ML, Scheinberg IH, Sternlieb I. Liver transplantation for Wilson’s disease: Indications and outcome. Hepatology 1994; 19:583-587. Suhr OB, Herlenius G, Friman S et al. Liver transplantation for hereditary transthyretin amyloidosis. Liver Transplantation 2000; 6:263-276. Lucey MR, Carr K, Beresford TP et al. Alcohol use after liver transplantation in alcoholics: a clinical cohort follow-up study. Hepatology 1997; 25:1223-1227. Mazzaferro V, Regalia E, Doci R et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334:693-699. Lehnert T. Liver transplantation for metastatic neuroendocrine carcinoma: An analysis of 103 patients. Transplantation 1998; 66:1307-1312. Charlton M, Kasparova P, Weston S, Lindor K, Maor-Kendler Y, Wiesner RH et al. Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease. Liver Transplantation 2001: 7;608-614.

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CHAPTER 9

Medical Management of the Liver Transplant Patient Anne Burke The 10-year survival rate after liver transplantation is approximately 65%. With increasing numbers of long-term liver transplant survivors has come an appreciation of some of the health problems facing these patients. This Chapter will focus on the long-term management of the liver transplant recipient with emphasis on general health concerns and routine health care maintenance.

Long Term Morbidity and Mortality of Liver Transplantation The main causes of late death after liver transplantation are shown in Table 1. Liver transplant patients also have an increased prevalence of many chronic conditions that have a significant impact on quality of life (see Table 2) and these conditions frequently occur at a younger age than in the general population.

Medical Consequences of Immunosuppression Cardiovascular Disease There is an excess mortality from cardiovascular disease in liver transplant recipients (see Table 1). This is due to a combination of factors: hyperlipidemia, diabetes mellitus, hypertension, cigarette smoking and obesity/sedentary lifestyle. In addition, oxidative stress and hyperhomocysteinemia may contribute to the risk.

Cardiovascular Risk Factors Many of the adverse health effects seen in liver transplant recipients are direct or indirect consequences of immunosuppression.

Systemic Hypertension Epidemiology: Systemic hypertension is defined as diastolic pressure > 90 mmHg or systolic pressure > 140 mmHg. Systemic hypertension occurs in 40-80% of liver transplant recipients. It typically occurs within a few weeks of transplantation and is largely due to the use of calcineurin inhibitors. Pathogenesis: The molecular mechanism underlying calcineurin inhibitor-induced hypertension is not fully understood but renal vasoconstriction is the predominant Liver Transplantation, edited by Michael R. Lucey, James Neuberger and Abraham Shaked. ©2003 Landes Bioscience.

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Table 1. Cause of death in liver transplant recipients after the first year Cause of death

% of all causes of death

Graft failure CVD Infection De novo malignancy Other

40% 18% 15% 8% 19%

Adapted from Abbasouglu O, Levy MF, Brkic B, Testa G, Jeyarahaj DR, Goldstein RM et al. Ten years of liver transplantation. Transplantation 1997; 64(12):1801-1807.

Table 2. Causes of morbidity in liver transplant recipients after the first year (not age-adjusted)

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Disease

Prevalence post transplant

Rate in US population

Hypertension (BP > 140/90) Hypercholesterolemia (>240mg%) HDL < 35mg% Diabetes mellitus Obesity (BMI > 30) Skin cancer (BCC and SCC) Other Cancers Renal Impairment Symptomatic Fractures

41-81% 20-66% 52% 21-32% 39-43% 10% 2% 77%-80% 10%

15.7% 14.9% 12% 3.7% 16.1% 0.3% 0.4% 4% .04%

abnormality seen. Corticosteroids add to the risk of hypertension. A history of hypertension prior to the development of liver disease is an important additional risk factor. Clinical Management: • Drug therapy: Drug therapy should be introduced early • Weight loss: Patients should be encouraged to lose weight if more than 15% above their ideal body weight • Sodium restriction: patients should be advised to restrict sodium intake to 2-4 g per day • Other measures: stop smoking and reduce alcohol intake and increase exercise Choice of drugs: • Calcium channel blockers − Nifedipine and drugs of a similar class are preferred. Nifedipine is associated with development of peripheral oedema. − Verapamil and diltiazem may inhibit cyp 450 drug metabolism of calcineurin inhibitors, and levels should be monitored • Angiotensin converting enzyme (ACE) inhibitors and angiotensin II (ATII) antagonists may also be used. ACE inhibitors and ATII antagonists may

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confer additional benefit by preventing left ventricular hypertrophy, a risk factor for cardiovascular disease. Initial concerns regarding worsening of renal function seem unfounded and these drugs are as effective and as well tolerated as calcium channel blockers. Patients should be monitored for hyperkalemia and hypomagnesemia. • Other drugs: Diuretics should be used to control peripheral edema or as second-line antihypertensives. The centrally acting sympatholytics such as clonidine are considered third-line agents against post-transplant hypertension.

Hyperlipidemia Epidemiology: See Table 1. Sirolimus causes a dose-dependant increase in triglycerides rather than in cholesterol. Pathogenesis: The mechanism whereby serum cholesterol levels are increased after liver transplantation is unclear. Clinical Management: • Review immunosuppression • Dietary modification: rarely successful in isolation in the post-liver transplant setting. • HMG CoA-reductase inhibitors (“statins”).

Diabetes Mellitus Diabetes mellitus is seen in 20-30% of liver transplant recipients. This arises from a combination of pre-liver transplant diabetes (13% in one study) and true post-liver transplant diabetes. This compares to less than 4% in the general population. Pathogenesis: • Corticosteroids increase insulin resistance. • Calcineurin inhibitors: The calcineurin inhibitors increase insulin resistance, injure pancreatic islet cells and impair insulin secretion. Tacrolimus and cyclosporin are associated with an increased incidence of diabetes. The effect may be transient. Chronic hepatitis C infection may potentiate the risk or severity of diabetes mellitus. Clinical Management: • General: diabetic liver allograft recipients should be managed in the same way as diabetic patients in the general population, with lifestyle modification and drug therapy as needed. • Modification of immunosuppressive protocol: where possible, corticosteroids should be withdrawn, and calcineurin inhibitor dose minimised. A conversion from tacrolimus to cyclosporin, Sirolimus or mycophenolate mofetil may be of help.

Obesity Prevalence: Up to 40% of patients are obese (>20% above ideal body weight) within 1 year of transplantation. Weight tends to increase for at least 2 years following

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transplantation and weight gains of 20%-30% above pre-operative weight are not uncommon. Clinical Management: • General: as in the general population, management of weight gain is to reduce caloric intake and to increase exercise.

Renal Insufficiency

9

Epidemiology: Prior to liver transplantation, renal insufficiency may go unrecognized in many cirrhotic patients. Poor muscle mass and impaired hepatic synthesis of creatinine may lead to an underestimation of glomerular filtration rate based on serum creatinine levels. Several liver diseases, including chronic viral hepatitis, autoimmune hepatitis, primary biliary cirrhosis are associated with glomerulonephritis. Early onset of chronic renal failure in patients transplanted for chronic hepatitis C infection may be due to cryoglobulinemia-associated glomerulonephritis. Key facts are: • The majority of recipients demonstrate decreased renal function within months of liver transplantation. • Serum creatinine concentrations > 1.6 mg/dl (140 mmol/l) are found in over 75% of liver transplant recipients after 3 years of follow up. • The progression to end-stage renal failure is predicted by significant renal impairment as early as one year after liver transplantation. • Between 4% and 10% of liver allograft recipients develop end-stage kidney failure by 10 years. Post liver transplant diabetes mellitus, hypertension and viral hepatitis may all increase the risk of progression to end-stage renal disease. Mortality has been shown to be higher in post-liver transplant patients whose renal failure progresses to the point of requiring dialysis. Pathogenesis: Post liver transplant renal insufficiency is a direct consequence of calcineurin inhibition. Acute elevation of serum creatinine is frequently the result of calcineurin inhibitor toxicity and responds to dose reduction. Chronic elevations in serum creatinine rarely return to normal levels after reduction of calcineurin inhibitor doses. Kidney biopsy in liver transplant recipients with sustained reduction in GFR shows interstitial fibrosis and patchy glomerular loss and hypertrophy of unaffected glomeruli. Clinical Management: The goals of therapy are to • Minimize the use of calcineurin inhibitors. If renal failure persists despite reducing calcineurin inhibition, consider switching to alternative immunosuppressive therapy. • Avoid other nephrotoxic drugs • Control hypertension • Control diabetes mellitus Renal transplantation is appropriate in established renal failure arising after liver transplantation.

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Osteoporosis and Osteopenia Prevalence: Chronic liver disease is associated with osteopenia due to low bone turnover. Risk factors: • Chronic cholestasis • Female gender • Older age • Cessation of menses • Cigarette smoking • Poor dietary calcium intake • Alcoholism • Calcineurin inhibitors • Maternal history of fracture Key facts are: • Bone turnover is greatly increased after transplantation due to excessive osteoclastic activity. Cyclosporin and tacrolimus increase osteoclastic activity and bone turnover. Corticosteroids reduce new bone formation. • Bone loss increases rapidly over the first 3 months following liver transplantation. Z-scores (number of standard deviations from the normal mean), a marker of bone mineral density, commonly reach -2 standard deviations—the range for osteoporosis. Each standard deviation decrease in bone mineral density is associated with a 1.5 – 2.8 fold increase in the risk of hip fracture in post-menopausal women. • Atraumatic vertebral fractures have been reported in up to 30% of liver transplant recipients within the first 6 months of transplant. Bone density tends to improve over the first post-liver transplant year approaching pretransplant levels, but remains below that of the general population. Clinical Management: Spontaneous fractures are a late sign of bone loss, therefore, management focuses on screening and prevention. Patients should be screened pre-transplant for osteopenia by (dual energy x-ray absorption) DEXA scan, or early post-transplant Medication: • Those with osteopenia z-scores between -1 and -2 should be treated with calcium (1g per day) and vitamin D (400 iU/ day) supplementation. • Those with z-scores less that -2 should receive bisphosphonates in addition to the calcium and vitamin D supplementation. Other measures: • Weight bearing exercise (e.g., walking) and strength training in conjunction with calcium and vitamin D supplementation decrease the rate of bone loss in post-menopausal women. It is advisable to recheck bone mineral density 1 year after transplantation. In patients with z-scores greater than -1, repeat DEXA can be deferred for about 5 years.

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Malignancy The risk of malignancy is increased in liver transplant recipients.

Post-Transplant Lymphoproliferative Disorder PTLD is discussed in Chapter 7.

Skin Cancer

9

Prevalance: skin cancer is the most common cancer after liver transplantation. It tends to behave more aggressively than in the non-transplant patient. Over 5% of cases are metastatic. This compares to <1% for the general population. The relative risks of individual immunosuppressive medicines either alone or in combination remain unknown. The prevalance of Kaposi’s sarcoma is also increased in solid-organ transplant recipients although less strikingly than in the HIV-positive population. Human herpes virus-8 (HHV-8) has been implicated in Kaposi’s sarcoma in both immunosuppressed and immunocompetent individuals. The increase in non-melanomatous skin cancer seen in liver transplant recipients seems to be largely due to increased prevalence and activity of human papilloma virus (HPV) in the immune-suppressed host. Clinical Management: • Education is key. All transplant recipients should be informed of their increased risk of skin cancer. • Avoidance of sun: They should be educated in sun-protective practices, including minimising sun exposure between 10:00 and 16:00, the use of protective clothing and broad brimmed hats, and the use of sun-screen and lip-balm with a sun protection factor of 15 or higher. • Self-examination: Patients should be encouraged to examine their skin. They should also have a formal skin inspection at least annually and should any suspicious lesions be seen, these should be referred to a dermatologist for further evaluation.

Oral Cancer • Oral cancer is associated with smokeless tobacco, alcohol consumption and sun exposure. • Both EBV and HPV are associated with hairy leukoplakia, which can be seen as feathery appearing plaques on the tongue or buccal mucosa. Macroscopically they are indistinguishable from pre-malignant leukoplakia and should be biopsied. • Erythroplakia – a red hyperplastic area of mucosa is a pre-malignant condition

Carcinoma of the Uterine Cervix Prevalence: The prevalence of cervical intraepithelial neoplasia in transplant recipients is approximately 5-fold that of immunocompetent controls. 75-93% of cervical cancers or carcinomas in-situ are associated with HPV.

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Clinical Management: all female liver transplant recipients over the age of 18 years who are sexually active should undergo annual cervical smear cytology tests. Patients with cervical dysplasia or carcinoma in situ should be referred to a gynecologist. The role of reduced immunosuppression as part of a treatment plan for cervical carcinoma in situ or cervical carcinoma is uncertain

Other Cancers Liver and other transplant recipients are at increased risk of cancer of the vulva and perineum, anal cancer, hepatobiliary tumours and colon cancer. Routine screening is important, and physicians should maintain a high index of suspicion for cancer development in liver transplant recipients.

Infections After Recovery from Liver Transplantation Infection accounts for 15-20% of deaths in long-term liver transplant survivors. • Viral infections: viral infection with CMV, EBV, HPV-6, VZV and parvovirus B19 tend to occur within 3 months of transplant, but may occur later. Patients seronegative for varicella zoster, who are exposed to varicella should receive immunoglobulin. The development of primary Varicella zoster infection should be considered a medical emergency in the post-transplant patient and intravenous acyclovir (10 mg/kd) should be started immediately

Tuberculosis Tuberculosis occurs in <1% of patients at any time after liver transplantation. The risk of disseminated tubercular disease (25%) and of death (20%) is much greater among solid organ recipients than for the general population. Diagnosis is made by a combination of staining for acid fast bacilli, culture of the organism, histopathology and tuberculin skin testing. Treatment with standard therapy is problematic. • Isoniazid: There is a high rate of hepatic dysfunction (33%) particularly with Isoniazid use • Rifampicin induces cytochrome P450 3a, and thereby greatly accelerates metabolism of cyclosporin and tacrolimus. Despite careful monitoring of levels, rejection is a common occurrence (30-50%) in liver transplant recipients receiving rifampicin in conjunction with cyclosporin. Conversely, there is a risk of cyclosporin or tacrolimus toxicity when the dose of rifampicin is reduced or withdrawn • Other drugs: Due to the high toxicity with conventional therapy, an alternative approach using ethambutol and ofloxacin as maintenance therapy has been suggested. Although promising, this regimen has not yet been widely tested

Vaccinations Immunosuppressed patients should not be given live or attenuated vaccines (Table 3) See also Table 2, Chapter 4.

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Table 3. Live and attenuated vaccines • Varicella • BCG • Yellow fever • Typhoid (for travellers) • Oral Polio • MMR: although an attenuated live vaccine has been deemed safe and is recommended in those liver transplant recipients who were not vaccinated prior to liver transplant. Recommendations for vaccinations in the liver transplant recipient are outlined in Table 4.

Common Causes of Morbidity in Liver Transplant Recipients Insomnia

9

Early post-operative insomnia is related to corticosteroids and/or calcineurin inhibitor. Patients frequently feel hyperalert and have difficulty achieving a sufficiently relaxed state in which to sleep. Postoperative pain, especially right posterior rib pain (which can last several months), and adjustment to the transplant compound the problem. Most patients respond to reassurance and analgesia. Relaxation exercises and good sleep practices may also help.

Lassitude Tiredness is a common complaint after liver transplantation and may have many contributing factors including medications. Recurrence of chronic hepatitis C is often associated with lassitude. Lassitude may be a manifestation of depression.

Cosmetic Concerns Hirsutism: may be due to cyclosporin and exacerbated by nifedepine or corticosteroids. Treatment is switching to tacrolimus. Gum hypertrophy: may be caused by poor dental hygiene and cyclosporin and is exacerbated by nifedepine. Acne: Corticosteroids can cause acne. Fortunately this tends to improve with dose reduction and with time. Cutaneous warts: are more common in transplant recipients, affecting 25%90% of recipients. They tend to be quite exuberant and difficult to treat. Flat warts may become the site of future squamous cell carcinoma.

Musculoskeletal Pain Back pain particularly over the right posterior ribs can persist for many months post-liver transplant. Its persistence and severity surprises many patients and

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reassurance is in order. Simple analgesia can be used. Other more focal, severe or persistent musculoskeletal pains should raise the suspicion for osteoporosis with secondary fracture, especially of the vertebrae, osteonecrosis particularly of the hip joints and osteomyelitis or abscess.

Seizures New seizures occur most commonly within the first post-operative week and are related to intraoperative metabolic changes, calcineurin inhibitor toxicity, central pontine myelinolysis, intracranial bleed or infection. Seizures occurring in the later weeks following liver transplant are less likely to be due to electrolyte disturbance or central pontine myelinolysis and drug toxicity and infection are more of a concern. Investigations: neurological examination for focal deficits, biochemical testing for electrolyte disturbances, including hypomagnesemia and cyclosporin or tacrolimus levels, blood count and coagulation profile to check for coagulopathy or infection, computed tomography (CT) or magnetic resonance imaging (MRI) of the head for space-occupying lesions and an examination of the CSF to rule out bacterial or opportunistic infection in the immunocompromised host. Both cyclosporin and tacrolimus can cause diffuse white matter changes which are seen on MRI more readily than on CT. Management focuses on correction of underlying metabolic or infectious problems and the use of anticonvulsant agents. Consideration must be given to the risk of interactions between immunosuppressive agents and anticonvulsants.

Headache Headache and tremor are common complaints. Milder headaches, often associated with tremulousness, are usually due to calcineurin inhibitor toxicity. An exacerbation of previously existing migraine headaches may also occur due to cyclosporin or tacrolimus. Evaluation consists of examination to rule out focal neurological deficits, screening for cyclosporin or tacrolimus toxicity or metabolic disturbances, and CT or MRI to rule out space occupying lesions. Treatment: simple analgesia and where possible reduction in the calcineurin inhibitor doses. Where headaches are severe, narcotic analgesia may be required. Anti-depressants, calcium channel blockers and β-blockers have also been used with varying success. Migraine may respond to sumatriptan, although systemic hypertension may limit its use.

Fine Tremor Fine tremor is common in the liver transplant recipient. It is related to calcineurin inhibitor use and may respond to lowering of the dose. Psychiatric disturbances such as short-term anxiety, depression or adjustment disorders are common after liver transplant. Less commonly they represent an atypical presentation of an organic syndrome for example, drug toxicity or infection. Liver transplant recipients with a history of addiction should be monitored for evidence of relapse. Prompt referral to substance abuse services may be helpful.

9

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Pregnancy and Reproductive Health

9

Menstrual function: Recovery of menstrual function in pre-menopausal females and of andrological function in males occurs after liver transplantation. Menses typically resume within a few months of transplantation. Preconception management: Most centers advise waiting 1-2 years after liver transplantation before becoming pregnant. Barrier or oral contraception should be considered during this period. The 1-2 year delay allows for the patients to fully recover from the transplant, for opportunistic infection prophylaxis to be discontinued and for immunosuppression to be reduced. Conception should be planned when graft function is stable and good. Some immunosuppressant drugs are teratogenic (see Chapter 6). The immunosuppressive regime may be modified to avoid these drugs. Due to the increased prevalence of both maternal and fetal complications, these are “high-risk” pregnancies and should be closely monitored by both the transplant and obstetrical teams. Pregnancy: Data from the National Transplant Pregnancy Registry (NTPR), record 2017 pregnancies in 732 women or fathered by 603 men who were recipients of solid organ transplants (See Armenti VT, Wilson GA, Radomski JS, Moritz MJ, McGrory CH, Coscia LA. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clinical Transplants 1999;111-119.) No pattern of congenital anomaly has been noted. Of the 175 offspring studied all of whom are children of female kidney transplant recipients, 76% were live born, 14% suffered spontaneous abortion and 10% were still-born, ectopic pregnancies or electively aborted. There was no significant developmental delay in 84% of the children, but 3 children (1.7%) had major disabilities. In 72 female liver transplant recipients, 119 pregnancies were associated with 91 (76%) live births. This compares with the general population wherein 10% of pregnancies are lost before 20 weeks with late fetal loss of approximately 0.5%. It is likely that there is underreporting of early pregnancy loss in the NTPR. 37% of live born children were premature (<37 weeks gestation) and 32% were low birth weight (<2500g). Regarding the health of the expectant mother, the risk of acute cellular rejection in the pregnant liver transplant recipient seems to be increased, either occurring during pregnancy or within 3 months of delivery. Acute cellular rejection was associated with poorer fetal outcome and increased risk of recurrent rejection. 33% of pregnant liver transplant recipients will develop hypertension, and 10-15% diabetes mellitus. Hypertension, diabetes and infections should be meticulously managed. Consideration should be given to stress dose steroids for mothers requiring caesarean section. Breast feeding: most immunosuppressive drugs are secreted in breast milk. Consequently breast feeding should be avoided.

Lifestyle Liver allograft recipients should be encouraged to return to a normal healthy lifestyle, with appropriate health maintenance (see Table 5)

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Table 5. Routine health screening of liver transplant recipients Routine Health Screening of Liver Transplant Recipients Disease

OLT pat

US pop

Hypertension

Every visit

Every 2 years if previously normotensive

Renal Insufficiency Serum creatinine every visit

No recommendations

Hypercholesterolemia

At 6 months, 1 year, 2 years and if normal every 3-5 years thereafter.

Every 5 years in men aged 35-65 years and in women aged 45-65 years

Diabetes mellitus

Gluc >160 on “routine labs” are grounds for a formal oral glucose tolerance test

Screening in the asymptomatic general population is not recommended.

Cigarettes

Counselling on smoking cessation

Counselling on smoking cessation

Osteoporosis

DEXA pre-OLT (or post-OLT)

DEXA in early postmenopausal women

Breast Cancer

Self-breast exam monthly Annual clinical breast exam age 40-69, possibly longer Mammography 50-69

Self-breast exam monthly Annual clinical breast exam age 40-69, possibly longer Mammography 50-69

Cervical cancer

Papanicolaou smear every year. Decrease to every 3 years if several normal tests

Papanicolaou smear every 3 years (assuming prior smears were normal) until age 65

Colon cancer

As for general population annual colonoscopy for those with history of IBD

Flexible sigmoidoscopy ever 3-5 years age 50-70 years old, begin earlier in those at higher risk

Prostate Cancer

Annual digital rectal exam +/- prostatic specific antigen after age 50

Annual digital rectal exam +/- prostatic specific antigen after age 50

Skin cancer

Monthly self-exam. Annual physician provided skin exam

Not recommended

Dental care

Routine oral hygiene (brushing and flossing of teeth) 6 monthly visit to dentist

Routine oral hygiene (brushing and flossing of teeth)

Oral cancer

Annual exam by dentist

Not recommended

9

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Selected Reading 1. 2. 3.

4. 5.

6.

9

Abbasouglu O, Levy MF, Brkic B, Testa G, Jeyarahaj DR, Goldstein RM et al. Ten years of liver transplantation. Transplantation 1997; 64(12):1801-1807. Midtvedt K, Neumayer HH. Management strategies for posttransplant hypertension. Transplantation 2000; 70(11):SS64-SS69. Feller RB, McDonald JA, Sherbon KJ, McCaughan GW. Evidence of continuing bone recovery at a mean of 7 years after liver transplantation. Liver Transplantation and Surgery 1999; 5(5):407-413. Otley CC, Pittelkow MR. Skin cancer in liver transplant recipients. Liver Transplantation 2000; 6(3):253-262. Meyers BR, Papanicolaou GA, Sheiner P, EMRe S, Miller C. Tuberculosis in orthotopic liver transplant patients: increased toxicity of recommended agents; cure of disseminated infection with nonconventional regimens. Transplantation 2000; 69(1):64-69. Armenti VT, Wilson GA, Radomski JS, Moritz MJ, McGrory CH, Coscia LA. Report from the National Transplantation Pregnancy Registry (NTPR): Outcomes of pregnancy after transplantation. Clinical Transplants 1999:111-119.

Pediatric Liver Transplantation

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CHAPTER 10

Pediatric Liver Transplantation Elizabeth B. Rand and Kim M. Olthoff Currently 1and 5-year survival for children undergoing liver transplantation equals or exceeds that of adults. For children in particular, the refinements in surgical technique, immunosuppressive therapy and nutritional support have led to expanded indications for liver transplantation while dramatically reducing death due to organ scarcity in the pediatric age group. Nevertheless, there are considerable differences in outcomes for specific pediatric subgroups. Small infants, particularly those that are chronically ill and malnourished have the highest risk for postoperative surgical and medical complications including hepatic artery or other vascular thrombosis, early and late biliary complications, and infection. Older children and teenagers have the best outcomes.

Indications for Liver Transplantation in Children Liver transplantation can be considered for any child with end stage liver disease due to acute or chronic liver disease. The common indications for OLT in children are listed in Table 1. In addition, liver transplantation may be indicated for children with inborn errors of metabolism that do not cause liver failure but which produce severe morbidity or mortality and are corrected by liver transplantation (for example ornithine transcarbamylase deficiency or Crigler-Najjar syndrome). Children with chronic liver disease due to systemic illnesses (i.e., cystic fibrosis) or primary hepatic malignancies may be appropriate candidates.

Evaluation of Pediatric Candidates and Timing of Liver Transplantation Children with acute or chronic liver disease will often come to transplantation for indications similar to those seen in adults, including fulminant liver failure, complications of cirrhosis, portal hypertension, variceal bleeding, encephalopathy. Health care providers for children should be aware of the consequences of liver disease that are specific to the pediatric population and indicate the need for early listing for transplantation: -Growth and nutrition: • Growth failure is a significant complication of liver disease

Liver Transplantation, edited by Michael Lucey, James Neuberger and Abraham Shaked. ©2003 Landes Bioscience.

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Table 1. Primary diagnosis of 395 children undergoing liver transplantation Primary Diagnosis

Number of Patients

Percentage

Biliary atresia Metabolic diseases (all types) Alpha-1-antitrypsin deficiency Tyrosinemia Wilson disease Glycogen storage disease Cystic fibrosis Other Fulminant hepatic failure Cryptogenic cirrhosis Familial cholestatic syndromes (Alagille syndrome, Byler syndrome, etc.) Chronic active hepatitis (infectious, autoimmune) Primary sclerosing cholangitis Neonatal hepatitis Biliary obstruction Tumors Miscellaneous

187 78 46 12 9 5 4 2 21 17 16

47 19 12 3 2 1 1 <1 5 4 4

10

2

9 8 3 11 13

2 2 <1 3 3

Data were compiled from published and personal series.

10 • Children with otherwise compensated cirrhosis may have poor weight gain and/or linear growth often followed by declining school performance or cognitive development. • If malnutrition cannot be reversed with supplemental tube feedings or other interventions, liver transplantation should be performed as soon as possible. • Due to the serious nature of growth failure and resulting developmental and cognitive delay in children, these findings qualify a child for higher UNOS listing status for transplantation. -Hepatic encephalopathy: • Encephalopathy must be evaluated in an age-appropriate manner and therefore experience in assessing pediatric cognitive skills and developmental milestones is of critical importance. • Ammonia levels correlate very poorly with degree of encephalopathy. -Metabolic Diseases: • Metabolic diseases causing primary hepatic injury are as a group, a common indication for liver transplantation in childhood. Children may also benefit from special exceptions to standard listing criteria in these cases if additional end organ or malignant risks are involved. Diseases in this category include tyrosinemia, cystic fibrosis and alpha-1-antitrypsin deficiency, for example.

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109

• Tyrosinemia is a disorder of tyrosine metabolism caused by deficiency of fumarylacetoacetate hydrolase (FAH). The enzyme defect results in injury to multiple organs via the generation of abnormal metabolites. In the liver, the primary site of tyrosine metabolism, the block of tyrosine catabolism produces a large variety of toxic intermediates that result in a range of phenotypes extending from neonatal fulminant hepatic failure to chronic relapsing liver disease. In all forms of disease, there is a sharply increased rate of hepatocellular carcinoma, estimated at 13 – 37% in various studies, occurring even as young as 2 years of age. Medical therapy comprised of dietary restrictions and supplements designed to redirect the formation of toxic intermediates has been very successful in stabilizing liver function, however development of hepatocellular carcinoma is still a problem. Liver transplantation restores liver function, reduces extrahepatic organ injury, and normalizes the hepatocellular cancer risk to that of the general transplant population. • Metabolic diseases with primarily extrahepatic manifestations may be cured by liver transplantation despite otherwise normal hepatic function. These diseases are accepted indications for liver transplantation and area eligible for exception status within the UNOS system. Children with urea cycle defects, Crigler-Najjar syndrome type I, or primary hyperoxaluria, for example, have automatic exceptions to standard listing practices. • Inborn errors of the urea cycle (for example ornithine transcarbamylase deficiency) lead to recurrent hyperammonemia and irreversible brain injury, despite aggressive medical therapy. Liver transplantation is curative; standard listing criteria are inappropriate, as all other hepatic functions are normal. • Crigler-Najjar syndrome: CNS injury from unconjugated hyperbilirubinemia is virtually unavoidable in Crigler-Najjar syndrome type I despite medical therapies. • Primary hyperoxyluria is an inborn error producing oxylate crystals throughout the body that ultimately causes renal failure and cardiac arrhythmia. Early liver transplantation can prevent renal failure and preclude the need for combined renal and hepatic transplantation.

PELD The MELD system used for allocation of livers to adults in the United States has been modified for children; the following variables are assessed: • Age at listing • Albumin • Bilirubin • INR • Growth failure (based on gender, height and weight) The score for an individual patient can be calculated on the UNOS website (www.unos.org). In addition to this scoring system, UNOS policy has several

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Liver Transplantation

advantages for pediatric recipients. The pediatric advantages were granted in response to concern that the small number of children waiting for liver transplant would be overwhelmed by the huge number of adults with equivalent higher scores, causing increases in deaths and lengthy waiting times. Lengthy waiting time has a disproportionate negative effect on young infants and children due to the impact of chronic liver disease on physical, cognitive and social development. For these reasons, pediatric donors (donors under 18 years of age) are offered to pediatric recipients at an equivalent status or score before potential adult recipients. Furthermore, standard UNOS exceptions exist for specific metabolic diseases, and additional exceptions may be granted by the regional review boards of UNOS on request.

Pre-Operative Management

10

• Medical therapy to correct metabolic abnormalities, coagulopathy, ascites, vitamin Deficiencies and malnutrition as much as is possible is a critical part of the management of any child with liver disease. • Malnutrition requires special attention as optimization of nutrition protects brain development prior to transplant and also improves outcome after surgery. Nutritional support can start with institution of a high-density caloric diet, but often infants and young children require supplemental tube feedings. The choice of formula is important, a partially hydrolyzed protein formula with increased medium-chain triglycerides is generally selected to optimize absorption in the face of cholestasis. • Meticulous attention to the delivery of normal “well-child” care is crucial. • Vaccination: children awaiting liver transplantation should receive all standard immunizations (Polio, DPT, HIB, HBV, MMR, Varicella) with particular attention given to live virus vaccines (which are generally not administered to immunosuppressed individuals). Furthermore, additional vaccinations (pneumococcus, influenza, etc.) are generally indicated. Serologic evaluation for prior virus infections (particularly varicella, CMV and EBV) are also of great importance and have considerable impact on post-transplant management and monitoring.

Surgical Issues and Options

• In the early era of liver transplantation the severe shortage of size-matched donors for infants and young children limited the application of transplantation to pediatric patients. Although the death rate on the waiting list remains significant for children, the risk of dying whilst waiting for a liver allograft has considerably improved for pediatric patients as shown in data in Table 2. • Innovative surgical techniques including reduced-size liver grafts, split and living related grafts has resulted in dramatic improvements in organ procurement for even very small infants and waiting times and deaths have been proportionately reduced. The surgical aspects of these forms of transplant operation are discussed in Chapter 5. • Biliary atresia

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Pediatric Liver Transplantation

Table 2. Deaths awaiting OLT in 1990, 1995 and 1999 Age of candidate:

< 1 year

1-5 years

6-10 years

11-17 years

1990 1995 1999

268/34/540 337/45/359 548/54/234

265/17/197 389/23/132 425/22/92

100/7/212 208/5/51.6 254/7/48

161/18/455 287/14/110 454/22/80

Data are shown as Patients listed/Deaths/Death rate per 1000 patient years at risk. (Adapted from the UNOS web-site: www.unos.org)

- Biliary atresia is the result of an inflammatory/obliterative process of the extrahepatic bile ducts of unknown etiology. Left untreated, this process results in obstructive cholestasis, biliary cirrhosis and death in 100% of children by age 2 years. Management with the Kasai procedure can restore bile flow in up to 80% of cases with the anastamosis of a bowel limb to the hepatic capsule. Despite the improvement in survival following the Kasai procedure, many of these children will develop complications of portal hypertension in late childhood or adolescence (variceal hemorrhage, ascites) and require transplantation at that time. - Biliary atresia is the most frequent underlying diagnosis in pediatric liver transplant recipients (See Table 1). - Since almost all of candidates undergoing liver transplantation for biliary atresia will have had a prior portoenterostomy, the biliary anastamosis is made to the existing or newly revised intestinal “Roux-en-Y” limb rather than to the native common duct (by definition absent in biliary atresia). • Even children with intact extrahepatic biliary structures may require implantation of the bile duct into a Roux limb due to size limitations or multiple donor ducts in a partial graft. Use of a Roux limb is an important feature, as future biliary problems can not be approached by ERCP. Direct visualization of the biliary system can only be achieved by percutaneous transhepatic cholangiogram in these patients. • Children may require vascular grafts or microsurgical techniques for the vascular anastamoses and the risks of thrombosis (particularly of the hepatic artery) are greatly increased for small infants. Vascular bypass is generally not required for children or infants and is rarely performed (then only in larger teenagers).

Early Post-Operative Management The immediate post-operative management of pediatric liver graft recipients is directed toward continued support of liver function, critical care issues and detection of early surgical complications. • Vascular problems: small children and infants are particularly at risk for vascular thromboses so the routine includes frequent Doppler ultrasound to evaluate flow. Pediatric recipients are routinely treated with intravenous Dextran to prevent thromboses in the peri-operative period and

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then receive oral aspirin for 1 year after transplantation. • Bile leaks: Reduced size, living related or split liver grafts have increased risk of bile leak and/or bleeding from the cut surface. • Nutrition: Feeding can be difficult in small children and infants with midline liver placement and short term trans-pyloric tube feeding may be needed. • Immunosuppression: in general immunosuppressive management is similar to that in adults, although the arguments for restricting corticosteroids is even greater. Drug dosages need be considered for the child’s weight.

Subsequent Management

10

This is similar to that of adult recipients in terms of monitoring for and management of changes in liver function, rejection, late biliary complications and infections, but there are a few important exceptions. • Nutrition is again of utmost importance in recovery and rehabilitation, though a standard formula can generally replace the specialized feedings used pre-transplant. Very young children and infants who received tube feedings pre-transplant often have delayed oral-motor development and may require feeding therapy in order to accept oral feedings. • Occupational or physical therapy may be necessary for children and infants with a lifetime history of chronic liver disease. Older children generally recover very quickly and are eager to return to school and normal activities, often much faster than their adult counterparts return to work. • Infections: Prophylaxis and surveillance for viral infections, particularly in those young children who did not have primary infections with EBV and CMV pre-transplant, is an ongoing issue. - EBV naïve children undergoing liver transplant are at high risk of developing chronic EBV infection and post transplant lymphoproliferative disease if the primary EBV infection occurs on immunosuppression. The use of new quantitative PCR analysis for EBV has improved the monitoring for EBV activity. PTLD is discussed in Chapter 7. In addition to the standard reduction or elimination of immune suppression and addition of ganciclovir or acyclovir antiviral therapy. - CMV negative children will often receive CMV positive grafts (especially if they receive a partial graft from an adult donor) and are at risk of CMV infection. - Exposure to other childhood viral illnesses is an ongoing issue for these children; varicella exposure for example is a frequent occurrence. Children should be vaccinated for varicella prior to transplant, however the vaccine is less effective if given under 1 year of age. Varicella antibody negative children should receive varicella immune globulin within 48 hours of known exposure (ideally within 12-24 hours) and are treated with intravenous acyclovir if clinical chicken pox develops. Even after an episode of clinical infection most of these children will not develop anti-

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bodies and they are therefore at risk for repeated infection with subsequent exposures. - Live vaccine administration to immunosuppressed transplant recipients is controversial, with standard recommendations against immunization. Even in those centers where MMR and/or varicella immunizations are given post transplant, reduced response to vaccination is observed. • Compliance: Compliance with medical therapy is a major issue with teenage liver graft recipients especially those transplanted in infancy or early childhood. Many of these teenagers do not remember their transplant experience and are entering a time of personality turbulence, testing of limits, and have acquired a general sense of invulnerability that extends from the usual adolescent risk taking (experimentation with drugs of abuse, exploration of sexuality) to failure to take medications. The response to this behavior must be tailored to the individual child and family and must take into account the social and cultural background. Parents, social workers, school guidance counselors and other resources are important partners in the effort to sustain delivery of medical care through adolescence. The adolescent patient: Children entering adolescence experience a variety of endocrinologic, physical and psychosocial changes. In most cases these young adults will be best served at a pediatric center but care should be transitioned to an adult transplant center when medically and psychosocially appropriate.

Suggested Reading 1. 2. 3. 4. 5. 6.

7. 8.

Kogan-Liberman D, EMRe S, Shneider BL. Recent advances in pediatric liver transplantation. Current Gastro Reports 2002; 4(1):84-97. Emre S. Living-donor liver transplantation in children. Pediatric Transplantation 2002; 6(1):43-46. Bucuvalas JC, Ryckman FC. Long-term outcome after liver transplantation in children. Pediatric Transplantation 2002; 6(1):30-36. Shneider BL. Pediatric liver transplantation in metabolic disease: Clinical decision making. Pediatric Transplantation 2002; 6(1):25-29. McDiarmid SV. Management of the pediatric liver transplant patient. Liver Transplantation 2001; 7(11suppl 1):S77-S86. Emond JC, Whitington PF, Thistlewaite JR et al. Transplantation of two patients with one liver: analysis of a preliminary experience with “split-liver” grafting. Annals of Surgery 1990; 212(1):14-22. McDiarmid SV, Gornbein JA, Desilva PJ et al. Factors affecting growth after pediatric liver transplantation. Transplantation 1999; 67(3):404-411. Gloss JA, Shackleton CR, McDiarmid SV et al. Long-term results of pediatric liver transplantation: An analysis of 569 patients. Annals of Surgery 1998; 228(3):411-420.

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A

Index

Acetaminophen 30-33 Acne 67, 102 Acute cellular rejection (ACR) 5, 8, 11, 12, 14, 16, 47, 60, 71, 74-77, 86, 104 Acyclovir 63, 79, 81, 101, 112 Addiction 28, 29, 41, 92, 103 Alcoholism 27, 29, 41, 92, 99 Alloimmune response 5, 7, 9 Alpha feto protein (AFP) 25, 39 Alpha-1-antitrypsin deficiency 108, 109 Amyloidosis 90, 91 Anergy 12-15 Angina pectoris 22 Angiotensin converting enzyme (ACE) 63, 96 Angiotensin II 96 Antibody dependent cellular cytotoxicity (ADCC) 13 Antigen presenting cells 5, 15 Apoptosis 11, 14, 15, 64 Argon beam coagulatorargon beam coagulator 54 Autoimmune hepatitis 28, 34, 64, 78, 89, 93, 98 Azathioprine (AZA) 12, 13, 61, 63, 68, 72, 79, 90

B B-cells 5-8, 11, 12, 14 Basiliximab 12, 71 Biliary atresia 4, 109, 110, 111 Biliary cast syndrome 83, 84 Biliary leaks 74, 83, 84 Bone densitometry 27 Breast feeding 72, 104 Burkholderia cepacia 23

C Calcineurin 12, 63, 64, 66, 68, 69, 72, 86, 95-98, 102, 103 Calcium 27, 64, 96, 97, 99, 103 CBD 44, 45, 50, 53 CD antigen 14 CD28 9, 15

Liver Transplantation CD3 8, 9, 12, 14, 68 Celiac sprue 28, 34 Central pontine myelinolysis 38, 103 Cerebral edema 29, 32 Cervical cancer 100 Cervical carcinoma 101 Chemoembolization 39 Chemokine 10, 15 Child-Pugh classification 17, 18 Cholangiocarcinoma 20, 26, 33, 39, 92 Cholangiogram 57, 59, 111 Cholestipol 20 Cholestyramine 20, 27, 63 Chronic ductopenic rejection (COPD) 11, 12, 15, 22, 34, 71, 74, 76-79, 84 Chronic obstructive pulmonary disease 22 Ciprofloxacin 38 Cirrhosis 3, 4, 18, 19, 27, 30, 33, 34, 36, 39, 41, 79, 86-88, 90, 93, 98, 107-109, 111 Co-amoxyclav 38 Co-stimulation 7 Coagulopathy 19, 29, 37, 74, 103, 110 Colon cancer 26, 33, 39, 101 Common bile duct 44, 50, 53, 57 Complement 11, 13 Cotrimoxazole 38 Creatinine 18, 24, 33, 38, 57, 67, 98 Crigler-Najjar syndrome 90, 107, 109 Cryoglobulinemia 98 Cryotherapy 39 Cryptogenic cirrhosis 34, 93, 109 CSA 13 CTLA-4 15, 63 Cutaneous warts 102 Cyclosporin 12, 13, 63-69, 71, 72, 76, 97, 99, 101-103 Cyclosporine 69 Cystic duct 49, 53, 57 Cystic fibrosis 23, 90, 107-109 Cytokine 7, 9-12, 15, 64, 66, 68 Cytomegalovirus (CMV) 27, 30, 40, 68, 72, 74, 76, 78, 79, 82, 86, 101, 110, 112 Cytotoxic T lymphocyte CTL) 14, 15

D

H

Daclizumab 12, 71 Deletion 12, 13 DEXA scan 99 Diabetes insipidus 42 Diabetes mellitus 25, 65, 67, 72, 95, 97, 98, 104 Diltiazem 66, 96 Direct antigen recognition 8 Diuretics 23, 24, 38, 97

Halothane 30, 32, 33 Headache 64-68, 103 Hemochromatosis 33, 90, 91 Hemochromatosis gene test 33 Hemorrhagic necrosis 34, 74 Heparin 44, 46 Hepatic artery stenosis 83 Hepatic artery thrombosis (HAT) 34, 69, 74, 79, 81-83 Hepatic osteodystrophy 20 Hepatitis A virus (HAV) 32, 41, 88 Hepatitis B immunoglobulin (HBIg) 33, 88 Hepatitis B virus (HBV) 32, 33, 41, 72, 74, 87, 88, 110 Hepatitis C virus (HCV) 2, 23, 30, 33, 39, 41, 72, 74, 86, 87, 89, 93, 97, 98, 102 Hepatitis D virus (HDV) 33, 78, 88, 93 Hepatoblastomas 26 Hepatocellular cancer 20, 21, 109 Hepatopulmonary syndrome 19, 23, 34 Herpes simplex virus 27 Heterotopic auxiliary transplants 32 HFE 33 HHV-8 100 Hirsutism 64, 102 HMG CoA-reductase inhibitors 97 HPV 100, 101 HPV-6 101 HSV 27, 41, 74 Human herpes virus-8 100 Human immunodeficiency virus (HIV) 20, 26, 42, 57, 100 Human papilloma virus 100 Hydrocortisone 46, 62 Hyperacute rejection 2, 11 Hyperhomocysteinemia 95 Hyperkalemia 64, 97 Hyperlipidemia 34, 67, 69, 95, 97 Hypertension 18, 20, 22, 23, 36-38, 41, 42, 63-65, 67, 68, 83, 95-98, 103, 104, 107, 111 Hypoalbuminemia 24 Hypomagnesemia 97, 103

E Ebstein-Barr virus 27 EBV 27, 40, 73, 74, 79, 80, 81, 100, 101, 110, 112 Etidronate 27 Extended criteria donors 46 Extended use organs 2 Extracorporeal perfusion 32

F Factor V 32 FAH 109 Fas 11 Fibrosing cholestatic hepatitis 86 FK506 13 FK506 binding protein 13 FKBP 13, 66 Foscarnet 79 Fulminant hepatic failure 20, 29-33, 34, 79, 109 Fumarylacetoacetate hydrolase 109

G Gadolinium angiography 28 Gallbladder 44, 53, 54, 57, 59 Ganciclovir 79, 81, 112 Gentamicin 38, 66, 72 Glomerulonephritis 72, 98 Glucocorticoids 12, 63, 64 Glypressin 23 Graft versus host disease (GVHD) 15 Granzymes 11 Gum hypertrophy 64, 102

Index

115

Index

116 Hyponatremia 38

I

Index

IBD 33 Immunoglobulin superfamily 11 Impotence 25 Inflammatory bowel disease 33 Innate immunity 16 Insomnia 63, 102 Insulin resistance 25, 34, 97 Integrins 11 Interferon 87 Interleukin-2 (IL-2) 7, 9, 12, 64, 66, 67, 71, 79 Interleukin-4 (IL-4) 7, 9, 66 Interleukin-6 (IL-6) 7, 9 Ischemic hepatitis 30 Isoniazid 26, 30, 72, 101

K Kasai procedure 111 Kidney transplantation 24

L Lamivudine 33, 88, 93 Lassitude 102 Lethargy 19 Live donor right lobe recipient operation 59 Live liver donation 20, 21 Living donation 2, 57 Lymphoma 30, 73, 80, 81

M Macrophages 5-7, 10, 11, 14 Magnetic resonance (MR) 25, 28, 33, 39, 41, 57, 82, 83, 89, 93, 103, 110, 113 Major histocompatibility complex (MHC) 5-9, 11, 13-16, 86 Malabsorption 27, 28 Mammography 26, 39 Marginal donors 2 MELD score 17, 18 Menstruation 25 Midodrine 23 Molecular mimicry 8

Liver Transplantation Musculoskeletal pain 102, 103 Mycophenolate 12, 13, 68, 72, 97 Mycophenolate mofetil 12, 13, 97 Myocardial infarction 22

N Nadalol 36 Naltrexone 20 NASH 34, 74, 93 Nephrotic syndrome 24 Neuroendocrine tumors 26, 93 Niemann-Pick disease 90 Nifedipine 96 NK cells 11 Non-alcoholic fatty liver disorder (NAFLD) 34, 93 Non-alcoholic steatohepatitis 34 Non-heart beating donors 2, 42, 84 Non-heart-beating donors 46 Non-steroidal anti-inflammatory agents 38 Norfloxacin 38

O Obesity 34, 95, 97 OKT-3 12 Oral cancer 100 Ornithine transcarbamylase deficiency 107, 109 Orthoclone 14 Osteopenia 36, 99 Osteoporosis 65, 99, 103

P Palmidronate 27 Pancreatitis 28, 34, 63, 92 Pap smears 39 Parvovirus B19 101 PELD 20, 109 Perforins 11 Peritonitis 19, 36, 37 Phenytoin 20, 32, 66 Plasmapheresis 20 Porcine endogenous retrovirus (PERVs) 2 Portal hypertension 18, 23, 36-38, 83, 107, 111

117

Index

R Radiofrequency ablation 39 Rapamycin 12, 63, 66, 69 Renal function 23, 24, 28, 57, 97, 98 Retransplantation 3, 4, 34, 35, 54, 72, 76, 83, 84, 86 Ribavirin 87 Rifampicin 65, 66, 101 Rifampin 20 Right lobe living donor operation 57 Roux-en-Y hepatico-jejunostomy 55

S Seizures 68, 103 Selectins 11 Sirolimus 12, 63, 66, 67, 69-72, 97 Skin cancer 20, 80, 97, 100 Somatostatin 23 Split liver grafts 47, 112 Spontaneous bacterial peritonitis (SBP) 19, 36, 37, 38 Statins 66, 97 Steatosis 57 Stent thrombosis 37 Steroid resistant rejection 76 Subacute hepatic necrosis 31 Subfulminant hepatic failure 29, 30 Suppression 3, 12, 16, 20, 60, 61, 63,

66, 68, 70-73, 76, 78, 79, 81, 86, 89, 90, 95, 97, 101, 104, 112

T T helper 7, 14-16 T-cell receptor 5-9 T-cells 5-8, 11-13 T-tube 53, 83, 84 Tacrolimus 12, 13, 63-67, 71-73, 76, 89, 97, 99, 101-103 Target of rapamycin (TOR) 63, 66 TCR 8, 14, 15, 16 Th lymphocytes 7 Th1 and Th2 paradigm 7 Th2 paradigm 7 Thyroid disease 25 Tobacco products 23 Tolerance 7, 12, 14, 16, 30, 60, 87, 104 Transjugular intrahepatic portosystemic shunt (TIPS) 23, 37, 56, 57 Tremor 63, 64, 66, 67, 103 Trimethoprim 38 Tuberculosis 26, 72, 101 Tyrosinemia 30, 90, 108, 109

U Ulcerative colitis 26, 39 UNOS 20, 25, 108-110 Ursodeoxycholic acid 20, 89

V Vaccinations 40, 101, 103, 110 Vanishing bile duct syndrome 12, 71, 76 Variceal hemorrhage 19, 36, 37, 41, 111 Varicella zoster 101 Verapamil 66, 96 Vertebral fractures 99 Vitamin A 27 Vitamin D 27, 99, 110 Vitamin K 27 VZV 74, 101

X Xenotransplants 2

Index

Portal vein thrombosis 36, 55, 83 Portal venous bypass 50 Porto-pulmonary hypertension 22, 23 Post-transplant lymphoproliferative disorders (PTLD) 80, 100, 112 PPD 26 Pregnancy 30, 67, 68, 72, 104 Primary biliary cirrhosis 18, 19, 34, 79, 88, 98 Primary graft non-function 2, 74 Primary hyperoxaluria 109 Primary sclerosing cholangitis 19, 33, 34, 79, 89, 109 Propranolol 36 Prostatic specific antigen 26, 40 Protoporphyria 90 PSA 26, 40 Psychological assessment 28 Purified protein derivative 26

LANDES BIOSCIENCE

V ad e me c u m

LANDES BIOSCIENCE

V ad e me c u m

Table of contents 1. Liver Transplantation: An Overview 2. The Allograft Immune Response

9. Medical Management of the Liver Transplant Patient 10. Pediatric Liver Transplantation

3. Assessment for Liver Transplantation

Liver Transplantation

4. Management on the Liver Transplant Waiting List 5. The Liver Transplant Operation 6. Immunosuppression after Liver Transplantation 7. Graft Dysfunction 8. Recurrence of Disease after Liver Transplantation The Vademecum series includes subjects generally not covered in other handbook series, especially many technology-driven topics that reflect the increasing influence of technology in clinical medicine. The name chosen for this comprehensive medical handbook series is Vademecum, a Latin word that roughly means “to carry along”. In the Middle Ages, traveling clerics carried pocket-sized books, excerpts of the carefully transcribed canons, known as Vademecum. In the 19th century a medical publisher in Germany, Samuel Karger, called a series of portable medical books Vademecum. The Landes Bioscience Vademecum books are intended to be used both in the training of physicians and the care of patients, by medical students, medical house staff and practicing physicians. We hope you will find them a valuable resource.

I SBN 1- 57059- 682- 4

All titles available at

www.landesbioscience.com

9 781570 596827

Michael R. Lucey James Neuberger Abraham Shaked