Liver transplantation

V m

Michael R. LuceyJames NeubergerAbraham Shaked

a d e m e c uV a d e m e c u m

Table of contents1. Liver Transplantation:

An Overview

2. The Allograft ImmuneResponse

3. Assessment for LiverTransplantation

4. Management on the LiverTransplant Waiting List

5. The Liver TransplantOperation

6. Immunosuppression afterLiver Transplantation

7. Graft Dysfunction

8. Recurrence of Disease afterLiver Transplantation

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LiverTransplantation

9. Medical Management of theLiver Transplant Patient

10. Pediatric 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.

Liver Transplantation

GEORGETOWN, TEXAS

U.S.A.

v a d e m e c u m

L A N D E SB I O S C I E N C E

VADEMECUMLiver Transplantation

LANDES BIOSCIENCEGeorgetown, Texas U.S.A.

Copyright ©2003 Landes BioscienceAll rights reserved.No part of this book may be reproduced or transmitted in any form or by anymeans, electronic or mechanical, including photocopy, recording, or anyinformation storage and retrieval system, without permission in writing from thepublisher.Printed in the U.S.A.

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ISBN: 1-57059-657-4

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While the authors, editors, sponsor and publisher believe that drug selection and dosage andthe specifications and usage of equipment and devices, as set forth in this book, are in accordwith current recommendations and practice at the time of publication, they make nowarranty, expressed or implied, with respect to material described in this book. In view of theongoing research, equipment development, changes in governmental regulations and therapid accumulation of information relating to the biomedical sciences, the reader is urged tocarefully review and evaluate the information provided herein.

Contents

1. Liver Transplantation: An Overview ................................. 1Michael R. Lucey

History ....................................................................................................... 1The Donor Organ Shortage ........................................................................ 1Outcome of Liver Transplantation .............................................................. 3

2. The Allograft Immune Response ....................................... 5Peter Abt and Abraham Shaked

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

3. Assessment for Liver Transplantation .............................. 17Michael R. Lucey

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

4. Management on the Liver Transplant Waiting List ......... 36James Neuberger

Introduction ............................................................................................. 36Prevention of Complications of End-Stage Liver Disease .......................... 36Cancer Development ................................................................................ 38

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

5. The Liver Transplant Operation...................................... 42Michael Crawford and Abraham Shaked

Cadaveric Donors ..................................................................................... 42The Cadaveric Donor Operation .............................................................. 42Extended criteria donors ........................................................................... 46The Recipient Operation .......................................................................... 48Special Operative Problems ....................................................................... 54Live Liver Donors ..................................................................................... 57

6. Immunosuppression after Liver Transplantation ............ 60James Neuberger

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

7. Graft Dysfunction ........................................................... 74Geoffrey H. Haydon

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

8. Recurrence of Disease after Liver Transplantation .......... 86Lisa Forman and Geoffery Haydon

Hepatitis C Virus Infection ....................................................................... 86Hepatitis B Virus Infection ....................................................................... 87Hepatitis D virus Infection ....................................................................... 88Hepatitis A Virus Infection ....................................................................... 88Autoimmune Disease ................................................................................ 88Metabolic Diseases .................................................................................... 90Malignancy ............................................................................................... 92

9. Medical Management of the Liver Transplant Patient ..... 95Anne Burke

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

10. Pediatric Liver Transplantation ..................................... 107Elizabeth B. Rand and Kim M. Olthoff

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

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

Editors

Michael R. Lucey M.D., F.R.C.P.I.Professor of Medicine

Chief, Section of Gastroenterology and HepatologyUniversity of Wisconsin School of Medicine

Madison, Wisconsin, U.S.A.

James Neuberger, D.M., F.R.C.P.Professor in Medicine

Liver UnitQueen Elizabeth Hospital

Birmingham, United Kingdom

Abraham Shaked, M.D., Ph.D.Professor of Surgery

Chief, Division of TransplantationUniversity of Pennsylvania Medical Center

Department of SurgeryPhiladelphia, Pennsylvania, U.S.A.

Peter Abt, M.D.Department of SurgeryUniversity of Pennsylvania Health SystemPhiladelphia, Pennsylvania, U.S.A.

Anne Burke, M.B., B.Ch., B.A.O.Division of GastroenterologyUniversity of Pennsylvania Health SystemPhiladelphia, Pennsylvania, U.S.A.

Michael Crawford, M.D.Departments of Upper Gastro-Intestinal

and Transplant SurgeryRoyal Prince Alfred HospitalSydney, New South WalesAustralia

Lisa Forman, M.D.Division of Gastroenterology

and HepatologyUniversity of Colorado Health Sciences

CenterDenver, Colorado, U.S.A.

Geoffrey H. Haydon, M.R.C.P., M.D.Liver UnitQueen Elizabeth HospitalBirmingham, United Kingdom

Kim M. Olthoff, M.D.Department of SurgeryFred and Suzanne Biesecker Center for

Pediatric Liver DiseaseUniversity of Pennsylvania Health

SystemPhiladelphia, Pennsylvania, U.S.A.

Elizabeth B. Rand, M.D.University of Pennsylvania School

of MedicineFred and Suzanne Biesecker Center

for Pediatric Liver DiseaseChildren’s Hospital of PhiladelphiaPhiladelphia, Pennsylvania, U.S.A.

Contributors

Preface

The purpose of this volume is to provide a short, didactic handbook forthose clinicians (medical, surgical, nursing and others) who are involved inthe care and management of people who may, are or have undergone livertransplantation. We are aware that there are several, large texts whichprovide a comprehensive account of liver transplantation. This volume isdesigned to complement and not replace them.

Liver transplantation has developed rapidly over the last two decades anddogma is changing rapidly. This leads to controversy and debate which arethe essence of academic medicine. We are also aware that different transplantprograms have their own approach to managing patients. It is inevitable thatmany views and arguments cannot be put in such a book as this one. Wherepossible, we have tried to provide a consensus view. We have provided selectedreferences for further reading and electronic addresses to source material, forthe reader who wishes to probe deeper into any aspect of liver transplantation.

We are grateful to the authors who have contributed to this book. Wehave tried to ensure a consistent style and hope the reader finds this usefuland helpful. Finally, if there are any errors or omissions, the editors wouldbe grateful if these could be identified, so that we may correct them in futureeditions.


August 2002

1Liver Transplantation: An Overview

1

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

CHAPTER 1

Liver Transplantation: An Overview

Michael R. Lucey

HistoryThomas Starzl carried out the first human liver transplant in 1963 in Denver.

Initially the outcomes were very poor; however, the persistence of Starzl and histeam was rewarded and in 1968 Calne set up the second transplant program inCambridge. Patients were usually very sick at the time of transplant and few survivedthe post-operative care. Over the next two decades, the numbers of patients graftedgradually increased and survival rates improved. There is no one reason for thisimprovement, but better selection, improved anesthetic and surgical techniques, theuse of powerful and specific anti-microbials and immunosuppressive agents all madesignificant contributions. In the 1980s, new programs developed primarily in NorthAmerica and in Europe. Now liver transplantation has become a routine procedurefor 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

therapy3. 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 appropriatetherapy 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 identifypotential donors, retrieve their organs, and transport the organs to the location ofthe potential recipient. At the same time, the number of potential recipients awaitingliver transplant continues to grow at a furious pace, outstripping the modest increasesin donor numbers. This has meant that there are many more recipients for everydonor liver. Thus in the United States in 2000, there were over 17000 patients onthe waiting list, only 4579 cadaveric transplants done and 371 living related trans-plants. There were 1347 deaths on the waiting list. (See www.unos.org for current data)

2 Liver Transplantation

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The disparity between donor availability and recipient number has led to grow-ing numbers of patients on the waiting list for liver transplant.

Innovative responses to the donor shortage have been introduced but while theseapproaches may help relieve the situation, they are unlikely to ease the effects of theorgan shortage:

1. Non-heart beating donors. Non-heart beating donors are uncommon,and the frequency of primary graft non-function and later, biliary stricturesare 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 willingfor living donation. Moreover, living segmental liver transplantation posesreal 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 higherprobability of primary non-function (the so-called marginal donor).Marginal organs include those from older or obese donors, or donorswho are unstable prior to organ retrieval. Other marginal graftsinclude steatotic livers, in which histology demonstrates greater than25% microvesicular or macrovesicular fat. These grafts are associatedwith a higher incidence of primary non-function of the allograft.• Extended use organs from patients infected with present or pastviral hepatitis B or C and those with extrahepatic malignancy ortreated bacterial infection. Organs from virus-infected donors arematched to a recipient already infected by the same virus, albeitonly after the recipient is apprised and has given consent. An examplewould be putting an anti-hepatitis C positive liver into an anti-hepatitis C positive recipient, or an anti-HBcore positive liver intoan HBsAg positive recipient.

5. Xenotransplants: the use of genetically modified animals, such as pigs orprimates, is still a very long way from clinical use. While some of theproblems of hyperacute rejection may be overcome, problems, such aschronic rejection, freedom from introducing infection (such as the porcineendogenous retrovirus (PERVs) as well as physiological concerns make itunlikely that this approach will provide a solution to the organ shortagein the next decade.

6. Increasing organ donation: there are wide variations in the rates of organdonation—between 8 and 37 donors per million. Attempts to increaseorgan donation by education have largely failed: the most successful modelin Spain is dependent on provision of a well-organized system of donorco-ordinators and acceptance of older donors.

7. Future approaches may include stem cell transplantation and hepatocytetransplantation.

Thus, it is unlikely that these methods will meet the needs of all potential recipients.

3Liver Transplantation: An Overview

1

Outcome of Liver TransplantationLiver transplantation has become the treatment of choice for many forms of life-

threatening liver disease because of the continuing lack of less radical therapies andthe 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 whohave survived more than 10 years after transplantation are commonplace in longestablished programs. The success of liver transplantation has occurred despite un-acceptably 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 longterm immunosuppression and recurrence of the original disease in the long-termsurvivor.

The outcome of liver transplantation is dependent on donor organ and recipientfactors. See Table 1. Donor factors, which reduce graft success, include donor ageand transplantation of a liver allograft from a female donor into a male recipient. Itis 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 transplanta-tion, nevertheless, the cause of the underlying liver disease significantly affects theoutcome after liver transplantation.

• The best outcomes are observed in patients with chronic cholestatic dis-orders and in chronic liver failure from cirrhosis of many causes.

• The outcome is worse among patients transplanted for fulminant liverfailure and significantly worse in patients with malignant disease of theliver.

• 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 inrecipients requiring intensive care unit management or among patients with multi-system failure, prior to transplant. The allocation system currently in use in the

Table 1. Factors influencing the outcome of orthotopic liver transplantation

Donor Factors:Donor age: older donors are less successfulDonor gender: Significantly worse results when a female liver is given to a malerecipientDonor liver fat content: >25% fat at increased risk of primary allograft nonfunction

Recipient Factors:Acutely ill: requiring ICU care before transplantationAcute renal failureRecipient diagnosis: (see Table 2)

Factors independent of Donor or Recipient:Center activity—small centers have been linked to poor outcome. This is acontroversial observation.


1

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

Suggested Reading1. The U.S. Scientific Registry of Transplant Recipients and The Organ Procurement

and Transplantation Network. Transplant Data 1988-1996. (See: www.unos.org)2. 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.

3. Edwards EB, Roberts JP, McBride MA, Schulak JA, Hunsicker LG. The effect ofthe volume of procedures at transplantation centers on mortality after liver trans-plantation. N Engl J Med 1999; 341:2049-2053.

4. Trotter JF, Wachs M, Everson GT, Kam I. Medical progress: Adult to adult trans-plantation of the right hepatic lobe from a living donor. N Engl J Med 2002;346:1074-1082.

Table 2. Outcome of liver transplantation in the United States

Primary Diagnosis N (94-95) 1 Year Std Err N 5 Year StdSurvival%

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 OrganProcurement and Transplantation Network. Transplant Data 1988-1996. Reference 1

5The Allograft Immune Response

2


CHAPTER 2

The Allograft Immune Response

Peter Abt and Abraham Shaked

The Alloimmune ResponseIn this Chapter there is a simplified account of the interaction between the host

immune system and the allograft.

Recognition of Self and Non-SelfThe 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 andtolerate self antigen, whereas the encounter with any non-self antigen will lead tothe initiation of immune response. The most recognized histocompatibility antigensare 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 isresponsible for activating T-cells bearing the CD8 surface molecule (CD8+). Of theseveral 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, andmacrophages. 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 anti-gens the stronger the immune response. Before being transported to the plasmamembrane of the cell, MHC class I and class II undergo intracellular processing andare loaded with peptides in the antigen presenting cell (Fig. 2). Peptides that arederived from the allograft are recognized as non-self by T-cells, leading to initiationof immune response against the transplanted organ. The peptides which stimulatethe immune response involved in acute cellular rejection of the liver allograft remainto be determined. The diagnosis of acute cellular rejection in liver allografts is de-pendent on the demonstration of a mixed inflammatory cell infiltrate in the portaltriads. Biliary epithelium and venous endothelium are the early targets of cellularrejection on account of their rich expression of class I and II MHC antigens. Incontrast, hepatocytes which express few class I or II MHC antigens are rarely thetarget of early acute cellular rejection

Recipient T- and B-Cell ActivationRecipient 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


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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 pre-sents exogenous protein bound to class II molecules to CD4+ T-cells and also pro-cesses intracellular protein and presents it with MHC class I to CD8+ T-cells. TheT-cell receptors recognize peptide bound to MHC.


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cell. T-cell recognition is associated with the initation of complex intracellular sig-naling 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 CD8molecules. CD4 and CD8 molecules bind to the same MHC on the antigen pre-senting cell as the T-cell receptor. CD4+ cells are known as helper cells and play animportant role in initiating and directing the immune response (Fig. 4). CD8+ cellsalso known as cytotoxic T-cells are responsible for cell directed cytotoxicity.

Whether a T-cell, whose receptor has bound the MHC-peptide displayed on theantigen presenting cell, becomes activated, depends on a receiving a second set ofsignals (co-stimulation) from the antigen presenting cell. These costimulatory inter-actions 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 re-

jection. Once activated the CD4+ T-cells undergo clonal expansion and differentia-tion. In doing so they secrete cytokines that attract other leukocytes to activate otherT-cells and facilitate the differentiation of B-cells to plasma and memory cells.

The pattern of cytokines elaborated by subsets of CD4+ and CD8+ stimulatedT-cells is important in directing the alloimmune response. CD4 bearing Th lym-phocytes (T helper) cells have been stratified into two classes of Th cells dependingon the type of cytokines elaborated by the cells in question. The subdivision of Thcells is called the Th1 and Th2 paradigm. Precursor CD4 cells producing interleukin-12promote 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 cy-totoxicity by activating macrophages and cytotoxic T cells. Th2 cells secrete IL-4and IL-6, cytokines which promote allergic inflammation and stimulate B cells toproduce antibodies. Furthermore, cytokines from Th 1 cells inhibit Th2 cells whereascytokines from Th 2 cells inhibit Th1 cells. It appears in certain experimental situa-tions that a Th 2 predominance is associated with the prolongation of graft survivalor even tolerance (Table 2).

While much attention has been given to T-cell activation, B-cells are also in-volved in the response. Donor antigen shed from the graft binds to surface Ig and isthen internalized by the B-cell. The antigen is processed and presented on the B-cell

Table 1. Characteristics of MHC molecules

Common features of MHC Class I and II glycoproteins� allelic diversity� antigen presentationDiffering characteristicsClass 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+)


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

Stages of Allograft ResponseThe immunologic events surrounding transplantation of an allograft can be

conceptualized as a series of steps starting with changes in the graft prior totransplantation and extending to the time of rejection.

Antigen Presentation and AllorecognitionWhen first transplanted, the liver allograft has the immune phenotype of the

donor. Initially therefore, the liver allograft expresses the MHC molecules of thedonor, resulting in two pathways of antigen recognition. Whereas in the non-transplant 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 asnon-self because their three-dimensional stoichiometry resembles a self MHC boundto a foreign peptide, a concept referred to as molecular mimicry. This process iscalled direct antigen recognition and is thought to be the main mechanism for theimmune response in acute cellular rejection. Later, there is migration of donordendritic 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

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


2

from catabolism of the donor MHC molecules are presented by self MHC on re-cipient APCs.

It is unclear whether the non-immunologic injury incurred by the donor liver inthe process of organ retrieval, preservation and reperfusion contribute to the initiationor maintenance of the alloimmune response. The period of cold preservation,ischemia, and reperfusion leads to the differential expression of endothelial cell surfacemolecules and cytokines. These include adhesion molecules, interleukins, and

Table 2. Th 1 and Th 2 paradigm

Differentiated by Cytokines Produced Function

Th1 IL-12 IL-2, IFN-γ cell mediated cytotoxicitysuppresses Th2-cellresponse

Th2 IL-4 IL-4, Il-5, IL-6 suppresses Th1-cellresponse

IL-10 promotes B-cell expansion

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


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chemokines which attract inflammatory cells. Oxygen radicals produced during is-chemia and reperfusion directly harm the graft.

Helper T cells are thought to be the most important cells for initiating allograftcellular rejection. They are responsible for the production of cytokines, such asinterleukin 2, which are necessary for clonal expansion of activated lymphocytes.The cytokines act in an autocrine fashion on CD4 expressing surface molecules (Thcells) and as a paracrine stimulus on other effector cells such as cytotoxic T cells

(CD8 cells), macrophages and B cells.

Leukocyte Migration into the AllograftAs part of the early evolution of the allograft immune response, recipient

leukocytes are recruited to the donor allograft. This involves the elaboration of aseries of soluble molecules as well as cell-to-cell interactions. Three main classes ofreceptors are credited with leukocyte migration.

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


2

� Selectins: primarily responsible for allowing the leukocyte to gently ad-here to the endothelial surface

� Integrins� Members of the immunoglobulin superfamily: responsible for

extravasation of leukocytes into the allograft.

Graft DestructionCD8+ T-cells are the main effectors of graft destruction and cause cell death

through direct cell contact. When activated by membrane binding to the allograftthey release cytotoxic molecules termed perforin and granzyme. Perforins create holesin the target cell membrane and granzymes disrupt intracellular processing. CytotoxicT-cells also have a cell surface protein termed Fas ligand which when bound to areceptor protein called Fas, which is present on target cells, results in death of thetarget cell by the process of apoptosis.

Macrophages which have been activated by CD4+ T-cells are capable of causingtissue destruction through the release of cytotoxic cytokines or through direct celllysis. The role of NK cells in organ allograft rejection is unclear. B-cells secrete specificantibody that binds to the allograft cell surface. The antibody induces tissue damagethrough the activation of the complement system (Fig. 6).

Classification of Allograft RejectionAllograft rejection is classified into three types based on the nature of the immune

response after transplantation:1. Hyperacute rejection2. Acute cellular rejection3. Chronic ductopenic rejection.

Hyperacute RejectionHyperacute rejection is characterized by a rapid response of the host immune

system to the allograft. Within minutes to hours of the transplant, preformedantibodies engage class I MHC or the ABO blood group antigens on the graft. Theantibodies facilitate complement mediated lysis of the endothelium and initiate aninflammatory cell infiltrate. Hyperacute rejection is rarely observed in liver transplants,even among those with a positive crossmatch.

Acute Cellular RejectionAcute cellular rejection is due to an immune reaction mediated by recipient T

lymphocytes’ response to donor MHC antigens. Antibodies and cytokines alsocontribute to the immunologic attack. The biliary epithelium and venousendothelium express MHC class I and II molecules and are the focus of the acutecellular rejection response. Hepatocytes which express few class I or II MHC antigensare rarely the target of acute cellular rejection.

The principal clinical features of acute cellular rejection are:1. Elevated liver transaminases and/or bilirubin2. Lymphocytic infiltrates in the portal triads seen on biopsy


2

3. The development of graft dysfunction manifested by hyperbilirubinemia andsubsequent impaired liver synthetic function.

Acute cellular rejection is usually controlled with additional corticosteroid-basedimmunosuppression with no significant impact on graft or patient survival.

Chronic Ductopenic RejectionChronic ductopenic rejection occurs months to years after transplantation. The

mechanisms which underlie chronic rejection in any of the solid organs are less wellunderstood than acute cellular rejection. Both immunologic and non-immunologicprocesses are implicated. The impact of chronic rejection on the liver allograft is onthe 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 episodesof chronic ductopenic rejection are preceded by acute cellular rejection.

Mechanisms of Immunosuppressive Drug ActionThe 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 theirmechanism of action. The antimetabolites include azathioprine and mycophenolatemofetil. 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 pro-tein responsible for promoting cytokine induced gene activation. By inhibiting IL-2 production they prevent activation of lymphocytes. Rapamycin (Sirolimus), oneof 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 thenucleus where they regulate gene transcription by binding to specific gene regulatoryregions. They interfere with many aspects of the immune system including theproduction of IL-1, IL-2, and IFN-γ.

Antibodies recognize many surface antigen epitopes (polyclonal) or single cellsurface antigen epitopes (monoclonal). Antithymocyte globulin and thymoglobulinare two polyclonal preparations of immunoglobulin to lymphocytes. OKT-3 isdirected against the CD3 receptor on T-cells. Basiliximab and daclizumab are twomonoclonal antibodies against the α chain of the IL-2 receptor. They are used forinduction therapy and like the other antibodies result in depletion of the cells thatbear the cell surface protein which they bind.

ToleranceThe development of an immunologic state wherein the recipient is unresponsive

to donor alloantigen, but yet the immune system is capable of recognizing andresponding to other foreign proteins such as bacterial or tumor antigens without theneed for immunosuppression is known as tolerance.

Mechanisms of tolerance can be grouped into suppression, anergy, deletion, andignorance. Suppression involves the inhibition of donor reactive T and B-cell responsesby a “suppressor” cell population. While functional examples exist, it has been difficult


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

Figure 6. Antibody mediated damage to graft endothelium. Recipient antibody bindsto MHC on graft endothelium. Antibody initiates graft damage through antibodydependent 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).


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GlossaryAcquired 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 andvascular endothelia, including portal veins and hepatic venules, and occasionally thehepatic artery and its branches.

Allele: Alternative forms of the same geneAllogeneic: 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 bear-

ing MHC cell surface molecules, by which they ‘present’ peptides which are theproduct of intracellular degradation of exogenous proteins recognized as non-self.Activated APCs also express co-stimulatory molecules. Macrophages and dendriticcells are paradigmatic APCs.

Apoptosis: Also called programmed cell death. A specific form of cell death dueto enzymatic degradation of DNA, without inflammation.

B-cells: Lymphocytes capable of antibody production. Most arise from stemcells in bone marrow. B lymphocytes produce antibodies as circulating proteins or asstationary molecules. The latter, which constitute the B cell receptor, contain ahydrophobic transgenic sequence which tethers the immune recognition segmentof the antibody to the cell surface membrane.

Cell mediated immunity: Immunologic response based on cellular elements ofthe 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 theirreactivity with specific monoclonal antibodies

CD3: A complex of molecules on the cell surface of T cells, that in associationwith the T cell receptor (TCR), activate intracellular signal transduction mechanismswhen 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 Tlymphocytes. CD4 binds to an invariant part of the MHC class II molecule. CD4bearing T cells usually act as T helper (Th) cells and recognize antigens processed byAPCs and presented in conjunction with MHC class II molecules.

CD8: Cell surface molecule expressed by functionally distinct subset of Tlymphocytes. CD8 binds to an invariant part of the MHC class I molecule. CD8bearing T cells usually act as cytotoxic T lymphocytes (CTLs) and recognize antigensprocessed by infected or injured nucleated cells and presented in conjunction withMHC class I molecules.


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CD28: The best characterized co-stimulatory molecule. Cell surface moleculeexpressed by T lymphocytes, activated by binding of TCR and antigen ligand. CD28 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 bindsB7-1 and B7-2. In contrast to the CD28-B7 interaction, linkage of CTLA-4 and B7leads to an inhibitory signal that terminates the inflammatory response.

Chemokine: Chemotactic cytokines that regulate leukocyte transit. Each typeof leukocyte bears chemokine receptors on its cell surface that guides it to chemokinessecreted 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 tobind to receptors on lymphocytes (e.g., CD 28 on lymphocytes and B7-1 on APC).Co-stimulatory signals enhance the immune response by promoting lymphocyteclonal expansion and cytokine production and are necessary for T cell activation.Interaction of T lymphocyte and APC in the absence of co-stimulatory signals leadsto anergy or apoptosis of the T cell. A parallel receptor ligand interaction which isinhibitory of the immune response is described through CTLA-4.

Cytokine: A large family of low molecular weight soluble proteins involved inregulating cellular activity. Includes the chemokines (see above).

Cytotoxic T lymphocyte (CTL): T lymphocyte that kills its target uponrecognizing 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 immunereaction of allogeneic lymphocytes contained within allograft tissue reacting againstalloantigens in the recipient (usually in skin, liver, and gastrointestinal tract).

Haplotype: Closely linked alleles on the same chromosome, usually inherited asa group and linked to inheritance of some phenotypic characteristic.

Helper T cell: T lymphocytes that secrete cytokines required for the immunefunction of other cells in the immune system. MosT helper T cells express the cellsurface molecule CD 4.

Human leukocyte antigens (HLA): The major histocompatibility complexesin 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 encoun-

ter with a specific antigen, and to generate a greater response in a subsequent expo-sure to the same alloantigen. Immunologic memory results from the generation of


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memory T and B cells during the initial encounter with an alloantigen, and is thecharacteristic feature of ‘acquired immunity’.

Innate immunity: All immunologic defenses that lack immunologic memory.The characteristic feature is that the response remains unchanged however often aspecific immunogenic moiety (immunogen) is encountered. This contrasts with‘acquired immunity’ (see above).

Isograft: Transplant between genetically identical members of the same speciessuch as inborn strain of animals or twins. Also known as a syngeneic transplant.

Major histocompatibility complexes: Histocompatibility antigens expressedon cell surfaces which are the markers by which the immune system distinguishesself 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 distinguishedby their cell surface receptor (TCR). T cells are subdivided into categories: T helpercells and T suppressor cells.

Tolerance: An immunologic state in the absence of immunosuppression whereinthe recipient is unresponsive to donor alloantigens, while retaining the capacity torecognize 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 pathogenicimmunogen (an altered pathogen, or molecular mimic) which in turn generatesmemory cells but not the pathologic consequences of the infection itself (the primaryimmune response). The immune system is thus primed to deliver an enhancedsecondary immune response in the event that the host is exposed to the infectiousagent in the future.

Xenotransplantation: Transplantation across species. The graft is called axenograft.

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 Reading1. Delves PJ, Roitt IM. The immune system-the first of two parts. New Engl J Medi-

cine 2000; 343:37-49. The immune system-the second of two parts. New Engl JMed 2000; 343:108-117.

2. Sayegh MH, Turka LA. The role of T-cell co-stimulatory activation pathways intransplant rejection. New Eng J Med 1998; 338(25):1813-1821.

3. Wiesner RH, Batts KP, Krom RA. Evolving concepts in the diagnosis, pathogen-esis, and treatment of chronic hepatic allograft rejection. Liver Trans Surg 1999;5:388-400.

4. 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.

17Assessment for Liver Transplantation

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CHAPTER 3

Assessment for Liver Transplantation

Michael R. Lucey

Selection for Liver TransplantationEvaluation 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 evaluationmay be carried out in an outpatient setting. The prospective candidate is assessed bytransplant surgeons and physicians, social workers, and selected subspecialistsincluding psychiatrists, cardiologists, pulmonologists and nephrologists. Previousinvestigations including radiographs and biopsies are retrieved and new investigationsare ordered where necessary. When the information gathering segment of theevaluation is complete, the patient is presented to the transplantation evaluationcommittee and a decision is made regarding placement on the transplant waiting list.

Liver transplant programs must inform and educate prospective recipients andtheir families of the risks and benefits of liver transplantation. It is important toprovide the patient with the opportunity to withdraw from transplant assessment ifthey do not wish to proceed. Conversely, whenever the transplant program determinesthat the patient is not a suitable candidate, the program should facilitate the patientin receiving a second opinion regarding their suitability, if they should so wish.

Assessment of Severity and Prognosisof Chronic Liver DiseaseThe 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-Pughclassification 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


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• Prothrombin time• Serum bilirubin• Serum albumin

It was developed originally as an instrument to predict outcome after portacavalshunt surgery. Later Pugh modified it for a study of esophageal transection for bleedingesophageal varices and modified the score for patients with cholestatic diseases. Ithas been adopted as the most easily administered clinical tool to assess severity ofcirrhosis. Survival of cirrhotic patients declines with worsening Child’s class. TheChild’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 portalhypertension make it less useful as a prognostic guide in many circumstances inwhich liver transplantation is under consideration. These include patients with chroniccholestatic diseases, liver tumors or fulminant liver failure. The Child-Pughclassification has not been verified in childhood disorders.

Table 1. Child-Turcotte-Pugh classification

PointsVariable 1 2 3

Encephalopathy None Moderate SevereAscites None Slight ModerateBilirubin (mg/dl) <2 2-3 >3Albumin (g/dl) >3.5 2.8-3.5 <2.8Prothrombin time (sec. prolonged) <4 4-6 >6 (INR) <1.7 1.7-2.3 >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 ScoreThe 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.orgor: 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


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aspartate transaminase and a history of variceal hemorrhage have beenconstructed into a prognostic instrument. Although the allocation prior-ity scheme in the United States does not incorporate prognostic scoringschemes specific to either primary biliary cirrhosis, or primary sclerosingcholangitis, these scoring schemes allow transplant physicians to recog-nize patients with poor prognosis.

Timing of Placement on the Waiting ListA 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 anyone 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 clinicalphenomena is defined as decompensated cirrhosis. The onset of decompensation isassociated with significantly impaired survival and indicates the need to evaluate forliver transplantation. Spontaneous bacterial peritonitis and/or hepatorenal failureare indicators of significantly worsened prognosis, and should prompt transplantationevaluation.

Indications for evaluation of liver transplantation are shown in Table 2.Paradoxically, some of these indications may, when severe, become contraindicationsto transplantation.

Transplantation for Non-Life Threatening DiseaseLiver 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

Table 2. Indications for consideration of liver transplantation in patients with chronic liver disease

Recurrent gastroesophageal variceal hemorrhageRefractory ascitesSpontaneous bacterial peritonitisSevere hepatic encephalopathyHepatorenal syndromeProfound non-responsive pruritus of cholestatic liver diseaseSevere hepatic osteopathyHepatocellular carcinomaProgressive rise in serum alpha-fetoprotein without massRefractory bacterial cholangitisSevere coagulopathy due to liver failureSevere sustained fatigue and weaknessSevere malnutritionHepatopulmonary syndrome


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to exclude treatable causes such as depression, hypothyroidism, or un-wanted effects of medication.

• Pruritus: All therapeutic options are tried before transplantation, whenliver function is well maintained. Such therapies include cholestyramine,cholestipol, rifampin, naltrexone, ursodeoxycholic acid, phenytoin, andplasmapheresis.

• Hepatic osteodystrophy: when progressive may be an indication fortransplantation.

Allocation and Distribution of Donor LiversDifferent 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 isgiven to patients with fulminant hepatic failure or primary allograft non-function,and for certain pediatric indications. For all other candidates, priority is determinedby the MELD or PELD (the pediatric scoring system) score. An adjustment hasbeen made for patients with hepatocellular cancer. For an up to date account ofthese variations on the MELD/PELD scheme, consult the UNOS website(www.unos.org).

UK: The number of centers designated for NHS (public funded) treatment iscontrolled by central government. The six transplant units have areas (according totheir contracted activity) and any organ offered in their area can be used for a listedpatient. Supra-urgent patients (those with fulminant hepatic failure) will have nationalpriority. The individual unit determine which recipient should receive donor organsoffered to that area. The units have agreed indications and contra-indications toensure 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 TransplantationAbsolute and relative contraindications to liver transplantation are shown in Tables

3 and 4.


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Live Liver DonationThe use of live donors for liver transplantation was developed in response to the

inadequate donor organ supply. Live liver donation began with left lobe resectionfrom adults for transplantation into babies and small children. More recently, adultto adult transplantation, in which the right lobe of a healthy adult is resected andtransplanted into an adult with severe liver disease, has been adopted by manytransplant programs in North America and Europe. Live liver donation places thehealthy living donor at risk and mandates that a careful selection process be appliedto 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 adultlive liver donation should be offered to patients who demonstrate increased urgencywithout requiring ICU-based life support. Very ill unstable patients (i.e., patientsrequiring ICU based life support) need of a full size graft. The very stable patientwho is not in danger of foreseeable death can wait safely and may get a cadavericorgan. The patients most appropriate for receiving a graft from adult to adult livingliver donation are those who have recovered from an episode of decompensation,

Table 3. Absolute contraindications

Severe (uncontrolled) infection outside the hepatobiliary systemMetastatic cancer (except some neuroendocrine cancers)Extra hepatic cancer (other than local skin cancer)CholangiocarcinomaAdvanced cardiopulmonary diseaseAIDSSevere pulmonary hypertensionTechnical considerations (e.g., widespread intra-abdominal venous thrombosis)

Table 4. Relative contraindications

Recent drug or alcohol abuseAge >70 yearsHIV infection, without AIDSInability to be compliant with immunosuppression protocol and/or participate inroutine post-transplant medical follow-upAdvanced chronic renal diseaseModerate pulmonary hypertension


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

Assessment of Medical, Surgicaland Psychological SuitabilityAll patients must undergo full history and examination. History of vaccination

and need for further vaccination is covered in Chapter 4.

Cardiac AssessmentA 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 beenestablished or agreed. The echocardiogram provides evidence of cardiac functionand an estimate of pulmonary artery pressure (see porto-pulmonary hypertensionbelow).

It is often difficult to interpret ejection fraction (EF) data in patients with end-stage liver failure and ascites. These patients have low systemic vascular resistance,and this lack of ‘afterload’ means that even a cardiomyopathic heart can have anapparently ‘low normal’ EF. No absolute thresholds of EF have achieved consensusfor acceptance as a suitable candidate for liver transplantation. Similarly, there is noconsensus on how to interpret a prior history of coronary artery bypass grafting ormyocardial infarction, but many of these patients may be excluded from livertransplantation.

A history of symptomatic peripheral vascular disease should lead to formalevaluation of peripheral arterial flow. Significant claudication supported by flowdata will usually exclude the patient from transplantation.

Pulmonary Assessment

Clinical EvaluationA 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, whichdeclines when the patient assumes a standing position (orthodeoxyia), suggests hepato-pulmonary syndrome. This requires full pulmonary investigation such as ‘bubbleechocardiography’ to assess vascular shunting.

Patients with symptomatic chronic obstructive pulmonary disease (COPD) orother 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 forsurgery or postoperative recovery.

Patients should be strongly advised to stop smoking cigarettes and other tobaccoproducts whether or not there is manifest lung damage. However, most programsdo not exclude patients who are unable to stop tobacco use.

Porto-Pulmonary HypertensionIdiopathic 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 heartcatheteriztion. Mild to moderate (MPAP <35 mm/Hg) poses no risk fortransplantation. Severe porto-pulmonary hypertension is associated with high intra-and post-operative mortality. The utility of liver transplantation with simultaneouscontinuous administration of prostacycline, or combined liver-lung transplantationin patients with porto-pulmonary hypertension is unknown.

Hepatopulmonary SyndromePortal 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 livertransplantation, although the restoration of arterial partial pressure of oxygen (PaO2) to normal may take months.

Cystic FibrosisThe colonization of the affected lungs by Burkholderia cepacia is an absolute

contraindication.

Renal AssessmentMany patients with acute or chronic liver failure have concomitant impairment

of renal function. The causes of renal failure in patients with serious liver diseaseinclude:

• Established parenchymal kidney injury either related to the cause of liverdisease (such as HCV infection) or independent of it.

• The patient with end-stage liver failure is at risk for acute insults to thekidney 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 contrastmedium

• Hypotension• Hepatorenal failure. This is a complex disorder in which homeostatic

mechanisms in the splanchnic and renal vasculature act together toproduce a ‘pre-renal type’ renal failure in which there isvasoconstriction of the intrarenal arterioles, and avid retention ofsodium from the glomerular fitrate. Treatment is by correction of


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intra-vascular volume contraction (usually with albumin) andoccasionally, 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.

MicroscopyMicroscopy of the urine may reveal nephritic sediment (red cell casts, white cell

casts).

Low Urinary SodiumHepatorenal 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 sodiumretention. This result is confounded by recent exposure to loop diuretics.

Urinary ProteinMany patients with end-stage liver failure have peripheral edema and reduced

serum albumin concentrations. Hypoalbuminemia in cirrhotic patients is oftenattributed to synthetic failure and it is easy to overlook renal protein loss. Diabeticrenal disease or glomerulonephrititis associated with chronic infection with hepatitisB or C are common causes of nephrotic syndrome in ‘liver patients’. Spot urineprotein levels should be checked in all candidates for liver transplantation, and aformal 24-hour collection made in anyone with detectable protein.

Glomerular FiltrationSerum creatinine is a inaccurate indicator of glomerular filtration in cirrhotic

patients, especially those with ascites or malnutrition. Formal measurement ofglomerular filtration rate is appropriate whenever there is concern that the full extentof renal impairment might be masked. An elevated serum creatinine has beenrepeatedly found to be an independent risk factor predicting a worse outcome afterliver transplantation.

There are many causes for lowered graft and patient survival in patients withelevated serum creatinine prior to transplantation suggesting that serum creatinineis acting as a surrogate for many high risk factors.

Combined Liver-Kidney TransplantationThere is controversy about the relative value of isolated orthotopic liver

transplantation in the face of established renal failure, compared with combinedliver 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 advancedintrinsic kidney disease, serious consideration must be given to dual organreplacement.


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Endocrine Assessment

DiabetesMany patients with end-stage liver failure are diabetic or have insulin resistance.

Retrospective analysis suggests that persons with diabetes mellitus requiring insulinor hypoglycemic tablets therapy have a worse outcome after transplantation, as aresult of cardiac, renal or microvascular damage. The value of pancreas transplantationin diabetic patients undergoing liver transplantation is controversial and probablyshould be confined to centers studying combined transplants according to aprospective protocol.

Sexual EndocrinologyMany women capable of menstruation experience amenorrhoea as a result of

end-stage liver failure. Specific investigation of ‘ovarian failure’ is not necessary inthese circumstances. Menstrual periods are restored in 80% of these women withinthree months of successful liver transplantation.

Male impotence is common in end stage liver failure. While liver transplantationmay restore male sexual function, the causes are often multifactorial (especiallydiabetes, and drugs such as anti-hypertensives).

Thyroid DiseaseThyroid disease (hypo- or hyper-thyroidism) is associated with many chronic

liver diseases and thyroid function should be routinely checked in all, and correctedwhere appropriate. In the sick patients, pseudo-hypothyroidism may be present butdoes not require intervention.

Assessment for Primary Hepatic Malignancy

Primary Liver Cell Cancers

Hepatocellular CarcinomaThe development of liver cell cancer is suggested by the development of space-

occupying 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 orMR imaging.

Analysis of the UNOS database up to 1996 shows a five year survival for allpatients 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 ingreatest diameter


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• Few multifocal hepatocellular carcinomas, defined as up to three tumorswhose greatest diameter is no more than 3 cm

• Without evidence of vascular invasion or extrahepatic spreadBiopsy confirmation of a tumor is usually contra-indicated, as it is likely to spread

the tumor along the biopsy track.

Other Primary Liver Cancers‘Slow growing’ tumors such as hepatoblastomas and neuroendocrine tumors are

occasionally considered appropriate for transplantation.

CholangiocarcinomaThere is general agreement that patients with cholangiocarcinoma should not

receive liver transplantation, except within a defined research protocol (see discussionpage 36).

The detection of cholangiocarcinoma is often difficult.

Extrahepatic Malignancy Screening and Those with a PastHistory of CancerA past history of malignancy provides a difficult challenge for the transplant

assessment team to determine how many disease free years are required to reduce thechance of recurrence to an acceptable minimum.

All adult women need gynecologic assessment including ‘Pap’ cervical cytologysmear. Women over 40 years should undergo mammography.

All patients greater than 40 years should be considered for occult colon cancerwith hemoccult testing followed by colonoscopy wherever the screening is positive.Where there is a higher risk, as those with ulcerative colitis, a colonoscopy should bedone. Sigmoidoscopy is inadequate, as there is a high incidence of right sided coloncancers

All men older than 45 years should undergo testing for prostatic specific antigen(PSA).

Assessment for Infection

TBScreening for tuberculosis includes chest radiograph and, in patients at risk,

placement of PPD (purified protein derivative). Candidates who are PPD positivemay be treated with antituberculosis monotherapy (e.g., Isoniazid for 6 months)prior to transplantation or treatment may be postponed until after the transplant.

HIVAll patients should be screened for antibodies to human immunodeficiency virus

(HIV). The role of liver transplantation in HIV-infected patients with end-stageliver failure is controversial.


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Other VirusesAntibodies to Hepatitis A, B and C, cytomegalovirus (CMV), Epstein-Barr vi-

rus (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 CaloriesMany patients with end-stage liver failure are malnourished and malnutrition is

associated with a poor outcome after transplantation. Unfortunately, it is difficult torestore nutritional well being in outpatients with liver failure. Many liver patientsare already on restricted diets: sodium restriction to diminish poorly controlled as-cites, protein restriction to control recurrent hepatic encephalopathy, and fluid re-striction in hyponatremic patients.

Most cirrhotic patients, even those with intermittent hepatic encephalopathy,can tolerate 80 grams of protein per day.

VitaminsPeople 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 DiseasePatients with chronic liver disease may have many reasons for excessive bone

loss: chronic cholestasis, corticosteroids, chronic alcoholism, and postmenopausalstate 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.

NutritionPatients with cirrhosis from any cause tend to be malnourished. Malnutrition is

associated with a poor outcome after liver transplantation. Reasons for malnutritioninclude:

• 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 perday. The risk of hepatic encephalopathy from dietary protein has beenoverstated.

• Malabsorption• Associated pancreatitis• Associated celiac sprue (associated with autoimmune hepatitis and PBC)

Where there is evidence of malnutrition, candidates for transplantation shouldhave 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 nutritionalsupplements.

Obese patients are at greater risk of morbidity and mortality after transplantationand therefore should be advised to lose weight.

Surgical AssessmentThere 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 mesentericvein may preclude transplantation. Careful radiological assessment is mandatory inthese patients. Angiography remains the gold standard, but in many instances,magnetic resonance (MR) scanning with gadolinium angiography has largely replacedformal angiography, avoiding intravenous contrast in patients with marginal renalfunction.

Psychological AssessmentAll patients should be assessed for any psychological factors that might affect the

survival and quality of life after transplantation. The transplant evaluating teammust seek the opinion of psychiatric experts to assess prognosis of the psychiatricdisorder. The psychological assessment may be confounded by hepaticencephalopathy. Patients with a combination of end stage liver failure, hepaticencephalopathy and a history of significant psychiatric disorder present some of themost difficult dilemmas which come before the transplant evaluating team.

Assessment for Patients with Alcoholic Liver Diseaseand a History of Drug AddictionMore 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 thecandidate will remain abstinent from addictive substances both before and aftertransplant and will comply with all aspects of follow-up.

Although it remains controversial as an indicator of future abstinence, the greatmajority of liver transplant programs in North America and Europe either requireor place a value on a period of abstinence in determining whether to place an alco-holic patient on the waiting list. Many programs will use an approach that alsoassesses the patient’s acceptance of alcoholism, their social support to remain absti-nent, and their use of behavior modifying programs such Alcoholics Anonymous.Whether such assessments distinguish accurately future drinkers from abstainersremains in doubt.

Many programs insist that the alcoholic or addicted candidate participate inaddiction therapy as a prerequisite to either placement on the transplant list, or toreception of a donor liver. The degree of physical impairment due to liver failuredictates 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 toalcohol use while waiting for transplantation. Many centers will ‘recycle’ the patientthough alcoholism assessment and reconsider replacement on the list after achievinga certain period of sobriety. This period is usually set arbitrarily at 6 months.

It remains uncertain whether the presence of a major psychotic disorder (bipolardisease, 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 almostalways resolves.

FHF is defined as the development of acute hepatic encephalopathy (see Table5) within 8 weeks of the onset of symptomatic hepatocellular disease in a previouslyhealthy person.

Sub-acute hepatic failure is also termed submassive hepatic necrosis, subfulminanthepatic failure, subacute hepatic failure and late-onset hepatic failure. It is definedby the development of acute hepatic encephalopathy within 9 to 26 weeks of theonset of symptomatic hepatocellular disease in a previously healthy person. It ischaracterized by a slow and fluctuating illness, with usually mild encephalopathyand progressive ascites. Unlike FHF, the INR is rarely more than 3.0. These patientsusually die unless they are transplanted.

Cerebral edema, leading to increased intracranial pressure (ICP), is a commonfeature of severe fulminant hepatic failure and may cause permanent cerebral injuryand death. The onset of cerebral edema may occur during surgery and in the first 48hours post-transplantation. Fulminant hepatic failure and submassive hepatic necrosisare always accompanied by severe coagulopathy.

The causes of fulminant hepatic failure are shown in Table 6.


3

Acetaminophen toxicity is the most common cause of acute liver injury andfulminant hepatic failure in Great Britain. Alcoholics, those on enzyme inducingdrugs and those who are malnourished, are at particular risk of acetaminophen-induced hepatic failure. Acetaminophen-induced liver injury in alcoholics is themost common cause of fulminant hepatic failure in the US.

Acute viral hepatitis is an important cause of both fulminant and subfulminantfailure.

In many cases, the cause of FHF is not clear and there are no serological clues asto the diagnosis. These patients are often classified as non-A non-B non C hepatitisbut a more accurate term is sero-negative hepatitis as there is usually no evidence fora viral cause

The causes of subfulminant hepatic failure are similar to those for FHF, once thecauses of the most acute forms of acute hepatic injury such as acetaminophen-inducedliver 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, wherevenous outflow obstruction has been excluded by imaging, a liver biopsy should beconsidered.

Table 5. Clinical grades of acute hepatic encephalopathy

Grade Mental State Asterixis ElectroencephalogramFindings

I. Altered affect, subtle loss Slight or none Normalof mental acuity, slurredspeech

II. Accentuation of stage I, Easily elicited Abnormal, generalizeddrowsiness, Inappropriate slowingbehavior, loss of sphinctercontrol

III. Sleepy but rousable, Present when Always abnormalmarked confusion, can patient cananswer simple cooperatequestions only

IV. Coma Cannot Always abnormalcooperate

IVa. Responds to pain IVb. No response to pain


3

Table 6. Causes of fulminant hepatic failure and subfulminant hepatic failure

Viral InfectionHepatitis AHepatitis BHepatitis B and DHepatitis COther viruses (less common)

Herpes (in immunosuppressed persons, including pregnant women)CytomegalovirusEpstein-BarrVaricellaAdenovirus

Poisons, Chemicals and Drugs(Note: assume that ANY drug, herbal remedy or toxin may be associated with liverdamage)

Amanita phalloidesAcetaminophen (paracetamol)Halogenated volatile anesthetics (especially halothane)Isoniazid and other anti-TB medicationValproateMonoamine oxidase inhibitorsEcstasy

Ischemia and HypoxiaHepatic vascular occlusionAcute circulatory strokeHeat strokeGram-negative sepsisMiscellaneousAcute fatty liver of pregnancyReyes syndromeWilson’s disease*Hodgkin’s disease and other lymphomasMalignant infiltrationHereditary fructose intoleranceGalactosemia, tyrosinemiaIdiopathic hepatitis (also called non-A to non-E)

*strictly not FHF as almost all patients have established cirrhosis at the time ofpresentation

Predicting Outcome in Fulminant hepatic failureand Subacute hepatic necrosisIn general, the deeper the coma, the worse the outcome. Paradoxically, rapid

onset of encephalopathy is a favorable prognostic sign, whereas delay in the onset ofencephalopathy after the onset of jaundice indicates a lack of spontaneous recoveryand is unfavorable prognostic factor. Consequently, most acetaminophen-inducedfulminant hepatic failure patients who experience grade III coma recoverspontaneously, while submassive hepatic necrosis has a particularly poor outcome.


3

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

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

Acetaminophen Toxicity:pH <7.3 (irrespective of grade of encephalopathy)orProthrombin 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)orAny 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 prothrombintime thresholds have been reduced for application in the US due to differences inlaboratory 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. Drug-induced hepatic failure, other than that caused by acetaminophen, has a poorprognosis. Examples include hepatic failure due to phenytoin or halothane. HBV-and HAV-induced hepatic failure have a better outcome than idiopathic (presumedviral) fulminant hepatic failure. Patients younger than 2 years or older than 40 yearshave a poor prognosis. Renal failure is also a poor prognostic factor. Some haverecommended 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 valuableprognostic 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 maketransplantation impossible. For this reason, human heterotopic auxiliary transplants,live donor segmental liver transplantation, extracorporeal perfusion through humanor pig livers or artificial hepatocyte perfusion devices, and xenografts have beenattempted to sustain the patient until spontaneous recovery develops or a suitableorgan is found.


3

Chronic Hepatitis CThe problem of chronic hepatitis C relates to the recurrence after transplantation.

Strategies to reduce HCV RNA are currently being evaluated. This is discussed inChapter 8.

Hepatitis B InfectionHBV: Markers for active viral replication such as HBeAg and HBV DNA used

to be considered relative contraindications to liver transplantation. The advent ofanti-viral agents including lamivudine and postoperative management protocols usingHBIg has allowed successful transplantation in high-risk patients. Patients who havecirculating HBV DNA should receive treatment with lamivudine while awaitingtransplantation. Antibodies to hepatitis D should be measured in HBsAg positivepatients. Co-infection by hepatitis D ameliorates the severity of post-transplanthepatitis B infection. Management of HBV after transplantation is discussed inChapter 8.

HemochromatosisPatients with hemochromatosis have a worse outcome after liver transplantation

than patients with other diagnoses. Some of this effect is due to failure to recognizehemochromatosis during the pre-transplant evaluation. All candidates should haveserum iron, transferrin and transferrin saturation, and ferritin estimated. We recom-mend the measurement of the hemochromatosis gene test (HFE) in anyone withiron saturation in excess of 45% or in anyone with a suggestive history forhemochromatosis (personal or family history of diabetes, cirrhosis, and arthritis).HFE is positive as a homozygous test for the major allele (C282Y) or heterozygousfor both the major and minor allele (H62D) in 80% or more of affected personsdepending on the ethnic diversity of the population in question. Diabetic candidatesfor liver transplantation need particularly careful cardiac assessment.

Primary Sclerosing Cholangitis

Colitis and Colon CancerThose with PSC and inflammatory bowel disease (IBD) have a greater risk of

both cholangiocarcinoma and colon cancer than patients with IBD alone. Since thecolon cancer is likely to develop in the right colon, all patients should have acolonoscopy to assess the presence and degree of colitis as well as exclude coloncancer. Colectomy at the time of transplantation does not seem to add to the risks ofthe procedure.

CholangiocarcinomaBecause the tumor spreads early along the lymphatics and nerves, the detection

of cholangiocarcinoma is a contraindication for transplantation. Exclusion ofcholangiocarcinoma is difficult as the tumors are often not visualized on imaging,whether by ultrasound, CT, MR or PET scanning. Bile cytology, while specific, isnot sensitive and ERCP is associated with a risk of inducing severe cholangitis and/


3

or pancreatitis. Serum markers, such as CEA and CA19-9 may help but have notthe specificity nor sensitivity required.

Non-Alcoholic Fatty LiverNon-alcoholic steatohepatitis (NASH) and it’s variant non-alcoholic fatty liver

disorder (NAFLD) are terms used to describe an idiopathic clinico-pathologicalspectrum of disorders characterized by macrovesicular and microvesicular depositionwithin hepatocytes. NASH is associated with histologic appearances of inflammationin the hepatic lobule often with Mallory’s hyaline, in the absence of alcoholconsumption. NASH occurs in conjunction with insulin resistance, obesity, andhyperlipidemia, 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 importantcause of cryptogenic cirrhosis. Some patients with cryptogenic cirrhosis thought tobe due to NASH progress to liver failure and are candidates for liver transplantation.

Celiac SprueBecause 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 forceliac disease by measurement of serum anti-endomysial antibodies. When positive,a duodenal biopsy is mandatory.

Retransplantation

Early RetransplantationEarly retransplantation (usually defined as within the first 30 days) is required

for primary allograft non-function, hepatic artery thrombosis and massivehemorrhagic necrosis. Such patients behave like those with fulminant hepatic failure,and require emergency placement on the waiting list.

Late RetransplantationLate retransplantation is required for management of graft failure due to recurrent

disease, vascular or biliary problems, or chronic ductopenic rejection. Survival is lessthan that observed for primary graft recipients. Retransplantation on account ofrecurrent viral hepatitis has a poor outcome due to aggressive recurrence of theunderlying disorder. Further attempts at rescue with second, third or fourth graftsare associated with progressively poorer outcomes in mortality and morbidity.

Suggested Reading1. Krowka MJ. Hepatopulmonary syndromes. Gut 2000; 46:1-4.2. Lee WM. Management of acute liver failure. Seminars in Liver Disease 1996;

16:369-378.3. Cardenas A, Uriz J, Gines P, Arroyo V. Hepatorenal syndrome. Liver Trans 2000;

6:S63-571.4. 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.


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5. Trotter J F, Wachs M, Everson GT, Kam I. Adult-to-Adult transplantation of theright hepatic lobe from a living donor. N Engl J Med 2002; 346:1074-1082.

6. 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.


4


CHAPTER 4

Management on the Liver TransplantWaiting List

James Neuberger

IntroductionWhilst 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 DiseaseThe patient awaiting liver transplantation, like any other patient with end-stage

cirrhosis, is at risk of complications which may affect survival or the successfuloutcome after transplantation (Table 1).

Variceal HemorrhageIn portal hypertension due to cirrhosis, the threshold of portal hypertension

necessary for variceal hemorrhage is a transinusoidal gradient (portal pressure lessinferior vena caval pressure) of 12 mm Hg. The likelihood of a variceal hemorrhageis 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 reducedby pharmacological or physical means. Prophylaxis is indicated in those patientswith 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

37Management on the Liver Transplant Waiting List

4

overestimate the decline in pressure.• reduction in measured portal pressure to either less than 12 mm Hg or

25-50% below the initial portal pressureAbout 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 an-

tagonists 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 tocause esophageal ulceration or peri-esophageal abscess in the post-opera-tive period. TIPS is effective in reducing portal pressure and preventingvariceal hemorrhage. However, there are potential problems:• The presence of the stent may complicate transplant surgery• Stent thrombosis and narrowing may occur. The benefits oflong- term anticoagulation as a means of preventing stentocclusion are uncertain• TIPS is associated with deterioration in hepatic function when

attempted in patients with severely compromisedhepatic function (elevated serum bilirubin, renal failure ormarked coagulopathy)

Spontaneous Bacterial PeritonitisPatients with ascites, which results from portal hypertension, are at risk of spon-

taneous 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 probabilityof developing SBP from Gram negative organisms but has no impact on the rarerinstances of SBP from Gram positive organisms. Furthermore, prophylaxis has notbeen shown to affect mortality among patients with a history of SBP or who have

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


4

‘high-risk’ indicators for a first episode. There are many regimens for prophylaxisagainst 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 BalancePatients with end-stage liver failure are at risk of renal failure, occurring

spontaneously (hepatorenal failure) or due to iatrogenic intervention. Patients withascites are at greatest risk, because the factors leading to ascites development (portalhypertension, splanchnic vasodilation, and peripheral vasodilatation) are also thefactors promoting renal impairment through the development of intrarenalvasoconstriction and renal sodium retention.

Renal function should be monitored carefully and any episode of renal impairmentshould 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 concentrationis less than 120 mmol/L, there is a high risk of central pontine myelinolysis duringor soon after liver transplantation. Treatment of hyponatremia includes withdrawalof diuretics, restriction of water intake, and in rare cases dialysis. Many programswill 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 HCCIn 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. Featuresindicating 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


4

recognized as clot formation and a presumption drawn that the clot ismalignant.

The serum alpha feto protein (AFP) level is a poor guide to the size of the cancerbut the rate of rise is a reasonable guide to the rate of growth. The frequency ofrepeat imaging of the tumor will depend on the size and location of the tumor: forexample, a large tumor close to the margin of the liver will require more frequentmonitoring than a small 1 cm tumor in the right lobe. As an approximate guide, wesuggest 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 establishedguidelines regarding the best screening protocol for at-risk patients.

• Serum AFP measurement: There are many causes of an elevated serumAFP. Elevations of serum AFP, often in the range of 100-500 ng/ml areparticularly 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 appropriatefor cirrhotic patients awaiting liver transplantation.

• Imaging of the abdomen (sonography or CT scanning) should be doneevery 6 months whilst awaiting a liver transplant.

CholangiocarcinomaIn general, the known presence of cholangiocarcinoma is a contra-indication for

liver transplantation. However, such cancers are very difficult to detect using eitherserological 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 serologicalor imaging is of value although the development of progressively dilated bile ductsmay herald the onset of a cholangiocarcinoma.

Other CancersPatients awaiting liver transplantation are susceptible to the development of extra-

hepatic malignancy. It remains uncertain whether the presence of cirrhosis or whichof the diseases predisposing to cirrhosis are associated with a greater probability ofdeveloping cancer. The most common extrahepatic cancers to bear in mind arecolon cancer in patients with ulcerative colitis. These patients should have fullcolonoscopy every year while awaiting liver transplantation.

Annual mammography and cervical screening (‘Pap smears’) should be main-tained in women of 40 years or more who are awaiting transplantation. Annual


4

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

VaccinationsMost candidates for liver transplantation will have been vaccinated against or

exposed to many of the viral pathogens which might prove harmful after livertransplantation. It is appropriate therefore to assess the immunity to potential viralpathogens as part of the transplant evaluation. Serologic markers to CMV, EBV,

Table 2. Immunizations in adults awaiting liver transplantation

Vaccine Type of Vaccine Dose Regimen Comment

Tetanus-diphtheria Toxoid vaccine 3 doses in naïve Persistent immunitypatients at 0, 4 up to 10 yearsweeks and 6-12months

Poliomyelitis Trivalent Naïve: 3 doses at Booster everyinactivated whole 0, 4 weeks and 10 yearsvirus vaccine (IPV) 6-12 months

Influenza Trivalent split or One dose. Annual boostersubunit vaccine prior to ‘flu season’

Hepatitis B Recombinant or 3 doses at 0, 4 Monitor anti-HBs;plasma-derived weeks and 6 if <10 IU/L repeatsubunit vaccine months booster dose

Hepatitis A Inactivated whole- 2 doses, at 0 and Persistent immunityvirus vaccine 3-6 months up to 10 years.

Pneumococcus 23-valent One dose. Persistent immunitypolysaccharide up to 6 yearsvaccine

H influenzae type b Polysaccharide One dose Completeconjugate vaccine immunization > 6

weeks prior to Tpx

Varicella Live-attenuated 2 doses 6 weeks Completevaccine apart immunization 4

weeks prior to Tpx

Mumps-measles- Live-attenuated One dose Complete rubellarubella (MMR) vaccine immunization 4

weeks prior to Tpx

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


4

HSV, varicella, HBV, HCV and HAV are checked as a routine measure. Patientswithout 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

HypertensionPatients 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 MellitusPatients with established diabetes mellitus will need careful monitoring to ensure

that the blood sugar is within acceptable limits; when normoglycemia cannot bemaintained by dietary methods or with oral hypoglycemic agents, then insulin shouldbe instituted.

Alcoholism and Other AddictionsAlcohol addicted persons should have their alcohol use monitoring whilst awaiting

transplantation. This can be achieved by asking the patient and their family aboutdrinking relapses and by random checks of blood and urine screens. Smokingcessation: patients are advised to stop smoking, and formal smoking cessationprograms are worth attempting.

Temporary Suspension from the Waiting ListPatients may be suspended from the waiting list for several reasons and returned

to the active list when the temporary problem is resolved. Temporary events leadingto suspension from the list include:

• Intercurrent infections• Variceal bleeding• Alcohol use by alcoholics

Suggested Reading1. Runyon BA. Management of adult patients with ascites caused by cirrhosis.

Hepatology 1998; 27:264-272.2. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F et al. Liver

transplantation for the treatment of small hepatocellular carcinomas in patientswith cirrhosis New Eng J Med 1996; 334:693-699.

3. Schafer DF, Sorrell MF. Hepatocellular carcinoma. Lancet 1999; 353:1253-1257.4. Sharara AI, Rockey DC. Gastroesophageal variceal hemorrhage. New Eng J Med

2001; 345:669-681.5. Stark K, Gunther M, Schonfeld, Tullius SG, Bienzle U. Immunizations in solid-

organ transplant recipients. Lancet 2002; 359:957-959.


5


CHAPTER 5

The Liver Transplant Operation

Michael Crawford and Abraham Shaked

Cadaveric Donors

Donor SelectionThe cadaveric liver transplant begins with a donor offer from an Organ

Procurement Organization (OPO) coordinator. The information in Table 1 shouldbe 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 sometimesonly be determined intra-operatively or with a liver biopsy.

Pre-Op Donor ManagementThe patients’ team carries out the pre-operative management of a potential donor.

Once a donor has been identified and consent obtained, a transplant coordinator isfrequently on site to give advice about management. Brain dead patients may undergosevere physiologic disturbances due to events such as Cushings’ response and diabetesinsipidus. These place the donor organs at risk and should be diagnosed early andtreated aggressively. Table 3 shows some of the common syndromes encountered indonors, and their management until procurement can be arranged.

The Cadaveric Donor OperationThe patient is positioned supine on the table, muscle relaxation given, gastric

tube placed, and prepped from neck to groins. An incision is made from sternalnotch to symphysis pubis. The round ligament is divided and falciform ligamenttaken down towards suprahepatic inferior vena cava (IVC). A median sternotomy isperformed and retractors are placed. (see Fig. 1)

The falciform dissection is continued to the IVC, the left triangular ligament istaken down. The gastrohepatic ligament is incised; any accessory or replaced lefthepatic artery is identified and preserved.

A full mobilization of the right colon and small intestine is performed beginningat 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 mesentericartery limits this dissection.

The infrahepatic IVC is thus exposed and the upper border of the renal veins aredefined as they enter it.

43The Liver Transplant Operation

5

Table 1. Donor information

ABODonor age and sexDonor size (height and weight)Cause of deathTime in hospitalHospital course, including history of arrest, and stability of blood pressure and requirement of inotropesPulmonary statusResults of virus screening for hepatitis, HIV etc.Pertinent past medical history (tumors, infections etc.)Previous surgical historyPrevious drug and alcohol historyResults of electrolytes and liver function studiesResults of relevant pre-operative imaging

Table 2. Donor definitions

Extended Criteria Livers which are less than perfect due to previousdonor history or current condition of donor

Brain Dead or Heart-Beating Heart still beating, brain deathDonors declared by clinical or investigational findings

Non-heart beating donors Fail brain death criteria, procurement occurs aftercardiac 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, Maintenance of good perfusion tolevo-thyroxine, donor organsEpinephrine

Hypertension Beta blockers or other Prevent acute hypertensive injury toanti-hypertensives donor organ.

Hypoxia Diuresis and oxygen Maintain adequate oxygenation ofdelivery donor organs

Diabetes Dextrose replacement Avoid hypernatremiainsipidusAcidosis Bicarbonate replacement Avoid end organ acidosisSevere Urgent procurement Minimize time of organ injuryinstability


5

The ligament of Treitz is taken down and the inferior mesenteric vein (IMV) isexposed and isolated. The aorta is then dissected just above its bifurcation, umbilicaltapes are placed around it for control later.

The bowel is returned and the common bile duct (CBD) is dissected just abovethe duodenum in the hepatoduodenal ligament. It is ligated distally and incisedabove the tie. The gallbladder is incised and emptied, then flushed with normalsaline 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 ligatedand the proximal aorta incised and cannulated with a large bore infusion catheter.

The inferior vena cava is exposed within the pericardium. The right pleura isopened to allow blood to pool in the right chest.

In a coordinated fashion, the IVC (or right atrium) is cut, the supraceliac aorta isclamped 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 ofthe IVC away from the liver. Infusion of preservation solution continues until theeffluent from the IVC is clear (usually around 4-5L total).

The IVC is completely transected in the chest and the posterior pericardium isopened from side to side exposing the esophagus and thoracic aorta.

Figure 1. Donor setup.


5

The diaphragm is divided sagitally in front of the esophagus well to the left ofthe suprahepatic IVC. The right diaphragm is then divided, well lateral to the rightcoronary ligament, and continued towards the infrahepatic IVC.

The IVC is transected above the renal veins and a suction catheter placed at thispoint.

The CBD is completely transected and the peritoneum above the duodenum isincised to allow the duodenum to peel downwards. The right gastric artery is ligatedand divided. The gastroduodenal artery (GDA) is exposed and followed to its originfrom 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 lymphaticand nervous tissue that overlies it here. The coronary vein will be seen and can bedivided. It usually lies over the origin of the splenic artery, which can be dissectedfor 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 crusof the diaphragm. The supraceliac aorta is transected at the level of the clamp andthe aorta just to the left of the celiac incised and continued superiorly to the point oftransection.

The duodenum is now further mobilized away from the porta hepatis. And thetissue lateral to the portal vein is dissected toward the portal vein (PV) taking care tolook for a replaced right hepatic artery. With the anterior surface of the vein exposed,

Figure 2. Donor porta-hepatis.


5

the pancreas is split at the neck to expose the portal vein origin. The superior mesen-teric and splenic veins are then transected. The portal vein segment is passed be-neath the duodenum to lie with the other hepatic structures. If there is no replacedright hepatic artery, the nerves and lymphatic tissue lying behind the portal vein aredivided all the way to the aorta between the celiac and SMA. If there is a replacedright 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 otherportal structures.

Cutting across the right adrenal gland and dividing the hepato-pulmonaryligament completes the donor hepatectomy. The liver is surrounded by Universityof 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 solutionsurrounded by ice. The coronary ligaments are first taken down exposing thesuprahepatic IVC. The diaphragm is carefully dissected off the IVC, ligating anyphrenic veins. The infrahepatic cava is dissected free, after dividing the diaphragmbetween the aorta and IVC. The right adrenal vein and any other external branchesare ligated and the adrenal gland removed.

The portal vein is dissected towards the liver with ligation of any small branchesalong its course until the bifurcation is seen. The PV is then cannulated withintravenous tubing, secured and tested for leaks.

The artery is then dissected in segments from aorta towards splenic, and thensplenic 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 theliver is covered by UW solution until required for implant.

Extended Criteria DonorsExtended 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 toexpand the donor pool. They should be carefully matched with appropriate recipients.

The cold ischemic time for extended criteria donors should be kept to a minimumso that the risk of primary non-function in the recipient is reduced. Extended criteriadonor 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 DonorsThis 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 ‘braindeath.’ The donor is brought to the operating room and prepped and draped.Perfusion lines are primed with University of Wisconsin Solution. Heparin (300unit/kg) and intravenous hydrocortisone 1000 mg are administered, and then ‘lifesupport’ is withdrawn. A physician from the donors’ treating team pronounces thepatient deceased according to clinical or electrical evidence. (If pronouncement doesnot occur within 1 hour after withdrawal of life support, then the procurement isabandoned and the donor is returned to the intensive care unit.) Following the


5declaration of death, a mandatory wait period, determined by local policy (usuallyaround five minutes), is allowed to elapse before the surgery begins.

The objective in this operation is for rapid perfusion of the organs with preserva-tion solution and cooling. A midline laparotomy and sternotomy is performed, theaorta is cannulated just above the bifurcation, and cold perfusion begun. The rightatrium is opened for venting, and the thoracic aorta is clamped. The abdomen isfilled 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 relevantorgans) is expeditiously removed. The bile duct is flushed on the back table.

Critical judgment is required if the time between discontinuation of life supportand death is prolonged, as these organs suffer from significant warm ischemia whichcan be manifest as primary non-function, acute cellular rejection or biliary strictureformation in the recipient.

Split Liver GraftsThe 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 tothe umbilical fissure. The left portal vein is now dissected and small caudate branchesof the portal vein are ligated and divided.

The liver bridge between segment VI and III is divided (if present) where itcrosses the umbilical fissure. This exposes the fissure with multiple small portal veinbranches that cross between the umbilical vein and segment IV here. These areligated and divided. After division of these branches, the left hepatic duct is identi-fied lying above the artery and divided. (see Fig. 3)

The left hepatic vein is dissected free of the middle hepatic vein over a shortdistance.

Parenchymal dissection can now begin just to the right of the falciform liga-ment. This is best done using electrocautery with ligation of any major structurescrossing between the left lateral segment and segment IV.

This dissection is continued until the entire left segment is freed and the caudatelobe is exposed near the insertion of the gastrohepatic ligament.

Table 4. Extended criteria donors

Age >70 yearsProlonged pre-mortal hospital stayHemodynamic instability or requirement for large doses of inotropesPre-mortal cardiac arrestAlcohol or drug dependencyElevated liver function tests or serum sodiumFatty liverHepatitis infected liverHistory of malignancyNon-heart beating donor


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

The Recipient OperationThe 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 catheterare generally used for intra-operative management and fluid replacement. Ifpercutaneous bypass is to be used, then the right internal jugular vein is cannulatedwith the large bore cannula at this time.

A nasogastric tube and a Foley catheter are placed and a warming blanket ordevice is set up. The patient is prepped and draped from neck to groins leavingparticularly the left groin exposed for cannulation for bypass.

A bilateral subcostal incision with a midline upper extension is made, the roundligament is divided, and the falciform ligament is taken down towards the suprahepatic IVC.

Subcostal retractors are placed and the dissection continues until the right andleft hepatic veins are exposed. The left triangular ligament is taken down and the left

Figure 3. Split donor technique.


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lateral segment retracted medially. The gastrohepatic ligament is incised and contin-ued cephalad, ligating any vessels crossing it.

Attention is turned to the porta hepatis, any adhesions are taken down and infe-rior retractors are placed. The peritoneum is scored level with the lower border ofthe caudate lobe. The cystic duct and artery are ligated and divided freeing the right

Figure 4. Incision.

Figure 5. Recipient portahepatis.


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edge of the hepatoduodenal ligament. The dissection is deepened stepwise until thehepatic arteries and common bile duct (CBD) are exposed. These are ligated anddivided.

Dissection continues through the neural and lymphatic tissue until the portalvein 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 hepato-duodenal ligament tissue can be divided. (see Fig. 5)

The left femoral vein is now cannulated using Seldinger technique and securedin place. Air in the lines is expelled and the patient is placed on systemic venousbypass.

The portal vein is isolated with umbilical tape and a ‘snugger.’ The assistantcontrols the vessel with a large Debakey forceps. The distal portal vein is ligated nearits bifurcation, and incised just below this.

The bypass cannula is inserted to the level of the portal vein origin and securedwith the umbilical tape snugger. The snugger is secured to the bypass tubing withfurther tape, and the portal vein transection is completed. The portal system is addedto the circuit placing the patient on portal venous bypass. (see Fig. 6) The dissectionof the infrahepatic IVC is begun by scoring the overlying peritoneum and extend-ing this line along the left side of the IVC up to the level of the phrenic vein, whileretracting the liver and caudate lobe to the right so that the posterior aspect can befreed.

Figure 6. Recipient setup with bypass lines.


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The right triangular and coronary ligaments are taken down with the liver re-tracted to the left, exposing the right posterior aspect of the IVC. The right adrenalvein is ligated and divided. The infrahepatic IVC is clamped below the level of theright adrenal vein stump. The suprahepatic IVC is clamped in a manner to ensurethat a good posterior length is available.

The liver is dissected off the IVC inferiorly ligating any caudate tributaries untila suitable length for anastamosis has been obtained. The infrahepatic IVC istransected. The hepatic veins are the transected and the suprahepatic IVC is transectedbelow the hepatics.

The liver is removed and careful hemostasis is obtained. The diaphragmatic peri-toneum corresponding to the bare area of the liver can be oversewn if desired forhemostasis.

The supra hepatic IVC is prepared for anastamosis by dividing the caval bridgebetween the middle and left hepatic veins and the dividing between this and theIVC. The bridge between the right hepatic vein and IVC is likewise divided. TheIVC is the checked at both ends for holes or tributaries. There are usually one or twophrenic veins which require over-sewing (knots tied on the outside.)

The donor liver is delivered to the table and re-checked for IVC integrity. Theposterior wall of the suprahepatic caval anastamosis is completed from the ‘inside’running from patients’ left to right, using an everting or ‘lipping’ technique. The

Figure 7. Caval anastomosis.


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same suture is continued along the front wall around half way from right to left andthen the remaining front wall is sutured from left to right and tied to the originalsuture. (see Fig. 7)

The cannula in the donor portal vein is flushed with 700-1000 cc of cold Ringer’slactate solution while surgical attention is turned to the infrahepatic IVC. Thisanastamosis is performed as described for the suprahepatic above.

The portal bypass line is clamped and the cannula removed from the recipientportal vein with a clamp placed.

The donor portal vein is measured up for length with the recipient vein. Theanastamosis is performed in the manner described for the IVC except 5 or 6/0 prolenesare 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 of30-50% the diameter of the portal vein is used for the final tie. This slack is taken upby expansion of the vein upon reperfusion.

Figure 8. Vascular anastamosis.


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The liver is now ready for reperfusion. The suprahepatic caval clamp is firstremoved and the suprahepatic anastamosis and cava is checked for leaks. The infra-hepatic clamp is released with warning given to the anesthesia team. When theanesthesia team are ready, the portal clamp is released and the liver reperfused. Thefemoral vein cannula can be clamped and removed once the patient is hemody-namically stable.

The recipient hepatic artery is dissected toward the celiac, beyond the level ofthe GDA where it is clamped. The GDA is ligated distally and divided well awayfrom the hepatic artery. A branch patch is created using the distal hepatic artery andGDA. The lumen can be gently dilated using a mosquito forceps. The anastomosisis 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 asystematic manner for hemostasis.

The donor gallbladder is dissected fundus down until it is suspended by thecystic 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. Therecipient 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 drainsare placed: 1) along the right border of IVC to suprahepatic caval area; 2) abuttingthe porta hepatis and bile duct anastamotic area; and 3) along the left side of theIVC to the suprahepatic area. The wound is closed in a careful manner to preventascitic leak and hernias.

Figure 9. Bile duct.


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Special Operative Problems

Previous Operation(s)The re-operative abdomen presents special operative challenges to the liver

transplant surgeon. Adhesions, formed after previous surgery, are generally denseand have large venous collaterals running through them.

The incision remains the same with special care when entering the abdomen, soas not to damage bowel stuck to previous incisions. The incision is gradually deepenedand continued into the peritoneal space using careful electrocautery dissection toseparate the abdominal contents from the wound. The round ligament is divided.

The liver surface is sought and abdominal contents are dissected down and offthe anterior surface of the liver. Once the incision edges and anterior surface of theliver are clear, subcostal retractors are placed. The left lobe of the liver should bemobilized in the normal fashion and the gastrohepatic ligament divided. This helpsdefine the left edge of the porta hepatis.

The key to this surgery is to start the dissection toward the porta hepatis fromthe 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 argonbeam coagulator is invaluable in this surgery for drying up the bleeding liver surface.Coming across the gallbladder fossa following prior cholecystectomy is usually difficultbecause the duodenum may be firmly adhered in this region. When dissecting fromthe right, the plane of dissection continues across the gallbladder fossa and thenshould leave the liver surface and continue between the porta hepatis and the falciformligament.

The duodenum and other adhesive elements are gently dissected down off theporta hepatis. From either side the epiploic foramen can be gently probed digitallyand reconstituted.

The remainder of the operation is as for the naïve abdomen except that care istaken to ensure hemostasis of all the previously adhered abdominal contents.

RetransplantationThe retransplant of the liver begins as described above for previous surgery. The

operation is essentially as for the primary graft except for the following potentialdeviations.

In the dissection of the porta hepatis; the hepatic artery from the previoustransplant is likely to be folded and redundant and is found to lie more superficialthan expected. Great care is taken when dissecting the portal vein to avoid closedissection of the previous anastamosis, lest it be inadvertently disrupted until proxi-mal control is gained.

The native suprahepatic IVC may be significantly shortened and weakened bythe previous anastamosis here, and if an attempt were made to replace the cava, asdescribed above, there can be significant risk for loss of integrity of the suprahepaticanastamosis. Therefore many surgeons elect to sew in the new liver with a ‘piggyback’ (end to side) technique. This of course preserves the first graft IVC.


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The arterial anastomosis should be made more proximally than the original andmay necessitate using a splenic artery branch patch. The portal venous anastomosisis rarely a concern, since the original anastomosis can be preserved if needed forextra length. The bile duct reconstruction frequently requires a Roux-en-Y hepatico-jejunostomy.

Portal vein ThrombosisPortal vein thrombosis leads to larger and higher pressure collateral vessels, and

extra care is required during the initial dissection. Most portal vein thromboses arepartial and can either be ignored or removed.

The technique for thrombectomy is as follows: The portal vein is controlledproximally by the assistant with a large forceps and ligated near the bifurcation. Alongitudinal incision is made in the anterior wall. 5/0 prolene stay sutures are placedon either side. A plane is developed between the vein wall and the thrombus using acarotid dissector. The distal end of the thrombus is grasped and delivered out of thevein. Gentle upwards traction is placed on the thrombus while the portal vein wall ispeeled off it proximally. (see Fig. 10) The controlling forcep will need to be releasedbriefly to deliver the proximal thrombus (which usually extends at least to the portalvein origin). Now a large Fogarty balloon catheter is passed proximally to sweep theportal vein of any further, loosely adherent thrombus. The portal vein is opened andflushed to determine flow and bypass proceeds in the usual manner.

In the unusual circumstance that the portal vein is completely thrombosed andcannot be cleared using the method above or if the flow is poor, a jump graft usingdonor iliac vein to superior mesenteric vein may be required.

Figure 10. Portal thrombectomy.


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Previous TIPS ProcedureA perfectly placed TIPS (Trans-jugular intra-hepatic porto-systemic shunt) is

intrahepatic in its course and does not present any particular problem. However, theTIPS 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 recipientbelow the shunt. If this cannot be done then a jump graft to the SMV may berequired.

Table 5. Selection criteria for right lobe donors

Test Ideal Exclude

Phase 1 Age Young adult <18, >50 y oldOver the History No significant Significantphone & illnesses or morbidities, previousLocal doctor previous cholecystectomy is a

abdominal surgery relative contra-indicationBlood group ABO identical ABO incompatibleLiver function tests Normal AbnormalBUN Creatinine Normal Significantly abnormal

renal function

Meet with transplant surgeon and briefing of procedures, risks, and benefits

Phase 2 Imaging No pathology Pathology identified inTransplant (Volumetric MRI identified. Suitable liver, steatosis,Center or CT scan) volume for donor segment <0.8% of

donation (donated body weight of recipient,segment >1% of remnant <0.7% ofweight of donor weight.recipient). Nosteatosis.

Further labs HIV, Hepatitis Positive HIV or hepatitisvirology negative serology

Psychosocial Stable with good Drug or alcoholevaluation social supports dependency, no social

support. Marginal ifsignificant psychiatrichistory.

Phase 3 Liver Biopsy Normal liver Fibrosis, hepatitis,Transplant (center variability significant steatosis >10%Center on its use)

Celiac and Normal anatomy, Accessory right hepaticSuperior or replaced left from SMA in the presentmesenteric hepatic artery, of normal right.angiography and completelyportal venography replaced right

hepatic arteryERC or MRC Normal biliary Large segment four duct(center variability anatomy. draining to right hepaticon their use) duct well above the

bifurcation


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The TIPS extending into the IVC or the right atrium is a more dangerous prob-lem. 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 hereand by ‘pinching’ off the right atrium with the suprahepatic clamp. A useful tech-nique is to place a smaller clamp on as high as possible and then placing a largerclamp outside and thereby above the first clamp.

Live Liver DonorsLiving donation for liver transplantation has been practiced in children since

1989. This has predominantly been the transplant of the left lateral segment of ahealthy 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, andthe 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 pastfew years this practice has increased greatly. The most common graft from a livedonor for an adult recipient is a right lobe (segments V-VIII) with or without themiddle hepatic vein. Healthy donors are selected according to criteria included inTtable 5.

The Right Lobe Living Donor OperationWith the patient positioned supine and a nasogastric tube and Foley catheter in

place, a subcostal incision, with vertical upper extension, is made. The falciformligament is taken down and the suprahepatic IVC is exposed with dissection of theright hepatic vein insertion.

Any adhesions around the gallbladder or porta hepatis are taken down and afundus down cholecystectomy is performed. After a limited exploratory dissectionof the porta hepatis, a cholangiogram is performed via the cystic duct. It is helpful tohave dissected some way up into the porta hepatis, taking down the hilar plate toexpose the confluence of the hepatic ducts, which is marked with a forceps forconfirmation on the cholangiogram. If a segment IV duct is joining the right hepaticduct, then an assessment needs to be made whether to proceed, as this portion of theright hepatic duct will need to remain with the donor.

All of the porta hepatis dissection should be limited to the right side of thecommon bile duct. Attention is turned to the right hepatic artery, which is identifiedas it passes beneath the common hepatic duct. It is dissected well up into the liver tofacilitate the dissection of the hepatic duct and portal vein. The right hepatic duct isdissected and transected several millimeters from the confluence, the donor side issuture ligated. It is more common than not to have two hepatic ducts on the donorside, and these are marked with prolene sutures to aid identification later. Retractingthe common bile duct and the hepatic artery to the patients left exposes the rightportal vein. Dissection of the right portal vein continues up towards the right lobeof the liver working on both sides of the hepatic artery until the bifurcation of theportal vein is clearly seen. Now the posterior portal vein is dissected and caudatebranches of the vein are ligated and divided. Approximately 2 cm of right portal


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vein should be freed on all sides in this manner until a right angle forceps can besafely passed around the right portal vein.

The right triangular and coronary ligaments are taken down exposing the rightposterolateral aspect of the inferior vena cava (IVC). The liver is returned to itsanatomical position and the peritoneum overlying the anterior surface of the infra-hepatic IVC is dissected and freed. Dissection is continued up towards the liver. Thecaudate lobe is elevated off the cava and small tributaries from the caudate lobe areligated and divided. Small tributaries from the right lobe are likewise ligated anddivided. Larger tributaries (> 5 mm) are preserved for re-implantation. In such amanner, the entire anterior and right lateral surfaces of the cava are exposed up tothe level of the right hepatic vein which is now dissected working both from aboveand below until it can be isolated with a vessel loop.

Figure 12. Hepatico-jejunostomy.

Figure 11. Right lobe vascularanastamosis.


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The caudate process between the right portal vein and the IVC is scored. Theline of resection is marked on the surface of the liver. This line runs from betweenthe middle and right hepatic veins to the left side of the gallbladder fossa, and thendown the inferior surface of the liver to the IVC.

Parenchymal dissection is undertaken using the technique preferred by theoperating team. During this dissection it is usual to encounter two significant middlehepatic vein tributaries; one from segment V and one from segment VIII. Whenthese are large some centers re-implant one or other of these into the recipient cavausing a venous conduit.

Once completed the two parts of the liver with their respective blood suppliesshould be left until the recipient hepatectomy is completed. A completioncholangiogram can be performed to exclude stricture or leak at the sight of theoversewn right hepatic stump. The liver segment is removed by clamping vessels(inflow before outflow) on the remnant side and dividing the vessels. The graft isimmediately placed on ice and flushed via the portal vein and hepatic artery withpreservation solution.

The donor ends of the vessels are oversewn and the wound is closed with drainsto the cut surface of the liver.

The Live Donor Right Lobe Recipient OperationThe 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 inplace by ligating caudate lobe tributaries. The left and middle hepatic veins are oversewn. The right hepatic vein opening can be extended into the IVC inferiorly for awide-open anastamosis.

The segment is sewn in beginning with the right hepatic vein which lies best ifsewn up-to-down instead of left-to-right (this is not tied down until after flushingthe liver). The hepatic arterial anastomosis is completed, usually using the hepaticartery bifurcation as a patch. The liver is flushed through the portal vein and thehepatic vein is tied down. The portal venous anastomosis is carried out as usual, andthe liver is reperfused with portal and arterial blood. The type of bile duct anastomosisis determined by the donor anatomy. A duct to duct anastomosis is usually possible,although a Roux-en-Y hepaticojejunostomy may be required for biliaryreconstruction.

Hemostasis is obtained, drains are placed and the abdomen is closed as usual.


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CHAPTER 6

Immunosuppression after LiverTransplantation

James Neuberger

The purpose of immunosuppression is to prevent the body’s immune systemdestroying or damaging the graft. Since currently available drugs are not specific forgraft alloantigens, the clinician must maintain a balance between under-immunosuppression, leading to graft rejection, and over-immunosuppression, leadingto the consequences of immunodeficiency such as sepsis and malignancy. The clinicianshould also be aware of, and attempt to minimize, the unwanted effects of long-term use of these agents.

In the early days of liver transplantation, the protocols for liver allograft recipientswere 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 rejectionmay inhibit the development of tolerance. While acute rejection is associated with apoor outcome in renal transplantation, there is no evidence that acute cellularrejection, which is reversed by short periods of increased immunosuppression (so-called ‘reversible acute cellular rejection’), has any untoward effect on liver graftsurvival.

There have been comparatively few studies on which to base a rational approachto immunosuppression: the success of liver transplantation has meant that todemonstrate significant improvement in graft survival or a reduction in theimmunosuppressive-related morbidity, a large number, of patients needs to befollowed for long periods of time. In the present climate, this is usually difficult.Furthermore, the introduction of newer agents, or improved formulations of existingdrugs, means that the conclusions of randomized trials may be superseded beforeresults are available.

Most centers have adopted a common approach to the principles ofimmunosuppression but differ significantly in the details. Therefore, in this Chapter,the principles of immunosuppression will be outlined together with a description ofthe consequences of over-immunosuppression. Details of those drugs that arecurrently available and those shortly to be licensed will be described.

61Immunosuppression after Liver Transplantation

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Drugs and Other Agents Used in ImmunosuppressionThe drugs and other agents and procedures used for immunosuppression are

shown in Table 1 and details of those drugs and agents licensed forimmunosuppression are shown in Tables 2 to 13.

Types of ImmunosuppressionImmunosuppression may be physical or pharmacological. Physical methods, as

shown in Table 1, are rarely used in liver transplantation.

Medications Used for Immunosuppression

Purine AnaloguesAzathioprine has been used for many years in transplantation (see Table 3). It is

metabolized by thiopurine methyltransferase to the active component 6-mercaptopurine (6-MP), an analogue of the natural purines hypoxanthine andadenine. 6-MP is then metabolized to thioinosine monophosphate which inhibitssynthesis of DNA precursor molecules and interferes with nucleic acid synthesisduring clonal expansion of lymphocytes. People who have low levels of thiopurinemethyltransferase are more susceptible to the side effects of azathioprine but maytolerate 6-MP.

The rationale for long-term use of azathioprine is not well established althoughseveral studies have suggested an increased probability of chronic rejection in patientsnot taking azathioprine. Following the introduction of azathioprine (usually at adose of 1-2 mg/kg/day), the white count should be monitored twice monthly for 3months: if the white count falls below 4.0 x 10.9/l, the dose should be halved; if thewhite count falls below 3.0 x 10.9/l, azathioprine should be discontinued. Veno-occlusive disease and hepatitis are the most serious forms of liver dysfunctionassociated 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’.

Table 1. Physical methods of immunosuppression

Types of physical immunosuppression include:Blood transfusionRemoval of lymphocytes:

LeucophoresisUV or total body irradiationThoracic duct drainageThymectomy, splenectomy

PlasmaphoresisPhotophoresis after lymphocyte priming


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Table 2. Pharmacological methods of immunosuppression

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 activationCorticosteroidsImmunophilin-binding drugs

Calcineurin-inhibitors:CyclosporinTacrolimus

TOR inhibitors: Sirolimus (formerly known as rapamycin)

Inhibitors of de novo nucleotide synthesisPurine synthesis inhibitors (IMPDH inhibition)

Mycophenolate mofetilMizoribine

Pyrimidine synthesis inhibitors ((DHODH inhibition)LeflunomideBrequinar

AntimetabolitesAzathioprineCyclophosphamide

Inhibition of lymphocyte activation/trafficcking/interactionInhibition of trafficking

FTY720Inhibition of interactions

Antibodies to ICAM-1Antibodies to IL2-RCTLA-4 Ig

Table 3. Immunosuppressive drugs: Azathioprine

Drug name Azathioprine

Mechanism of action Anti-metabolite; metabolised to 6-mercaptopurine and then active agent interfereswith DNA and RNA synthesis so inhibits T andB lymphocyte differentiation and proliferation

Side-effects Leukopenia (significant 15%)Nausea and vomitingHepatotoxicity (especially veno-occlusive disease)PancreatitisPneumonitisMegaloblastosis

Doseage 1-2 mg/kg/dayDrug interactions Allopurinol (avoid) ACE inhibitorsNotes Used as a second-line drug


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GlucocorticoidsThese agents have both anti-inflammatory and immunosuppressive effects. The

glucocorticoids bind to the glucocorticoid receptor and the complex then translo-cates to the nucleus where, after binding to DNA, protein synthesis is affected.

Table 4. Immunosuppressive drugs: Mycophenolate mofetil

Drug name Mycophenolate mofetil

Mechanism of action Prevents T and B cell proliferation by inhibition ofde novo purine synthesis by inhibition of

inosine monophosphate dehydroge-nase (IMPDH)

Side-effects Diarrhea (15%) Leucopenia (5%) anemia,thrombocytopenia, Rarely GI

hemorrhage and perforation hematuria,hypertension, hyperglycemia,disturbances of electrolytes and blood lipids, peripheraledema, dyspnea, cough, dizziness, insomnia, tremor.Hypersensitivity reactions

Dosage 1 to 2g/day in divided doses

Drug interactions May compete with drugs that undergo active renaltubular secretion

ProbenecidAcyclovir

Some antacids and cholestyramine reduce absorp-tion

Notes Teratogenic in animals. Used asalternative to azathioprine or incalcineurin-inhibitor sparing protocols

Table 5. Equivalence of corticosteroids

Prednisolone/Prednisone 5 mgBetamethasone 750 µgCortisone acetate 25 mgDeflazacort 6 mgDexamethasone 750 µgHydrocortisone 20 mgMethylprednisolone 4 mgTriamcinolone 4 mg

(Derived from the British National Formulary, 2000)


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Among the intra-nuclear functions altered by glucocorticoids is synthesis of nuclearfactor kappa B (NF-κB), resulting in apoptosis of lymphocytes. There are manydifferent glucocorticoids used in transplantation and the potency on a weight forweight basis varies and is summarised in Table 5.

There is increasing evidence that corticosteroids can be withdrawn by threemonths or earlier in most liver transplant recipients. In contrast, some centers main-tain corticosteroids in patients grafted for autoimmune hepatitis to prevent recur-rent 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 andtacrolimus to the FK-binding protein which results in inhibition of calcineurin whichinhibits activation of transcription factors such as NFATc, a transcriptional factorresponsible for the calcium activation of cytokine genes during the immune response.

Table 6. Immunosuppressive drugs: Corticosteroids

Drug name Prednisolone/prednisone

Mechanism of action Anti-inflammatory; stimulates migration of T cellsfrom intravascular tissue to lymph nodes; inhibitsproduction of T cell lymphokines

Side-effects Increased tendency to diabetes mellitusOsteoporosisImpaired wound healing and increased skin bruisingSodium and fluid retention, potassium depletionHypertensionMuscular weakness, myopathy and muscle wastingAseptic necrosis especially of femoral headCataracts, glaucoma, raised intra-ocular pressureCushingoid faciesRetardation of growthHeadaches, pseudotumor cerebriMood change (euphoria, hypomanic psychosis, depression)Weight gainMay increase risk of peptic ulceration or retard ulcer healing

Dosage Maintenance up to 20 mg/day; treatment ofrejection 200 mg/day for 3 dats or 3 days

Drug interactions NSAIDs

Notes Other forms of steroids—see Table 5


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Other down-stream effects are thought to relate some of the side effects of this classof drugs including diabetes and renal impairment.

Tacrolimus is well absorbed from the upper GI tract. Consequently, there israrely an indication to give tacrolimus intravenously. The starting dose is 0.1 mg/kg/day intwo 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 thereaf-ter.

Cyclosporin is fat soluble, and absorption is variable from the gut, especially inthe 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 rarelya need to administer cyclosporin intravenously. The starting dose is 8 mg/kg/dayand the dose adjusted to trough whole blood levels between 150 and 200 ng/ml forthe first three months and 100-150 ng/ml thereafter. However, measurement ofblood levels taken 2 hours post dose (otherwise called C-2) may provide a betterassessment of drug monitoring.

Tacrolimus and cyclosporin are metabolized by oxidation through the cytochromeP450 system. The liver is the main site of metabolism, although minor metabolismoccurs in the gut. Drugs which induce or inhibit cytochromes P450, such aserythromycin, ketoconazole or rifampicin, interact with tacrolimus and cyclosporinand may affect drug levels. Drug interactions are listed in Table 9.

Table 7. Immunosuppressive drugs: Cyclosporin

Drug Name Cyclosporin

Mechanism of action Binds to immunophilins (cyclophilin). Inhibition of Tcells; suppresses T-cell activation by inhibiting synthesisand 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%)HyperkalemiaHyperuricemiaGout

Dosage Adjust to maintain trough whole blood levels (measuredby RIA) between 100-250 ng/ml (target levels varybetween centers and according to time aftertransplantation and graft function)

Drug interactions See Table 8

Notes Several formulations available: as they have differentabsorption profiles the different formulations may notbe interchangeable


6

Calcineurin inhibitors (cyclosporin and tacrolimus) are the current mainstays ofmaintenance immunosuppression. Both agents are associated with significant sideeffects in the long term. There are several studies comparing the two drugs and thesesuggest that tacrolimus may be superior. For both drugs, target levels have beenderived from clinical experience although the dose should be adjusted in the light ofcomplications (such as renal impairment or symptoms such as headaches or trem-ors) 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 tothe immunophilin called FK binding protein (FKBP) but it does not inhibit thecalcineurin pathway. The Sirolimus-immunophilin complex interacts with a proteinkinase called TOR (‘target of rapamycin’) that is integral to a signal transductionpathway regulating the synthesis of proteins required for cell-cycle progression inboth 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 transplantrecipients and is considerably lengthened in patients with chronic liver dysfunction.The most frequently reported adverse effects in subjects receiving Sirolimus are mild

Table 8. Immunosuppressive drugs: Tacrolimus

Drug Name Tacrolimus

Mechanism of action Binds to FK-binding protein 12; inhibitssynthesis and release of IL-2

Side-effects Diabetes mellitusHypertensionHeadachesTremorConvulsionsNephrotoxicityRenal impairmentMyocardial hypertrophy

Dosage Maintain trough whole blood levelsmeasured by RIA between 5-15 ng/ml.

Target levels vary between centres, time aftertransplantation and renal and hepaticfunction

Drug interactions See Table 8

Notes Not licencsed for use in pregnancy(although no evidence of increasedteratogenicity compared with cyclosporin


6

dose-related thrombocytopenia and leukopenia, and hyperlipidemia, affecting bothserum triglycerides and cholesterrol. Among the other effects reported include nausea,vomiting, hypertension, elevations in serum creatinine, elevations in liver-associatedenzymes and acne. Isolated cases of interstitial pneumonitis or hepatic arterial throm-bosis 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 subsetsof lymphocytes only. All are profoundly immunosuppressive. Some centers usepolyclonal antibodies to lymphocytes (e.g., ALG, Thymoglobulin) for induction(see Table 9).

Table 9. Drugs which affect levels and toxicity of the calcineurin inhibitors and Sirolimus

Increase levels (usually by inhibition Bromocryptineof cytochrome P450 3A4 or reduced Cimetidineclearance) Cisapride

ClarithromycinDanazolDiltiazemErythromycinFluconazoleGrapefruit juiceItraconazoleKetoconazoleMethylprednisoloneMetoclopramideNicardepineStatins (HMG CoA reductase inhibitors)VerapamilProtease inhibitors

Decrease levels (usually induction Barbituratesof cytochrome P450 3A4) Carbamazepine

PhenytoinRifampicinSt. John’s wort (Hypericum)

Increase toxicity Amphotericin BCimetidineGentamicinNSAIDsRanitidineTobramycinVancomycin

Decrease toxicity -


6

Principles of ImmunosuppressionThe management of immunosuppression can be considered in five phases:

� Induction� Maintenance� Treatment of acute rejection� Treatment of chronic rejection� Withdrawal of immunosuppression

Induction of ImmunosuppressionThere is no consensus for the optimal method for induction of

immunosuppression. Some centers use mono- or polyclonal antibodies, incombination with other immunosuppressive agents. Other centers use intra-operativecorticosteroids.

Maintenance of ImmunosuppressionCurrently 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

Table 10. Immunosuppressive drugs: Sirolimus

Drug name Sirolimus (AKA rapamycin)

Mechanism of action Inhibits T cell activation

Side-effects Hyperlipidemia (40%)Hypercholesterolaemia (40%)ThrombocytopeniaGastrointestinal disturbancesInterstitial pneumonitisHepatic artery thrombosisMay impair wound healing

Dosage 2 mg/dayShould be taken 4 hours aftercyclosporinMonitoring of drug levels is not requiredin most patients (except in children,renal or hepatic impairment, withconcurrent administration of enzymeinducers/inhibitors of CYP 3A4 or ifcyclosporine discontinued)

Drug interactions As for calcineurin inhibitors

Notes Anti-proliferative in vitro. May beeffective in reducing malignant cellproliferation and in intimal callproliferation


6

Table 11. Immunosuppressive drugs: Polyclonal antibody preparations

Drug name Anti-thymocyte globulin (ATG), Anti-lymphocyte globulin (ATGAM)

Mechanism of action Polyclonal antibodies raised in mammalsagainst human lymphocytes orlymphocyte subsets.

Side-effects Hypersensitivity; anaphylaxis; headache,dizziness, muscle pain, lymphopenia,leukopenia, thrombocytopenia (usuallytransient); nephrotoxicity

Dosage Different preparations vary in theiractivity. See manufacturers instructions

Drug interactions

Notes Test for sensitivity before administrationof first dose. Increases the risk of CMV.Use CMV prophylaxis in selectedpatients

Table 12. Immunosuppressive drugs: Monoclonal antibodies to T lymphocytes

Drug name Anti-CD3Mechanism of action Binds to and blocks the CD3 receptor on T cells

and prevents signal transductionSide-effects Treatment is associated with a cytokine release

reaction (‘shake and bake syndrome’) which maybe severe. Pre-treatment with methylprednisolonemay prevent the syndrome. Other side-effectsinclude profound lymphopenia, seizures,encephalopathy, aseptic meningitis, cerebraledema, and anaphylactic responses (such aswheezing, rigors and hypertension).

Dosage 5 mg/day intravenously for 10-14 daysDrug interactions Avoid the concomitant use of NSAIDs and

cyclosporin (increased CNS side-effects),corticosteroids (increased risk of psychosis)

Notes Muromonab-CD3 is a monoclonal antibody ;should be avoided in patients with anti-murineantibody titres >1:1000; uncompensated fluidoverload or patients with heart failure or with ahistory of seizures. Avoid in pregnancy or breastfeeding.


6

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

Treatment of Acute RejectionAcute rejection should, whenever possible, be confirmed prior to treatment us-

ing histology obtained either by liver biopsy; fine needle aspiration biopsy is usedoccasionally. Although many serological markers in blood and bile have beendescribed, none has been shown to be of adequate sensitivity and specificity to con-firm rejection. It is rarely possible to distinguish reliably between rejection and in-fection without histology.

The mainstay of immunosuppression for early acute rejection is high dose corti-costeroids: regimes vary between centers and there are no good data to demonstratesuperiority 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 fromcenter to center.

Table 13. Immunosuppressive drugs: Antibodies to IL-2 receptor

Drug name Basiliximab; daclizumab (antibodies to IL-2receptor)Mechanism of action These bind to and block the alpha unit of the IL-2

receptor on activated T cells and so inhibits IL-2binding and inhibits IL-2 activation

Side-effects Anaphylaxis

Dosage See below

Drug interactions None known

Notes There are two preparations: Basiliximab is achimeric monoclonal antibody and is given at adose of 20 mg within 2 hours of surgery and at 4days (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 within24 hours of transplantationThe initial dose required for liver transplants may begreater than for other solid organ recipients due toloss of antibody in ascites drained at laparotomy,and in ascitic or pleural fluid drained during theperi-operative period.


6

Treatment of Chronic RejectionChronic rejection of the liver allograft has many names: chronic ductopenic

rejection, vanishing bile duct syndrome, chronic rejection. Chronic ductopenicrejection 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 ImmunosuppressionThe observation that some patients have maintained long-term good graft func-

tion after discontinuing immunosuppression has led some centers to embark oncarefully controlled trials of withdrawal of all immunosuppression in long-term (>5years) survivors with good graft function, or in subjects with major impediments tocontinued use of immunosuppressant, such as malignant disease. These studies havedemonstrated that it is possible to withdraw all immunosuppression in about 20%of carefully selected patients. The remainder required maintenance immunosup-pressants or their reintroduction if they had been stopped. The usual reason forfailure to withdraw immunospressants was late onset acute cellular rejection, whichwas then controlled by adjusted phamacotherapy. Those recipients grafted for non-autoimmune diseases, without episodes of acute rejection and with a good HLAmatch are more likely to be able to withdraw immunosuppression.

Side-Effects of ImmunosuppressionThe side-effects of immunosuppression may be due either to

� The effect of immunosuppression itself (especially infection andmalignancy)

� The effects of individual drugsThese are discussed in detail in Chapter 9.

Tailoring the Immunosuppression to the IndividualSince 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 tailorthe drug regime for the individual. The probability of developing acute rejection is,in part, dependent on the indication for transplantation so that patients grafted forviral hepatitis (especially B) and alcohol-associated liver disease have a much lowerprobability of developing early rejection than those grafted for autoimmune diseasessuch as PBC or AIH.

Inter-Current Bacterial InfectionsCurrently available immunosuppressants will not only reduce the risk of rejection

but will predispose the patient to infection. The balance between over- and under-immunosuppression is even more difficult to maintain in the presence of activesepsis. The general approach is to reduce the immunosuppression but the onset ofgraft rejection may not only herald the need for high-dose immunosuppression buthepatic impairment is associated with a further reduction in the host defences againstinfection. In the presence of bacterial infection, early detection and vigorous treatmentwith appropriate antimicrobials is clearly required; depending on liver function,


6

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

Intercurrent Viral InfectionThe most common viral infection during the early post-operative period is cy-

tomegalovirus (CMV). CMV is associated with chronic rejection: this may be re-lated to a direct effect of CMV on the biliary epithelial cells and, in part, to thereduction in immunosuppression. It is important, therefore, to reduce theimmunosuppressive therapy in association with active antiviral treatment. A com-mon practice is to stop azathioprine and reduce the calcineurin inhibitor.

TuberculosisBecause of the severe course of reactivation of tuberculosis in the patient on

immunosuppression, most centers use prophylactic treatment with Isoniazid 100mg/day in those at risk. Isoniazid should be given with pyridoxine. Treatment shouldbe 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 AcuteRejection and Early Ductopenic RejectionThese are associated with an increased risk of developing graft loss and therefore

many centers are using a combination of corticosteroids, tacrolimus andmycophenolate or Sirolimus.

Co-Morbid Conditions

Pregnancy and Breast FeedingSee Chapter 9: if the recipient is likely to become pregnant after transplantation,

consideration should be given to the appropriate choice of drugs.

Diabetes MellitusThe tendency of calcineurin inhibitors to induce diabetes mellitus is controversial.

Tacrolimus may be more diabetogenic than cyclosporin. Most transplant programsdo not switch from tacrolimus to cyclosporin, on account of diabetes mellitus. Thosediabetics given corticosteroids may have an increased requirement for insulin or oral agents.

Renal ImpairmentRenal impairment may occur following transplantation for many reasons (such

as IgA nephropathy, HCV associated glomerulonephritis, diabetic nephropathy orassociated with the inappropriate prescription of non-steroidal anti-inflammatorydrugs or nephrotoxic drugs such as gentamicin). In the presence of peri-operativerenal failure, some centers avoid the use calcineurin inhibitors. If renal impairmentdevelops in associated with calcineurin inhibitor use, most centers will reduce ordiscontinue the calcineurin inhibitor (see Chapter 9).


6

Development of Lymphoma and Other MalignancyThis is discussed in Chapter 7. Lymphoma post transplantation may be associ-

ated with EBV infection. Treatment is with aggressive therapy of the lymphoma anda reduction in the immunosuppressive regime; some centers discontinue all immu-nosuppression during chemotherapy.

Suggested Reading1. Micromedex Information System; http://www.micromedex.com; [email protected]. Devlin J, Doherty D, Thomson L, Wong T, Donaldson P, Portmann B et al. De-

fining the outcome of immunosuppression withdrawal after liver transplantation.Hepatology 1998; 27:926-933.

3. Jain A, Kashyap R, Marsh W, Rohal S, Khanna A, Fung JJ. Reasons for long-termuse of steroid in primary adult liver transplantation under tacrolimus. Transplanta-tion 2001; 71(8):1102-1106.


7


CHAPTER 7

Graft Dysfunction

Geoffrey H. Haydon

IntroductionThe causes of graft dysfunction occurring after liver transplantation may be

classified either according to the time period post-transplantation (Table 1) or to theetiology of the graft dysfunction. It should be emphasised that any of these conditionsmay become evident at any time after liver transplantation, and Table 1 lists themost common times for presentation.

Investigation of Graft DysfunctionThe general diagnostic approach is outlined in Table 2. Investigation of each of

the complications above is considered under the appropriate heading.

Primary graft non-functionPrimary 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 earlypoor function wherein graft function will return to normal after a period of systematicsupport. The value of agents such as prostaglandins and n-acetyl cysteine in thesecircumstances is uncertain.

Immunological Complications

Acute Cellular Rejection (ACR)-Definition:

• “Inflammation of the allograft elicited by genetic disparity between the

75Graft Dysfunction

7

donor and recipient, primarily affecting interlobular bile ducts and vas-cular endothelia, including portal veins and hepatic venules, and occa-sionally 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 occurthereafter.

-Clinical Findings:• Usually asymptomatic, although in late or severe cases, fever and hepatome-

galy occur. When bile is collected, it is noted to be pale and watery.

Table 1. Etiology of graft dysfunction more than one-month post transplantation.

Time Period Post-OLT Diagnosis

1-6 months Acute cellular rejectionOpportunistic infection -Viral: CMV; EBV (HSV, VZV less common)Vascular -Hepatic artery thrombosisRecurrent viral hepatitisBiliary tract abnormalities

6-12 months Acute cellular rejectionRecurrent viral hepatitisBiliary tract abnormalitiesChronic ductopenic rejectionHepatic artery thrombosis

>12 months Recurrent viral hepatitisBiliary tract abnormalitiesAcute cellular rejectionChronic ductopenic rejectionRecurrent autoimmune disease (PSC; PBC; AICAH)Hepatic artery thrombosisSteatohepatitis

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


7 -Investigations:• Liver chemistry tests are usually abnormal (but non-specific) and blood

leukocytosis and eosinophilia are frequently present. The gold standardfor diagnosis of acute cellular rejection remains liver histology. Thehistological features are mixed inflammatory infiltrate in the portal triads,bile duct damage, and vascular endothelial damage. The Banff criteriagrade of the severity of histological injury (see Table 3).

The differential diagnosis of deteriorating graft function is infection, graft ischemiaand biliary obstruction. The gold standard for diagnosis of ACR remains liverhistology.

-Treatment (this is described in Chapter 6)-Prognosis:

• A single episode of easily reversed acute cellular rejection confers a betterpatient and graft survival than observed in patients who never experiencerejection. In contrast, acute cellular rejection that does not respond toincreased immunosuppression (steroid resistant rejection) is associatedwith 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 chronicrejection and chronic vanishing bile duct syndrome.

-Incidence:• Most programs report less than 5% of grafts develop chronic ductopenic

rejection.

Table 3. Banff criteria grade of histologic injury

Subjective Grade Criteria

Indeterminate Portal inflammatory infiltrate that fails to meet criteria for thediagnosis of acute rejection

Mild Rejection infiltrate in a minority of the triads, that is generallymild and confined within the portal spaces

Moderate Rejection infiltrate expanding most or all of the triadsSevere As above for moderate, with spillover into periportal areas

and moderate to severe perivenular inflammation that extendsinto hepatic parenchyma and is associated with perivenularhepatocyte necrosis

Banff grading of acute liver allograft rejection. Global assessment of rejectiongrade made on review of the biopsy and after diagnosis of rejection has beenestablished.

77Graft Dysfunction

7

-Timing:• Chronic ductopenic rejection may occur at any time after liver transplan-

tation, but is usually seen in the first postoperative year.-Clinical Findings:

• As with ACR, most patients are free of symptoms. Some have generalizedsystemic symptoms or complain of increasing jaundice and cholestaticsymptoms.

• Risk factors for chronic ductopenic rejections are shown in Table 4.-Investigations:

• Liver chemistry tests usually demonstrate a relentless rise in markers ofcholestasis. Liver biopsy is essential to make the diagnosis of chronicductopenic rejection. Special cytokeratin stains to identify biliary epitheliaare useful when assessing bile duct loss. Vascular lesions may be absent on

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, orhepatocyte ballooning or necrosis and dropoutBile 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


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 respondto conventional additional immunosuppressive therapy. In those who donot respond to standard immunosuppression, re-grafting is the only otheroption.

De Novo Autoimmune HepatitisIn a small number of liver transplant recipients a syndrome resembling autoim-

mune hepatitis Develops. It is characterised by biochemical hepatitis, autoantibod-ies and histologic appearances of inflammatory hepatitis. The hepatitis usuallyresponds to reintroduction or increased doses of corticosteroids.

Graft InfectionInfection 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 trans-plantation

-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

Table 6. Differential diagnosis of cholestatic liver disease in the transplantedliver

Chronic ductopenic rejectionBiliary obstructionViral hepatitis (viral cholestatic hepatitis)SepsisDrug hepatotoxicityRecurrent primary biliary cirrhosisRecurrent primary sclerosing cholangitis

79Graft Dysfunction

7

• CMV PCR of liver biopsy-Risk Factors for CMV Infection:

• The respective serological status of the donor and recipient is most im-portant and must be documented: seronegative recipients of a graft froma seropositive donor have the highest risk of infection

• Infection may be transmitted by the graft; blood products; reactivation ofprevious infection or superinfection by a CMV variant

• Patients with septic biliary complications (including hepatic arterythrombosis)

• 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 receptorremains 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 arenot 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:


7

• None is necessary-Treatment of EBV hepatitis:

• A decrease in the immunosuppressive therapy will result in resolution ofboth 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 10-

1000 times that of the normal population. After skin cancer, lymphoma has thesecond highest incidence in the immunosuppressed patient. The association of EBVwith post-transplant lymphoproliferative disorders has been well described and thepresence of EBV-specific proteins and fragments of EBV genome demonstratedconsistently in PTLD. There are three clinical disorders of differing presentationsand prognosis, which may involve graft dysfunction in PTLD.

Polyclonal B-cell Hyperplasia-Clinical Presentation:

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

Disease/ Clinical features Histology Therapy Outcomedisorder

Post-transplant Fatigue, fever, Mild increase in Acyclovir Self-limitedinfectious rash, sore throat, portal infiltrates disease/mononucleosis lymphadenopathy resolved(IM)

Polyclonal B- Similar to acute Prominent Decreased Responds tocell hyperplasia IM with severe portal immunosup- antiviral

hepatitis, bone lymphocyte pression; treatment/marrow failure and (plasma treat with resolvesand ARDS cell) infiltrate acyclovir or

ganciclovir

Polyclonal Nodal and extra- Polymorphic Withdraw Most progressproliferation B- nodal lympho- lymphocytic immunosup- to lymphomacell lymphoma cytic proliferation infiltrate pression; treat and have a

in patients treated with acyclovir, low survivalwith immunosup- ganciclovir or ratepressive anti-B cellmedication monoclonal Ab

Monoclonal Nodal and extra- Polymorphic to Withdraw Aggressivepolymorphic nodal lympho- monomorphic immunosup- disease withB-cell cytic proliferation lymphocytic pression; treat survival ratelymphoma in patients treated proliferation with chemo- of less than

with immuno- depending on therapy; radio- 1 yearsuppressive the stage of therapy ormedications disease surgical resection

81Graft Dysfunction

7

• As for infectious mononucleosis.-Subpopulation:

• Young patients in second to fourth decade, who are profoundly immuno-suppressed

-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 thendevelop 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. Prominentextranodal masses develop in the central nervous system, gastrointestinaltract and liver

-Histology:• Non-Hodgkin’s lymphoma with a monomorphic pattern and monoclonal

immunoglobulin expression-Treatment:

• Withdraw immunosuppression. Surgical resection of masses with adjuvantradiotherapy 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 arterialanastomosis are important particularly for early thrombosis, but with


7improvement in surgical technique it is likely that the incidence is falling.It is a recognized component of the small sized graft syndrome in recipi-ents 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

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 HATpresenting immediately after transplantation.

Unexplained septicaemia

Biliary tract problems-Leaks-Abscess-Breakdown of biliary anastomosis

Liver abscess (may be sterile, also called a biloma)

83Graft Dysfunction

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Hepatic Artery StenosisStenosis of the hepatic artery may present with unexplained elevated liver chem-

istry tests. Doppler sonography and hepatic arteriography are required to confirmthe diagnosis. Resection of the stenosed portion or angioplasty are the treatments ofchoice when graft function is well preserved. Hepatic artery stenosis presenting withseverely compromised graft function may require urgent retransplantation.

Portal Vein ThrombosisThis can occur in up to 3% of recipients; the diagnosis is often suggested by the

subsequent development of gastroesophageal varices or other signs of portalhypertension. Treatment is usually management of the complications of portalhypertension. Thrombectomy or angioplasty are rarely feasible.

Biliary ComplicationsBiliary tract complications are the most frequent late complication of liver

transplantation with an incidence of 15-20%. Biliary leaks occur at T-tube withdrawalin 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 ofbiliary strictures or leaks are:

• The arterial supply to the biliary tree: biliary epithelial cells are particularlysusceptible to interruption of their arterial blood supply; so that if this iscompromised by even relative ischemia, bile duct necrosis will follow

• Bile composition: the composition of bile is altered followingtransplantation, predisposing to supersaturation with cholesterol and stoneformation

• 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 andthe 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 resonancecholangiopancreatography. Biliary leaks may resolve if stented by ERC


7

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

Biliary LeaksThese 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 becaused by long warm ischemic times during transplant surgery or bythrombosis of hepatic artery radicals (ischemic cholangiopathy); they areassociated with ABO mismatches, and are a feature of recurrent PSC (seeChapter 8). Bile leaks that heal spontaneously may result in anastomoticstricturing.

• Biliary leaks following the removal of a T-tube are best stented via theendoscopic or percutaneous route. Anastomotic strictures usually requiresurgical reconstruction with excision of the stricture and re-anastomosisto a Roux loop of jejunum. Stenting may be palliative in selected cases.

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’. Inaddition to strictures the extrahepatic and ultimately the intrahepatic biliarytrees are clogged with cast material/sludge. Cholesterol is the maincomponent 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 TransplantationRecurrence 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 underlyingdisease process. Recurrent disease is described in Chapter 8.

Suggested Reading1. Demetris AJ, Batts KP, Dhillon AP et al. Banff scheme for grading liver allograft

rejection: an international consensus document. Hepatology 1997; 25:658-663.2. Dousset B, Conti F, Cherruau B et al. Is acute rejection deleterious to long-term

liver allograft rejection? J Hepatol 1998; 29:660-668.3. Demetris AJ, Seaberg E, Batts KP et al. Reliability and predictive value of the

NIDDK transplantation database nomenclature and grading system for cellularrejection of liver allografts. Hepatology 1995; 21:408-416.

4. Demetris A, Adams D, Bellamy C et al Update of the International Banff Schema

85Graft Dysfunction

7

for Liver Allograft Rejection: Working recommendations for the histopathologicstaging and reporting of chronic rejection. An International Panel. Hepatology2000; 31:792-799.

5. 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.

6. Heneghan MA, Portmann BC, Norris SM, Williams R, Paolo Muiesan P, MohamedRela M et al. Graft dysfunction mimicking autoimmune hepatitis following livertransplantation in adults. Hepatology 2001; 34:464-470.


8


CHAPTER 8

Recurrence of Disease after LiverTransplantation

Lisa Forman and Geoffery Haydon

Recurrence of disease following liver transplantation remains a problem for thelong-term survivor in several indications and may affect graft function and survival.It does however, provide useful information about the pathogenesis of the underlyingdisease process.

Hepatitis C Virus Infection-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. Afterwardsthe concentrations of circulating HCV RNA increases as early as day 3post-transplantation and the levels at 1-3 months are greater than pre-transplant levels.

� An acute hepatitic syndrome occurs in many HCV infected patients inthe first 4 months post-OLT. It may be difficult to distinguish HCVrecurrence from acute cellular rejection or a combination of the two.

� Chronic hepatitis is found in 50% of patients at 2 years and 70% at 4years.

� The prevalence of hepatic cirrhosis in graft recipients at 5 years is at least10%

� Up to 10 % of HCV infected recipients develop a cholestatic syndromeassociated with ballooning degeneration of hepatocytes, which has beencalled ‘fibrosing cholestatic hepatitis’. It occurs in the first year and isassociated with very high circulating HCV RNA levels. It has a poorprognosis.

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).

87Recurrence of Disease after Liver Transplantation

8

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 intol-erance of patients with cirrhosis for combination antiviral therapy

Post Transplant Therapy� Interferon and ribavirin

The unwanted effects of therapy have hampered attempts at treatment inthe 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 investiga-tional studies.

Late Therapy (>6 Months After Transplantation)� Viral eradication has been recorded in 20% of patients receiving combi-

nation interferon alfa 2b and ribavirin. Dose reductions of either agenthave 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 graftand patient survival are reduced.

Hepatitis B Virus Infection-Incidence and Prevalence:

� The early experience of liver transplantation for chronic HBV infectionhighlighted a significant adverse effect of infection on graft and patientsurvival. Aggressive re-infection and progression to cirrhosis and sub-acute

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


8

graft failure were almost universal; the overall outcome was inferior toother etiologies. HBV infection presenting as FHF had a better prognosisfor post transplant hepatitis on account of the low level of pre-transplantHBV 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 statusThe 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, modeof administration and duration of treatment with HBIg is uncertain. Somecenters 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 chestpain

� 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 aminority of patients following the emergence of lamivudineresistance (YMDD mutations)

- Other strategies being evaluated include the use of other antiviraldrugs, such as adefovir, tenofavir and entecavir, and HBVvaccination

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 positivein 72-100% of cases; however, the persistence of these antibodies doesnot indicate recurrent disease


8

� 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 increasedsusceptibility 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 CholangitisMost patients transplanted for PSC have a choledochojejunostomy with a Roux

loop. Differentiation of recurrent PSC from secondary sclerosing cholangitis maybe difficult in the transplant setting. Causes of non-anastomotic biliary stricturesare 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 literatureon this topic is confusing.

-Incidence and Prevalence


8

� 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), althoughimmunosuppression should be tapered to the minimum tolerated regimenfor each patient. This requires close supervision and regular liver biopsies.

-Prognosis:� Long-term follow up data are awaited

Metabolic DiseasesRecurrence 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 primarydefect resides in the hepatocyte itself. These include metabolic disorders in whichthe liver is damaged, and those disorders in which liver function remains intact butwhich are associated with severe damage to other organs (See Table 2). In the lattergroup, the recipient ‘explanted’ liver may be perfectly healthy except for the singlemetabolic defect. Occasionally these explants have then been used to provide a livergraft to another recipient in whom the metabolic defect will is not of immediateconcern. This has been called ‘the domino procedure’.

Other metabolic diseases are associated with a more generalized metabolic defectand the original disease may recur. Examples include hemochromatosis, Niemann-Pick 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 follow-

up is needed to establish the rate and risk for hepatic iron reaccumulationin 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 relatedto cardiac and infectious complications and may also be related to lack ofpre-transplant diagnosis and treatment. Several reports have suggestedthat iron depletion prior to transplant can improve postoperative sur-


8

vival.Clinical approach:

� Monitor serum ferritin and iron saturation in these patients on an annualbasis

� 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 showna 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 oftenseen.

� Liver transplantation does not fully correct copper kinetic measurementsto normal, although it does result in normalization of serum copper andceruloplasmin.

� Transplantation converts the response to one similar to that found in aheterozygote for WD.

� Despite incomplete metabolic normalization, transplantation effectivelycures the patient as the heterozygote state is not associated with clinicaldisease.

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. Aftertransplant, improvement in extrahepatic symptoms may occur, especiallyin gastrointestinal disturbances. Liver transplant may prevent further de-

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 diseaseNot associated with liver damage:� primary oxaluria� amyloidosis� primary hypercholesterolemia


8

cline and the onset of new complications� Survival after transplantation is determined by disease duration, hereditary

and geographic factors, nutritional status, gastrointestinal and cardiacinvolvement. 5-year survival of 75% has been reported

Alcoholic Liver Disease (ALD)Survival rates after liver transplantation are similar among alcoholics and non-

alcoholics, at least in the short and intermediate term. Long term follow-up data areneeded.

-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 unprovenbut all such patients should be offered support and therapy

Malignancy

Hepatocellular CarcinomaLiver transplantation is potentially curative in a subset of patients with HCC

with a small tumor burdenIncidence

� Initial series described a very high tumor recurrence rate, but the majorityof included patients with advanced HCC. Recurrence is negligible if thecriteria outlined in Chapter 3 are met and survival is excellent with a 4-year survival rate of 75%, and rate of recurrence-free survival of 83%

� Tumor recurrence is usually observed in the liver and less frequently thelungs. Recurrence has been observed at the site of prior liver biopsysuggesting seeding of tumor along biopsy site tract

� Therapy of HCC after liver transplantation is ineffective, and the prognosisis poor

CholangiocarcinomaThe 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%


8

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

Metastatic Neuroendocrine TumorsThere has been little experience with liver transplantation in secondary hepatic

tumors. In contrast to many other carcinomas, neuroendocrine tumors generallybehave less aggressively and have a slower growth rate and patients with such tumorsare more likely to benefit from liver transplantation. Reports have been confined tosmall numbers of patients and short follow-up,

Despite overall good medium-term survival, tumor recurrence is common (mostcommonly in liver, followed by bone) and recurrence free 5-year survival does notexceed 24%. Despite this, transplantation offers relief of symptoms from theneuroendocrine 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 fataccumulation

Suggested Readings1. Perrillo R, Rakela J, Dienstag J et al. Multicenter study of lamivudine for hepatitis

B after liver transplantation. Hepatology 1999; 29:1581-1586.2. Samuel D, Muller R, Alexander G et al. Liver transplantation in European patients

with the hepatitis B surface antigen. N Engl J Med 1993; 329:1842-1847.3. Ottobrelli A, Marzano A, Smedlie A et al. Patterns of hepatitis Delta virus re-

infection and disease in liver transplantation. Gastroenterology 1991;101:1649-1655.

4. Feray C, Caccamo L, Alexander GJM et al. European collaborative study on fac-tors influencing outcome after liver transplantation for hepatitis C. Gastroenterol-ogy 1999; 117:619-625.

5. Ratziu V, Samuel D, Sebagh M et al. Long-term follow-up after liver transplanta-tion for autoimmune hepatitis: evidence of recurrence of primary disease. JHepatology 1999; 30:131-141.

6. Forman LM, Lewis JD, Berlin JA, Feldman HA, Lucey MR. The association be-tween hepatitis C infection and survival after orthotopic liver transplantationGastroenterology 2002; 122:889-896.

7. Harrison RF, Davies MH, Neuberger JM et al. Fibrous and obliterative cholangitisin liver allografts: Evidence for recurrent primary sclerosing cholangitis. Hepatology1994; 20:356-361.

8. Garcia RFL, Garcia CE, McMaster P, Neuberger J. Transplantation for primarybiliary cirrhosis: Retrospective analysis of 400 patients in a single centerHepatology 2001; 33:22-27.


8

9. Brandhagen DJ, Alvarez W, Therneau TM et al. Iron overload in cirrhosis-HFEgenotypes and outcome after liver transplantation. Hepatology 2000; 31:456-460.

10. Schilsky ML, Scheinberg IH, Sternlieb I. Liver transplantation for Wilson’s dis-ease: Indications and outcome. Hepatology 1994; 19:583-587.

11. Suhr OB, Herlenius G, Friman S et al. Liver transplantation for hereditarytransthyretin amyloidosis. Liver Transplantation 2000; 6:263-276.

12. Lucey MR, Carr K, Beresford TP et al. Alcohol use after liver transplantation inalcoholics: a clinical cohort follow-up study. Hepatology 1997; 25:1223-1227.

13. Mazzaferro V, Regalia E, Doci R et al. Liver transplantation for the treatment ofsmall hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693-699.

14. Lehnert T. Liver transplantation for metastatic neuroendocrine carcinoma: Ananalysis of 103 patients. Transplantation 1998; 66:1307-1312.

15. Charlton M, Kasparova P, Weston S, Lindor K, Maor-Kendler Y, Wiesner RH etal. Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease.Liver Transplantation 2001: 7;608-614.

95Management of the Liver Transplant Patient

9


CHAPTER 9

Medical Management of the LiverTransplant Patient

Anne Burke

The 10-year survival rate after liver transplantation is approximately 65%. Withincreasing numbers of long-term liver transplant survivors has come an appreciationof some of the health problems facing these patients. This Chapter will focus on thelong-term management of the liver transplant recipient with emphasis on generalhealth concerns and routine health care maintenance.

Long Term Morbidity and Mortalityof Liver TransplantationThe 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 theseconditions frequently occur at a younger age than in the general population.

Medical Consequences of Immunosuppression

Cardiovascular DiseaseThere 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 FactorsMany of the adverse health effects seen in liver transplant recipients are direct or

indirect consequences of immunosuppression.

Systemic HypertensionEpidemiology: Systemic hypertension is defined as diastolic pressure > 90 mmHg

or systolic pressure > 140 mmHg. Systemic hypertension occurs in 40-80% of livertransplant recipients. It typically occurs within a few weeks of transplantation and islargely due to the use of calcineurin inhibitors.

Pathogenesis: The molecular mechanism underlying calcineurin inhibitor-inducedhypertension is not fully understood but renal vasoconstriction is the predominant


9

abnormality seen. Corticosteroids add to the risk of hypertension. A history of hy-pertension prior to the development of liver disease is an important additional riskfactor.

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

exerciseChoice of drugs:

� Calcium channel blockers− Nifedipine and drugs of a similar class are preferred. Nifedipine is asso-ciated with development of peripheral oedema.− Verapamil and diltiazem may inhibit cyp 450 drug metabolism ofcalcineurin 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

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

Cause of death % of all causes of death

Graft failure 40%CVD 18%Infection 15%De novo malignancy 8%Other 19%

Adapted from Abbasouglu O, Levy MF, Brkic B, Testa G, Jeyarahaj DR, GoldsteinRM 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)

Disease Prevalence post Rate in UStransplant population

Hypertension (BP > 140/90) 41-81% 15.7%Hypercholesterolemia (>240mg%) 20-66% 14.9%HDL < 35mg% 52% 12%Diabetes mellitus 21-32% 3.7%Obesity (BMI > 30) 39-43% 16.1%Skin cancer (BCC and SCC) 10% 0.3%Other Cancers 2% 0.4%Renal Impairment 77%-80% 4%Symptomatic Fractures 10% .04%


9

confer additional benefit by preventing left ventricular hypertrophy, arisk factor for cardiovascular disease. Initial concerns regarding worseningof renal function seem unfounded and these drugs are as effective and aswell tolerated as calcium channel blockers. Patients should be monitoredfor hyperkalemia and hypomagnesemia.

� Other drugs: Diuretics should be used to control peripheral edema or assecond-line antihypertensives. The centrally acting sympatholytics suchas clonidine are considered third-line agents against post-transplanthypertension.

HyperlipidemiaEpidemiology: 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 MellitusDiabetes 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 truepost-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 ofdiabetes. The effect may be transient.

Chronic hepatitis C infection may potentiate the risk or severity of diabetesmellitus.

Clinical Management:� General: diabetic liver allograft recipients should be managed in the same

way as diabetic patients in the general population, with lifestylemodification and drug therapy as needed.

� Modification of immunosuppressive protocol: where possible,corticosteroids should be withdrawn, and calcineurin inhibitor doseminimised. A conversion from tacrolimus to cyclosporin, Sirolimus ormycophenolate mofetil may be of help.

ObesityPrevalence: 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


9

transplantation and weight gains of 20%-30% above pre-operative weight are notuncommon.

Clinical Management:� General: as in the general population, management of weight gain is to

reduce caloric intake and to increase exercise.

Renal InsufficiencyEpidemiology: Prior to liver transplantation, renal insufficiency may go

unrecognized in many cirrhotic patients. Poor muscle mass and impaired hepaticsynthesis of creatinine may lead to an underestimation of glomerular filtration ratebased on serum creatinine levels. Several liver diseases, including chronic viralhepatitis, autoimmune hepatitis, primary biliary cirrhosis are associated withglomerulonephritis. Early onset of chronic renal failure in patients transplanted forchronic hepatitis C infection may be due to cryoglobulinemia-associatedglomerulonephritis.

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, hypertensionand viral hepatitis may all increase the risk of progression to end-stagerenal disease. Mortality has been shown to be higher in post-liver transplantpatients whose renal failure progresses to the point of requiring dialysis.

Pathogenesis: Post liver transplant renal insufficiency is a direct consequence ofcalcineurin inhibition. Acute elevation of serum creatinine is frequently the result ofcalcineurin inhibitor toxicity and responds to dose reduction. Chronic elevations inserum creatinine rarely return to normal levels after reduction of calcineurin inhibitordoses. Kidney biopsy in liver transplant recipients with sustained reduction in GFRshows interstitial fibrosis and patchy glomerular loss and hypertrophy of unaffectedglomeruli.

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 alternativeimmunosuppressive therapy.

� Avoid other nephrotoxic drugs� Control hypertension� Control diabetes mellitus

Renal transplantation is appropriate in established renal failure arising after livertransplantation.


9

Osteoporosis and OsteopeniaPrevalence: 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 osteoclasticactivity and bone turnover. Corticosteroids reduce new bone formation.

� Bone loss increases rapidly over the first 3 months following livertransplantation. Z-scores (number of standard deviations from the normalmean), a marker of bone mineral density, commonly reach -2 standarddeviations—the range for osteoporosis. Each standard deviation decreasein bone mineral density is associated with a 1.5 – 2.8 fold increase in therisk of hip fracture in post-menopausal women.

� Atraumatic vertebral fractures have been reported in up to 30% of livertransplant recipients within the first 6 months of transplant. Bone densitytends to improve over the first post-liver transplant year approaching pre-transplant 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-rayabsorption) 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 conjunctionwith calcium and vitamin D supplementation decrease the rate of boneloss in post-menopausal women.

It is advisable to recheck bone mineral density 1 year after transplantation. Inpatients with z-scores greater than -1, repeat DEXA can be deferred for about 5years.


9

MalignancyThe risk of malignancy is increased in liver transplant recipients.

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

Skin CancerPrevalance: skin cancer is the most common cancer after liver transplantation. It

tends to behave more aggressively than in the non-transplant patient. Over 5% ofcases are metastatic. This compares to <1% for the general population. The relativerisks of individual immunosuppressive medicines either alone or in combinationremain unknown.

The prevalance of Kaposi’s sarcoma is also increased in solid-organ transplantrecipients although less strikingly than in the HIV-positive population. Human herpesvirus-8 (HHV-8) has been implicated in Kaposi’s sarcoma in both immunosuppressedand immunocompetent individuals.

The increase in non-melanomatous skin cancer seen in liver transplant recipientsseems to be largely due to increased prevalence and activity of human papillomavirus (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 ofprotective clothing and broad brimmed hats, and the use of sun-screenand 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 shouldany suspicious lesions be seen, these should be referred to a dermatologistfor 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 leukoplakiaand should be biopsied.

� Erythroplakia – a red hyperplastic area of mucosa is a pre-malignantcondition

Carcinoma of the Uterine CervixPrevalence: The prevalence of cervical intraepithelial neoplasia in transplant re-

cipients is approximately 5-fold that of immunocompetent controls. 75-93% ofcervical cancers or carcinomas in-situ are associated with HPV.


9

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

Other CancersLiver and other transplant recipients are at increased risk of cancer of the vulva

and perineum, anal cancer, hepatobiliary tumours and colon cancer. Routine screeningis important, and physicians should maintain a high index of suspicion for cancerdevelopment in liver transplant recipients.

Infections After Recovery from Liver TransplantationInfection accounts for 15-20% of deaths in long-term liver transplant survivors.

� Viral infections: viral infection with CMV, EBV, HPV-6, VZV andparvovirus B19 tend to occur within 3 months of transplant, but mayoccur later. Patients seronegative for varicella zoster, who are exposed tovaricella should receive immunoglobulin. The development of primaryVaricella zoster infection should be considered a medical emergency inthe post-transplant patient and intravenous acyclovir (10 mg/kd) shouldbe started immediately

TuberculosisTuberculosis occurs in <1% of patients at any time after liver transplantation.

The risk of disseminated tubercular disease (25%) and of death (20%) is muchgreater among solid organ recipients than for the general population.

Diagnosis is made by a combination of staining for acid fast bacilli, culture ofthe 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 oflevels, rejection is a common occurrence (30-50%) in liver transplantrecipients receiving rifampicin in conjunction with cyclosporin.Conversely, there is a risk of cyclosporin or tacrolimus toxicity when thedose of rifampicin is reduced or withdrawn

� Other drugs: Due to the high toxicity with conventional therapy, analternative approach using ethambutol and ofloxacin as maintenancetherapy has been suggested. Although promising, this regimen has notyet been widely tested

VaccinationsImmunosuppressed patients should not be given live or attenuated vaccines (Table

3) See also Table 2, Chapter 4.


9

Common Causes of Morbidityin Liver Transplant Recipients

InsomniaEarly post-operative insomnia is related to corticosteroids and/or calcineurin

inhibitor. Patients frequently feel hyperalert and have difficulty achieving a suffi-ciently relaxed state in which to sleep. Postoperative pain, especially right posteriorrib pain (which can last several months), and adjustment to the transplant com-pound the problem. Most patients respond to reassurance and analgesia. Relaxationexercises and good sleep practices may also help.

LassitudeTiredness is a common complaint after liver transplantation and may have many

contributing factors including medications. Recurrence of chronic hepatitis C isoften associated with lassitude. Lassitude may be a manifestation of depression.

Cosmetic ConcernsHirsutism: may be due to cyclosporin and exacerbated by nifedepine or corticos-

teroids. 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 wartsmay become the site of future squamous cell carcinoma.

Musculoskeletal PainBack pain particularly over the right posterior ribs can persist for many months

post-liver transplant. Its persistence and severity surprises many patients and

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.


9

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

SeizuresNew seizures occur most commonly within the first post-operative week and are

related to intraoperative metabolic changes, calcineurin inhibitor toxicity, centralpontine myelinolysis, intracranial bleed or infection. Seizures occurring in the laterweeks following liver transplant are less likely to be due to electrolyte disturbance orcentral pontine myelinolysis and drug toxicity and infection are more of a concern.

Investigations: neurological examination for focal deficits, biochemical testingfor electrolyte disturbances, including hypomagnesemia and cyclosporin or tacrolimuslevels, blood count and coagulation profile to check for coagulopathy or infection,computed tomography (CT) or magnetic resonance imaging (MRI) of the head forspace-occupying lesions and an examination of the CSF to rule out bacterial oropportunistic infection in the immunocompromised host. Both cyclosporin andtacrolimus can cause diffuse white matter changes which are seen on MRI morereadily than on CT.

Management focuses on correction of underlying metabolic or infectious problemsand the use of anticonvulsant agents. Consideration must be given to the risk ofinteractions between immunosuppressive agents and anticonvulsants.

HeadacheHeadache and tremor are common complaints. Milder headaches, often associated

with tremulousness, are usually due to calcineurin inhibitor toxicity. An exacerbationof previously existing migraine headaches may also occur due to cyclosporin ortacrolimus.

Evaluation consists of examination to rule out focal neurological deficits, screeningfor cyclosporin or tacrolimus toxicity or metabolic disturbances, and CT or MRI torule out space occupying lesions.

Treatment: simple analgesia and where possible reduction in the calcineurininhibitor doses. Where headaches are severe, narcotic analgesia may be required.Anti-depressants, calcium channel blockers and β-blockers have also been used withvarying success. Migraine may respond to sumatriptan, although systemichypertension may limit its use.

Fine TremorFine 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 atypicalpresentation of an organic syndrome for example, drug toxicity or infection. Livertransplant recipients with a history of addiction should be monitored for evidenceof relapse. Prompt referral to substance abuse services may be helpful.


9

Pregnancy and Reproductive HealthMenstrual function: Recovery of menstrual function in pre-menopausal females

and of andrological function in males occurs after liver transplantation. Mensestypically resume within a few months of transplantation.

Preconception management: Most centers advise waiting 1-2 years after livertransplantation before becoming pregnant. Barrier or oral contraception should beconsidered during this period. The 1-2 year delay allows for the patients to fullyrecover from the transplant, for opportunistic infection prophylaxis to be discontinuedand for immunosuppression to be reduced.

Conception should be planned when graft function is stable and good. Someimmunosuppressant drugs are teratogenic (see Chapter 6). The immunosuppressiveregime may be modified to avoid these drugs. Due to the increased prevalence ofboth maternal and fetal complications, these are “high-risk” pregnancies and shouldbe 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 recipientsof solid organ transplants (See Armenti VT, Wilson GA, Radomski JS, Moritz MJ,McGrory CH, Coscia LA. Report from the National Transplantation PregnancyRegistry (NTPR): outcomes of pregnancy after transplantation. Clinical Transplants1999;111-119.) No pattern of congenital anomaly has been noted. Of the 175 off-spring studied all of whom are children of female kidney transplant recipients, 76%were live born, 14% suffered spontaneous abortion and 10% were still-born, ectopicpregnancies or electively aborted. There was no significant developmental delay in84% of the children, but 3 children (1.7%) had major disabilities. In 72 female livertransplant recipients, 119 pregnancies were associated with 91 (76%) live births.This compares with the general population wherein 10% of pregnancies are lostbefore 20 weeks with late fetal loss of approximately 0.5%. It is likely that there isunderreporting of early pregnancy loss in the NTPR. 37% of live born childrenwere premature (<37 weeks gestation) and 32% were low birth weight (<2500g).

Regarding the health of the expectant mother, the risk of acute cellular rejectionin the pregnant liver transplant recipient seems to be increased, either occurringduring pregnancy or within 3 months of delivery. Acute cellular rejection wasassociated with poorer fetal outcome and increased risk of recurrent rejection. 33%of pregnant liver transplant recipients will develop hypertension, and 10-15% diabetesmellitus. Hypertension, diabetes and infections should be meticulously managed.Consideration should be given to stress dose steroids for mothers requiring caesareansection.

Breast feeding: most immunosuppressive drugs are secreted in breast milk.Consequently breast feeding should be avoided.

LifestyleLiver allograft recipients should be encouraged to return to a normal healthy

lifestyle, with appropriate health maintenance (see Table 5)


9

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 previouslynormotensive

Renal Insufficiency Serum creatinine every visit No recommendations

Hyper- At 6 months, 1 year, 2 years Every 5 years in men agedcholesterolemia and if normal every 3-5 years 35-65 years and in women

thereafter. aged 45-65 years

Diabetes mellitus Gluc >160 on “routine labs” Screening in theare grounds for a formal oral asymptomatic generalglucose tolerance test population is not

recommended.

Cigarettes Counselling on smoking Counselling on smokingcessation cessation

Osteoporosis DEXA pre-OLT (or post-OLT) DEXA in early post-menopausal women

Breast Cancer Self-breast exam monthly Self-breast exam monthlyAnnual clinical breast exam Annual clinical breast examage 40-69, possibly longer age 40-69, possibly longerMammography 50-69 Mammography 50-69

Cervical cancer Papanicolaou smear every Papanicolaou smear every 3year. Decrease to every 3 years (assuming prior smearsyears if several normal tests were normal) until age 65

Colon cancer As for general population Flexible sigmoidoscopy everannual colonoscopy for those 3-5 years age 50-70 yearswith history of IBD old, begin earlier in those at

higher risk

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

Skin cancer Monthly self-exam. Annual Not recommendedphysician provided skin exam

Dental care Routine oral hygiene (brushing Routine oral hygieneand flossing of teeth) 6 (brushing and flossing ofmonthly visit to dentist teeth)

Oral cancer Annual exam by dentist Not recommended


9

Selected Reading1. Abbasouglu O, Levy MF, Brkic B, Testa G, Jeyarahaj DR, Goldstein RM et al. Ten

years of liver transplantation. Transplantation 1997; 64(12):1801-1807.2. Midtvedt K, Neumayer HH. Management strategies for posttransplant hyperten-

sion. Transplantation 2000; 70(11):SS64-SS69.3. Feller RB, McDonald JA, Sherbon KJ, McCaughan GW. Evidence of continuing

bone recovery at a mean of 7 years after liver transplantation. Liver Transplanta-tion and Surgery 1999; 5(5):407-413.

4. Otley CC, Pittelkow MR. Skin cancer in liver transplant recipients. Liver Trans-plantation 2000; 6(3):253-262.

5. Meyers BR, Papanicolaou GA, Sheiner P, EMRe S, Miller C. Tuberculosis in ortho-topic liver transplant patients: increased toxicity of recommended agents; cure ofdisseminated infection with nonconventional regimens. Transplantation 2000;69(1):64-69.

6. Armenti VT, Wilson GA, Radomski JS, Moritz MJ, McGrory CH, Coscia LA.Report from the National Transplantation Pregnancy Registry (NTPR): Outcomesof pregnancy after transplantation. Clinical Transplants 1999:111-119.

107Pediatric Liver Transplantation

10

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

CHAPTER 10

Pediatric Liver Transplantation

Elizabeth B. Rand and Kim M. Olthoff

Currently 1and 5-year survival for children undergoing liver transplantation equalsor exceeds that of adults. For children in particular, the refinements in surgicaltechnique, immunosuppressive therapy and nutritional support have led to expandedindications for liver transplantation while dramatically reducing death due to organscarcity in the pediatric age group.

Nevertheless, there are considerable differences in outcomes for specific pediatricsubgroups. Small infants, particularly those that are chronically ill and malnourishedhave the highest risk for postoperative surgical and medical complications includinghepatic artery or other vascular thrombosis, early and late biliary complications, andinfection. Older children and teenagers have the best outcomes.

Indications for Liver Transplantation in ChildrenLiver 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 childrenare listed in Table 1. In addition, liver transplantation may be indicated for childrenwith inborn errors of metabolism that do not cause liver failure but which producesevere morbidity or mortality and are corrected by liver transplantation (for exampleornithine transcarbamylase deficiency or Crigler-Najjar syndrome). Children withchronic liver disease due to systemic illnesses (i.e., cystic fibrosis) or primary hepaticmalignancies may be appropriate candidates.

Evaluation of Pediatric Candidates and Timingof Liver TransplantationChildren 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 liverdisease that are specific to the pediatric population and indicate the need for earlylisting for transplantation:

-Growth and nutrition:• Growth failure is a significant complication of liver disease


10• Children with otherwise compensated cirrhosis may have poor weight

gain and/or linear growth often followed by declining school performanceor cognitive development.

• If malnutrition cannot be reversed with supplemental tube feedings orother interventions, liver transplantation should be performed as soon aspossible.

• Due to the serious nature of growth failure and resulting developmentaland cognitive delay in children, these findings qualify a child for higherUNOS listing status for transplantation.

-Hepatic encephalopathy:• Encephalopathy must be evaluated in an age-appropriate manner and

therefore experience in assessing pediatric cognitive skills anddevelopmental 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 commonindication for liver transplantation in childhood. Children may also benefitfrom special exceptions to standard listing criteria in these cases if additionalend organ or malignant risks are involved. Diseases in this category includetyrosinemia, cystic fibrosis and alpha-1-antitrypsin deficiency, for example.

Table 1. Primary diagnosis of 395 children undergoing liver transplantation

Primary Diagnosis Number of PercentagePatients

Biliary atresia 187 47Metabolic diseases (all types) 78 19Alpha-1-antitrypsin deficiency 46 12Tyrosinemia 12 3Wilson disease 9 2Glycogen storage disease 5 1Cystic fibrosis 4 1Other 2 <1Fulminant hepatic failure 21 5Cryptogenic cirrhosis 17 4Familial cholestatic syndromes 16 4(Alagille syndrome, Bylersyndrome, etc.)Chronic active hepatitis 10 2(infectious, autoimmune)Primary sclerosing cholangitis 9 2Neonatal hepatitis 8 2Biliary obstruction 3 <1Tumors 11 3Miscellaneous 13 3

Data were compiled from published and personal series.


10

• Tyrosinemia is a disorder of tyrosine metabolism caused by deficiency offumarylacetoacetate hydrolase (FAH). The enzyme defect results in injuryto multiple organs via the generation of abnormal metabolites. In theliver, the primary site of tyrosine metabolism, the block of tyrosine ca-tabolism produces a large variety of toxic intermediates that result in arange of phenotypes extending from neonatal fulminant hepatic failureto chronic relapsing liver disease. In all forms of disease, there is a sharplyincreased rate of hepatocellular carcinoma, estimated at 13 – 37% invarious studies, occurring even as young as 2 years of age. Medical therapycomprised of dietary restrictions and supplements designed to redirectthe formation of toxic intermediates has been very successful in stabilizingliver function, however development of hepatocellular carcinoma is still aproblem. Liver transplantation restores liver function, reduces extrahepaticorgan injury, and normalizes the hepatocellular cancer risk to that of thegeneral transplant population.

• Metabolic diseases with primarily extrahepatic manifestations may be curedby liver transplantation despite otherwise normal hepatic function. Thesediseases are accepted indications for liver transplantation and area eligiblefor exception status within the UNOS system. Children with urea cycledefects, Crigler-Najjar syndrome type I, or primary hyperoxaluria, forexample, have automatic exceptions to standard listing practices.

• Inborn errors of the urea cycle (for example ornithine transcarbamylasedeficiency) lead to recurrent hyperammonemia and irreversible braininjury, despite aggressive medical therapy. Liver transplantation is curative;standard listing criteria are inappropriate, as all other hepatic functionsare normal.

• Crigler-Najjar syndrome: CNS injury from unconjugatedhyperbilirubinemia is virtually unavoidable in Crigler-Najjar syndrometype I despite medical therapies.

• Primary hyperoxyluria is an inborn error producing oxylate crystalsthroughout the body that ultimately causes renal failure and cardiacarrhythmia. Early liver transplantation can prevent renal failure andpreclude the need for combined renal and hepatic transplantation.

PELDThe 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


10

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

Pre-Operative Management• Medical therapy to correct metabolic abnormalities, coagulopathy, ascites,

vitamin Deficiencies and malnutrition as much as is possible is a criticalpart of the management of any child with liver disease.

• Malnutrition requires special attention as optimization of nutrition protectsbrain development prior to transplant and also improves outcome aftersurgery. Nutritional support can start with institution of a high-densitycaloric diet, but often infants and young children require supplementaltube feedings. The choice of formula is important, a partially hydrolyzedprotein formula with increased medium-chain triglycerides is generallyselected 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) withparticular attention given to live virus vaccines (which are generally notadministered to immunosuppressed individuals). Furthermore, additionalvaccinations (pneumococcus, influenza, etc.) are generally indicated.Serologic evaluation for prior virus infections (particularly varicella, CMVand EBV) are also of great importance and have considerable impact onpost-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 oftransplantation to pediatric patients. Although the death rate on the waitinglist remains significant for children, the risk of dying whilst waiting for aliver allograft has considerably improved for pediatric patients as shownin data in Table 2.

• Innovative surgical techniques including reduced-size liver grafts, splitand living related grafts has resulted in dramatic improvements in organprocurement for even very small infants and waiting times and deathshave been proportionately reduced. The surgical aspects of these forms oftransplant operation are discussed in Chapter 5.

• Biliary atresia


10

- Biliary atresia is the result of an inflammatory/obliterative process of theextrahepatic bile ducts of unknown etiology. Left untreated, this processresults in obstructive cholestasis, biliary cirrhosis and death in 100% ofchildren by age 2 years. Management with the Kasai procedure can re-store bile flow in up to 80% of cases with the anastamosis of a bowel limbto the hepatic capsule. Despite the improvement in survival following theKasai procedure, many of these children will develop complications ofportal hypertension in late childhood or adolescence (variceal hemorrhage,ascites) and require transplantation at that time.- Biliary atresia is the most frequent underlying diagnosis in pediatricliver transplant recipients (See Table 1).- Since almost all of candidates undergoing liver transplantation for bil-iary atresia will have had a prior portoenterostomy, the biliary anastamosisis made to the existing or newly revised intestinal “Roux-en-Y” limb ratherthan to the native common duct (by definition absent in biliary atresia).

• Even children with intact extrahepatic biliary structures may require im-plantation of the bile duct into a Roux limb due to size limitations ormultiple donor ducts in a partial graft. Use of a Roux limb is an impor-tant feature, as future biliary problems can not be approached by ERCP.Direct visualization of the biliary system can only be achieved by percuta-neous transhepatic cholangiogram in these patients.

• Children may require vascular grafts or microsurgical techniques for thevascular anastamoses and the risks of thrombosis (particularly of the he-patic artery) are greatly increased for small infants. Vascular bypass is gen-erally not required for children or infants and is rarely performed (thenonly in larger teenagers).

Early Post-Operative ManagementThe immediate post-operative management of pediatric liver graft recipients is

directed toward continued support of liver function, critical care issues and detec-tion of early surgical complications.

• Vascular problems: small children and infants are particularly at risk forvascular thromboses so the routine includes frequent Doppler ultrasoundto evaluate flow. Pediatric recipients are routinely treated with intrave-nous Dextran to prevent thromboses in the peri-operative period and

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 268/34/540 265/17/197 100/7/212 161/18/4551995 337/45/359 389/23/132 208/5/51.6 287/14/1101999 548/54/234 425/22/92 254/7/48 454/22/80

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


10

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 beneeded.

• Immunosuppression: in general immunosuppressive management issimilar to that in adults, although the arguments for restrictingcorticosteroids is even greater. Drug dosages need be considered for thechild’s weight.

Subsequent ManagementThis is similar to that of adult recipients in terms of monitoring for and

management of changes in liver function, rejection, late biliary complications andinfections, 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 feedingsused pre-transplant. Very young children and infants who received tubefeedings pre-transplant often have delayed oral-motor development andmay require feeding therapy in order to accept oral feedings.

• Occupational or physical therapy may be necessary for children and infantswith a lifetime history of chronic liver disease. Older children generallyrecover 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, particularlyin those young children who did not have primary infections with EBVand CMV pre-transplant, is an ongoing issue.- EBV naïve children undergoing liver transplant are at high risk of devel-oping chronic EBV infection and post transplant lymphoproliferative dis-ease if the primary EBV infection occurs on immunosuppression. Theuse of new quantitative PCR analysis for EBV has improved the monitor-ing for EBV activity. PTLD is discussed in Chapter 7. In addition to thestandard reduction or elimination of immune suppression and additionof ganciclovir or acyclovir antiviral therapy.- CMV negative children will often receive CMV positive grafts (espe-cially if they receive a partial graft from an adult donor) and are at risk ofCMV infection.- Exposure to other childhood viral illnesses is an ongoing issue for thesechildren; varicella exposure for example is a frequent occurrence. Chil-dren should be vaccinated for varicella prior to transplant, however thevaccine is less effective if given under 1 year of age. Varicella antibodynegative children should receive varicella immune globulin within 48hours of known exposure (ideally within 12-24 hours) and are treatedwith intravenous acyclovir if clinical chicken pox develops. Even after anepisode of clinical infection most of these children will not develop anti-


10

bodies and they are therefore at risk for repeated infection with subse-quent exposures.- Live vaccine administration to immunosuppressed transplant recipientsis controversial, with standard recommendations against immunization.Even in those centers where MMR and/or varicella immunizations aregiven post transplant, reduced response to vaccination is observed.

• Compliance: Compliance with medical therapy is a major issue with teen-age liver graft recipients especially those transplanted in infancy or earlychildhood. Many of these teenagers do not remember their transplantexperience and are entering a time of personality turbulence, testing oflimits, and have acquired a general sense of invulnerability that extendsfrom the usual adolescent risk taking (experimentation with drugs of abuse,exploration of sexuality) to failure to take medications. The response tothis behavior must be tailored to the individual child and family andmust take into account the social and cultural background. Parents, socialworkers, school guidance counselors and other resources are importantpartners in the effort to sustain delivery of medical care throughadolescence.

The adolescent patient: Children entering adolescence experience a variety ofendocrinologic, physical and psychosocial changes. In most cases these young adultswill be best served at a pediatric center but care should be transitioned to an adulttransplant center when medically and psychosocially appropriate.

Suggested Reading1. Kogan-Liberman D, EMRe S, Shneider BL. Recent advances in pediatric liver

transplantation. Current Gastro Reports 2002; 4(1):84-97.2. Emre S. Living-donor liver transplantation in children. Pediatric Transplantation

2002; 6(1):43-46.3. Bucuvalas JC, Ryckman FC. Long-term outcome after liver transplantation in chil-

dren. Pediatric Transplantation 2002; 6(1):30-36.4. Shneider BL. Pediatric liver transplantation in metabolic disease: Clinical decision

making. Pediatric Transplantation 2002; 6(1):25-29.5. McDiarmid SV. Management of the pediatric liver transplant patient. Liver Trans-

plantation 2001; 7(11suppl 1):S77-S86.6. Emond JC, Whitington PF, Thistlewaite JR et al. Transplantation of two patients

with one liver: analysis of a preliminary experience with “split-liver” grafting. An-nals of Surgery 1990; 212(1):14-22.

7. McDiarmid SV, Gornbein JA, Desilva PJ et al. Factors affecting growth after pedi-atric liver transplantation. Transplantation 1999; 67(3):404-411.

8. Gloss JA, Shackleton CR, McDiarmid SV et al. Long-term results of pediatric livertransplantation: An analysis of 569 patients. Annals of Surgery 1998;228(3):411-420.


Index

A

Acetaminophen 30-33Acne 67, 102 Acute cellular rejection (ACR) 5, 8,

11, 12, 14, 16, 47, 60, 71, 74-77,86, 104

Acyclovir 63, 79, 81, 101, 112Addiction 28, 29, 41, 92, 103Alcoholism 27, 29, 41, 92, 99Alloimmune response 5, 7, 9Alpha feto protein (AFP) 25, 39Alpha-1-antitrypsin deficiency 108,

109Amyloidosis 90, 91Anergy 12-15Angina pectoris 22Angiotensin converting enzyme (ACE)

63, 96Angiotensin II 96Antibody dependent cellular cytotoxic-

ity (ADCC) 13Antigen presenting cells 5, 15Apoptosis 11, 14, 15, 64Argon beam coagulatorargon beam

coagulator 54Autoimmune hepatitis 28, 34, 64, 78,

89, 93, 98Azathioprine (AZA) 12, 13, 61, 63,

68, 72, 79, 90

B

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

C

Calcineurin 12, 63, 64, 66, 68, 69, 72,86, 95-98, 102, 103

Calcium 27, 64, 96, 97, 99, 103CBD 44, 45, 50, 53CD antigen 14CD28 9, 15

CD3 8, 9, 12, 14, 68Celiac sprue 28, 34Central pontine myelinolysis 38, 103Cerebral edema 29, 32Cervical cancer 100Cervical carcinoma 101Chemoembolization 39Chemokine 10, 15Child-Pugh classification 17, 18Cholangiocarcinoma 20, 26, 33, 39,

92Cholangiogram 57, 59, 111Cholestipol 20Cholestyramine 20, 27, 63Chronic ductopenic rejection (COPD)

11, 12, 15, 22, 34, 71, 74, 76-79,84

Chronic obstructive pulmonary disease22

Ciprofloxacin 38Cirrhosis 3, 4, 18, 19, 27, 30, 33, 34,

36, 39, 41, 79, 86-88, 90, 93, 98,107-109, 111

Co-amoxyclav 38Co-stimulation 7Coagulopathy 19, 29, 37, 74, 103,

110Colon cancer 26, 33, 39, 101Common bile duct 44, 50, 53, 57Complement 11, 13Cotrimoxazole 38Creatinine 18, 24, 33, 38, 57, 67, 98Crigler-Najjar syndrome 90, 107, 109Cryoglobulinemia 98Cryotherapy 39Cryptogenic cirrhosis 34, 93, 109CSA 13CTLA-4 15, 63Cutaneous warts 102Cyclosporin 12, 13, 63-69, 71, 72, 76,

97, 99, 101-103Cyclosporine 69Cystic duct 49, 53, 57Cystic fibrosis 23, 90, 107-109Cytokine 7, 9-12, 15, 64, 66, 68Cytomegalovirus (CMV) 27, 30, 40,

68, 72, 74, 76, 78, 79, 82, 86,101, 110, 112

Cytotoxic T lymphocyte CTL) 14, 15

115

Inde

x

Index

D

Daclizumab 12, 71Deletion 12, 13DEXA scan 99Diabetes insipidus 42Diabetes mellitus 25, 65, 67, 72, 95,

97, 98, 104Diltiazem 66, 96Direct antigen recognition 8Diuretics 23, 24, 38, 97

E

Ebstein-Barr virus 27EBV 27, 40, 73, 74, 79, 80, 81, 100,

101, 110, 112Etidronate 27Extended criteria donors 46Extended use organs 2Extracorporeal perfusion 32

F

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

34, 79, 109Fumarylacetoacetate hydrolase 109

G

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

H

Halothane 30, 32, 33Headache 64-68, 103Hemochromatosis 33, 90, 91Hemochromatosis gene test 33Hemorrhagic necrosis 34, 74Heparin 44, 46Hepatic artery stenosis 83Hepatic artery thrombosis (HAT) 34,

69, 74, 79, 81-83Hepatic osteodystrophy 20Hepatitis A virus (HAV) 32, 41, 88Hepatitis B immunoglobulin (HBIg)

33, 88Hepatitis 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 26Hepatocellular cancer 20, 21, 109Hepatopulmonary syndrome 19, 23,

34Herpes simplex virus 27Heterotopic auxiliary transplants 32HFE 33HHV-8 100Hirsutism 64, 102HMG CoA-reductase inhibitors 97HPV 100, 101HPV-6 101HSV 27, 41, 74Human herpes virus-8 100Human immunodeficiency virus (HIV)

20, 26, 42, 57, 100Human papilloma virus 100Hydrocortisone 46, 62Hyperacute rejection 2, 11Hyperhomocysteinemia 95Hyperkalemia 64, 97Hyperlipidemia 34, 67, 69, 95, 97Hypertension 18, 20, 22, 23, 36-38,

41, 42, 63-65, 67, 68, 83, 95-98,103, 104, 107, 111

Hypoalbuminemia 24Hypomagnesemia 97, 103


Index

Hyponatremia 38

I

IBD 33Immunoglobulin superfamily 11Impotence 25Inflammatory bowel disease 33Innate immunity 16Insomnia 63, 102Insulin resistance 25, 34, 97Integrins 11Interferon 87Interleukin-2 (IL-2) 7, 9, 12, 64, 66,

67, 71, 79Interleukin-4 (IL-4) 7, 9, 66Interleukin-6 (IL-6) 7, 9Ischemic hepatitis 30Isoniazid 26, 30, 72, 101

K

Kasai procedure 111Kidney transplantation 24

L

Lamivudine 33, 88, 93Lassitude 102Lethargy 19Live donor right lobe recipient

operation 59Live liver donation 20, 21Living donation 2, 57Lymphoma 30, 73, 80, 81

M

Macrophages 5-7, 10, 11, 14Magnetic 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, 28Mammography 26, 39Marginal donors 2MELD score 17, 18Menstruation 25Midodrine 23Molecular mimicry 8

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

N

Nadalol 36Naltrexone 20NASH 34, 74, 93Nephrotic syndrome 24Neuroendocrine tumors 26, 93Niemann-Pick disease 90Nifedipine 96NK cells 11Non-alcoholic fatty liver disorder

(NAFLD) 34, 93Non-alcoholic steatohepatitis 34Non-heart beating donors 2, 42, 84Non-heart-beating donors 46Non-steroidal anti-inflammatory agents

38Norfloxacin 38

O

Obesity 34, 95, 97OKT-3 12Oral cancer 100Ornithine transcarbamylase deficiency

107, 109Orthoclone 14Osteopenia 36, 99Osteoporosis 65, 99, 103

P

Palmidronate 27Pancreatitis 28, 34, 63, 92Pap smears 39Parvovirus B19 101PELD 20, 109Perforins 11Peritonitis 19, 36, 37Phenytoin 20, 32, 66Plasmapheresis 20Porcine endogenous retrovirus (PERVs)

2Portal hypertension 18, 23, 36-38, 83,

107, 111

117

Inde

x

Index

Portal vein thrombosis 36, 55, 83Portal venous bypass 50Porto-pulmonary hypertension 22, 23Post-transplant lymphoproliferative

disorders (PTLD) 80, 100, 112PPD 26Pregnancy 30, 67, 68, 72, 104Primary biliary cirrhosis 18, 19, 34,

79, 88, 98Primary graft non-function 2, 74Primary hyperoxaluria 109Primary sclerosing cholangitis 19, 33,

34, 79, 89, 109Propranolol 36Prostatic specific antigen 26, 40Protoporphyria 90PSA 26, 40Psychological assessment 28Purified protein derivative 26

R

Radiofrequency ablation 39Rapamycin 12, 63, 66, 69Renal function 23, 24, 28, 57, 97, 98Retransplantation 3, 4, 34, 35, 54, 72,

76, 83, 84, 86Ribavirin 87Rifampicin 65, 66, 101Rifampin 20Right lobe living donor operation 57Roux-en-Y hepatico-jejunostomy 55

S

Seizures 68, 103Selectins 11Sirolimus 12, 63, 66, 67, 69-72, 97Skin cancer 20, 80, 97, 100Somatostatin 23Split liver grafts 47, 112Spontaneous bacterial peritonitis (SBP)

19, 36, 37, 38Statins 66, 97Steatosis 57Stent thrombosis 37Steroid resistant rejection 76Subacute hepatic necrosis 31Subfulminant hepatic failure 29, 30Suppression 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, 14-16T-cell receptor 5-9T-cells 5-8, 11-13T-tube 53, 83, 84Tacrolimus 12, 13, 63-67, 71-73, 76,

89, 97, 99, 101-103Target of rapamycin (TOR) 63, 66TCR 8, 14, 15, 16Th lymphocytes 7Th1 and Th2 paradigm 7Th2 paradigm 7Thyroid disease 25 Tobacco products 23Tolerance 7, 12, 14, 16, 30, 60, 87,

104Transjugular intrahepatic porto-

systemic shunt (TIPS) 23, 37,56, 57

Tremor 63, 64, 66, 67, 103Trimethoprim 38Tuberculosis 26, 72, 101Tyrosinemia 30, 90, 108, 109

U

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

V

Vaccinations 40, 101, 103, 110Vanishing bile duct syndrome 12, 71,

76Variceal hemorrhage 19, 36, 37, 41,

111Varicella zoster 101Verapamil 66, 96Vertebral fractures 99Vitamin A 27Vitamin D 27, 99, 110Vitamin K 27VZV 74, 101

X

Xenotransplants 2

V m


a d e m e c uV a d e m e c u m

Table of contents1. Liver Transplantation:

An Overview

2. The Allograft ImmuneResponse

3. Assessment for LiverTransplantation

4. Management on the LiverTransplant Waiting List

5. The Liver TransplantOperation

6. Immunosuppression afterLiver Transplantation

7. Graft Dysfunction

8. Recurrence of Disease afterLiver Transplantation

The Vademecum series includes subjects generally not covered in other handbookseries, especially many technology-driven topics that reflect the increasinginfluence of technology in clinical medicine.

The name chosen for this comprehensive medical handbook series isVademecum, a Latin word that roughly means “to carry along”. In the MiddleAges, traveling clerics carried pocket-sized books, excerpts of the carefullytranscribed canons, known as Vademecum. In the 19th century a medical publisherin Germany, Samuel Karger, called a series of portable medical booksVademecum.

The Landes Bioscience Vademecum books are intended to be used both in thetraining of physicians and the care of patients, by medical students, medical housestaff and practicing physicians. We hope you will find them a valuable resource.

All titles available at

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I SBN 1- 57059- 682- 4

9 7 8 1 5 7 0 5 9 6 8 2 7


LiverTransplantation

9. Medical Management of theLiver Transplant Patient

10. Pediatric Liver Transplantation

Liver transplantation

Health & Medicine

Transcript of Liver transplantation